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.     

Probability-based current dipole localization from biomagneticfields

Focal biomagnetic sources are described as pointlike current dipoles. The dipole parameters, position, and moment coordinates are commonly determined from biomagnetic data using iterative nonlinear optimization algorithms such as the Levenberg-Marquardt algorithm. However, even for single-dipole sources, mislocalizations can occur due to side minima of the cost function or due to a wrong choice of the start vector. This can be shown by introducing a cost function where the independent variables are only the position coordinates instead of position and moment coordinates. This dimensional reduction-which is also possible for multiple dipole sources-is achieved by calculating the cost function at each position with the position and data-dependent, optimum dipole moments. The authors call these dipoles with-in a least squares sense-optimum moments, locally optimal dipoles. The visualization of such a single-dipole cost function and of the iteration steps of the Levenberg-Marquardt algorithm show why mislocalizations cannot be avoided. Therefore, the authors propose an alternative noniterative localization algorithm for single-dipole sources without this drawback. It uses localization probabilities calculated by means of the locally optimal dipoles. Besides the determination of the dipole parameters, the proposed algorithm furnishes a reliable error for each localization. Its effectiveness is shown with simulated and real patient data     

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.     

The Electrochemistry of Liposomes

This review aims to summarize the current state of research concerning the interaction of electrodes with liposomes suspended in solutions. Main attention is given to the complex mechanism of adhesion and spreading of liposomes on mercury electrodes. That mechanism can be studied with the help of chronoamperometry, where each adhesion-spreading event appears as a capacitive current spike. Integration of these spikes produces charge versus time transients that can be modeled and simulated, revealing the details of the multi-step adhesion-spreading process. Whereas the number of spikes per time mirrors the macro-kinetics, the analysis of the time behavior of each spike mirrors the micro-kinetics of each adhesion-spreading event. The reviewed studies show that this approach provides a new tool to study the properties of liposome membranes. The adhesion-spreading of liposomes on mercury electrodes has strong similarities to the process of vesicle fusion, which makes these studies a biomimetic model allowing one to deduce the effects of foreign molecules in bilayer membranes.     

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.