微生物源农用抗生素的研发与高产策略

开发高效、低毒、低残留的绿色农药是农药研发的发展趋势,其中微生物源农药抗生素占据了重要地位。随着基因组学、代谢工程、高通量筛选等技术的发展,新型微生物源农用抗生素的研究进入了新的阶段。文中简要总结了近10年来研发的新型微生物源农用抗生素的种类、农用抗生素产生菌株的高产育种与发酵研究策略等,为未来农用抗生素的研发提供参考。     

农用抗生素7072可湿性粉剂的研究

农用抗生素７０７２可湿性粉剂的研究刘树良,鲍秀芬,王志,胡永兰,宗玉丽,张爱玲（辽宁省微生物研究所,朝阳１２２０００）７０７２是我所自行筛选的一株产厂一谱性抗生素的菌株,经中科院微生物所鉴定为不吸水链霉菌（ＳｔｅｒＰｔｏ。。ｘｏｅｓａ抑ａ。“ｏ’ｅ－...     

微生物学检测技术在食品抗生素残留检测的研究应用

抗生素的普遍应用使得其在食品中广泛残留,对人体健康造成严重危害。目前,用于食品抗生素残留检测方法较多,微生物法是常用的筛选方法之一,具有简便、经济、高通量、特异性及灵敏度好等优点。本研究综述了微生物法在检测食品中抗生素残留的优缺点和影响因素等应用情况。     

武夷菌素对土壤微生物群落及抗生素抗性基因的影响

抗生素抗性基因(antibiotic resistance genes, ARGs)作为一种新型环境污染物近年来受到广泛关注。目前关于抗生素的环境污染研究主要集中于医疗和养殖业,对植物保护领域的农用抗生素环境污染研究很少。武夷菌素是一种环保、高效、广谱的农用抗生素,在农业生产中得到了广泛应用,对农作物真菌性病害具有良好的防治效果。本研究分别选取了未使用武夷菌素和使用武夷菌素的蔬菜大棚中的土壤,通过高通量测序分析了土壤中微生物群落结构,发现两份土壤中主要的微生物群落种类没有发生明显改变,但是优势菌群的丰度有显著差异。通过荧光定量PCR技术,对18个典型的抗生素抗性基因进行了检测,发现aadA、aac(3)-Ⅱ、strA、strB、aacA4、tetX、sulI和intI1 8个基因在两份土壤中的绝对含量和丰度均有显著差异,表明武夷菌素对土壤中微生物的群落结构及抗生素抗性基因的绝对含量和丰度均会造成一定影响。本研究为评估武夷菌素的环境安全性及合理正确使用武夷菌素提供了理论依据,也为其它农用抗生素的相关研究提供了借鉴。     

农用抗生素产生菌菌种选育的研究进展

农用抗生素产生菌的原始菌株 ,往往产量很低或质量较差 ,不能满足工业生产的需要 ,必须对它的某些性状进行改良。改良菌种的主要手段是通过育种 ,筛选出高产菌株。传统的诱变育种是最广泛的选育方法 ,以基因工程为核心的现代生物技术也应用于农用抗生素产生菌的菌种选育中 ,并逐渐成为农用抗生素菌种选育的主导技术。     

β—内酰胺类抗生素超敏感菌的分离与特性

在β-内酰胺抗生素筛选过程中,超敏感菌是主要的筛选模型之一。这种菌株一般由耐药性革兰氏阴性菌经诱变而产生,它对β—内酰胺类抗生素具有高度敏感性,而对其(?)抗生素存在一定的耐性,利用它可检测微生物产生的微量的β-内酰胺类抗生素。本文叙述了一株来源于绿脓杆菌的超敏感菌的分离过程,并观察了它对抗生素的敏感性等有关的微生物学特性。     

环境抗生素污染的微生物修复进展

近年来随着抗生素在畜牧业、水产养殖业以及医疗行业的广泛应用,大量抗生素通过排泄物进入环境,导致我国大面积水体及土壤环境中抗生素残留量急剧增高。环境中不同种类的抗生素的残留导致微生物种群结构失衡,对生态环境及人类造成极大危害。因此,解决抗生素残留问题是21世纪新型环境污染物领域的一个重要课题。已有研究显示,一些微生物能够以抗生素为碳源生存,可用于降解环境中残留抗生素,但人们对微生物降解抗生素的降解机制了解较少。文中概括了近十年来抗生素降解菌株和菌群对抗生素的去除情况,以及应用微生物菌群处理抗生素残留的技术方法,同时对未来利用微生物修复法减少环境中抗生素残留进行了展望。     

环境介质中的抗生素及其微生物生态效应

环境介质中的抗生素因存在浓度较低被称为微量污染物,其对生态系统和人类健康的影响已逐步得到认知。长期以来,抗生素被用于人和畜禽细菌性感染疾病的治疗。然而,随着集约化养殖业的发展,抗生素被大量添加于饲料中来预防畜禽和鱼虾的养殖疾病。因此,环境介质中抗生素种类和含量随着畜禽和水产养殖业的快速发展逐年增加。本文综述了环境中抗生素的来源、残留浓度及其环境微生物生态学效应。医用、兽用抗生素和人畜粪便的农用是抗生素进入环境的主要来源,其在不同环境介质中残留浓度不一：地表水含量为μg?L-1,土壤含量为?g?kg-1,沉积物含量为μg?kg-1—mg?kg-1之间。抗生素进入土壤、水和沉积物等环境介质,经吸附-解吸、迁移和降解等过程重新分配,其降解方式主要有水解、光解和生物降解。抗生素影响环境介质中微生物的生物量、活性和群落结构,并诱导产生抗性基因,但对生态系统服务及其功能的干扰和影响尚有待进一步研究。     

灯台树内生放线菌

放线菌一直是用于生产抗生素最多的微生物类群,临床和农牧业上应用的抗生素有60%以上就是由放线菌生产的[1],但随着从来源于普通土壤环境的放线菌中筛选到新化合物几率的不断下降,人们已经逐步将注意力转向了一些生活在特殊生境的微生物[2]。由于植物内生菌在植物体内经过与植物宿主的长期协同进化,使植物内生菌能够产生结构新颖、功能     

微生物中抗耐药菌活性天然产物的研究进展

近年来,细菌耐药性已成为全球性问题。微生物作为抗生素的重要来源,在发掘抗耐药菌新型抗生素的研究中承担了重要角色,许多微生物来源天然化合物展现了显著的抗耐药菌活性。本文主要综述了近十年发现的微生物源抗耐药菌天然化合物,并概括了抗耐药菌活性天然产物的筛选方法,以期对抗耐药菌新型抗生素的发现做铺垫。     

Engaging New Migrants in Infectious Disease Screening: A Qualitative Semi-Structured Interview Study of UK Migrant Community Health-Care Leads

Migration to Europe - and in particular the UK - has risen dramatically in the past decades, with implications for public health services. Migrants have increased vulnerability to infectious diseases (70% of TB cases and 60% HIV cases are in migrants) and face multiple barriers to healthcare. There is currently considerable debate as to the optimum approach to infectious disease screening in this often hard-to-reach group, and an urgent need for innovative approaches. Little research has focused on the specific experience of new migrants, nor sought their views on ways forward. We undertook a qualitative semi-structured interview study of migrant community health-care leads representing dominant new migrant groups in London, UK, to explore their views around barriers to screening, acceptability of screening, and innovative approaches to screening for four key diseases (HIV, TB, hepatitis B, and hepatitis C). Participants unanimously agreed that current screening models are not perceived to be widely accessible to new migrant communities. Dominant barriers that discourage uptake of screening include disease-related stigma present in their own communities and services being perceived as non-migrant friendly. New migrants are likely to be disproportionately affected by these barriers, with implications for health status. Screening is certainly acceptable to new migrants, however, services need to be developed to become more community-based, proactive, and to work more closely with community organisations; findings that mirror the views of migrants and health-care providers in Europe and internationally. Awareness raising about the benefits of screening within new migrant communities is critical. One innovative approach proposed by participants is a community-based package of health screening combining all key diseases into one general health check-up, to lessen the associated stigma. Further research is needed to develop evidence-based community-focused screening models - drawing on models of best practice from other countries receiving high numbers of migrants.     

The Development and Application of the Glucose Uptake Stimulating Cell Model

The plants are great resources for digging leading compounds, and many current anti diabetic drugs are derived from plants. The key to discover compounds with anti diabetic activities from plants relies on the application of anti diabetic drug screening models. In order to establish a more stable and reliable anti diabetic drug screening model, we optimized the screening model based on the glucose uptake of adipocytes. In the previous models, insulin was used as the only positive control, while in our model both insulin and rosiglitazone were used as positive controls, which made the model more stable and reliable. Furthermore, we expanded the application of the model to screen the insulin signaling pathway inhibitors, and Akt1/2 inhibitor which was an inhibitor of insulin signaling pathway was used as positive control. In the end, we screened 16 compounds isolated from plants using this model and identified three active compounds with glucose uptake stimulating activities. We also performed the dose response experiments of compound X15 and X16. Both showed significant dose responses. These activities were first reported at the cell level, providing fundamental data for their mechanisms study of the activities and for the potential development of the drugs in future.     

水平潜流人工湿地模型

人工湿地作为一种新型的处理技术,在水污染控制与水环境修复中具有重要的作用和广阔的应用前景.人工湿地处理工程数量的增多和日趋严格的水质标准促进了其设计手段的进步.本文从水动力学、污染物降解动力学和参数的不确定性3方面入手,系统回顾、评价了水平潜流人工湿地的设计模型,包括负荷法、衰减方程、一级k-C*模型及其若干改进型模型和动态机理模型.在比较上述模型的建立依据和方法的基础上,分析水平潜流人工湿地模型发展的内在关系,指出在工程设计中应用各类模型时需要考虑的主要事项,并对该领域的发展方向进行了展望.     

Rich parameterization improves RNA structure prediction

Current approaches to RNA structure prediction range from physics-based methods, which rely on thousands of experimentally measured thermodynamic parameters, to machine-learning (ML) techniques. While the methods for parameter estimation are successfully shifting toward ML-based approaches, the model parameterizations so far remained fairly constant. We study the potential contribution of increasing the amount of information utilized by RNA folding prediction models to the improvement of their prediction quality. This is achieved by proposing novel models, which refine previous ones by examining more types of structural elements, and larger sequential contexts for these elements. Our proposed fine-grained models are made practical thanks to the availability of large training sets, advances in machine-learning, and recent accelerations to RNA folding algorithms. We show that the application of more detailed models indeed improves prediction quality, while the corresponding running time of the folding algorithm remains fast. An additional important outcome of this experiment is a new RNA folding prediction model (coupled with a freely available implementation), which results in a significantly higher prediction quality than that of previous models. This final model has about 70,000 free parameters, several orders of magnitude more than previous models. Being trained and tested over the same comprehensive data sets, our model achieves a score of 84% according to the F?-measure over correctly-predicted base-pairs (i.e., 16% error rate), compared to the previously best reported score of 70% (i.e., 30% error rate). That is, the new model yields an error reduction of about 50%. Trained models and source code are available at www.cs.bgu.ac.il/?negevcb/contextfold.     

Zebrafish disease models in hematology: Highlights on biological and translational impact

Zebrafish (Danio rerio) has proven to be a versatile and reliable in vivo experimental model to study human hematopoiesis and hematological malignancies. As vertebrates, zebrafish has significant anatomical and biological similarities to humans, including the hematopoietic system. The powerful genome editing and genome-wide forward genetic screening tools have generated models that recapitulate human malignant hematopoietic pathologies in zebrafish and unravel cellular mechanisms involved in these diseases. Moreover, the use of zebrafish models in large-scale chemical screens has allowed the identification of new molecular targets and the design of alternative therapies. In this review we summarize the recent achievements in hematological research that highlight the power of the zebrafish model for discovery of new therapeutic molecules. We believe that the model is ready to give an immediate translational impact into the clinic.     

Human pluripotent stem cells for disease modelling and drug screening

Considerable hope surrounds the use of disease-specific pluripotent stem cells to generate models of human disease allowing exploration of pathological mechanisms and search for new treatments. Disease-specific human embryonic stem cells were the first to provide a useful source for studying certain disease states. The recent demonstration that human somatic cells, derived from readily accessible tissue such as skin or blood, can be converted to embryonic-like induced pluripotent stem cells (hiPSCs) has opened new perspectives for modelling and understanding a larger number of human pathologies. In this review, we examine the opportunities and challenges for the use of disease-specific pluripotent stem cells in disease modelling and drug screening. Progress in these areas will substantially accelerate effective application of disease-specific human pluripotent stem cells for drug screening.     

A new class of salicylic acid derivatives for inhibiting YopH of Yersinia pestis

Previously, we identified a class of salicylic acid derivatives that display inhibitory activity against the protein tyrosine phosphatase YopH from Yersinia pestis. Because docking study suggested that the large phenyl ring attaching to the salicylic acid core might be exposed to the solvent and might not contribute significantly to binding, we have developed a new class of compounds that no longer contain this phenyl ring. We first devised a synthetic scheme for the compounds and then developed an automated computational screening model surrounding this synthetic scheme to help select a small number of compounds for synthesis and experimental testing. Based on this computational screening model and the analysis of the structure–activity relationship of our previous class of compounds, we have synthesized eight compounds and found five that yield micromolar activity. When applying in a larger scale, the synthetic scheme and the computational screening model developed here should help to identify even more potent inhibitors in the future.     

Comparative study of viscoelastic arterial wall models in nonlinear one-dimensional finite element simulations of blood flow

It is well known that blood vessels exhibit viscoelastic properties, which are modeled in the literature with different mathematical forms and experimental bases. The wide range of existing viscoelastic wall models may produce significantly different blood flow, pressure, and vessel deformation solutions in cardiovascular simulations. In this paper, we present a novel comparative study of two different viscoelastic wall models in nonlinear one-dimensional (1D) simulations of blood flow. The viscoelastic models are from papers by Holenstein et al. in 1980 (model V1) and Valdez-Jasso et al. in 2009 (model V2). The static elastic or zero-frequency responses of both models are chosen to be identical. The nonlinear 1D blood flow equations incorporating wall viscoelasticity are solved using a space-time finite element method and the implementation is verified with the Method of Manufactured Solutions. Simulation results using models V1, V2 and the common static elastic model are compared in three application examples: (i) wave propagation study in an idealized vessel with reflection-free outflow boundary condition; (ii) carotid artery model with nonperiodic boundary conditions; and (iii) subject-specific abdominal aorta model under rest and simulated lower limb exercise conditions. In the wave propagation study the damping and wave speed were largest for model V2 and lowest for the elastic model. In the carotid and abdominal aorta studies the most significant differences between wall models were observed in the hysteresis (pressure-area) loops, which were larger for V2 than V1, indicating that V2 is a more dissipative model. The cross-sectional area oscillations over the cardiac cycle were smaller for the viscoelastic models compared to the elastic model. In the abdominal aorta study, differences between constitutive models were more pronounced under exercise conditions than at rest. Inlet pressure pulse for model V1 was larger than the pulse for V2 and the elastic model in the exercise case. In this paper, we have successfully implemented and verified two viscoelastic wall models in a nonlinear 1D finite element blood flow solver and analyzed differences between these models in various idealized and physiological simulations, including exercise. The computational model of blood flow presented here can be utilized in further studies of the cardiovascular system incorporating viscoelastic wall properties.     

玉米叶片三维形态的数学模拟研究

根据玉米叶片三维形态特征,应用悬臂梁模型来描述玉米叶曲线,对描述玉米叶片边缘扭曲的数学模型进行改进后,提出了基于特征参数的玉米叶片三维形态数学模型及其实现方法,本模型大大减少了描述全米叶片三维形态的信息量,并具有较高的逼真性,同时适用于描述其它禾谷类作物叶片的三维形态。     

Virtual screening approaches for the identification of non-lipid autotaxin inhibitors

Autotaxin (ATX, NPP-2) catalyzes the conversion of lysophosphatidyl choline (LPC) to lysophosphatidic acid (LPA), a mitogenic cell survival factor that stimulates cell motility. The high expression of both ATX and receptors for LPA in numerous tumor cell types has produced substantial interest in exploring ATX as an anticancer chemotherapeutic target. ATX inhibitors reported to date are analogs of LPA, a phospholipid, and are more hydrophobic than is typical of orally bioavailable drugs. This study applied both structure-based and ligand-based virtual screening techniques with hit rates of 20% and 37%, respectively, to identify a promising set of non-lipid, drug-like ATX inhibitors. Structure-based virtual screening necessitated development of a homology model of the ATX catalytic domain due to the lack of structural information on any mammalian NPP family member. This model provided insight into the interactions necessary for ATX inhibition, and produced a suitably diverse training set for the development and application of binary QSAR models for virtual screening. The most efficacious compound identified in this study was able to completely inhibit ATX-catalyzed hydrolysis of 1 microM FS-3 (a synthetic, fluorescent LPC analog) at a 10 microM concentration.