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.     

The Critical Role of Passive Permeability in Designing Successful Drugs

Passive permeability is a key property in drug disposition and delivery. It is critical for gastrointestinal absorption, brain penetration, renal reabsorption, defining clearance mechanisms and drug-drug interactions. Passive diffusion rate is translatable across tissues and animal species, while the extent of absorption is dependent on drug properties, as well as in vivo physiology/pathophysiology. Design principles have been developed to guide medicinal chemistry to enhance absorption, which combine the balance of aqueous solubility, permeability and the sometimes unfavorable compound characteristic demanded by the target. Permeability assays have been implemented that enable rapid development of structure-permeability relationships for absorption improvement. Future advances in assay development to reduce nonspecific binding and improve mass balance will enable more accurately measurement of passive permeability. Design principles that integrate potency, selectivity, passive permeability and other ADMET properties facilitate rapid advancement of successful drug candidates to patients.     

Alloy optimisation of bainitic steel for large plastic mould

Based on the phase transformation theories, especially the T₀ concept of bainite transformation, alloy optimisation of bainitic steel with carbides has been carried out aiming at the produce of plastic mould with large cross-section. The effect of manganese and silicon on proeutectoid ferrite and bainite transformation is explored by dilatometric analysis, XRD and different microscopy techniques. The results show that after the alloy optimisation, the transformation of proeutectoid ferrite is suppressed and when the cooling rate is lower than 0·1°C?s^??1, the new lower bainite transformation appears by decreasing carbon capacity of austenite and promoting carbide precipitation. Industrial production proves that the optimised alloy SDP1 can meet the demand for the plastic mould with the thickness of 1050?mm.     

基于振动实测的非均质地层钻头失效分析与对策

四川盆地作为国内页岩气开发的重点区域,通过近几年的不断攻关和实践,机械钻速得到了提高,但由于受地层复杂、可钻性差、非均质性强等地质因素的影响,导致井下钻柱系统不良振动剧烈,容易出现钻头损坏严重、钻速较低等问题,严重影响了钻井时效。为了解决上述难题,以该盆地涪陵工区上二叠统龙潭组—中二叠统茅口组为例,采用井下振动高频测量工具的实测手段,测量了钻头—钻柱系统的动态振动加速度参数,结合地层的岩性和矿物组分分析,研究钻头失效原因与对策,并开展了现场试验。研究结果表明:①在非均质地层中钻进的钻头—钻柱系统产生了大于40 m/s~2的高幅值瞬时冲击振动,高幅值的瞬时冲击是导致钻头先期失效的主要原因;②提出了抑制高幅值的瞬时冲击振动采用"减振+增压"工具组合和避免井下工具共振的钻井参数;③采用钻井新参数的试验井比邻井的高幅值瞬时振动降低了17%,单只钻头进尺增加24%,钻头工作环境得到了较大的改善,钻头使用数量减少。结论认为,该研究成果能够有效地改善钻头—钻柱系统的振动状态,有利于达成延长钻头使用寿命的目标。     

Structural,magnetic and magnetostrictive properties of Co1-xLixFe2O4 synthesized by cathode materials of spent Li-ion batteries

In this study, we investigated the effects of substituting Li⁺ for Co²⁺ at the B sites of the spinel lattice on the structural, magnetic and magnetostrictive properties of cobalt ferrites. The Li⁺ substituted cobalt ferrites, Co_1-xLi_xFe₂O₄, with x varying from 0 to 0.7 in 0.1 increments, were synthesized with a sol-gel auto-combustion method using the cathode materials of spent Li-ion batteries. X-ray diffraction analysis revealed that all the Co_1-xLi_xFe₂O₄ nanopowders had a single-phase spinel structure and the lattice parameters decreased with increasing Li⁺ content, which can be proved by slight shifts towards higher diffraction angle values of the (311) peak. Field emission scanning electron microscopy was used to observe the fractured inner surface of the sintered cylindrical rods and the increased porosity resulted in a decreased magnetostriction. The oxidation states of Co and Fe in the cobalt ferrite samples were examined by X-ray photoelectron spectroscopy. High resolution transmission electron microscopy micrographs showed that most particles were roughly spherical and with sizes of 25–35?nm. Li⁺ substitution had a strong effect on the saturation magnetization and coercivity, which were characterized with a vibrating sample magnetometer. The Curie temperature was reduced due to the decrease in magnetic cations and the weakening of the exchange interactions. The magnetostrictive properties were influenced by the incorporation of Li⁺ at the B sites of the spinel structure and correlated with the changes in porosity, magnetocrystalline anisotropy and the cation distribution.     

Comparative studies on thermal and toughness properties of polybenzoxazine composites with two functionalized graphene oxides

Abstract

Graphene oxide (GO) was functionalized by polyether amine (PEA) via two methods which were one-pot modification in acetone (GON) and two steps with the intermediate product of GOCO-Cl generated (GONS). There were more PEA successfully grafted onto GO for GONS than GON. The onset polymerization temperatures of the benzoxazine (Bz) composites decreased by the inclusion of 1?wt% of GO, GON or GONS. Thermal stability of the polybenzoxazine (PBz) composites was significantly improved indicated from the increase of weight loss temperature. T₁₀, T₂₀ and T₅₀ values of the composites with GONS were higher than that of the others. Toughness of PBzs may be enhanced by the incorporation of nanofillers, and GONS had stronger interfacial interaction with PBz matrix than GON.     

The origin of the modulated structure in Sr2CuO3+δ (δ = 0.4): [CuO2] in-plane oxygen vacancy or apical oxygen vacancy?

We propose the question of the modulated structures of copper oxide is caused by the [CuO₂] in-plane oxygen vacancy or apical oxygen vacancy. Sr₂CuO_3+δ single-crystal samples were prepared using high-temperature and high-pressure methods. The major phase of Sr₂CuO_3+δ (δ = 0.4) single-crystal system is found to be constituted by the 5 a modulated structure with the Fmmm space group, which originates from the [CuO₂] in-plane oxygen vacancy appearing in octahedral Cu-O. Besides, the presence of the [CuO₂] in-plane oxygen vacancy may obliterate the superconductivity of the system. Experimental results deduce that the oxygen vacancy may appear in the apical oxygen sites in high-temperature copper oxide superconductors.     

关于当前钢材市场形势的看法

从今年3月初以来,钢材市场行情呈现明显恢复性上扬态势。据中国钢铁工业协会财务资产部和冶金价格信息中心发布的钢材价格指数,5月15日-5月19日板材平均已恢复到110.34点,比去年末上升17.92点,价格恢复性上涨19.38%,但比去年5月份的146.1点仍低24.5%;长材价格指数略有同升,在94.37点,比去年末只回升3.56点,价格只恢复性上涨3.92%,比去年5月份的102.19点仍低7.65。掘国家统计局数据,一季度全国规模以上工业企业销售收入同比增长25.3%,实现利润同比增长21.3%,但钢铁企业由于去年下半年价格大幅度下降,今年一季度钢协会员企业(钢产量占全国81.8%)销售收入同比下降5.18%,实现利润同比下降