The hardening on surface of complex profles such as thread and spline manufactured by cold rolling can efectively improve the mechanical properties and surface quality of rolled parts. The distribution of hardness in ...The hardening on surface of complex profles such as thread and spline manufactured by cold rolling can efectively improve the mechanical properties and surface quality of rolled parts. The distribution of hardness in superfcial layer is closely related to the deformation by rolling. To establish the suitable correlation model for describing the relationship between strain and hardness during cold rolling forming process of complex profles is helpful to the optimization of rolling parameters and improvement of rolling process. In this study, a physical analog experiment refecting the uneven deformation during complex-profle rolling process has been extracted and designed, and then the large date set (more than 400 data points) of training samples refecting the local deformation characteristics of complexprofle rolling have been obtained. Several types of polynomials and power functions were adopted in regression analysis, and the regression correlation models of 45# steel were evaluated by the single-pass and multi-pass physical analog experiments and the complex-profle rolling experiment. The results indicated that the predicting accuracy of polynomial regression model is better in the strain range (i.e., ε < 1.2) of training samples, and the correlation relationship between strain and hardness out strain range (i.e., ε > 1.2) of training samples can be well described by power regression model;so the correlation relationship between strain and hardness during complex-profle rolling process of 45# steel can be characterized by a segmented function such as third-order polynomial in the range ε < 1.2 and power function with a ftting constant in the range ε > 1.2;and the predicting error of the regression model by segmented function is less than 10%.展开更多
A three-dimensional conjugate tooth surface design method for Harmonic Drive with a double-circular-arc tooth profle is proposed. The radial deformation function of the fexspline (FS), obtained through Finite Element ...A three-dimensional conjugate tooth surface design method for Harmonic Drive with a double-circular-arc tooth profle is proposed. The radial deformation function of the fexspline (FS), obtained through Finite Element (FE) analysis, is incorporated into the kinematics model. By analyzing the FS tooth enveloping process, the optimization of the overlapping conjugate tooth profle is achieved. By utilizing the hobbing process, the three-dimensional machinable tooth surface of FS can be acquired. Utilizing the coning deformation of the FS, simulations are conducted to analyze the multi-section assembly and meshing motion of the machinable tooth surface. The FE method is utilized to analyze and compare the loaded contact characteristics. Results demonstrate that the proposed design method can achieve an internal gear pair consisting of a circular spline with a spur gear tooth surface and the FS with a machinable tooth surface. With the rated torque, approximately 24% of the FS teeth are engaged in meshing, and more than 4/5 of the tooth surface in the axial direction carries the load. The contact patterns, maximum contact pressure, and transmission error of the machinable tooth surface are 227.2%, 40.67%, and 71.24% of those on the spur gear tooth surface, respectively. It clearly demonstrates exceptional transmission performance.展开更多
Background: Chicken is the most consumed meat worldwide and the industry has been facing challenging myopathies. Wooden breast(WB), which is often accompanied by white striping(WS), is a serious myopathy adversely aff...Background: Chicken is the most consumed meat worldwide and the industry has been facing challenging myopathies. Wooden breast(WB), which is often accompanied by white striping(WS), is a serious myopathy adversely affecting meat quality of breast muscles. The underlying lipid metabolic mechanism of WB affected broilers is not fully understood.Results: A total of 150 chickens of a white-feathered, fast-growing pure line were raised and used for the selection of WB, WB + WS and control chickens. The lipids of the breast muscle, liver, and serum from different chickens were extracted and measured using ultra performance liquid chromatography(UPLC) plus Q-Exactive Orbitrap tandem mass spectrometry. In the breast, 560 lipid molecules were identified. Compared to controls, 225/225 of 560 lipid molecules(40.2%) were identified with differential abundance(DA), including 92/100 significantly increased neutral lipids and 107/98 decreased phospholipids in the WB/WB + WS groups, respectively. The content of monounsaturated fatty acids(MUFA) was significantly higher, and the polyunsaturated fatty acids(PUFA) and saturated fatty acids(SFA) were significantly lower in the affected breasts. In the liver, 434 lipid molecules were identified, and 39/61 DA lipid molecules(6.7%/14.1%) were detected in the WB and WB + WS groups, respectively. In the serum, a total of 529 lipid molecules were identified and 4/44 DA lipid molecules(0.8%/8.3%) were detected in WB and WB + WS group, respectively. Compared to controls, the content of MUFAs in the serum and breast of the WB + WS group were both significantly increased, and the content of SFAs in two tissues were both significantly decreased. Only five lipid molecules were consistently increased in both liver and serum in WB + WS group.Conclusions: We have found for the first time that the dominant lipid profile alterations occurred in the affected breast muscle. The relative abundance of 40.2% of lipid molecules were changed and is characteristic of increased neutral lipids and decreased phospholipids in the affected breasts. Minor changes of lipid profiles in the liver and serum of the affected groups were founded. Comprehensive analysis of body lipid metabolism indicated that the abnormal lipid profile of WB breast may be independent of the liver metabolism.展开更多
Background Drug‑resistant epilepsy(DRE)exerts substantial clinical,humanistic and economic burdens on patients,their families and the healthcare system.Vagus nerve stimulation(VNS)has been extensively tested in clinic...Background Drug‑resistant epilepsy(DRE)exerts substantial clinical,humanistic and economic burdens on patients,their families and the healthcare system.Vagus nerve stimulation(VNS)has been extensively tested in clinical trial settings to decrease the frequency of seizures in patients with DRE who are not candidates for surgery;the results indicate promising efcacy and a well‑tolerated safety profle.However,real‑world evidence is still lacking.This retro‑spective study evaluated the safety and efcacy of VNS in patients with DRE.Methods The current study was a retrospective chart review of the medical records of children and adults with DRE treated with VNS between December 2006 and November 2022.The primary outcome of the present study was the percentage of patients who experienced a reduction in seizure frequency of more than 50%compared with the frequency at baseline(the period before VNS device insertion).Results A total of 103 patients were included.The percentage of patients who achieved a reduction of more than 50%in seizure frequency was 23%at six months,36%at 12 months,65%at 18 months,and 72%at 24 months.Similarly,the percentage of patients with complete resolution of interictal epileptiform discharges(IEDs)increased from 30%at six months to 60%after 24 months.The overall Quality of Life in Epilepsy(QOLIE‑31)score at the end of follow‑up was 39.46±13.68 points.Two patients(1.9%)reported experiencing side efects at the end of follow‑up.Conclusions VNS implementation led to a signifcant reduction in the seizure frequency and resolution of IEDs,with a well‑tolerated safety profle.The fndings highlight the potential role of VNS in managing DRE and warrant its consideration for treating patients with DRE.展开更多
Objectives:This study aimed to investigate microbial contamination in seafood-contacted ice,with a particular focus on the prevalence of pathogenic bacteria,antimicrobial resistance of isolates,and bacterial diversity...Objectives:This study aimed to investigate microbial contamination in seafood-contacted ice,with a particular focus on the prevalence of pathogenic bacteria,antimicrobial resistance of isolates,and bacterial diversity.Materials and Methods:Seafood-contacted ice samples were collected from 12 districts in Shanghai,China,during August and September 2023.The sanitary conditions were assessed using Plate Count Agar(PCA)and Violet Red Bile Agar(VRBA)plates for serial dilution and plating.Microbial prevalence was determined by streaking on selective agar plates.Antimicrobial susceptibility of the isolates was evaluated using the disk diffusion method.Bacterial diversity was analyzed using the Illumina high-throughput sequencing platform.Results:The results revealed that the total plate count in the samples ranged from 1.89 to 5.94 log colony-forming units(CFU)/mL,with an average of 4.15 log CFU/mL.Coliform counts were present in 98.50%of the samples,with counts ranging from 0.70 to 4.06 log CFU/mL,with an average of 2.05 log CFU/mL.Pathogenic bacteria detected included Vibrio parahaemolyticus in 31 samples(31/200,15.50%),Escherichia coli in 16 samples(16/200,8.00%),and Staphylococcus aureus in nine samples(9/200,4.50%).V.parahaemolyticus showed a high ampicillin resistance rate of 96.8%(30/31).E.coli exhibited general resistance to most antibiotics.S.aureus isolates demonstrated greater resistance to ampicillin(6/9,66.7%),but remained sensitive to other antibiotics.High-throughput sequencing has demonstrated that certain microorganisms exhibit resistance to low temperature through mechanisms such as bioflm formation,contributing to their pathogenicity and posing a threat to the safety of seafood-contacted ice.Specifcally,Pseudomonas,Aeromonas,and Shewanella should be prioritized in future preventive and control measures.Conclusions:The sanitary conditions of seafood-contacted ice in Shanghai are concerned.Certain bacteria exhibit high detection rates and signifcant antimicrobial resistance,while some microorganisms capable of surviving at low temperature pose a serious threat to the safety of these products.展开更多
While chemo-immunotherapy has been established as the frontline therapeutic regimen for extensive-stage small cell lung cancer(ES-SCLC),durable responses persist predominantly in a minor population of patients.This un...While chemo-immunotherapy has been established as the frontline therapeutic regimen for extensive-stage small cell lung cancer(ES-SCLC),durable responses persist predominantly in a minor population of patients.This underscores critical need to elucidate underlying local tumor microenvironment and systematic immune profles for biomarker discovery.In this phase ll trial(ChiCTR2000038354),the efficacy,safety,and immune-genomic signatures of sintilimab(anti-PD-1 antibody)synergized with chemotherapy as first-line regimen for ES-SCLC were evaluated.The regimen demonstrated a median progression-free survival(PFS)of 6.9 months and median overall survival of 17.1 months,accompanied by a 12-month PFS rate of 16.9%,fulflling the primary endpoint.Manageable grade 3 or 4 treatment-related adverse events developed in 27.3%(12/44)of patients.The exploratory study indicated a higher infiltration of CD4^(+)/CD8^(+)CXCR5^(+)T follicle helper cell,CD8^(+)CD103^(+)tissue-resident memory T cells,and B cells in tumor tissue,associated with better response and prognosis.The study also indicated the presence of tumor macrophages(CD68^(+)CD163^(+)CSF1R^(+)SIGLEC5^(+))associated with immunotherapy resistance.Higher levels of monocyte-dendritic cells in pre-treatment peripheral blood mononuclear cells were found in durable clinical benefit group.Also,higher CD83,CD244,IL-12,and CD70,which are hallmarks of dendritic cells and activated T cells,were discovered by plasma proteomics to be connected with enhanced outcomes,while chemoattractant of macrophage,CSF-1,CCL3,CCL4,and IL-8,were found to predict a worse prognosis.Furthermore,a multimodal model was constructed and validated for stratifying ES-SCLC into high or low risk to predict the immunotherapy efficacy.This study sheds light on harnessing local and systematic immune profiles to better stratify patients with ES-SCLC for immunotherapy and putative combinational treatment.展开更多
The gut microbiota crucially regulates the efficacy of immune checkpoint inhibitor(ICl)based immunotherapy,but the underlying mechanisms remain unclear at the single-cell resolution.Using single-cell RNA sequencing an...The gut microbiota crucially regulates the efficacy of immune checkpoint inhibitor(ICl)based immunotherapy,but the underlying mechanisms remain unclear at the single-cell resolution.Using single-cell RNA sequencing and subsequent validations,we investigate gut microbiota-ICl synergy by profling the tumor microenvironment(TME)and elucidating critical cellular interactions in mouse models.Our findings reveal that intact gut microbiota combined with ICls may synergistically increase the proportions of CD8^(+),CD4^(+),and yδ T cells,reduce glycolysis metabolism,and reverse exhausted CD8^(+)T cells into memory/effector CD8^(+)T cells,enhancing antitumor response.This synergistic effect also induces macrophage reprogramming from M2 protumor Spp1^(+)tumorassociated macrophages(TAMs)to Cd74^(+)TAMs,which act as antigen-presenting cells(APCs).These macrophage subtypes show a negative correlation within tumors,particularly during fecal microbiota transplantation.Depleting Spp1^(+)TAMs in Spp1 conditional knockout mice boosts ICl efficacy and T cell infiltration,regardless of gut microbiota status,suggesting a potential upstream role of the gut microbiota and highlighting the crucial negative impact of Spp1^(+)TAMs during macrophage reprogramming on immunotherapy outcomes.Mechanistically,we propose aγδT cell-APC-CD8^(+)T cell axis,where gut microbiota and ICls enhance Cd40lg expression onγδT cells,activating Cd40 overexpressing APCs(e.g.,Cd74^(+)TAMs)through CD40-CD40L-related NF-kB signaling and boosting CD8^(+)T cell responses via CD86-CD28 interactions.These findings highlight the potential importance of y8 T cells and SPP1-related macrophage reprogramming in activating CD8^(+)T cells,as well as the synergistic effect of gut microbiota and ICls in immunotherapy through modulating the TME.展开更多
基金Supported by National Natural Science Foundation of China(Grant No.51675415)Key Research and Development Program of Shaanxi,China(Grant No.2021GXLH-Z-049).
文摘The hardening on surface of complex profles such as thread and spline manufactured by cold rolling can efectively improve the mechanical properties and surface quality of rolled parts. The distribution of hardness in superfcial layer is closely related to the deformation by rolling. To establish the suitable correlation model for describing the relationship between strain and hardness during cold rolling forming process of complex profles is helpful to the optimization of rolling parameters and improvement of rolling process. In this study, a physical analog experiment refecting the uneven deformation during complex-profle rolling process has been extracted and designed, and then the large date set (more than 400 data points) of training samples refecting the local deformation characteristics of complexprofle rolling have been obtained. Several types of polynomials and power functions were adopted in regression analysis, and the regression correlation models of 45# steel were evaluated by the single-pass and multi-pass physical analog experiments and the complex-profle rolling experiment. The results indicated that the predicting accuracy of polynomial regression model is better in the strain range (i.e., ε < 1.2) of training samples, and the correlation relationship between strain and hardness out strain range (i.e., ε > 1.2) of training samples can be well described by power regression model;so the correlation relationship between strain and hardness during complex-profle rolling process of 45# steel can be characterized by a segmented function such as third-order polynomial in the range ε < 1.2 and power function with a ftting constant in the range ε > 1.2;and the predicting error of the regression model by segmented function is less than 10%.
基金Supported by Guangdong Provincial Key-Area Research and Development Program(Grant No.2019B090917002).
文摘A three-dimensional conjugate tooth surface design method for Harmonic Drive with a double-circular-arc tooth profle is proposed. The radial deformation function of the fexspline (FS), obtained through Finite Element (FE) analysis, is incorporated into the kinematics model. By analyzing the FS tooth enveloping process, the optimization of the overlapping conjugate tooth profle is achieved. By utilizing the hobbing process, the three-dimensional machinable tooth surface of FS can be acquired. Utilizing the coning deformation of the FS, simulations are conducted to analyze the multi-section assembly and meshing motion of the machinable tooth surface. The FE method is utilized to analyze and compare the loaded contact characteristics. Results demonstrate that the proposed design method can achieve an internal gear pair consisting of a circular spline with a spur gear tooth surface and the FS with a machinable tooth surface. With the rated torque, approximately 24% of the FS teeth are engaged in meshing, and more than 4/5 of the tooth surface in the axial direction carries the load. The contact patterns, maximum contact pressure, and transmission error of the machinable tooth surface are 227.2%, 40.67%, and 71.24% of those on the spur gear tooth surface, respectively. It clearly demonstrates exceptional transmission performance.
基金supported by grants from the National Natural Science Foundation of China(31772591)the Agricultural Science and Technology Innovation Program(CAAS-ZDRW202005)the China Agriculture Research System of MOF and MARA(CARS-41).
文摘Background: Chicken is the most consumed meat worldwide and the industry has been facing challenging myopathies. Wooden breast(WB), which is often accompanied by white striping(WS), is a serious myopathy adversely affecting meat quality of breast muscles. The underlying lipid metabolic mechanism of WB affected broilers is not fully understood.Results: A total of 150 chickens of a white-feathered, fast-growing pure line were raised and used for the selection of WB, WB + WS and control chickens. The lipids of the breast muscle, liver, and serum from different chickens were extracted and measured using ultra performance liquid chromatography(UPLC) plus Q-Exactive Orbitrap tandem mass spectrometry. In the breast, 560 lipid molecules were identified. Compared to controls, 225/225 of 560 lipid molecules(40.2%) were identified with differential abundance(DA), including 92/100 significantly increased neutral lipids and 107/98 decreased phospholipids in the WB/WB + WS groups, respectively. The content of monounsaturated fatty acids(MUFA) was significantly higher, and the polyunsaturated fatty acids(PUFA) and saturated fatty acids(SFA) were significantly lower in the affected breasts. In the liver, 434 lipid molecules were identified, and 39/61 DA lipid molecules(6.7%/14.1%) were detected in the WB and WB + WS groups, respectively. In the serum, a total of 529 lipid molecules were identified and 4/44 DA lipid molecules(0.8%/8.3%) were detected in WB and WB + WS group, respectively. Compared to controls, the content of MUFAs in the serum and breast of the WB + WS group were both significantly increased, and the content of SFAs in two tissues were both significantly decreased. Only five lipid molecules were consistently increased in both liver and serum in WB + WS group.Conclusions: We have found for the first time that the dominant lipid profile alterations occurred in the affected breast muscle. The relative abundance of 40.2% of lipid molecules were changed and is characteristic of increased neutral lipids and decreased phospholipids in the affected breasts. Minor changes of lipid profiles in the liver and serum of the affected groups were founded. Comprehensive analysis of body lipid metabolism indicated that the abnormal lipid profile of WB breast may be independent of the liver metabolism.
文摘Background Drug‑resistant epilepsy(DRE)exerts substantial clinical,humanistic and economic burdens on patients,their families and the healthcare system.Vagus nerve stimulation(VNS)has been extensively tested in clinical trial settings to decrease the frequency of seizures in patients with DRE who are not candidates for surgery;the results indicate promising efcacy and a well‑tolerated safety profle.However,real‑world evidence is still lacking.This retro‑spective study evaluated the safety and efcacy of VNS in patients with DRE.Methods The current study was a retrospective chart review of the medical records of children and adults with DRE treated with VNS between December 2006 and November 2022.The primary outcome of the present study was the percentage of patients who experienced a reduction in seizure frequency of more than 50%compared with the frequency at baseline(the period before VNS device insertion).Results A total of 103 patients were included.The percentage of patients who achieved a reduction of more than 50%in seizure frequency was 23%at six months,36%at 12 months,65%at 18 months,and 72%at 24 months.Similarly,the percentage of patients with complete resolution of interictal epileptiform discharges(IEDs)increased from 30%at six months to 60%after 24 months.The overall Quality of Life in Epilepsy(QOLIE‑31)score at the end of follow‑up was 39.46±13.68 points.Two patients(1.9%)reported experiencing side efects at the end of follow‑up.Conclusions VNS implementation led to a signifcant reduction in the seizure frequency and resolution of IEDs,with a well‑tolerated safety profle.The fndings highlight the potential role of VNS in managing DRE and warrant its consideration for treating patients with DRE.
基金supported by the Project of the China National Center for Food Safety Risk Assessment,2023the Natural Science Foundation of Shanghai(No.22ZR1427500),China.
文摘Objectives:This study aimed to investigate microbial contamination in seafood-contacted ice,with a particular focus on the prevalence of pathogenic bacteria,antimicrobial resistance of isolates,and bacterial diversity.Materials and Methods:Seafood-contacted ice samples were collected from 12 districts in Shanghai,China,during August and September 2023.The sanitary conditions were assessed using Plate Count Agar(PCA)and Violet Red Bile Agar(VRBA)plates for serial dilution and plating.Microbial prevalence was determined by streaking on selective agar plates.Antimicrobial susceptibility of the isolates was evaluated using the disk diffusion method.Bacterial diversity was analyzed using the Illumina high-throughput sequencing platform.Results:The results revealed that the total plate count in the samples ranged from 1.89 to 5.94 log colony-forming units(CFU)/mL,with an average of 4.15 log CFU/mL.Coliform counts were present in 98.50%of the samples,with counts ranging from 0.70 to 4.06 log CFU/mL,with an average of 2.05 log CFU/mL.Pathogenic bacteria detected included Vibrio parahaemolyticus in 31 samples(31/200,15.50%),Escherichia coli in 16 samples(16/200,8.00%),and Staphylococcus aureus in nine samples(9/200,4.50%).V.parahaemolyticus showed a high ampicillin resistance rate of 96.8%(30/31).E.coli exhibited general resistance to most antibiotics.S.aureus isolates demonstrated greater resistance to ampicillin(6/9,66.7%),but remained sensitive to other antibiotics.High-throughput sequencing has demonstrated that certain microorganisms exhibit resistance to low temperature through mechanisms such as bioflm formation,contributing to their pathogenicity and posing a threat to the safety of seafood-contacted ice.Specifcally,Pseudomonas,Aeromonas,and Shewanella should be prioritized in future preventive and control measures.Conclusions:The sanitary conditions of seafood-contacted ice in Shanghai are concerned.Certain bacteria exhibit high detection rates and signifcant antimicrobial resistance,while some microorganisms capable of surviving at low temperature pose a serious threat to the safety of these products.
基金funded by the Clinical Research Foundation of Shanghai Pulmonary Hospital(FKLY20013)National Key R&D Program of China(grant number 2023YFC2508604,2023YFC2508605)+2 种基金Tongji University Medicine-X Interdisciplinary Research Initiative(2025-0554-ZD-08)"Young Eagle Soaring"Talent Project of Shanghai Pulmonary Hospital(Fkcy2408)Innovent Biologics,Inc and Amoy Diagnostics Co.,Ltd.The IRB of Shanghai Pulmonary Hospital(L20-411-1)approved the protocol,all patients provided written informed consent.
文摘While chemo-immunotherapy has been established as the frontline therapeutic regimen for extensive-stage small cell lung cancer(ES-SCLC),durable responses persist predominantly in a minor population of patients.This underscores critical need to elucidate underlying local tumor microenvironment and systematic immune profles for biomarker discovery.In this phase ll trial(ChiCTR2000038354),the efficacy,safety,and immune-genomic signatures of sintilimab(anti-PD-1 antibody)synergized with chemotherapy as first-line regimen for ES-SCLC were evaluated.The regimen demonstrated a median progression-free survival(PFS)of 6.9 months and median overall survival of 17.1 months,accompanied by a 12-month PFS rate of 16.9%,fulflling the primary endpoint.Manageable grade 3 or 4 treatment-related adverse events developed in 27.3%(12/44)of patients.The exploratory study indicated a higher infiltration of CD4^(+)/CD8^(+)CXCR5^(+)T follicle helper cell,CD8^(+)CD103^(+)tissue-resident memory T cells,and B cells in tumor tissue,associated with better response and prognosis.The study also indicated the presence of tumor macrophages(CD68^(+)CD163^(+)CSF1R^(+)SIGLEC5^(+))associated with immunotherapy resistance.Higher levels of monocyte-dendritic cells in pre-treatment peripheral blood mononuclear cells were found in durable clinical benefit group.Also,higher CD83,CD244,IL-12,and CD70,which are hallmarks of dendritic cells and activated T cells,were discovered by plasma proteomics to be connected with enhanced outcomes,while chemoattractant of macrophage,CSF-1,CCL3,CCL4,and IL-8,were found to predict a worse prognosis.Furthermore,a multimodal model was constructed and validated for stratifying ES-SCLC into high or low risk to predict the immunotherapy efficacy.This study sheds light on harnessing local and systematic immune profiles to better stratify patients with ES-SCLC for immunotherapy and putative combinational treatment.
基金supported by the National Key R&D Program of China(No.2021YFA1301200,and 2023YFC3405200)National Natural Science Foundation of China(No.82273445)+4 种基金Sichuan Science and Technology Program(No.2025ZNSFSC0046)Sichuan Provincial Youth Foundation(No.2025ZNSFSC1903)China Postdoctoral Science Foundation(No.2024M762235)Postdoctor Research Fund of West China Hospital,Sichuan University(2024HXBH033)1.3.5 Project for Disciplines of Excellence from West China Hospital of Sichuan University(No.ZYYC23025,ZYYC23013).
文摘The gut microbiota crucially regulates the efficacy of immune checkpoint inhibitor(ICl)based immunotherapy,but the underlying mechanisms remain unclear at the single-cell resolution.Using single-cell RNA sequencing and subsequent validations,we investigate gut microbiota-ICl synergy by profling the tumor microenvironment(TME)and elucidating critical cellular interactions in mouse models.Our findings reveal that intact gut microbiota combined with ICls may synergistically increase the proportions of CD8^(+),CD4^(+),and yδ T cells,reduce glycolysis metabolism,and reverse exhausted CD8^(+)T cells into memory/effector CD8^(+)T cells,enhancing antitumor response.This synergistic effect also induces macrophage reprogramming from M2 protumor Spp1^(+)tumorassociated macrophages(TAMs)to Cd74^(+)TAMs,which act as antigen-presenting cells(APCs).These macrophage subtypes show a negative correlation within tumors,particularly during fecal microbiota transplantation.Depleting Spp1^(+)TAMs in Spp1 conditional knockout mice boosts ICl efficacy and T cell infiltration,regardless of gut microbiota status,suggesting a potential upstream role of the gut microbiota and highlighting the crucial negative impact of Spp1^(+)TAMs during macrophage reprogramming on immunotherapy outcomes.Mechanistically,we propose aγδT cell-APC-CD8^(+)T cell axis,where gut microbiota and ICls enhance Cd40lg expression onγδT cells,activating Cd40 overexpressing APCs(e.g.,Cd74^(+)TAMs)through CD40-CD40L-related NF-kB signaling and boosting CD8^(+)T cell responses via CD86-CD28 interactions.These findings highlight the potential importance of y8 T cells and SPP1-related macrophage reprogramming in activating CD8^(+)T cells,as well as the synergistic effect of gut microbiota and ICls in immunotherapy through modulating the TME.
