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.     

大豆磷脂产品质量控制——大豆磷脂的颜色和风味

综述了大豆磷脂颜色的来源 ,大豆磷脂褐色物质的生成。介绍了磷脂中产生各种气味的物质和油脂加工过程中混合油吸附过滤和脱色、水化脱胶工艺条件、脱胶剂对大豆磷脂颜色的影响。对磷脂制备工艺中常采用的过氧化苯甲酰、过氧化氢化学脱色法以及浓缩磷脂的白土脱色、浓缩磷脂活性炭吸附脱色作了介绍     

Calcium: A comprehensive review on quantification,interaction with milk proteins and implications for processing of dairy products

Calcium (Ca) is a key micronutrient of high relevance for human nutrition that also influences the texture and taste of dairy products and their processability. In bovine milk, Ca is presented in several speciation forms, such as complexed with other milk components or free as ionic calcium while being distributed between colloidal and serum phases of milk. Partitioning of Ca between these phases is highly dynamic and influenced by factors, such as temperature, ionic strength, pH, and milk composition. Processing steps used during the manufacture of dairy products, such as preconditioning, concentration, acidification, salting, cooling, and heating, all contribute to modify Ca speciation and partition, thereby influencing product functionality, product yield, and fouling of equipment. This review aims to provide a comprehensive understanding of the influence of Ca partition on dairy products properties to support the development of kinetics models to reduce product losses and develop added-value products with improved functionality. To achieve this objective, approaches to separate milk phases, analytical approaches to determine Ca partition and speciation, the role of Ca on protein–protein interactions, and their influence on processing of dairy products are discussed.     

Pretherapeutic staging of laryngeal carcinoma. Clinical findings, computed tomography, and magnetic resonance imaging compared with histopathology

BACKGROUND: An accurate pretherapeutic staging of laryngeal carcinoma is required for most treatment planning as well as for evaluation and comparison of the results of different treatment modalities. Neoplastic invasion of the laryngeal cartilage may have important therapeutic implications. To our knowledge, no data are available comparing the impact of endoscopic examination, computed tomography (CT), and magnetic resonance (MR) imaging on pretherapeutic staging accuracy. The purpose of our study was to determine which imaging should be used as an adjunct to other clinical examinations in the pretherapeutic staging of laryngeal carcinoma. METHODS: In this study, 40 consecutive patients with neoplasms of the larynx, who were treated surgically, were included in a prospective pretherapeutic staging protocol that included indirect laryngoscopy, direct microlaryngoscopy, contrast-enhanced CT, and gadolinium-diethylenetriamine pentaacetic acid-enhanced MR imaging at 1.5 Tesla. The surgical specimens were cut in whole-organ slices parallel to the plane of the axial CT and MR images. The histologic findings were compared with the clinical findings including the CT and MR images. The impact of each diagnostic method on pretherapeutic staging was analyzed. RESULTS: Clinical/endoscopic evaluation failed to correctly stage 17 tumors due to invasion of the paraglottic space (1 tumor), preepiglottic space (2 tumors), and extralaryngeal soft tissues (14 tumors), resulting in a pretherapeutic staging accuracy of 57.5%. Neoplastic invasion of cartilage was present in 28 patients and absent in 12 patients. Although MR imaging was more sensitive in detecting neoplastic invasion of cartilage than CT (94% vs. 67%; P = 0.001), MR imaging was less specific than CT (74% vs. 87%; P = 0.007). There was no difference between the overall accuracy of CT and MR imaging in detecting neoplastic invasion of cartilage (80% vs. 82%). The accuracy of combined clinical/endoscopic examination and CT staging was 80% and the accuracy of combined clinical/endoscopic examination and MR imaging staging was 87.5%; the difference was not statistically significant. CONCLUSIONS: Clinical/endoscopic examination alone failed to identify tumor invasion of the laryngeal cartilages and of the extralaryngeal soft tissues, resulting in a low staging accuracy (57.5%). Many pT4 (according to the International Union against Cancer TNM Staging System) tumors were clinically unrecognized. The combination of clinical/endoscopic evaluation and an additional radiologic examination, either CT or MR imaging, resulted in significantly improved staging accuracy (80% vs. 87.5%). MR imaging is significantly more sensitive but less specific than CT in detecting neoplastic cartilage invasion. Therefore, MR imaging tends to overestimate neoplastic cartilage invasion and may result in overtreatment, whereas CT tends to underestimate neoplastic cartilage invasion and may lead to inadequate therapy.     

Fluoride exposure in cervids inhabiting areas adjacent to aluminum smelters in Norway. I. Residue levels

Mandibular fluorine concentrations were determined in 1,425 red deer (Cervus elaphus), 240 moose (Alces alces), and 424 roe deer (Capreolus capreolus) collected in Norway from 1990 to 1993 in seven municipalities in which aluminum smelters are located, in eight neighboring municipalities, and in eight reference areas representing background levels. Background fluorine concentration was significantly correlated with age in all three species. Roe deer had the highest mean background fluorine level in each age group, followed by red deer. Due to differences in fluoride exposure, large variations in bone fluorine residues were evident between locations. In Ardal, the district most severely exposed to fluoride contamination, nine of ten cervids had fluorine concentrations exceeding background levels. The proportions of red deer with fluorine residues exceeding background levels also were high in neighboring municipalities to Ardal. We propose that roe deer are a better biomonitor of local fluoride exposure than red deer and moose, due to their more sedentary behavior.     

舰船纵摇运动函数变换型GM(1,1)模型研究

以往曾有人利用时间序列法、周期图法、神经网络法及灰色系统理论等方法来研究船的运动,目前还没有一种有效的方法解决船的纵摇,针对船的纵摇运动利用灰色系统理论建立系统模型,在灰色系统模型的基础上,通过函数变换法（三角变换及平移变换）对纵摇角度数据的周期振荡性进行处理,得到单调增加的数列,再利用灰色GM（1,1）模型建模预报,数值试验表明,这种改进方法较GM（1,1）模型效果好。