Spatio-temporal tumour model for analysis and mechanism of action of intracellular drug accumulation

We have developed a one-dimensional tumour simulator to describe the biodistribution of chemotherapeutic drugs to a tumoral lesion and the tumour cell’s response to therapy. A three-compartment model is used for drug dynamics within the tumour. The first compartment represents the extracellular space in which cells move, the second corresponds to the intracellular fluid space (including cell membrane) which is in direct equilibrium with the extracellular space, and the third is a non-exchangeable compartment that represents sequestered drug which is trapped in the nucleus to damage the cellular DNA, directly triggering cell death. Analytical and numerical techniques (Finite Element Method) are used to describe the tumour’s response to therapy and the effect of parameter variation on the drug concentration profiles in the three compartments.     

Selective antibacterial activity of the cationic peptide PaDBS1R6 against Gram-negative bacteria

Infections caused by Gram-negative bacteria, Escherichia coli and Pseudomonas aeruginosa foremost among them, constitute a major worldwide health problem. Bioinformatics methodologies are being used to rationally design new antimicrobial peptides, a potential alternative for treating these infections. One of the algorithms used to develop antimicrobial peptides is the Joker, which was used to design the peptide PaDBS1R6. This study evaluates the antibacterial activities of PaDBS1R6 in vitro and in vivo, characterizes the peptide interaction to target membranes, and investigates the PaDBS1R6 structure in contact with mimetic vesicles. Moreover, we demonstrate that PaDBS1R6 exhibits selective antimicrobial activity against Gram-negative bacteria. In the presence of negatively charged and zwitterionic lipids the structural arrangement of PaDBS1R6 transits from random coil to α-helix, as characterized by circular dichroism. The tertiary structure of PaDBS1R6 was determined by NMR in zwitterionic dodecylphosphocholine (DPC) micelles. In conclusion, PaDBS1R6 is a candidate for the treatment of nosocomial infections caused by Gram-negative bacteria, as template for producing other antimicrobial agents.     

社会竞争失败病因学的抑郁症树鼩模型

抑郁症是一种常见精神疾病,主要表现为持续两周以上的情绪低落。世界卫生组织预测在2030年抑郁症的疾病负担将高居所有疾病、伤残总负担的榜首。抑郁症面临三大难题:1)发病机理不完全清楚,因而缺乏有效的预测预防途径和生物学诊断;2)现有单胺类抗抑郁症药物起效慢,也可能导致患者自杀风险增加;3)缺乏副作用小的非单胺类快速起效抗抑郁症药物。针对这三大难题,长期以来,应用抑郁症啮齿类模型的众多研究并未取得实质性进展,至少部分因素归咎于啮齿类与人类大脑功能的极大种属差异。树鼩是灵长类近亲,具有更接近于人类的大脑功能。本文针对抑郁症发病机理假说、临床表象和抗抑郁症药物疗效等内容,综述了社会竞争失败病因学的抑郁症树鼩模型可能会具有更好的疾病同源性、表象一致性和药物预见性。这一被长期忽视的抑郁症树鼩模型尽管还需要进一步完善,但对其进一步深入研究可能为解决抑郁症的三大难题提供了一条新途径。     

大孢虫花菌丝体多糖提取工艺优化及其测定方法优选

通过采用3,5-二硝基水杨酸法、蒽酮-硫酸法和苯酚-硫酸法测定大孢虫花PaecilomycestenuipesPeck菌丝体多糖含量,比较精密度、样品回收率、稳定性三个指标,得出最佳测定方法为蒽酮-硫酸法。根据一次一因素实验和Box-Behnken中心组合实验,应用SAS软件分析得出大孢虫花菌丝体多糖提取的最佳条件为:100℃沸水浴,提取2h,重复4次,料液比(菌丝体质量:蒸馏水体积)为1︰20,此条件下大孢虫花菌丝体多糖为4.12g/100g。     

酚酸类物质的抑草效应分析

运用正交旋转回归试验设计分析5种常见的化感物质替代物水饧酸、对羟基苯甲酸、肉桂酸、香草酸和阿魏酸对田间伴生杂草稗草的抑制效应．结果表明,肉桂酸对稗草根长抑制率的影响最显著。其关系函数的二次项系数为-6．18,达极显著水平,水杨酸、对羟基苯甲酸和阿魏酸对稗草根长的抑制效应趋势与肉桂酸相同,效应曲线均为“n”形抛物线;而香草酸的效应曲线则为“U”形抛物线．当水饧酸、对羟基苯甲酸、肉桂酸、香草酸和阿魏酸浓度水平分别为0．06、0．60、0．24、0．02和0．02mmol·L^-1时,混合物对稗草根长的抑制率最大,达到78．65％。     

Chemical genomics: a challenge for de novo drug design

De novo design provides an in silico toolkit for the design of novel small molecular structures to a set of specified structural constraints. With the avalanche of bioinformatics data, de novo design is ideally suited for exploring molecules that could be useful for chemical genomics. The design process involves manipulation of the input, modification of structural constraints, and further processing of the de novo generated molecules using various modular toolkits. The development of a theoretical framework for each of these stages will provide novel practical solutions to the problem of creating compounds with maximal chemical diversity. This short review describes the fundamental problems encountered in the application of novel chemical design technologies to chemical genomics by means of a formal representation. This notation helps to outline and clarify ideas and hypotheses that can then be explored using mathematical algorithms. It is only by developing this rigorous foundation that in silico design can progress in a rational way.     

氮源和真菌诱导子对铁皮石斛原球茎悬浮培养的影响

利用正交实验设计研究不同种类和浓度的氮源对铁皮石斛原球茎生长的影响,利用完全随机实验设计研究不同真菌诱导子对铁皮石斛原球茎生长和多糖积累的影响.结果表明硝态氮促进铁皮石斛原球茎鲜重和干重的增加( P ＜0.05);铵态氮促进铁皮石斛原球茎鲜重增加( P ＜0.05).无论鲜重还是干重,硝态氮和铵态氮的影响均不存在互作,最佳组合为:67-V培养液 100 mg/L (NH4)2SO4 800 mg/L KNO3 30 g/L蔗糖 200 g/L马铃薯提取汁.F检验的结果表明,14种真菌诱导子对铁皮石斛原球茎生物量的增加(鲜重与干重)均无显著性影响( P ＞0.05).但与对照铁皮石斛原球茎的多糖含量相比,真菌诱导子g6、g14、g5、g4处理可使其多糖含量分别提高14%、9%、6%、4%.本研究获得了有利于铁皮石斛原球茎生长的硝态氮和铵态氮的最佳搭配方案以及有利于铁皮石斛原球茎积累多糖的四种真菌诱导子,表明通过液体悬浮培养生产铁皮石斛原球茎及其多糖成分具有较好的开发应用前景.     

Adapting Stand‐Alone Renewable Energy Technologies for the Circular Economy through Eco‐Design and Recycling

Renewable energy (RE) technologies are looked upon favorably to provide for future energy demands and reduce greenhouse gas (GHG) emissions. However, the installation of these technologies requires large quantities of finite material resources. We apply life cycle assessment to 100 years of electricity generation from three stand‐alone RE technologies—solar photovoltaics, run‐of‐river hydro, and wind—to evaluate environmental burden profiles against baseline electricity generation from fossil fuels. We then devised scenarios to incorporate circular economy (CE) improvements targeting hotspots in systems’ life cycle, specifically (1) improved recycling rates for raw materials and (ii) the application of eco‐design. Hydro presented the lowest environmental burdens per kilowatt‐hour of electricity generation compared with other RE technologies, owing to its higher efficiency and longer life spans for main components. Distinct results were observed in the environmental performance of each system based on the consideration of improved recycling rates and eco‐design. CE measures produced similar modest savings in already low GHG emissions burdens for each technology, while eco‐design specifically had the potential to provide significant savings in abiotic resource depletion. Further research to explore the full potential of CE measures for RE technologies will curtail the resource intensity of RE technologies required to mitigate climate change.     

利用正交设计法对叉叶苏铁ISSR-PCR反应体系的优化研究

比较CTAB法和SDS法提取叉叶苏铁（Cycas micholitzii）的总DNA,发现CTAB法是提取叉叶苏铁总DNA的较好方法;对叉叶苏铁ISSR-PCR反应体系中的4个主要因素dNTPs,Taq DNA聚合酶,引物及Mg²⁺进行最优条件筛选;采用单因素法探讨DNA模板量、退火温度和循环次数的最佳反应条件,建立了适合于叉叶苏铁的最佳ISSR-PCR反应体系 （20 μL体系）： 1×Buffer,75 ng DNA模板,dNTPs 250 μmol·L^-1, Taq酶1.0U,引物0.2 μmol·L^-1,Mg2+ 2.5mmol·L^-1,反应程序为：94℃预变性5 min,94℃变性1 min,52℃退火1 min,72℃延伸2 min,循环40次,72℃延伸10 min,4℃保存。本研究结果为苏铁纲植物的分子生物学和分子系统学研究提供理论参考。     

Mechanistic aspects of CPP-mediated intracellular drug delivery: Relevance of CPP self-assembly

In recent years, cell-penetrating peptides have proven to be an efficient intracellular delivery system. The mechanism for CPP internalisation, which first involves interaction with the extracellular matrix, is followed in most cases by endocytosis and finally, depending on the type of endocytosis, an intracellular fate is reached. Delivery of cargo attached to a CPP requires endosomal release, for which different methods have recently been proposed. Positively charged amino acids, hydrophobicity and/or amphipathicity are common to CPPs. Moreover, some CPPs can self-assemble. Herein is discussed the role of self assembly in the cellular uptake of CPPs. Sweet Arrow Peptide (SAP) CPP has been shown to aggregate by CD and TEM (freeze-fixation/freeze-drying), although the internalised species have yet to be identified as either the monomer or an aggregate.