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.     

Determination of the uranium enrichment with the NaIGEM code

The traditional method used to non-destructively determine the uranium enrichment with an NaI detector is based on the “enrichment meter principle” (Progress report LA-4605-MS, Los Alamos National Laboratory, NNM, 1970, p. 19), which involves measuring the intensity of the 186 keV line of ²³⁵U by selecting two regions of interest for the peak and the background. This type of method suffers from several limitations, the most limiting of which are the impossibility to make wall thickness correction or to take the inference of foreign radioisotopes into account. The NaIGEM software (A guide for using NaIGEM code, version 1.5 for DOS and Windows, 2001; Nucl. Instr. and Meth. A 458 (2001) 196) was developed to overcome these limitations by calculating the 186 keV line intensity with a fitting procedure. The code was tested in different measurement conditions on the wide variety of certified samples, in particular, on reprocessed uranium and on depleted material with thick steel filters interposed between the source and the detector. The results are presented to illustrate the performance and limitations of the tested version (A guide for using NaIGEM code, version 1.5 for DOS and Windows, 2001). The general performance is good except in the case of low-enriched uranium in thick containers.     

Keine Mautdaten für Ermittlungsverfahren

Das Autobahnmautgesetz zeichnet sich durch eine strenge Zweckbindung für die Mautdaten aus. Diese dürfen ausschlie?lich für die Zwecke des Mautgesetzes erhoben und verarbeitet werden. Diese Vorgabe hat das LG Magdeburg in einem Beschluss richtungsweisend auch für die Verbindungsdaten der GSM-Kommunikation best?tigt.     

Trifluoromethanesulphonic acid catalysed transalkylation between tetrabromobisphenol-a and toluene for the production of 2,6-dibromophenol

The preparation of 2,6-dibromophenol is described. This compound, useful as raw material for brominated poly(phenyleneoxide) and pyrogallol or derived pharmaceuticals/pesticides, was prepared in 80% (isolated) yield by a transalkylation reaction between tetrabromobisphenol-A and toluene. The catalyst, trifluoromethanesulphonic acid, can be simply recovered and recycled. Perfluorinated resin sulphonic acid (NAFION-H®, DuPont) did not effectively catalyse this transalkylation.     

Mena, a relative of VASP and Drosophila Enabled, is implicated in the control of microfilament dynamics

This paper examines the effects of exposure to mass media messages promoting family planning on the reproductive behaviour of married women in Nigeria using cross-sectional data. Longitudinal data are also used to ensure that exposure to media messages pre-dates the indicators of reproductive behaviour. Cross-sectional analysis suggests that: (1) contraceptive use and intention are positively associated with exposure to mass media messages, and (2) women who are exposed to media messages are more likely to desire fewer children than those who are not exposed to such messages. Similarly, analysis of the longitudinal data shows that exposure to mass media messages is a significant predictor of contraceptive use. Thus, exposure to mass media messages about family planning may be a powerful tool for influencing reproductive behaviour in Nigeria.     

Vakuumgerechte Werkstoffe und Verbindungstechnik

In Part 1 (Henning, Materials used in Vacuum Technology), the application possibilities of different materials in vacuum technology were described. Part 2 describes the most important non-detachable connections of these materials to produce components that can be used in vacuum technology. The following processes are suitable for this purpose:

• ○ Welding

• ○ Soldering

• ○ Glueing

• ○ Fusion

For this reason, these four processes will be discussed in detail here; their advantages and disadvantages described and their worthiness for use in vacuum technology indicated. It should be noted here that other nondetachable connections such as rivets, point welding, projection seam welding or roll seam welding do not meet the demands of gas tightness made in vacuum technology and cannot, therefore, be used for such purposes.     

Method for determining musculotendon parameters in subject-specific musculoskeletal models of children developed from MRI data

Accurate knowledge of muscle-tendon parameters in biomechanical models is critical for accurate simulation and analyses of human movement. An excellent example of this is the creation of subject-specific models from magnetic resonance imaging (MRI). When Hill-type muscle models are used to calculate muscle forces, the determination of muscle attachment points, optimal fiber length, tendon slack length and maximum isometric force all have a significant influence on the joint moment-angle behavior of the model. In the present study a method was developed for customizing the values of muscle-tendon parameters in a generic model to create subject-specific biomechanical models from MRI. The method was applied by generating musculoskeletal models for the biomechanical simulation platform OpenSim, but the workflow is equally well applicable to other simulation platforms. New computational algorithms are described for identifying joint centers and for reconstructing the centroids of the muscle bellies from MRI. A?process is also described for the extraction of the muscle paths and for identifying the positions of ??via-points?? used to model muscles wrapping over bones. Finally, a new algorithm is described for adjusting the values of optimal fiber length, tendon slack length and maximum isometric force based on a comparison of the model results with experiment. We tested our computational algorithms by developing subject-specific biomechanical models of five typically developed children (age 9.5±1.7?years) from MRI. The joint moment-angle relationships calculated for the subject-specific models were similar to those determined for corresponding scaled generic models. The results indicate that the proposed methodology is suitable for developing subject-specific models of healthy children. Future studies should investigate how abnormalities of the musculoskeletal system, such as tibial torsion and muscle spasticity, can be integrated into the modeling process.     

Gaschromatographisch-massenspektrometrische Untersuchung der im Modellsystem Cystein/Methionin/Furfural unter R?stbedingungen gebildeten Aromastoffe

Zusammenfassung Das Modellsystem Cystein/Methionin/Furfural lieferte unter Röstbedingungen ein komplexes Reaktionsgemisch, das sich mittels Adsorptionschromatographie auf Kieselgel und Capillar-GC in ca. 130 Komponenten auftrennen ließ, von denen 85 capillargaschromatographisch-massenspektrometrisch charakterisiert wurden. Furfural und die aus Cystein und Methionin resultierenden reaktiven Abbauprodukte H₂S, Cysteamin und Methylmercaptan sind wichtige Precursor für heterocyclische Flavorkomponenten. Neben Furanen, (Furan)-aldiminen und schwefelsubstituierten Furanderivaten werden auchN-Furfurylpyrrole, Pyridine, Thiazole, Thiazoline, Thiazolidine, Thiophene sowie aliphatische Schwefelverbindungen und cyclische Methylenpolysulfide gebildet. Beim Kaffeerösten entsteht Furfural als eine der Furanhauptkomponenten und spielt bei der Genese wesentlicher Kaffeearomastoffe eine zentrale Rolle.

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Gaschromatographic-mass spectrometric investigation of aroma compounds from the reaction of cysteine and methionine with furfural under roasting conditions

Summary The model-system cysteine/methionine/furfural produced under roasting conditions a complex mixture of compounds which was separated by adsorption chromatography on silica gel, according to the increasing polarity of the components, into six fractions. The fractions were investigated by capillary gas chromatography with and without mass spectrometry. Of the approx. 130 compounds detected, 85 were identified and quantified. Furfural and the reactive degradation products H₂S, cysteamine and methylmercaptan, resulting from cysteine and methionine, are important precursors for heterocyclic flavor components. Besides furans, (furan)aldimines, and sulphur-substituted furan derivates, the following compounds are also formed:N-furfurylpyrroles, pyridines, thiazoles, thiazolines, thiazolidines, thiophenes, as well as aliphatic sulphur compounds and cyclic methylene polysulfides. During coffee roasting, furfural is produced as one of the major components of the furans and is essential for the formation of important coffee aroma constituents.

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Poster-Präsentation beim Deutschen Lebensmittelchemikertag in Bremen (14.–16. Sept. 1988)