AB5 toxins: structures and inhibitor design

High-resolution crystal structures of AB₅ toxins in their native form or in complex with a variety of ligands have led to the structure-based design and discovery of inhibitors targeting different areas of the toxins. The most significant progress is the development of highly potent multivalent ligands that block binding of the toxins to their receptors.     

红豆杉细胞悬浮培养中不同添加物对细胞生长和紫杉醇合成的影响

采用正交实验检测红豆杉（Ｔａｘｕｓ ｃｈｉｎｅｎｓｉｓ（Ｐｉｌｇｅｒ）Ｒｅｈｄ．）细胞悬浮培养中水杨酸、Ｄ－果糖、甘露醇和硫酸镧对细胞生长和紫杉醇（ｔａｘｏｌ）积累的影响。添加１０ｇ／ＬＤ－果糖,可使细胞的鲜重和干重明显增加;添加６０ｇ／Ｌ甘露醇使细胞的鲜重和干重明显减少;１ｍｇ／Ｌ水杨酸仅使细胞鲜重增加,对干重影响不明显;硫酸镧对细胞生长无明显影响。单独添加这４种物质,紫杉醇含量均下降,同时添加     

Design of Array-Type Compound Libraries that Combine Information from Natural Products and Synthetic Molecules

A new approach to the design of compound libraries, named MetaFocus (Metabolite-Focused library), is presented that exploits information encoded in natural molecules and combines naturally occurring and synthetic compounds. An important goal of the MF approach is the identification of synthetic compounds that mimic properties of natural molecules that are difficult to obtain in sufficient quantities or to synthesize. Compounds in MetaFocus (MF) arrays are focused on natural molecules with attractive therapeutic effects. Similarity search and diversity design techniques are employed to generate compound arrays that start from a selected natural molecule, add similar molecules, either from natural or synthetic sources, and diversify scaffolds derived from these molecules. Since the identification of similar molecules from natural and synthetic sources plays a significant role in our library design efforts, the performance of fingerprint-type search tools was systematically assessed in a newly assembled test database consisting of 16 biological activity classes. MF arrays are organized as an easily expandable and searchable data structure and serve as a knowledge base for drug discovery applications. Here we introduce the design principles and organization of MF arrays and present example applications.     

微生物学模块式自设计研究性实验的构建与教学实践

为了以低成本、低课时、高个性化方式让低年级学生既能学习基本实验技术,又都有机会参与研究性实验,构思了以基本实验技术为依托的微生物学模块式自设计研究性实验,即教师以模块式专题形式提出系列实验项目,学生自主选择题目、思考和设计、实施操作、分析结果而教师恰当指导的实验教学方式,并将其在3年4轮的微生物学实验教学中应用。详细叙述了模块式自设计研究性实验设计思路和实施方法及实施中学生和教师的行为与表现,并分析了从3个班级收回的包含34个问题的实验教学效果调查问卷,深入探讨了该方法存在的不足和改进方法。教学实践表明,这种教学方法不会导致教师数量、实验成本、学时数的显著增加,对于较大规模学生的研究性实验具有较强的实用性和可行性;144份学生反馈问卷中每个问题平均得分均在4分以上(满分5分),表明有利于提高学生的多方面素质,使学生受到基本的科学研究素质和能力的初步训练;88%-96%的学生认为它是有效的教学方式;研究性实验的形式、学生主动性、实验方案设计的科学性、实验结果分析和讨论等方面还有待完善。     

城市生态安全格局构建:目标、原则和基本框架

随着人口增长和经济快速发展,城市化已经成为人类社会发展的必然趋势。快速城市化必将导致生态用地流失、生态系统服务下降和环境健康风险加剧,由此影响到城市生态安全。尽管生态安全的概念已经为社会广泛接受,但对生态安全的内涵和如何构建生态安全格局仍然缺乏统一认识。在分析生态安全内涵、生态安全概念辨析和生态安全格局构建基本原则基础上,结合城市生态系统特点,提出了城市生态安全格局构建的目的、基本原则和基本框架。认为城市生态安全格局构建是一个涉及多尺度的区域性、综合性问题,除了要遵循生态安全格局构建的一般性原则外,还必须考虑以下原则:以人为本原则、流域适应原则、区域协调原则和有限目标原则。同时,需要重点关注宏观与微观尺度之间的关系协调、城市内部与外部之间的关系协调、理想与现实目标之间的权衡、人类生存需求与生态服务需求之间的权衡关系。通过城市生态安全格局构建,需要实现以下目标:控制城市化过程中出现的问题、维持城市地区正常的物质循环与代谢功能、维持城市生态系统健康运行与可持续发展、保证城市人居环境健康和居民的正常生活,以及满足现有城市居民可预见时期内生态服务需求。从景观、城市和区域三个尺度上,分析了城市生态安全格局构建需要面对的实体、解决的问题和实现的目标。     

Weibull分布参数辨识改进及对浙江毛竹林胸径年龄分布的测度

非线性模型迭代参数初始值的选取及拟合的结果能否可用非常重要且一直是一个难题.传统的方法只是凭感觉偿试不进行定量评估,对于用阻尼最小二乘进行拟合只注重精度高低,没有从理论上研究和分析评价得出的结果能否可用.为了克服这一不足,使参数选取较好,阻尼最小二乘得出结果可用.利用非线性回归原理在这两方面做了探讨,提出了二个判别指标：β^T＜1,β^N＜1,分析了每一指标在参数不同状态的控制作用,并在Weibull分布函数参数辨识中做了应用.针对目前毛竹林林分结构规律研究的不足,利用浙江省230个毛竹林样地资料研究了省域尺度的毛竹林胸径分布规律,经SPSS软件中的P-P图检验与柯尔莫哥洛夫检验,表明毛竹林胸径结构服从Weibull分布;再经对Weibull分布模型拟合求解与作图对比,结果显示Weibull分布能很好地描述毛竹林胸径分布规律.利用Weibull分布三参数与林分特征因子间的相关关系,经分析研究,导出了一个改进的二元分布模型,用该二元分布模型很好地测度了浙江省毛竹林胸径和年龄分布规律,最后得到了浙江省毛竹林株数按胸径年龄分布的理论频数.     

解淀粉芽胞杆菌PC2产抑菌物质培养基及发酵条件优化

【目的】优化解淀粉芽胞杆菌PC2产抑菌活性物质发酵培养基及发酵条件。【方法】以马铃薯葡萄糖液体培养基为基础,依据发酵液对金黄色葡萄球菌抑菌圈的单因素试验结果,采用Box-Behnken响应面法优化发酵培养基,二次通用旋转组合设计,频率分析法优化发酵条件。【结果】影响发酵液抑菌活性的培养基主要组分为马铃薯、蔗糖和L-谷氨酸钠,最优发酵培养基配方为:马铃薯188.0 g/L,蔗糖22.0 g/L,L-谷氨酸钠1.80 g/L,培养基成本为0.81元/L;最佳发酵条件为:接种量6%、发酵温度30°C、装液量40 mL/250 mL、摇床转速185 r/min、发酵时间24 h、初始pH 7.0。优化后发酵液对金黄色葡萄球菌抑菌圈直径为30.82 mm,较优化前的18.22 mm增加了12.60 mm。【结论】优化后的培养基和发酵条件提高了解淀粉芽胞杆菌PC2发酵液的抑菌活性,为该菌株的工业化生产应用提供了依据。     

防治荒漠化的“三圈”生态-生产范式机理及其功能

防治荒漠化的“三圈”生态-生产范式,是干旱生态系统优化与重建的新结构。根据在鄂尔多斯和新疆等地的研究和实践,从干旱生态系统结构、过程和功能来讨论荒漠化防治的“三圈”范式。地理圈层结构（地理地带性）是“三圈”范式的自然地理背景。从宏观尺度和功能方面划分,“三圈”范式在空间尺度上有大“三圈”和小“三圈”之分,大“三圈”控制洲际范围的荒漠化扩展及沙尘暴蔓延,小“三圈”则以控制区域性风沙活动、沙尘暴和就地起沙的危害。防治荒漠化工程是复杂的多元组合和多功能的系统,我国西北地区受荒漠化影响严重,宏观的大“三圈”与多区域的小“三圈”有机结合,形成圈圈相护、层层设防的严密防护与生产系统,有效地控制大范围风沙危害、改善地方气候与小气候,并对发展经济,提高人民生活发挥重要作用。因此,“三圈”范式的概念与结构既是以自然地理地带性为基础,又是人类对自然、环境与生态系统格局的规律认识,更是科学的人类恢复、重建干旱区生态环境与可持续发展的生态设计范式。     

Tertiary motifs as building blocks for the design of protein‐binding peptides

Despite advances in protein engineering, the de novo design of small proteins or peptides that bind to a desired target remains a difficult task. Most computational methods search for binder structures in a library of candidate scaffolds, which can lead to designs with poor target complementarity and low success rates. Instead of choosing from pre‐defined scaffolds, we propose that custom peptide structures can be constructed to complement a target surface. Our method mines tertiary motifs (TERMs) from known structures to identify surface‐complementing fragments or “seeds.” We combine seeds that satisfy geometric overlap criteria to generate peptide backbones and score the backbones to identify the most likely binding structures. We found that TERM‐based seeds can describe known binding structures with high resolution: the vast majority of peptide binders from 486 peptide‐protein complexes can be covered by seeds generated from single‐chain structures. Furthermore, we demonstrate that known peptide structures can be reconstructed with high accuracy from peptide‐covering seeds. As a proof of concept, we used our method to design 100 peptide binders of TRAF6, seven of which were predicted by Rosetta to form higher‐quality interfaces than a native binder. The designed peptides interact with distinct sites on TRAF6, including the native peptide‐binding site. These results demonstrate that known peptide‐binding structures can be constructed from TERMs in single‐chain structures and suggest that TERM information can be applied to efficiently design novel target‐complementing binders.