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.     

郭庄煤业选煤厂振动筛筛选形式的优化研究

针对郭庄煤业选煤厂振动筛振动筛分方式可靠性差、筛分效率低下、物料筛分率低的难题,本文提出了三种新的振动筛分方案,对不同筛分方案的实际应用效果进行了分析。结果表明三移动一摆动的振动筛分方式对物料的综合分散度最高,稳定性好,该筛分方案已在郭庄煤业选煤厂煤炭筛分过程中得到了全面的应用。     

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.     

Effects of hydrolysis of precursor on the structures and properties of polymer-derived SiBN ceramic fibers

In this paper, polyborosilazane precursor was synthesied from HMDZ, HSiCl₃, BCl₃ and CH₃NH₂ using a multistep method. By controlling the storage conditions, parts of the polyborosilazane fibers were hydrolyzed. FT-IR, NMR, XRD, TEM and monofilament tensile strength test were employed to study the effects of hydrolysis of precursor on the structures and properties of polymer-derived SiBN ceramic fibers. FT-IR and NMR results indicate that Si-N group in PBSZ reacts with H₂O to form Si-O-Si group. After pyrolysis reaction at 1400℃, Si-O-Si group will finally transformed into highly ordered cristobalite and β-quartz, resulting in formation of the wrinkled surface of the obtained SiBN ceramic fiber. The strip-like defects on fiber surface, according to monofilament tensile strength test, had a significant effect on mechanical property of the obtained SiBN ceramic fiber and caused no increase in fiber tensile strength of hydrolytic polyborosilazane fiber before and after pyrolytic process.     

平煤六矿大埋深高瓦斯切顶留巷技术应用与实践#br#

为保证矿井安全高效生产，针对平煤股份公司六矿戊8 32010工作面机巷平均埋深700 m、瓦斯原始含量5.12 m3/t，原始瓦斯压力0.52 MPa的情况，开展卸压切顶留巷工作。通过对留巷全过程矿压监测，分析成巷矿压分布规律，将留巷分为动压剧烈影响区、动压缓慢影响区和成巷稳定区三部分，矿压分别来源于超前支承压力和留巷内顶板短悬臂梁失稳。留巷进入稳定区后，随着巷道超前支护液压支架等支护设施的撤除，巷道会出现二次稳定过程，主要源于顶板对于巷道超前支护液压支架工作阻力的再平衡。切顶留巷技术提高了工作效率，很好地解决了矿井采掘接替紧张的问题。