Supramolecular Assembly of Aminoethylene‐Lipopeptide PMO Conjugates into RNA Splice‐Switching Nanomicelles

Phosphorodiamidate morpholino oligomers (PMOs) are oligonucleotide analogs that can be used for therapeutic modulation of pre‐mRNA splicing. Similar to other classes of nucleic acid‐based therapeutics, PMOs require delivery systems for efficient transport to the intracellular target sites. Here, artificial peptides based on the oligo(ethylenamino) acid succinyl‐tetraethylenpentamine (Stp), hydrophobic modifications, and an azide group are presented, which are used for strain‐promoted azide‐alkyne cycloaddition conjugation with splice‐switching PMOs. By systematically varying the lead structure and formulation, it is determined that the type of contained fatty acid and supramolecular assembly have a critical impact on the delivery efficacy. A compound containing linolenic acid with three cis double bonds exhibits the highest splice‐switching activity and significantly increases functional protein expression in pLuc/705 reporter cells in vitro and after local administration in vivo. Structural and mechanistic studies reveal that the lipopeptide PMO conjugates form nanoparticles, which accelerate cellular uptake and that the content of unsaturated fatty acids enhances endosomal escape. In an in vitro Duchenne muscular dystrophy exon skipping model using H2K‐mdx52 dystrophic skeletal myotubes, the highly potent PMO conjugates mediate significant splice‐switching at very low nanomolar concentrations. The presented aminoethylene‐lipopeptides are thus a promising platform for the generation of PMO‐therapeutics with a favorable activity/toxicity profile.     

International Trade

Values of net oil imports(-)/exports for Austria, Belgium, Denmark, Finland, France, Germany, Italy, Netherlands, Norway, Portugal, Spain, Sweden, Switzerland, the United Kingdom, Japan, Canada, the United States and Australia. Updated on a monthly basis. Number of imports for Belgium, France, Germany, Greece, Republic of Ireland, Italy, Netherlands, Portugal, Spain, Sweden, the United Kingdom, and Other EU-15 (EU-15), Norway, Poland, Switzerland, Turkey, and Other Europe (OECD Europe), Canada, Chile, Mexico, and the United States (OECD Western Hemisphere), and Australia, Japan, Republic of Korea, New Zealand, (OECD Asia-Pacific), and Total OECED. Current data for Austria, Belgium, Finland, France, Germany, Greece, Italy, Netherlands, Portugal, Spain, Sweden, the United Kingdom, Other EU-15 (EU-15), Czech Republic, Hungary, Poland, Slovakia, Turkey, and Other Europe (OECD Europe), Canada, Mexico, and the United States (OECD Western Hemisphere), Australia, Japan, Republic of Korea, and New Zealand (OECD Asia-Pacific). Updated on a monthly basis. Current data for principal importers of natural gas and the amount in which they import from United States, Republic of Korea, United Kingdom, France, Japan, Italy, Germany and Spain (Table 19.1). Current data for principal exporters of natural gas and the amount they export to Canada, Trinidad and Tobago, the United States, Netherlands, Norway, Russia, Turkmenistan, Qatar, Algeria, Nigeria, Indonesia, Malaysia and Australia (Table 19.2). Updated on a monthly basis.     

Efficacious Doxorubicin Delivery Using Glutathione-Responsive Hollow Non-phospholipid Vesicles Bearing Lipoyl Cholesterols

In this study, we developed redox-sensitive vesicles using synthesised lipoyl cholesterol derivatives, a non-ionic surfactant and an optimum level of free cholesterol. Interestingly, concentration-dependent self-assembly was observed by scanning electron microscopy, wherein vesicles manifested as hollow spherical (at 0.15 mm ) and triangular (0.50 mm ). The redoxresponsive characteristics of the vesicles was probed in the presence of dithiothreitol; they underwent a clear increase in size as observed by dynamic light scattering measurements. These vesicles could easily encapsulate an anticancer drug, doxorubicin, and were observed to be stable in the presence of serum. They showed substantial release of the drug in response to biologically relevant stimulus, that is, glutathione. A toxicity assessment on HeLa and HepG2 cancer cells demonstrated activities of the drug-loaded vesicles comparable to that of free drug, whereas significantly enhanced toxicity and apoptotic induction were observed against drug-resistant HeLa cells, which was determined by studying the cellular internalisation of doxorubicin.     

The Emerging Role of Tetrazines in Drug-Activation Chemistries

Traditionally, prodrug activation has been limited to enzymatic triggers or gross physiological aberrations, such as pH, that offer low selectivity and control over dosage. In recent years, the field of prodrug activation chemistry has been transformed by the use of bioorthogonal reactions that can be carried out under biological conditions at sub-millimolar concentrations, with the tetrazine-mediated inverse electron demand Diels–Alder reaction amongst the most recognised. Their high reaction rates, chemoselectivity and excellent biocompatibility make tetrazines ideal small molecules for activating prodrugs. Recently the tetrazine moiety has been used as a prodrug for a pyridazine thus broadening the scope of prodrug systems. This article discusses the concept of using tetrazines as small-molecule activators for prodrugs, and provides an overview of tetrazine-based prodrug systems, with a particular focus on the recently reported prodrug–prodrug activation strategy.     

等级反馈蚁群算法求解成品油二次配送问题

针对成品油二次配送路径优化问题，提出了一种可变成本与动态载荷相关的评价指标。考虑蚁群算法求解路径优化问题的高效性，设计了一种等级反馈蚁群（HFAC）算法。采用局部距离等级策略代替基本蚁群算法的随机选取；利用较优（较差）个体对其所在路线进行正（负）反馈调整信息素浓度；对最优路线的子路线进行末端优化调整。通过15组不同类型算例进行仿真实验表明，HFAC算法在成品油二次配送路径优化中优于基本蚁群算法。     

基于瓦斯涌出特征的钱家营矿掘进工作面突出预警系统应用

为实现钱家营矿掘进工作面煤与瓦斯突出实时预警,提出一种基于瓦斯涌出特征的预警方法。依据巷道高低浓度甲烷传感器实时监测数据,通过离散回归理论分析煤与瓦斯突出前的瓦斯涌出量,建立预警指标特征序列,确定掘进工作面煤与瓦斯突出预警指标危险临界值:方差0.018,波峰差0.41,波动斜率±0.027。在此基础上构建了非接触式煤与瓦斯突出可视化预警系统并在钱家营矿进行现场应用。结果表明,以瓦斯涌出特征值作为预警指标,能够准确监测到井下瓦斯异常现象,达到瓦斯数据实时解算和可视化预警的目的,为钱家营矿掘进工作面防突工作提供技术借鉴。     

基于实车状态的发动机均值模型研究

基于实车状态下发动机的测试运行参数，提出了一种改进发动机均值模型仿真精度的方法。首先基于五电机台架对实车搭载环境下的一款自然吸气发动机进行了性能测试，分别获得发动机水温、发动机转速、发动机缸内压力、进气道压力和温度、进气歧管压力和温度、燃油体积流量、发动机飞轮端扭矩、排气歧管压力和温度、排气歧管过量空气系数、三元催化后排气压力和温度等参数；然后运用Amesim/MATLAB软件联合仿真对发动机进行了基于实车搭载环境边界下的数值建模和模型标定。研究结果表明，标定后的发动机均值模型预测结果与实际测试结果最大差值可以控制在8%以内。     

A comparison of Zayandehrood River water values for agriculture and the environment

River water management is challenging not only since they are open systems with changing physical structures, but also because the water values are mostly unknown over varied sectors. If policymakers grasp water values, water management will be more efficient. This research intends to examine the values of water in agriculture, which receives the most substantial portion of water resources, with the values of water in the environment in Isfahan located in the Zayandehrood River basin of Iran. The consequences of contingent valuation and production function methods revealed that per cubic metre value of water is 13 times higher in the environment than agriculture. The government should reconsider the higher value of the environment despite it is a non‐market value. The contingent valuation model additionally proved that women exhibited 21% more willingness to pay than men in order to protect the environment; however, they are paid less by 36%.     

肠靶向海藻酸钙基微胶囊的制备及控释性能研究

利用毛细管共挤出技术结合静电吸附和仿生硅化的方法，制备了海藻酸钙-壳聚糖/精蛋白/二氧化硅(ACPSi)复合微胶囊。ACPSi复合微胶囊的平均粒径约3.18 mm，单分散性好，囊壁最外层的二氧化硅层可抑制其在肠液pH环境中的溶胀，增强囊的机械稳定性。将羟丙甲基纤维素邻苯二甲酸酯(HPMCP)肠溶微球作为释药“微阀门”，嵌入囊壁可以更好地控制微胶囊的释药行为。以吲哚美辛为模型药物，当药物浓度为22.5 mg/ml时，ACPSi载药微胶囊在pH 2.5模拟胃液中3 h时累计释药率仅为0.33%，而转移至pH 6.8模拟肠液中19 h时累计释药率为77.78%；囊壁嵌入HPMCP微球后，22 h时累计释药率可提高约4%。因此，该复合微胶囊具有良好的肠靶向作用和控释特性，作为口服肠靶向缓控释制剂具有良好的应用前景。