目的通过网络药理和分子对接探讨黄芪葛根汤治疗糖尿病的作用机制。方法基于中药系统药理学数据库与分析平台(traditional Chinese medicine systems pharmacology database and analysis platform,TCMSP)数据库筛选黄芪葛根汤有效成分...目的通过网络药理和分子对接探讨黄芪葛根汤治疗糖尿病的作用机制。方法基于中药系统药理学数据库与分析平台(traditional Chinese medicine systems pharmacology database and analysis platform,TCMSP)数据库筛选黄芪葛根汤有效成分及靶点基因,通过GeneCards和OMIM查找疾病的相关靶点基因,将药物有效成分靶标与疾病靶标映射;采用Cytoscape构建药物-成分-靶点-疾病网络图。运用STRING数据库,分析蛋白-蛋白互作核心基因。将活性成分与核心基因的前3个做分子对接。利用Bioconductor进行GO功能富集和KEGG通路富集分析。结果通过筛选得到黄芪葛根汤的活性成分59个,药物与疾病共同作用靶点135个;蛋白互作网络中核心基因为EGFR,IL6,MYC涉及Prostate cancer,p53 signaling pathway,Fluid shear stress and atherosclerosis,AGE-RAGE signaling pathway indiabetic complications等通路。结论初步揭示了黄芪葛根汤是以多成分、多靶点、多通路的复杂形式发挥治疗糖尿病作用,为黄芪葛根汤的临床应用提供理论依据。展开更多
Increasing the self-resistance levels of Streptomyces is an effective strategy to improve the production of antibiotics.To increase the oxytetracycline(OTC) production in Streptomyces rimosus,we investigated the coope...Increasing the self-resistance levels of Streptomyces is an effective strategy to improve the production of antibiotics.To increase the oxytetracycline(OTC) production in Streptomyces rimosus,we investigated the cooperative effect of three co-overexpressing OTC resistance genes:one gene encodes a ribosomal protection protein(otrA) and the other two express efflux proteins(otrB and otrC).Results indicated that combinational overexpression of otrA,otrB,and otrC(MKABC) exerted a synergetic effect.OTC production increased by 179%in the recombinant strain compared with that of the wild-type strain M4018.The resistance level to OTC was increased by approximately two-fold relative to the parental strain,thereby indicating that applying the cooperative effect of self-resistance genes is useful to improve OTC production.Furthermore,the previously identified cluster-situated activator OtcR was overexpressed in MKABC in constructing the recombinant strain MKRABC;such strain can produce OTC of approximately7.49 g L^((-1)),which represents an increase of 19%in comparison with that of the OtcR-overexpressing strain alone.Our work showed that the cooperative overexpression of self-resistance genes is a promising strategy to enhance the antibiotics production in Streptomyces.展开更多
Streptomycetes are Gram-positive bacteria with high GC DNA content. They produce the most abundant secondary metabolites including over two-thirds of the clinically used antibiotics of natural origin (Barka et al., 20...Streptomycetes are Gram-positive bacteria with high GC DNA content. They produce the most abundant secondary metabolites including over two-thirds of the clinically used antibiotics of natural origin (Barka et al., 2016), for example,the important broad-spectrum antimicrobials oxytetracycline(OTC) and chlortetracycline, which are the tetracycline antibiotics。展开更多
<b>Objectives:</b> Allogeneic myoblast transplantation (AMT), cyclosporine immunosuppression and coronary artery bypass grafting (CABG) were used to treat end-stage heart failure (HF) subjects without hope...<b>Objectives:</b> Allogeneic myoblast transplantation (AMT), cyclosporine immunosuppression and coronary artery bypass grafting (CABG) were used to treat end-stage heart failure (HF) subjects without hope of obtaining a heart transplant. <b>Background:</b> Severe myocardial infarction conveys serious complications such as ventricular aneurysm, wall thinning and rupture with fatal consequences. <b>Methods: </b>After meeting Inclusion/Exclusion criteria and signing Patient Informed Consents, 10 HF subjects having mean thinnest wall thickness of 2.21 ± 0.55 mm and ventricular aneurysms were admitted under intensive care. Each subject took daily cyclosporine for three weeks. On the third day of cyclosporine administration, approximately 1 billion myoblasts were implanted <span>through 20 injections into the infarcted myocardium following CABG. <b>Results: </b><u>Safety</u> No subject suffered death, viral infection, malignant arrhythmia, reduction in cardiac output, immune rejection, or aneurysm growth. No significant difference was found before versus after treatment in the mean levels of blood routine, liver and kidney enzymes, electrolytes and fibrinogen. <u>Efficacy</u> Emission computed tomography (ECT) and magnetic resonance (MR) demonstrated significant increases in viability and perfusion. Mean left ventricular ejection fraction (LVEF) significantly increased (P < 0.05) by 20.1% and 19.3% at 6 months and at 2 years postoperatively. New York Heart Association (NYHA) class improved by 2 grades, including 6-minute walk test (6 MWT) distance increase, and reductions in the number of episodes of angina pectoris, chest tightness, shortness of breath after exercise, and nighttime sit-up breathing. <b>Conclusions: </b>For the first time, AMT in adjunct use with CABG and cyclosporine demonstrated that cell survived and engrafted in patients with ischemic cardiomyopathy;in this small study the cell transplant was safe. The improvement in heart function and quality of life could be secondary to combined effect of bypa展开更多
This paper presents a novel neural-fuzzy-based adaptive sliding mode automatic steering control strategy to improve the driving performance of vision-based unmanned electric vehicles with time-varying and uncertain pa...This paper presents a novel neural-fuzzy-based adaptive sliding mode automatic steering control strategy to improve the driving performance of vision-based unmanned electric vehicles with time-varying and uncertain parameters.Primarily,the kinematic and dynamic models which accurately express the steering behaviors of vehicles are constructed,and in which the relationship between the look-ahead time and vehicle velocity is revealed.Then,in order to overcome the external disturbances,parametric uncertainties and time-varying features of vehicles,a neural-fuzzy-based adaptive sliding mode automatic steering controller is proposed to supervise the lateral dynamic behavior of unmanned electric vehicles,which includes an equivalent control law and an adaptive variable structure control law.In this novel automatic steering control system of vehicles,a neural network system is utilized for approximating the switching control gain of variable structure control law,and a fuzzy inference system is presented to adjust the thickness of boundary layer in real-time.The stability of closed-loop neural-fuzzy-based adaptive sliding mode automatic steering control system is proven using the Lyapunov theory.Finally,the results illustrate that the presented control scheme has the excellent properties in term of error convergence and robustness.展开更多
Angucyclines are one of the largest families of aromatic polyketides with various chemical structures and bioactivities.Decades of studies have made it easy for us to depict the picture of their early biosynthetic pat...Angucyclines are one of the largest families of aromatic polyketides with various chemical structures and bioactivities.Decades of studies have made it easy for us to depict the picture of their early biosynthetic pathways.Two families of oxygenases,the FAD-dependent oxygenases and the ring opening oxygenases,contribute to the formation of some unique skeletons of atypical angucyclines.The FAD-dependent oxygenases involved in the biosynthetic gene clusters of typical angucyclines catalyze two hydroxylation reactions at C-12 and C-12b of prejadomycin,while their homolog JadH in jadomycin gene cluster catalyze the C-12 hydroxylation and 4a,12b-dehydration reactions of prejadomycin,which leads to the production of dehydrorabelomycin,a common intermediate during the biosynthesis of atypical angucyclines.Ring opening oxygenases of a unique family of oxygenases catalyze the oxidative CeC bond cleavage reaction of dehydrorabelomycin,followed by different rearrangement reactions,resulting in the formation of the various chemical skeletons of atypical angucyclines.These results suggested that the functional differentiation of these oxygenases could apparently enrich the sources of aromatic polyketides with greater structure diversities.展开更多
Streptomyces produces many valuable and important biomolecules with clinical and pharmaceutical applications.The development of simple and highly efficient gene editing tools for genetic modification of Streptomyces i...Streptomyces produces many valuable and important biomolecules with clinical and pharmaceutical applications.The development of simple and highly efficient gene editing tools for genetic modification of Streptomyces is highly desirable.In this study,we developed a screening system for targeted gene knockout using a uracil auxotrophic host(ΔpyrF)resistant to the highly toxic uracil analog of 5-fluoroorotic acid(5-FOA)converted by PyrF,and a non-replicative vector pKC1132-pyrF carrying the complemented pyrF gene coding for orotidine-5'-phosphate decarboxylase.The pyrF gene acts as a positive selection and counterselection marker for recombinants during genetic modifications.Single-crossover homologous integration mutants were selected on minimal medium without uracil by reintroducing pyrF along with pKC1132-pyrF into the genome of the mutantΔpyrF at the targeted locus.Double-crossover recombinants were generated,from which the pyrF gene,plasmid backbone,and targeted gene were excised through homologous recombination exchange.These recombinants were rapidly screened by the counterselection agent,5-FOA.We demonstrated the feasibility and advantage of using this pyrF-based screening system through deleting the otcR gene,which encodes the cluster-situated regulator that directly activates oxytetracycline biosynthesis in Streptomyces rimosus M4018.This system provides a new genetic tool for investigating the genetic characteristics of Streptomyces species.展开更多
文摘目的通过网络药理和分子对接探讨黄芪葛根汤治疗糖尿病的作用机制。方法基于中药系统药理学数据库与分析平台(traditional Chinese medicine systems pharmacology database and analysis platform,TCMSP)数据库筛选黄芪葛根汤有效成分及靶点基因,通过GeneCards和OMIM查找疾病的相关靶点基因,将药物有效成分靶标与疾病靶标映射;采用Cytoscape构建药物-成分-靶点-疾病网络图。运用STRING数据库,分析蛋白-蛋白互作核心基因。将活性成分与核心基因的前3个做分子对接。利用Bioconductor进行GO功能富集和KEGG通路富集分析。结果通过筛选得到黄芪葛根汤的活性成分59个,药物与疾病共同作用靶点135个;蛋白互作网络中核心基因为EGFR,IL6,MYC涉及Prostate cancer,p53 signaling pathway,Fluid shear stress and atherosclerosis,AGE-RAGE signaling pathway indiabetic complications等通路。结论初步揭示了黄芪葛根汤是以多成分、多靶点、多通路的复杂形式发挥治疗糖尿病作用,为黄芪葛根汤的临床应用提供理论依据。
基金supported by funding from Shengxue Dacheng Pharmaceutical Co.,Ltd,National Natural Science Foundation of China(31400034 and 31570031)the Ministry of Science and Technology of China(2013CB734001)
文摘Increasing the self-resistance levels of Streptomyces is an effective strategy to improve the production of antibiotics.To increase the oxytetracycline(OTC) production in Streptomyces rimosus,we investigated the cooperative effect of three co-overexpressing OTC resistance genes:one gene encodes a ribosomal protection protein(otrA) and the other two express efflux proteins(otrB and otrC).Results indicated that combinational overexpression of otrA,otrB,and otrC(MKABC) exerted a synergetic effect.OTC production increased by 179%in the recombinant strain compared with that of the wild-type strain M4018.The resistance level to OTC was increased by approximately two-fold relative to the parental strain,thereby indicating that applying the cooperative effect of self-resistance genes is useful to improve OTC production.Furthermore,the previously identified cluster-situated activator OtcR was overexpressed in MKABC in constructing the recombinant strain MKRABC;such strain can produce OTC of approximately7.49 g L^((-1)),which represents an increase of 19%in comparison with that of the OtcR-overexpressing strain alone.Our work showed that the cooperative overexpression of self-resistance genes is a promising strategy to enhance the antibiotics production in Streptomyces.
基金supported by grants from Shengxue Dacheng Pharmaceutical Co.,Ltd in Shijiazhuang,Chinathe National Natural Science Foundation of China(31570031)
文摘Streptomycetes are Gram-positive bacteria with high GC DNA content. They produce the most abundant secondary metabolites including over two-thirds of the clinically used antibiotics of natural origin (Barka et al., 2016), for example,the important broad-spectrum antimicrobials oxytetracycline(OTC) and chlortetracycline, which are the tetracycline antibiotics。
文摘<b>Objectives:</b> Allogeneic myoblast transplantation (AMT), cyclosporine immunosuppression and coronary artery bypass grafting (CABG) were used to treat end-stage heart failure (HF) subjects without hope of obtaining a heart transplant. <b>Background:</b> Severe myocardial infarction conveys serious complications such as ventricular aneurysm, wall thinning and rupture with fatal consequences. <b>Methods: </b>After meeting Inclusion/Exclusion criteria and signing Patient Informed Consents, 10 HF subjects having mean thinnest wall thickness of 2.21 ± 0.55 mm and ventricular aneurysms were admitted under intensive care. Each subject took daily cyclosporine for three weeks. On the third day of cyclosporine administration, approximately 1 billion myoblasts were implanted <span>through 20 injections into the infarcted myocardium following CABG. <b>Results: </b><u>Safety</u> No subject suffered death, viral infection, malignant arrhythmia, reduction in cardiac output, immune rejection, or aneurysm growth. No significant difference was found before versus after treatment in the mean levels of blood routine, liver and kidney enzymes, electrolytes and fibrinogen. <u>Efficacy</u> Emission computed tomography (ECT) and magnetic resonance (MR) demonstrated significant increases in viability and perfusion. Mean left ventricular ejection fraction (LVEF) significantly increased (P < 0.05) by 20.1% and 19.3% at 6 months and at 2 years postoperatively. New York Heart Association (NYHA) class improved by 2 grades, including 6-minute walk test (6 MWT) distance increase, and reductions in the number of episodes of angina pectoris, chest tightness, shortness of breath after exercise, and nighttime sit-up breathing. <b>Conclusions: </b>For the first time, AMT in adjunct use with CABG and cyclosporine demonstrated that cell survived and engrafted in patients with ischemic cardiomyopathy;in this small study the cell transplant was safe. The improvement in heart function and quality of life could be secondary to combined effect of bypa
基金Supported by National Basic Research Project of China(Grant No.2016YFB0100900)National Natural Science Foundation of China(Grant No.61803319)+2 种基金Shenzhen Municipal Science and Technology Projects of China(Grant No.JCYJ20180306172720364)Fundamental Research Funds for the Central Universities of China(Grant No.20720190015)State Key Laboratory of Automotive Safety and Energy of China(Grant No.KF2011).
文摘This paper presents a novel neural-fuzzy-based adaptive sliding mode automatic steering control strategy to improve the driving performance of vision-based unmanned electric vehicles with time-varying and uncertain parameters.Primarily,the kinematic and dynamic models which accurately express the steering behaviors of vehicles are constructed,and in which the relationship between the look-ahead time and vehicle velocity is revealed.Then,in order to overcome the external disturbances,parametric uncertainties and time-varying features of vehicles,a neural-fuzzy-based adaptive sliding mode automatic steering controller is proposed to supervise the lateral dynamic behavior of unmanned electric vehicles,which includes an equivalent control law and an adaptive variable structure control law.In this novel automatic steering control system of vehicles,a neural network system is utilized for approximating the switching control gain of variable structure control law,and a fuzzy inference system is presented to adjust the thickness of boundary layer in real-time.The stability of closed-loop neural-fuzzy-based adaptive sliding mode automatic steering control system is proven using the Lyapunov theory.Finally,the results illustrate that the presented control scheme has the excellent properties in term of error convergence and robustness.
基金National Natural Science Foundation of China(Grants:31670800,31470176,and 31130001)Ministry of Science and Technology of China(Grants:2014CB910400).
文摘Angucyclines are one of the largest families of aromatic polyketides with various chemical structures and bioactivities.Decades of studies have made it easy for us to depict the picture of their early biosynthetic pathways.Two families of oxygenases,the FAD-dependent oxygenases and the ring opening oxygenases,contribute to the formation of some unique skeletons of atypical angucyclines.The FAD-dependent oxygenases involved in the biosynthetic gene clusters of typical angucyclines catalyze two hydroxylation reactions at C-12 and C-12b of prejadomycin,while their homolog JadH in jadomycin gene cluster catalyze the C-12 hydroxylation and 4a,12b-dehydration reactions of prejadomycin,which leads to the production of dehydrorabelomycin,a common intermediate during the biosynthesis of atypical angucyclines.Ring opening oxygenases of a unique family of oxygenases catalyze the oxidative CeC bond cleavage reaction of dehydrorabelomycin,followed by different rearrangement reactions,resulting in the formation of the various chemical skeletons of atypical angucyclines.These results suggested that the functional differentiation of these oxygenases could apparently enrich the sources of aromatic polyketides with greater structure diversities.
基金This work is supported by the Natural Science Foundation of Hebei Province(No.C2019209399)Tangshan Science and Technology Project(No.20130208b)+1 种基金the Science and Technology Program of Hebei(No.18222916)the Research Fund for Top Discipline Construction of North China University of Science and Technology(No.18060720),China.
文摘Streptomyces produces many valuable and important biomolecules with clinical and pharmaceutical applications.The development of simple and highly efficient gene editing tools for genetic modification of Streptomyces is highly desirable.In this study,we developed a screening system for targeted gene knockout using a uracil auxotrophic host(ΔpyrF)resistant to the highly toxic uracil analog of 5-fluoroorotic acid(5-FOA)converted by PyrF,and a non-replicative vector pKC1132-pyrF carrying the complemented pyrF gene coding for orotidine-5'-phosphate decarboxylase.The pyrF gene acts as a positive selection and counterselection marker for recombinants during genetic modifications.Single-crossover homologous integration mutants were selected on minimal medium without uracil by reintroducing pyrF along with pKC1132-pyrF into the genome of the mutantΔpyrF at the targeted locus.Double-crossover recombinants were generated,from which the pyrF gene,plasmid backbone,and targeted gene were excised through homologous recombination exchange.These recombinants were rapidly screened by the counterselection agent,5-FOA.We demonstrated the feasibility and advantage of using this pyrF-based screening system through deleting the otcR gene,which encodes the cluster-situated regulator that directly activates oxytetracycline biosynthesis in Streptomyces rimosus M4018.This system provides a new genetic tool for investigating the genetic characteristics of Streptomyces species.
