Objective: DNA damage response(DDR) deficiency has emerged as a prominent determinant of tumor immunogenicity. This study aimed to construct a DDR-related immune activation(DRIA) signature and evaluate the predictive ...Objective: DNA damage response(DDR) deficiency has emerged as a prominent determinant of tumor immunogenicity. This study aimed to construct a DDR-related immune activation(DRIA) signature and evaluate the predictive accuracy of the DRIA signature for response to immune checkpoint inhibitor(ICI) therapy in gastrointestinal(GI) cancer.Methods: A DRIA signature was established based on two previously reported DNA damage immune response assays. Clinical and gene expression data from two published GI cancer cohorts were used to assess and validate the association between the DRIA score and response to ICI therapy. The predictive accuracy of the DRIA score was validated based on one ICI-treated melanoma and three pan-cancer published cohorts.Results: The DRIA signature includes three genes(CXCL10, IDO1, and IFI44L). In the discovery cancer cohort, DRIA-high patients with gastric cancer achieved a higher response rate to ICI therapy than DRIA-low patients(81.8% vs. 8.8%;P < 0.001), and the predictive accuracy of the DRIA score [area under the receiver operating characteristic curve(AUC) = 0.845] was superior to the predictive accuracy of PD-L1 expression, tumor mutational burden, microsatellite instability, and Epstein–Barr virus status. The validation cohort demonstrated that the DRIA score identified responders with microsatellite-stable colorectal and pancreatic adenocarcinoma who received dual PD-1 and CTLA-4 blockade with radiation therapy. Furthermore, the predictive performance of the DRIA score was shown to be robust through an extended validation in melanoma, urothelial cancer, and pan-cancer.Conclusions: The DRIA signature has superior and robust predictive accuracy for the efficacy of ICI therapy in GI cancer and pancancer, indicating that the DRIA signature may serve as a powerful biomarker for guiding ICI therapy decisions.展开更多
With less extra stress on the testing sample, a free-stress sample holder was designed to place the sample horizontally. With the free-stress sample holder, a magnetoelectric (ME) coefficient measurement system was de...With less extra stress on the testing sample, a free-stress sample holder was designed to place the sample horizontally. With the free-stress sample holder, a magnetoelectric (ME) coefficient measurement system was developed based on dynamic method. This measurement system has the hardware part and the software part, integrated by the DC magnetic field generation module, the AC magnetic field generation module, the induced ME voltage detecting module and PC software module. Then, a sample of Terfenol-D/PZT/Terfenol-D trilayer was designed and fabricated, and the relationships of its ME coefficient influenced by the DC magnetic field and the frequency of the AC magnetic field were tested using the measurement system. And the results showed that the free-stress sample holder was proven to improve the accuracy of the measurement system by less stress interference.展开更多
Mulberry fruits with high concentrations of anthocyanins are favored by consumers because of their good taste,bright color,and high nutritional value.However,neither the regulatory mechanism controlling flavonoid bios...Mulberry fruits with high concentrations of anthocyanins are favored by consumers because of their good taste,bright color,and high nutritional value.However,neither the regulatory mechanism controlling flavonoid biosynthesis in mulberry nor the molecular basis of different mulberry fruit colors is fully understood.Here,we report that a flavonoid homeostasis network comprising activation and feedback regulation mechanisms determines mulberry fruit color.In vitro and in vivo assays showed that MYBA-bHLH3-TTG1 regulates the biosynthesis of anthocyanins,while TT2L1 and TT2L2 work with bHLH3 or GL3 and form a MYB-bHLH-WD40(MBW)complex with TTG1 to regulate proanthocyanidin(PA)synthesis.Functional and expression analyses showed that bHLH3 is a key regulator of the regulatory network controlling mulberry fruit coloration and that MYB4 is activated by MBW complexes and participates in negative feedback control of the regulatory network to balance the accumulation of anthocyanins and proanthocyanidins.Our research demonstrates that the interaction between bHLH3 and MYB4 in the homeostasis regulatory network ensures that the fruits accumulate desirable flavonoids and that this network is stable in pigmentrich mulberry fruits.However,the abnormal expression of bHLH3 disrupts the balance of the network and redirects flavonoid metabolic flux in pale-colored fruits,resulting in differences in the levels and proportions of anthocyanins,flavones,and flavonols among differently colored mulberry fruits(red,yellow,and white).The results of our study reveal the molecular basis of the diversity of mulberry fruit colors.展开更多
Horizon control, maintaining the alignment of the shearer's exploitation gradient with the coal seam gradient, is a key technique in longwall mining automation. To identify the coal seam gradient, a geological mod...Horizon control, maintaining the alignment of the shearer's exploitation gradient with the coal seam gradient, is a key technique in longwall mining automation. To identify the coal seam gradient, a geological model of the coal seam was constructed using in-seam seismic surveying technology. By synthesizing the control resolution of the range arm and the geometric characteristics of the coal seam, a gradient identification method based on piecewise linear representation(PLR) is proposed. To achieve the maximum exploitation rate within the shearer's capacity, the control resolution of the range arm is selected as the threshold parameter of PLR. The control resolution significantly influenced the number of line segments and the fitting error. With the decrease of the control resolution from 0.01 to 0.02 m, the number of line segments decreased from 65 to 15, which was beneficial to horizon control. However, the average fitting error increased from 0.055 to 0.14 m, which would induce a decrease in the exploitation rate. To avoid significant deviation between the cutting range and the coal seam, the control resolution of the range arm must be lower than 0.02 m. In a field test, the automated horizon control of the longwall face was realized by coal seam gradient identification.展开更多
Perovskite solar cells have developed rapidly in the past decades.However,there are large amounts of ionic defects at the surface and grain boundaries of perovskte films which are detrimental to both the efficiency an...Perovskite solar cells have developed rapidly in the past decades.However,there are large amounts of ionic defects at the surface and grain boundaries of perovskte films which are detrimental to both the efficiency and stability of perovskite solar cells.Here,an organic halide salt pyridinium iodide(PyI) is used in cation-anion-mixed perovskite for surface defect passivation.Different from the treatment with Lewis base pyridine(Py) which can only bind to the under-coordinated Pb ions,zwitterion molecule PyI can not only fill negative charged iodine vacancies,but also interact with positive charged defects.Compared with Py treatment,PyI treatment results in smoother surface,less defect densities and nonradiative recombination in perovskite,leading to an improved VOC, negligible J-V hysteresis and stable performance of devices.As a result,the champion PyI-treated planar perovskite solar cell with a high VOC of 1.187 V achieves an efficiency of 21.42%,which is higher than 20.37% of Py-treated device,while the pristine device without any treatment gets an efficiency of 18.83% at the same experiment conditions.展开更多
Although chimeric antigen receptor-modified(CAR)T cell therapy has been successfully applied in the treatment of acute B lymphocytic leukemia,its effect on Burkitt lymphoma(BL)and chronic B lymphocytic leukemia(B-CLL)...Although chimeric antigen receptor-modified(CAR)T cell therapy has been successfully applied in the treatment of acute B lymphocytic leukemia,its effect on Burkitt lymphoma(BL)and chronic B lymphocytic leukemia(B-CLL)is unsatisfactory.Moreover,fatal side effects greatly impede CAR T cell application.Extracellular vesicles(EVs)are excellent carriers of therapeutic agents.Nevertheless,EVs mainly accumulate in the liver when administered without modification.As an envelope glycoprotein of Epstein–Barr viruses,gp350 can efficiently bind CD21 on B cells.Here,gp350 was directly anchored onto red blood cell EVs(RBC-EVs)via its transmembrane region combined with low-voltage electroporation.The results showed that gp350 could anchor to RBC-EVs with high efficiency and that the resulting gp350-anchored RBC-EVs(RBC-EVs/gp350^(Etp))exhibited increased targeting to CD21+BL and B-CLL relative to RBC-EVs.After the loading of doxorubicin or fludarabine,RBC-EVs/gp350^(Etp) had powerful cytotoxicity and therapeutic efficacy on CD21+BL or B-CLL,respectively.Moreover,RBC-EVs/gp350^(Etp) loaded with a drug did not exhibit any apparent systemic toxicity and specifically induced the apoptosis of tumor B cells but not normal Bcells.Therefore,our findings indicate that drug-loaded RBC-EVs/gp350^(Etp) may be adopted in the treatment of CD21+B cell malignancies.展开更多
A sensitive,specific and rapid high-performance liquid chromatography-electronic spray ionization-tandem mass spectrometric method was developed and validated for the determination of 7,4'-dihydroxylflavone(7,4...A sensitive,specific and rapid high-performance liquid chromatography-electronic spray ionization-tandem mass spectrometric method was developed and validated for the determination of 7,4'-dihydroxylflavone(7,4'-DHF)in rat plasma.Genistein(internal standard,IS)was added in the collected plasma samples and subsided together by a simple one-step protein precipitation using acetonitrile-methanol(1:1,v/v).Chromatographic separation was performed on an Agilent Zorbax XDB C18 chromatography column and gradient elution with the mobile phase consisting of methanol and 0.1%formic acid was used.The mass spectrometric detection was performed by negative ion electro-spray ionization in multiple selected reactions monitoring(MRM)mode,with the transitions of m/z 253.1→113.0 for 7,4'-DHF and m/z 268.9→158.8 for IS.The calibration curve has liner relationship over the concentration range of 0.1-50.ng/mL(r=0.995.4).The intra-and inter-day precision(RSD%)was less than 10%,and the accuracy(RE%,relative error)ranged from-5.2%to 8.0%.The fully validated method was applied to the pharmacokinetics(PK)of 7,4'-dihydroxylflavone(7,4'-DHF)in rat plasma after oral administration(two doses:15 and 30.mg/kg)and intravenous injection(5.mg/kg).The result showed that Tmax and Cmax was 1.33±0.29.h and 0.12±0.02.ng/mL(15.mg/kg),and 1.17±0.29.h and 0.17±0.04.ng/mL(30.mg/kg),respectively.The bioavailability was 0.078%(15.mg/kg)and 0.070%(30.mg/kg),respectively.展开更多
The present study proposes a novel method based on the geometric theory for measuring the distribution of bubble swarms in the circular region of a direct-contact heat exchanger.It was determined that the mixing is un...The present study proposes a novel method based on the geometric theory for measuring the distribution of bubble swarms in the circular region of a direct-contact heat exchanger.It was determined that the mixing is uniform when the average distance between the bubble swarms in the unit circular region is approximately 0.9054,which is the standard reference value.The effect of sample size(i.e.,the number of bubbles)on mixing uniformity was investigated to determine the optimal sample size.It was verified that the metric's accuracy and stability were higher with a sample size of 155.Accordingly,it was proposed to increase the sample size by filling irregular bubbles using a segmentation method,which enabled a further accurate assessment of the mixing uniformity.The mixing uniformity of bubble swarms in the circular region and its maximum internal connection with the square region was accurately quantified.It was revealed that the relative average error increased by approximately 3.47% due to information loss.The proposed method was demonstrated to be rotationally invariant.The present study provided novel insights into evaluating mixing uniformity,which would guide enhanced heat transfer and the effective evaluation of the spatiotemporal characteristics of transient mixing in circular regions or the cross-sections of chemical transport pipelines.展开更多
To the Editor:Probiotics are a promising treatment modality for functional constipation(FC);however,the factors affecting individual responses to probiotics remain unclear.Growing evidence has identified that there is...To the Editor:Probiotics are a promising treatment modality for functional constipation(FC);however,the factors affecting individual responses to probiotics remain unclear.Growing evidence has identified that there is a strong relationship among the gut microbiota and constipation and related gut-brain axis.[1]The gut microbiota may modulate the gut functions via gut metabolites or trigger the release of gut hormones,such as peptide YY,gastric inhibitory polypeptide,and 5-hydroxytryptamine.[2]In turn,gut hormones affect gut secretion,motility,and sensation through their receptors located on epithelial,enteric,and smooth muscle cells.[2]Based on these findings,exogenous probiotics have been used in patients with constipation;however,few have produced consistent results.[3]In this study,we investigated the efficacy and safety of several specific probiotics strains for constipation,and also examined the potential reasons for the individualized effects of probiotics,which may facilitate interventional decisionmaking for FC patients.展开更多
Surface enhanced Raman scattering(SERS)is a rapid and nondestructive technique that is capable of detecting and identifying chemical or biological compounds.Sensitive SERS quantification is vital for practical applica...Surface enhanced Raman scattering(SERS)is a rapid and nondestructive technique that is capable of detecting and identifying chemical or biological compounds.Sensitive SERS quantification is vital for practical applications,particularly for portable detection of biomolecules such as amino acids and nucleotides.However,few approaches can achieve sensitive and quantitative Raman detection of these most fundamental components in biology.Herein,a noblemetal-free single-atom site on a chip strategy was applied to modify single tungsten atom oxide on a lead halide perovskite,which provides sensitive SERS quantification for various analytes,including rhodamine,tyrosine and cytosine.The single-atom site on a chip can enable quantitative linear SERS responses of rhodamine(10^(−6)-1 mmol L^(−1)),tyrosine(0.06-1 mmol L^(−1))and cytosine(0.2-45 mmol L^(−1)),respectively,which all achieve record-high enhancement factors among plasmonic-free semiconductors.The experimental test and theoretical simulation both reveal that the enhanced mechanism can be ascribed to the controllable single-atom site,which can not only trap photoinduced electrons from the perovskite substrate but also enhance the highly efficient and quantitative charge transfer to analytes.Furthermore,the label-free strategy of single-atom sites on a chip can be applied in a portable Raman platform to obtain a sensitivity similar to that on a benchtop instrument,which can be readily extended to various biomolecules for low-cost,widely demanded and more precise point-of-care testing or in-vitro detection.展开更多
PD-L1+tumor-derived extracellular vesicles(TEVs)cause systemic immunosuppression and possibly resistance to anti-PD-L1 antibody(αPD-L1)blockade.However,whether and how PD-L1+TEVs mediateαPD-L1 therapy resistance is ...PD-L1+tumor-derived extracellular vesicles(TEVs)cause systemic immunosuppression and possibly resistance to anti-PD-L1 antibody(αPD-L1)blockade.However,whether and how PD-L1+TEVs mediateαPD-L1 therapy resistance is unknown.Here,we show that PD-L1+TEVs substantially decoyαPD-L1 and that TEV-boundαPD-L1 is more rapidly cleared by macrophages,causing insufficient blockade of tumor PD-L1 and subsequentαPD-L1 therapy resistance.Inhibition of endogenous production of TEVs by Rab27a or Coro1a knockout reversesαPD-L1 therapy resistance.Either an increasedαPD-L1 dose or macrophage depletion mediated by the clinical drug pexidartinib abolishesαPD-L1 therapy resistance.Moreover,in the treatment cycle with the same total treatment dose ofαPD-L1,high-dose and low-frequency treatment had better antitumor effects than low-dose and highfrequency treatment,induced stronger antitumor immune memory,and eliminatedαPD-L1 therapy resistance.Notably,in humanized immune system mice with human xenograft tumors,both increasedαPD-L1 dose and high-dose and low-frequency treatment enhanced the antitumor effects ofαPD-L1.Furthermore,increased doses ofαPD-L1 andαPD-1 had comparable antitumor effects,butαPD-L1 amplified fewer PD-1+Treg cells,which are responsible for tumor hyperprogression.Altogether,our results reveal a TEV-mediated mechanism ofαPD-L1-specific therapy resistance,thus providing promising strategies to improveαPD-L1 efficacy.展开更多
Herein,the rational design micromilieus involved silk fibroin(SF)-based materials have been used to encapsulate the osteoblasts,forming an extracellular coated shell on the cells,which exhibited the high potential to ...Herein,the rational design micromilieus involved silk fibroin(SF)-based materials have been used to encapsulate the osteoblasts,forming an extracellular coated shell on the cells,which exhibited the high potential to shift the regulation of osteoblasts to osteocytes by encapsulation cues.SF coating treated cells showed a change in cell morphology from osteoblasts-like to osteocytes-like shape comparedwith untreated ones.Moreover,the expression of alkaline phosphatase(ALP),collagen I(Col I)and osteocalcin(OcN)further indicated a potential approach for inducingosteoblasts regulation,which typically accelerates calcium deposition and cell calcification,presenting a key role for the SF encapsulation in controlling osteoblasts behavior.This discovery showed that SF-based cell encapsulation could be used for osteoblasts behavior regulation,which offers a great potential to modulate mammalian cells'phenotype involvingalternatingsurrounding cues.展开更多
基金supported by the National Natural Science Foundation of China (Grant Nos. 81972761 and 82202837)the National Key R&D Program of China (Grant Nos. 2016YFC1303200 and 2022YFC2505100)。
文摘Objective: DNA damage response(DDR) deficiency has emerged as a prominent determinant of tumor immunogenicity. This study aimed to construct a DDR-related immune activation(DRIA) signature and evaluate the predictive accuracy of the DRIA signature for response to immune checkpoint inhibitor(ICI) therapy in gastrointestinal(GI) cancer.Methods: A DRIA signature was established based on two previously reported DNA damage immune response assays. Clinical and gene expression data from two published GI cancer cohorts were used to assess and validate the association between the DRIA score and response to ICI therapy. The predictive accuracy of the DRIA score was validated based on one ICI-treated melanoma and three pan-cancer published cohorts.Results: The DRIA signature includes three genes(CXCL10, IDO1, and IFI44L). In the discovery cancer cohort, DRIA-high patients with gastric cancer achieved a higher response rate to ICI therapy than DRIA-low patients(81.8% vs. 8.8%;P < 0.001), and the predictive accuracy of the DRIA score [area under the receiver operating characteristic curve(AUC) = 0.845] was superior to the predictive accuracy of PD-L1 expression, tumor mutational burden, microsatellite instability, and Epstein–Barr virus status. The validation cohort demonstrated that the DRIA score identified responders with microsatellite-stable colorectal and pancreatic adenocarcinoma who received dual PD-1 and CTLA-4 blockade with radiation therapy. Furthermore, the predictive performance of the DRIA score was shown to be robust through an extended validation in melanoma, urothelial cancer, and pan-cancer.Conclusions: The DRIA signature has superior and robust predictive accuracy for the efficacy of ICI therapy in GI cancer and pancancer, indicating that the DRIA signature may serve as a powerful biomarker for guiding ICI therapy decisions.
文摘With less extra stress on the testing sample, a free-stress sample holder was designed to place the sample horizontally. With the free-stress sample holder, a magnetoelectric (ME) coefficient measurement system was developed based on dynamic method. This measurement system has the hardware part and the software part, integrated by the DC magnetic field generation module, the AC magnetic field generation module, the induced ME voltage detecting module and PC software module. Then, a sample of Terfenol-D/PZT/Terfenol-D trilayer was designed and fabricated, and the relationships of its ME coefficient influenced by the DC magnetic field and the frequency of the AC magnetic field were tested using the measurement system. And the results showed that the free-stress sample holder was proven to improve the accuracy of the measurement system by less stress interference.
基金funded by the“111”Project(No.B12006)the National Key Research and Development Program(No.2018YFD1000602)+3 种基金the Special Fund for Agro-scientific Research in the Public Interest of China(No.201403064)the Natural Science Foundation of China(No.31572323)Fundamental Research Funds for the Central Universities(No.SW118040)the Chongqing Research Program of Basic Research and Frontier Technology(No.cstc2018jcyjAX0407).
文摘Mulberry fruits with high concentrations of anthocyanins are favored by consumers because of their good taste,bright color,and high nutritional value.However,neither the regulatory mechanism controlling flavonoid biosynthesis in mulberry nor the molecular basis of different mulberry fruit colors is fully understood.Here,we report that a flavonoid homeostasis network comprising activation and feedback regulation mechanisms determines mulberry fruit color.In vitro and in vivo assays showed that MYBA-bHLH3-TTG1 regulates the biosynthesis of anthocyanins,while TT2L1 and TT2L2 work with bHLH3 or GL3 and form a MYB-bHLH-WD40(MBW)complex with TTG1 to regulate proanthocyanidin(PA)synthesis.Functional and expression analyses showed that bHLH3 is a key regulator of the regulatory network controlling mulberry fruit coloration and that MYB4 is activated by MBW complexes and participates in negative feedback control of the regulatory network to balance the accumulation of anthocyanins and proanthocyanidins.Our research demonstrates that the interaction between bHLH3 and MYB4 in the homeostasis regulatory network ensures that the fruits accumulate desirable flavonoids and that this network is stable in pigmentrich mulberry fruits.However,the abnormal expression of bHLH3 disrupts the balance of the network and redirects flavonoid metabolic flux in pale-colored fruits,resulting in differences in the levels and proportions of anthocyanins,flavones,and flavonols among differently colored mulberry fruits(red,yellow,and white).The results of our study reveal the molecular basis of the diversity of mulberry fruit colors.
基金supported in part by the Funds of the National Natural Science Foundation of China (Nos. 51874279 and U1610251)the Priority Academic Program Development of Jiangsu Higher Education Institutions。
文摘Horizon control, maintaining the alignment of the shearer's exploitation gradient with the coal seam gradient, is a key technique in longwall mining automation. To identify the coal seam gradient, a geological model of the coal seam was constructed using in-seam seismic surveying technology. By synthesizing the control resolution of the range arm and the geometric characteristics of the coal seam, a gradient identification method based on piecewise linear representation(PLR) is proposed. To achieve the maximum exploitation rate within the shearer's capacity, the control resolution of the range arm is selected as the threshold parameter of PLR. The control resolution significantly influenced the number of line segments and the fitting error. With the decrease of the control resolution from 0.01 to 0.02 m, the number of line segments decreased from 65 to 15, which was beneficial to horizon control. However, the average fitting error increased from 0.055 to 0.14 m, which would induce a decrease in the exploitation rate. To avoid significant deviation between the cutting range and the coal seam, the control resolution of the range arm must be lower than 0.02 m. In a field test, the automated horizon control of the longwall face was realized by coal seam gradient identification.
基金the joint financial support from the National Natural Science Foundation of China (No. U1705256, 51972123, 21771066 and 61804058)the Cultivation Program for Postgraduate in Scientific Research Innovation Ability of Huaqiao University (No. 18014087027)。
文摘Perovskite solar cells have developed rapidly in the past decades.However,there are large amounts of ionic defects at the surface and grain boundaries of perovskte films which are detrimental to both the efficiency and stability of perovskite solar cells.Here,an organic halide salt pyridinium iodide(PyI) is used in cation-anion-mixed perovskite for surface defect passivation.Different from the treatment with Lewis base pyridine(Py) which can only bind to the under-coordinated Pb ions,zwitterion molecule PyI can not only fill negative charged iodine vacancies,but also interact with positive charged defects.Compared with Py treatment,PyI treatment results in smoother surface,less defect densities and nonradiative recombination in perovskite,leading to an improved VOC, negligible J-V hysteresis and stable performance of devices.As a result,the champion PyI-treated planar perovskite solar cell with a high VOC of 1.187 V achieves an efficiency of 21.42%,which is higher than 20.37% of Py-treated device,while the pristine device without any treatment gets an efficiency of 18.83% at the same experiment conditions.
基金supported by the Natural Science Foundation of Zhejiang Province(LY19H160009 and LY20H120007)the National Natural Science Foundation of China(82130053,81971871,31970845 and 81901571)+1 种基金the Joint Preresearch Fund for Clinical Scientific Research of Hangzhou First People’s Hospital Affiliated to Zhejiang University(YYJJ2019Z07)the Major Project of Hangzhou Health Science and Technology Plan(Z20200134).
文摘Although chimeric antigen receptor-modified(CAR)T cell therapy has been successfully applied in the treatment of acute B lymphocytic leukemia,its effect on Burkitt lymphoma(BL)and chronic B lymphocytic leukemia(B-CLL)is unsatisfactory.Moreover,fatal side effects greatly impede CAR T cell application.Extracellular vesicles(EVs)are excellent carriers of therapeutic agents.Nevertheless,EVs mainly accumulate in the liver when administered without modification.As an envelope glycoprotein of Epstein–Barr viruses,gp350 can efficiently bind CD21 on B cells.Here,gp350 was directly anchored onto red blood cell EVs(RBC-EVs)via its transmembrane region combined with low-voltage electroporation.The results showed that gp350 could anchor to RBC-EVs with high efficiency and that the resulting gp350-anchored RBC-EVs(RBC-EVs/gp350^(Etp))exhibited increased targeting to CD21+BL and B-CLL relative to RBC-EVs.After the loading of doxorubicin or fludarabine,RBC-EVs/gp350^(Etp) had powerful cytotoxicity and therapeutic efficacy on CD21+BL or B-CLL,respectively.Moreover,RBC-EVs/gp350^(Etp) loaded with a drug did not exhibit any apparent systemic toxicity and specifically induced the apoptosis of tumor B cells but not normal Bcells.Therefore,our findings indicate that drug-loaded RBC-EVs/gp350^(Etp) may be adopted in the treatment of CD21+B cell malignancies.
基金National Natural Science Foundation of China(81573693)。
文摘A sensitive,specific and rapid high-performance liquid chromatography-electronic spray ionization-tandem mass spectrometric method was developed and validated for the determination of 7,4'-dihydroxylflavone(7,4'-DHF)in rat plasma.Genistein(internal standard,IS)was added in the collected plasma samples and subsided together by a simple one-step protein precipitation using acetonitrile-methanol(1:1,v/v).Chromatographic separation was performed on an Agilent Zorbax XDB C18 chromatography column and gradient elution with the mobile phase consisting of methanol and 0.1%formic acid was used.The mass spectrometric detection was performed by negative ion electro-spray ionization in multiple selected reactions monitoring(MRM)mode,with the transitions of m/z 253.1→113.0 for 7,4'-DHF and m/z 268.9→158.8 for IS.The calibration curve has liner relationship over the concentration range of 0.1-50.ng/mL(r=0.995.4).The intra-and inter-day precision(RSD%)was less than 10%,and the accuracy(RE%,relative error)ranged from-5.2%to 8.0%.The fully validated method was applied to the pharmacokinetics(PK)of 7,4'-dihydroxylflavone(7,4'-DHF)in rat plasma after oral administration(two doses:15 and 30.mg/kg)and intravenous injection(5.mg/kg).The result showed that Tmax and Cmax was 1.33±0.29.h and 0.12±0.02.ng/mL(15.mg/kg),and 1.17±0.29.h and 0.17±0.04.ng/mL(30.mg/kg),respectively.The bioavailability was 0.078%(15.mg/kg)and 0.070%(30.mg/kg),respectively.
基金the National Natural Science Foundation of China(project No.52166004)Yunnan Major Scientific and Technological Projects(grant No.202202AG050002)+2 种基金Scientific Research Fund Project of Yunnan Education Department,China(grant No.2021j0063)Natural Science FoundationofYunnan Province,China(grant No.202101AU070031)the teaching projects A Quality Course for Graduate Students in Yunnan Province"Numerical Analysis","Advanced Mathematics Teaching Team of Engineering Subjects of Kunming University of Science and Technology".
文摘The present study proposes a novel method based on the geometric theory for measuring the distribution of bubble swarms in the circular region of a direct-contact heat exchanger.It was determined that the mixing is uniform when the average distance between the bubble swarms in the unit circular region is approximately 0.9054,which is the standard reference value.The effect of sample size(i.e.,the number of bubbles)on mixing uniformity was investigated to determine the optimal sample size.It was verified that the metric's accuracy and stability were higher with a sample size of 155.Accordingly,it was proposed to increase the sample size by filling irregular bubbles using a segmentation method,which enabled a further accurate assessment of the mixing uniformity.The mixing uniformity of bubble swarms in the circular region and its maximum internal connection with the square region was accurately quantified.It was revealed that the relative average error increased by approximately 3.47% due to information loss.The proposed method was demonstrated to be rotationally invariant.The present study provided novel insights into evaluating mixing uniformity,which would guide enhanced heat transfer and the effective evaluation of the spatiotemporal characteristics of transient mixing in circular regions or the cross-sections of chemical transport pipelines.
基金National Natural Science Foundation of China(Nos.81900483 and 81730016)National Clinical Research Center for Digestive Diseases,Xi’an,China(No.2015BAI13 B07)
文摘To the Editor:Probiotics are a promising treatment modality for functional constipation(FC);however,the factors affecting individual responses to probiotics remain unclear.Growing evidence has identified that there is a strong relationship among the gut microbiota and constipation and related gut-brain axis.[1]The gut microbiota may modulate the gut functions via gut metabolites or trigger the release of gut hormones,such as peptide YY,gastric inhibitory polypeptide,and 5-hydroxytryptamine.[2]In turn,gut hormones affect gut secretion,motility,and sensation through their receptors located on epithelial,enteric,and smooth muscle cells.[2]Based on these findings,exogenous probiotics have been used in patients with constipation;however,few have produced consistent results.[3]In this study,we investigated the efficacy and safety of several specific probiotics strains for constipation,and also examined the potential reasons for the individualized effects of probiotics,which may facilitate interventional decisionmaking for FC patients.
基金supported by the Natural Science Foundation of Beijing Municipality(Z180014)。
文摘Surface enhanced Raman scattering(SERS)is a rapid and nondestructive technique that is capable of detecting and identifying chemical or biological compounds.Sensitive SERS quantification is vital for practical applications,particularly for portable detection of biomolecules such as amino acids and nucleotides.However,few approaches can achieve sensitive and quantitative Raman detection of these most fundamental components in biology.Herein,a noblemetal-free single-atom site on a chip strategy was applied to modify single tungsten atom oxide on a lead halide perovskite,which provides sensitive SERS quantification for various analytes,including rhodamine,tyrosine and cytosine.The single-atom site on a chip can enable quantitative linear SERS responses of rhodamine(10^(−6)-1 mmol L^(−1)),tyrosine(0.06-1 mmol L^(−1))and cytosine(0.2-45 mmol L^(−1)),respectively,which all achieve record-high enhancement factors among plasmonic-free semiconductors.The experimental test and theoretical simulation both reveal that the enhanced mechanism can be ascribed to the controllable single-atom site,which can not only trap photoinduced electrons from the perovskite substrate but also enhance the highly efficient and quantitative charge transfer to analytes.Furthermore,the label-free strategy of single-atom sites on a chip can be applied in a portable Raman platform to obtain a sensitivity similar to that on a benchtop instrument,which can be readily extended to various biomolecules for low-cost,widely demanded and more precise point-of-care testing or in-vitro detection.
基金This work was supported by the National Natural Science Foundation of China(82130053,31970845,31870876,81971871 and 81901571).
文摘PD-L1+tumor-derived extracellular vesicles(TEVs)cause systemic immunosuppression and possibly resistance to anti-PD-L1 antibody(αPD-L1)blockade.However,whether and how PD-L1+TEVs mediateαPD-L1 therapy resistance is unknown.Here,we show that PD-L1+TEVs substantially decoyαPD-L1 and that TEV-boundαPD-L1 is more rapidly cleared by macrophages,causing insufficient blockade of tumor PD-L1 and subsequentαPD-L1 therapy resistance.Inhibition of endogenous production of TEVs by Rab27a or Coro1a knockout reversesαPD-L1 therapy resistance.Either an increasedαPD-L1 dose or macrophage depletion mediated by the clinical drug pexidartinib abolishesαPD-L1 therapy resistance.Moreover,in the treatment cycle with the same total treatment dose ofαPD-L1,high-dose and low-frequency treatment had better antitumor effects than low-dose and highfrequency treatment,induced stronger antitumor immune memory,and eliminatedαPD-L1 therapy resistance.Notably,in humanized immune system mice with human xenograft tumors,both increasedαPD-L1 dose and high-dose and low-frequency treatment enhanced the antitumor effects ofαPD-L1.Furthermore,increased doses ofαPD-L1 andαPD-1 had comparable antitumor effects,butαPD-L1 amplified fewer PD-1+Treg cells,which are responsible for tumor hyperprogression.Altogether,our results reveal a TEV-mediated mechanism ofαPD-L1-specific therapy resistance,thus providing promising strategies to improveαPD-L1 efficacy.
基金supported by the National Natural Science Foundation of China(Grant Nos.51902289 and 51672250)the Natural Science Foundation of Zhejiang Province(Grant No.LQ19E020010)+2 种基金the Project of Zhejiang Provincial Department of Education(Grant No.Y201840323)the Key Project of Zhejiang Science and Technology(Grant Nos.2021C01180 and 2019C04020)the Research Foundation of ZSTU(Grant Nos.18012134-Y and 2020Q008).
文摘Herein,the rational design micromilieus involved silk fibroin(SF)-based materials have been used to encapsulate the osteoblasts,forming an extracellular coated shell on the cells,which exhibited the high potential to shift the regulation of osteoblasts to osteocytes by encapsulation cues.SF coating treated cells showed a change in cell morphology from osteoblasts-like to osteocytes-like shape comparedwith untreated ones.Moreover,the expression of alkaline phosphatase(ALP),collagen I(Col I)and osteocalcin(OcN)further indicated a potential approach for inducingosteoblasts regulation,which typically accelerates calcium deposition and cell calcification,presenting a key role for the SF encapsulation in controlling osteoblasts behavior.This discovery showed that SF-based cell encapsulation could be used for osteoblasts behavior regulation,which offers a great potential to modulate mammalian cells'phenotype involvingalternatingsurrounding cues.
