Numerous c-mesenchymal-epithelial transition(c-MET)inhibitors have been reported as potential anticancer agents.However,most fail to enter clinical trials owing to poor efficacy or drug resistance.To date,the scaffold...Numerous c-mesenchymal-epithelial transition(c-MET)inhibitors have been reported as potential anticancer agents.However,most fail to enter clinical trials owing to poor efficacy or drug resistance.To date,the scaffold-based chemical space of small-molecule c-MET inhibitors has not been analyzed.In this study,we constructed the largest c-MET dataset,which included 2,278 molecules with different struc-tures,by inhibiting the half maximal inhibitory concentration(IC_(50))of kinase activity.No significant differences in drug-like properties were observed between active molecules(1,228)and inactive mol-ecules(1,050),including chemical space coverage,physicochemical properties,and absorption,distri-bution,metabolism,excretion,and toxicity(ADMET)profiles.The higher chemical diversity of the active molecules was downscaled using t-distributed stochastic neighbor embedding(t-SNE)high-dimensional data.Further clustering and chemical space networks(CSNs)analyses revealed commonly used scaffolds for c-MET inhibitors,such as M5,M7,and M8.Activity cliffs and structural alerts were used to reveal“dead ends”and“safe bets”for c-MET,as well as dominant structural fragments consisting of pyr-idazinones,triazoles,and pyrazines.Finally,the decision tree model precisely indicated the key structural features required to constitute active c-MET inhibitor molecules,including at least three aromatic het-erocycles,five aromatic nitrogen atoms,and eight nitrogeneoxygen atoms.Overall,our analyses revealed potential structure-activity relationship(SAR)patterns for c-MET inhibitors,which can inform the screening of new compounds and guide future optimization efforts.展开更多
A comprehensive understanding of the molecular details at spatial levels within heterogeneous cardiac tissue in heart failure(HF)is paramount for enhancing our knowledge of the pathophysiology of HF and pinpointing po...A comprehensive understanding of the molecular details at spatial levels within heterogeneous cardiac tissue in heart failure(HF)is paramount for enhancing our knowledge of the pathophysiology of HF and pinpointing potential therapeutic targets.Here,we present an analytical strategy for the deep discovery of heterogeneous metabolism and drug response in the heart tissue of rats with HF using airflow-assisted desorption electrospray ionization mass spectrometry imaging(AFADESI-MSI)coupled with bulk RNAsequencing.Spatial metabolomics illustrated pronounced metabolic heterogeneity between the infarct(I),infarct margin(IM),and non-infarct(NI)areas of heart tissue in HF.Integrated transcriptomics showed that increased mRNA expression of ATP citrate lyase disrupted the tricarboxylic acid(TCA)cycle in the NI area.Impairment of the carnitine shuttle system led to a significant accumulation of carnitines,suggesting potential abnormalities in fatty acid(FA)oxidation.Coupling on-tissue chemical derivatization with AFADESI-MSI enabled us to confirm the occurrence of incomplete oxidation of FAs in the NI area.Additionally,we observed a heterogeneous drug response between the anti-HF medications valsartan and Qishen Yiqi Dripping Pills(QDP).Valsartan exhibited a more pronounced effect on metabolic regulation in the I area,whereas QDP exerted stronger regulatory effects on metabolism in the NI area.Utilizing this method,four potential therapeutic targets were identified in HF:CPT1A,PDHB,ACLY,and BCAT2,which were preliminarily validated by western blotting.Overall,integrating spatial metabolomics with transcriptomics facilitates comprehensive analyses that link differential metabolites and genes,enabling a more precise characterization of metabolic changes in heart injury microareas and providing effective methods for elucidating molecular mechanisms and identifying potential therapeutic targets for HF.展开更多
Aiming at the problems of incomplete characterization of text relations,poor guidance of potential representations,and low quality of model generation in the field of controllable long text generation,this paper propo...Aiming at the problems of incomplete characterization of text relations,poor guidance of potential representations,and low quality of model generation in the field of controllable long text generation,this paper proposes a new GSPT-CVAE model(Graph Structured Processing,Single Vector,and Potential Attention Com-puting Transformer-Based Conditioned Variational Autoencoder model).The model obtains a more comprehensive representation of textual relations by graph-structured processing of the input text,and at the same time obtains a single vector representation by weighted merging of the vector sequences after graph-structured processing to get an effective potential representation.In the process of potential representation guiding text generation,the model adopts a combination of traditional embedding and potential attention calculation to give full play to the guiding role of potential representation for generating text,to improve the controllability and effectiveness of text generation.The experimental results show that the model has excellent representation learning ability and can learn rich and useful textual relationship representations.The model also achieves satisfactory results in the effectiveness and controllability of text generation and can generate long texts that match the given constraints.The ROUGE-1 F1 score of this model is 0.243,the ROUGE-2 F1 score is 0.041,the ROUGE-L F1 score is 0.22,and the PPL-Word score is 34.303,which gives the GSPT-CVAE model a certain advantage over the baseline model.Meanwhile,this paper compares this model with the state-of-the-art generative models T5,GPT-4,Llama2,and so on,and the experimental results show that the GSPT-CVAE model has a certain competitiveness.展开更多
AIM:To study the relationship between the cyclooxy-genase(COX)-2 gene and the proliferation and apopto-sis of esophageal squamous carcinoma EC109 cells.METHODS:The techniques of RNA interference(RNAi)and cell transfec...AIM:To study the relationship between the cyclooxy-genase(COX)-2 gene and the proliferation and apopto-sis of esophageal squamous carcinoma EC109 cells.METHODS:The techniques of RNA interference(RNAi)and cell transfection,as well as the levels of oncogenic-ity in nude mice,were used to study the role of COX-2 in the esophageal squamous carcinoma cell(ESCC)line EC109.Following RNAi and transfection,Western blot-ting analysis was used to determine the expression of the COX-2 protein.The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide(MTT)reduction assay was used to evaluate cell growth,and flow cytometry was used to detect cell apoptosis.RESULTS:Western blotting analysis demonstrated that COX-2 expression was significantly reduced in EC109 cells treated with COX-2-specif ic short interfering RNA(siRNA)but was increased in EC109 cells transfected with COX-2.Furthermore,COX-2 siRNA treatment in-hibited cell proliferation(P < 0.01)and induced apop-tosis in EC109 cells,as determined by an MTT assay and by flow cytometry,respectively.In contrast,trans-fected COX-2 led to increased cell proliferation(P < 0.05)and decreased apoptosis in EC109 cells.In addition,combination treatment of cells with COX-2 siRNA and aspirin had a synergistic effect(P < 0.01).For experi-ments measuring tumorigenicity,xenograft tumors of a greater volume and weight were found in the COX-2 group compared with other groups(P < 0.05).A large dose of aspirin inhibited tumor growth in nude mice ef-fectively(P < 0.05),and the rate of tumor suppression was 51.8% in the high-dose aspirin group.CONCLUSION:COX-2 plays a very critical role in ESCC carcinogenesis,and COX-2 siRNA combined with aspirin has the potential to be an anticancer therapy for the treatment of ESCC.展开更多
Endosperm mutants are critical to the studies on both starch synthesis and metabolism and genetic improvement of starch quality in maize.In the present study,a novel maize endosperm mutant A0178 of natural variation w...Endosperm mutants are critical to the studies on both starch synthesis and metabolism and genetic improvement of starch quality in maize.In the present study,a novel maize endosperm mutant A0178 of natural variation was used as the experimental material and identified and then characterized.Through phenotypic identification,genetic analysis,main ingredients measurement and embryo rescue,development of genetic mapping population from A0178,the endosperm mutant gene was located.The results showed that the mutant exhibited extremely low germination ability as attributed to the inhibited embryo development,and amounts of sugars were accumulated in the mutant seeds and more sugars content was detected at 23 days after pollination(DAP)in A0178 than B73.Employing genetic linkage analysis,the mutant trait was mapped in the bin 5.04 on chromosome 5.Sequence analysis showed that two sites of base transversion and insertion presented in the protein coding region and non-coding region of the mutant brittle-1(bt1),the adenylate translocator encoding gene involved in the starch synthesis.The single base insertion in the coding region cause frameshift mutation,early termination and lose of function of Brittle-1(BT1).All results suggested that bt1 is a novel allelic gene and the causal gene of this endosperm mutant,providing insights on the mechanism of endosperm formation in maize.展开更多
Background Cognitive decline is a significant concern for stroke survivors,affecting their quality of life and increasing their burden on the healthcare system.DL-3-n butylphthalide(butylphthalide)has shown efficacy i...Background Cognitive decline is a significant concern for stroke survivors,affecting their quality of life and increasing their burden on the healthcare system.DL-3-n butylphthalide(butylphthalide)has shown efficacy in the short-term treatment of various cognitive impairments.This study evaluated the efficacy of butylphthalide in preventing cognitive decline over a 12-month period in patients with ischaemic stroke.Methods This prospective following-up study involved patients newly diagnosed with ischaemic stroke between 1 month and 6 months after stroke onset and not in the acute phase.Patients were assigned to either the butylphthalide or control group.Cognitive function was assessed using the mini-mental state examination(MMSE)at baseline and at the 12-month follow-up.Statistical analyses included t-tests,χ2 tests and multivariate regression analyses.Results Butylphthalide was negatively associated with the MMSE D-value(β=−0.122;95%CI−1.932 to−0.298;p=0.003)and the MMSE D-value percentage(β=−0.117;95%CI−0.057 to−0.011;p=0.004).A multivariate analysis indicated that butylphthalide treatment was negatively associated with both changes in orientation and language score.Additionally,the incidence of cognitive decline was significantly lower in the butylphthalide group(OR,0.612;p=0.020)than the control group.An age of≥60 years and lower educational level were identified as risk factors for lower cognitive score and cognitive decline.Conclusion This study demonstrated that butylphthalide is effective in preventing cognitive decline in patients with ischaemic stroke.These findings have significant implications for clinical practice,suggesting that butylphthalide could be incorporated into standard post-stroke care regimens to improve patient outcomes and reduce the healthcare burden.Additional multicentre double-blind trials are recommended to confirm these results in diverse populations.展开更多
Air-coupled ultrasonic transducers(ACUTs)have been applied in industrial non-destructive testing,structural health monitoring,and medical ultrasound.However,conventional passive focusing methods often result in undesi...Air-coupled ultrasonic transducers(ACUTs)have been applied in industrial non-destructive testing,structural health monitoring,and medical ultrasound.However,conventional passive focusing methods often result in undesired effects on sensitivity due to variations in acoustic impedance matching conditions,which are critical in ACUT design,where sensitivity is the top priority.Accordingly,a novel active focusing method for ACUTs is proposed in this study.The key idea is to create multiple concentric ring electrode patterns on a bulk planar piezoelectric plate so that a quarter-wavelength acoustic impedance matching layer of uniform thickness can be attached onto the plate.The initial structural parameters of the electrode patterns are determined based on the design methodology of a Fresnel zone plate(FZP).Those parameters are optimized through finite element simulation,with the transducer’s sensitivity as the objective function,while ensuring only slight variations to the focal length and lateral resolution.Single-sided multiple concentric ring electrode patterns are then fabricated on 1-3 piezoelectric fiber/epoxy resin composite plate by screen printing and combined with a high-performance acoustic impedance matching layer made from epoxy resin composite filled with hollow glass microspheres.The planar active focusing ACUT is developed,while two types of conventional passive focusing ACUTs using FZP and concave lens are fabricated with the same piezoelectric and acoustic matching materials.Comparative experimental testing is carried out.The developed planar active-focusing ACUT achieves significant sensitivity improvements of 7.1 and 17.4dB,respectively,while maintaining comparable radial and axial full-width at half maximum.The results of this study offer a novel approach for the design of high-performance ACUTs.展开更多
基金supported by the National Natural Science Foundation of China(Grant Nos.:82173699 and 32200531)Shanghai Jiao Tong University Trans-Med Awards Research,China(STAR Project No.:20230101)Shanghai Science and Technol-ogy Commission,China(Grant No.:23DZ2290600).
文摘Numerous c-mesenchymal-epithelial transition(c-MET)inhibitors have been reported as potential anticancer agents.However,most fail to enter clinical trials owing to poor efficacy or drug resistance.To date,the scaffold-based chemical space of small-molecule c-MET inhibitors has not been analyzed.In this study,we constructed the largest c-MET dataset,which included 2,278 molecules with different struc-tures,by inhibiting the half maximal inhibitory concentration(IC_(50))of kinase activity.No significant differences in drug-like properties were observed between active molecules(1,228)and inactive mol-ecules(1,050),including chemical space coverage,physicochemical properties,and absorption,distri-bution,metabolism,excretion,and toxicity(ADMET)profiles.The higher chemical diversity of the active molecules was downscaled using t-distributed stochastic neighbor embedding(t-SNE)high-dimensional data.Further clustering and chemical space networks(CSNs)analyses revealed commonly used scaffolds for c-MET inhibitors,such as M5,M7,and M8.Activity cliffs and structural alerts were used to reveal“dead ends”and“safe bets”for c-MET,as well as dominant structural fragments consisting of pyr-idazinones,triazoles,and pyrazines.Finally,the decision tree model precisely indicated the key structural features required to constitute active c-MET inhibitor molecules,including at least three aromatic het-erocycles,five aromatic nitrogen atoms,and eight nitrogeneoxygen atoms.Overall,our analyses revealed potential structure-activity relationship(SAR)patterns for c-MET inhibitors,which can inform the screening of new compounds and guide future optimization efforts.
基金supported by the National Natural Science Foundation of China(No.82374158)National Science and Technology Major Project(No.2018ZX09711001-002-004)+1 种基金the Jiangxi University of Chinese Medicine Science and Technology Innovation Team Development Program(No.CXTD22007)the Medical and Health Technology Innovation Project(No.2022-I2M-1-020).
文摘A comprehensive understanding of the molecular details at spatial levels within heterogeneous cardiac tissue in heart failure(HF)is paramount for enhancing our knowledge of the pathophysiology of HF and pinpointing potential therapeutic targets.Here,we present an analytical strategy for the deep discovery of heterogeneous metabolism and drug response in the heart tissue of rats with HF using airflow-assisted desorption electrospray ionization mass spectrometry imaging(AFADESI-MSI)coupled with bulk RNAsequencing.Spatial metabolomics illustrated pronounced metabolic heterogeneity between the infarct(I),infarct margin(IM),and non-infarct(NI)areas of heart tissue in HF.Integrated transcriptomics showed that increased mRNA expression of ATP citrate lyase disrupted the tricarboxylic acid(TCA)cycle in the NI area.Impairment of the carnitine shuttle system led to a significant accumulation of carnitines,suggesting potential abnormalities in fatty acid(FA)oxidation.Coupling on-tissue chemical derivatization with AFADESI-MSI enabled us to confirm the occurrence of incomplete oxidation of FAs in the NI area.Additionally,we observed a heterogeneous drug response between the anti-HF medications valsartan and Qishen Yiqi Dripping Pills(QDP).Valsartan exhibited a more pronounced effect on metabolic regulation in the I area,whereas QDP exerted stronger regulatory effects on metabolism in the NI area.Utilizing this method,four potential therapeutic targets were identified in HF:CPT1A,PDHB,ACLY,and BCAT2,which were preliminarily validated by western blotting.Overall,integrating spatial metabolomics with transcriptomics facilitates comprehensive analyses that link differential metabolites and genes,enabling a more precise characterization of metabolic changes in heart injury microareas and providing effective methods for elucidating molecular mechanisms and identifying potential therapeutic targets for HF.
文摘Aiming at the problems of incomplete characterization of text relations,poor guidance of potential representations,and low quality of model generation in the field of controllable long text generation,this paper proposes a new GSPT-CVAE model(Graph Structured Processing,Single Vector,and Potential Attention Com-puting Transformer-Based Conditioned Variational Autoencoder model).The model obtains a more comprehensive representation of textual relations by graph-structured processing of the input text,and at the same time obtains a single vector representation by weighted merging of the vector sequences after graph-structured processing to get an effective potential representation.In the process of potential representation guiding text generation,the model adopts a combination of traditional embedding and potential attention calculation to give full play to the guiding role of potential representation for generating text,to improve the controllability and effectiveness of text generation.The experimental results show that the model has excellent representation learning ability and can learn rich and useful textual relationship representations.The model also achieves satisfactory results in the effectiveness and controllability of text generation and can generate long texts that match the given constraints.The ROUGE-1 F1 score of this model is 0.243,the ROUGE-2 F1 score is 0.041,the ROUGE-L F1 score is 0.22,and the PPL-Word score is 34.303,which gives the GSPT-CVAE model a certain advantage over the baseline model.Meanwhile,this paper compares this model with the state-of-the-art generative models T5,GPT-4,Llama2,and so on,and the experimental results show that the GSPT-CVAE model has a certain competitiveness.
基金Supported by The National Natural Science Foundation of China,No.81071974The National 863 High Technology Research and Development Plan of China,No.2007AA02Z4Z4
文摘AIM:To study the relationship between the cyclooxy-genase(COX)-2 gene and the proliferation and apopto-sis of esophageal squamous carcinoma EC109 cells.METHODS:The techniques of RNA interference(RNAi)and cell transfection,as well as the levels of oncogenic-ity in nude mice,were used to study the role of COX-2 in the esophageal squamous carcinoma cell(ESCC)line EC109.Following RNAi and transfection,Western blot-ting analysis was used to determine the expression of the COX-2 protein.The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide(MTT)reduction assay was used to evaluate cell growth,and flow cytometry was used to detect cell apoptosis.RESULTS:Western blotting analysis demonstrated that COX-2 expression was significantly reduced in EC109 cells treated with COX-2-specif ic short interfering RNA(siRNA)but was increased in EC109 cells transfected with COX-2.Furthermore,COX-2 siRNA treatment in-hibited cell proliferation(P < 0.01)and induced apop-tosis in EC109 cells,as determined by an MTT assay and by flow cytometry,respectively.In contrast,trans-fected COX-2 led to increased cell proliferation(P < 0.05)and decreased apoptosis in EC109 cells.In addition,combination treatment of cells with COX-2 siRNA and aspirin had a synergistic effect(P < 0.01).For experi-ments measuring tumorigenicity,xenograft tumors of a greater volume and weight were found in the COX-2 group compared with other groups(P < 0.05).A large dose of aspirin inhibited tumor growth in nude mice ef-fectively(P < 0.05),and the rate of tumor suppression was 51.8% in the high-dose aspirin group.CONCLUSION:COX-2 plays a very critical role in ESCC carcinogenesis,and COX-2 siRNA combined with aspirin has the potential to be an anticancer therapy for the treatment of ESCC.
基金This work was financially supported in part by grants from National Science and Technology Support Project of China(2016YFD0101205)the Natural Science Foundation of Jiangsu Province,China(BK20160586)+1 种基金National Transgenic Major Project of China(2019ZX08010-004)as well as Six Talent Peaks Project of Jiangsu Province,China(NY-020).
文摘Endosperm mutants are critical to the studies on both starch synthesis and metabolism and genetic improvement of starch quality in maize.In the present study,a novel maize endosperm mutant A0178 of natural variation was used as the experimental material and identified and then characterized.Through phenotypic identification,genetic analysis,main ingredients measurement and embryo rescue,development of genetic mapping population from A0178,the endosperm mutant gene was located.The results showed that the mutant exhibited extremely low germination ability as attributed to the inhibited embryo development,and amounts of sugars were accumulated in the mutant seeds and more sugars content was detected at 23 days after pollination(DAP)in A0178 than B73.Employing genetic linkage analysis,the mutant trait was mapped in the bin 5.04 on chromosome 5.Sequence analysis showed that two sites of base transversion and insertion presented in the protein coding region and non-coding region of the mutant brittle-1(bt1),the adenylate translocator encoding gene involved in the starch synthesis.The single base insertion in the coding region cause frameshift mutation,early termination and lose of function of Brittle-1(BT1).All results suggested that bt1 is a novel allelic gene and the causal gene of this endosperm mutant,providing insights on the mechanism of endosperm formation in maize.
基金funded by Tianjin Municipal Health Commission(TJWJ2023QN115)。
文摘Background Cognitive decline is a significant concern for stroke survivors,affecting their quality of life and increasing their burden on the healthcare system.DL-3-n butylphthalide(butylphthalide)has shown efficacy in the short-term treatment of various cognitive impairments.This study evaluated the efficacy of butylphthalide in preventing cognitive decline over a 12-month period in patients with ischaemic stroke.Methods This prospective following-up study involved patients newly diagnosed with ischaemic stroke between 1 month and 6 months after stroke onset and not in the acute phase.Patients were assigned to either the butylphthalide or control group.Cognitive function was assessed using the mini-mental state examination(MMSE)at baseline and at the 12-month follow-up.Statistical analyses included t-tests,χ2 tests and multivariate regression analyses.Results Butylphthalide was negatively associated with the MMSE D-value(β=−0.122;95%CI−1.932 to−0.298;p=0.003)and the MMSE D-value percentage(β=−0.117;95%CI−0.057 to−0.011;p=0.004).A multivariate analysis indicated that butylphthalide treatment was negatively associated with both changes in orientation and language score.Additionally,the incidence of cognitive decline was significantly lower in the butylphthalide group(OR,0.612;p=0.020)than the control group.An age of≥60 years and lower educational level were identified as risk factors for lower cognitive score and cognitive decline.Conclusion This study demonstrated that butylphthalide is effective in preventing cognitive decline in patients with ischaemic stroke.These findings have significant implications for clinical practice,suggesting that butylphthalide could be incorporated into standard post-stroke care regimens to improve patient outcomes and reduce the healthcare burden.Additional multicentre double-blind trials are recommended to confirm these results in diverse populations.
基金supported by the National Natural Science Foundation of China(Grant No.52205564)the Foundation of Natural Science Foundation of Hubei Province,China(Grant No.2022CFB898).
文摘Air-coupled ultrasonic transducers(ACUTs)have been applied in industrial non-destructive testing,structural health monitoring,and medical ultrasound.However,conventional passive focusing methods often result in undesired effects on sensitivity due to variations in acoustic impedance matching conditions,which are critical in ACUT design,where sensitivity is the top priority.Accordingly,a novel active focusing method for ACUTs is proposed in this study.The key idea is to create multiple concentric ring electrode patterns on a bulk planar piezoelectric plate so that a quarter-wavelength acoustic impedance matching layer of uniform thickness can be attached onto the plate.The initial structural parameters of the electrode patterns are determined based on the design methodology of a Fresnel zone plate(FZP).Those parameters are optimized through finite element simulation,with the transducer’s sensitivity as the objective function,while ensuring only slight variations to the focal length and lateral resolution.Single-sided multiple concentric ring electrode patterns are then fabricated on 1-3 piezoelectric fiber/epoxy resin composite plate by screen printing and combined with a high-performance acoustic impedance matching layer made from epoxy resin composite filled with hollow glass microspheres.The planar active focusing ACUT is developed,while two types of conventional passive focusing ACUTs using FZP and concave lens are fabricated with the same piezoelectric and acoustic matching materials.Comparative experimental testing is carried out.The developed planar active-focusing ACUT achieves significant sensitivity improvements of 7.1 and 17.4dB,respectively,while maintaining comparable radial and axial full-width at half maximum.The results of this study offer a novel approach for the design of high-performance ACUTs.
