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.     

Acoustic Properties of Amorphous Solids at Very Low Temperatures: The Quest for Interacting Tunneling States

We discuss the strain dependence of the acoustic properties of amorphous metals in both normal and superconducting states, in the temperature range 0.1 mK<T<1 K. A crossover is found when the strain energy is of the order of the effective interaction energy between tunneling systems at the corresponding temperature. Our results provide clear evidence for the interaction between tunneling systems, whose energy is in quantitative agreement with theoretical expectations, and reveal that without the knowledge of the corresponding strain dependences, the measured temperature dependences below ～50 mK of the acoustic properties of disordered solids are rather meaningless.     

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.     

Selectivity of partial hydrogenation reactions performed in a pore-through-flow catalytic membrane reactor

The selectivity of partial hydrogenation reactions of unsaturated substrates was studied in a membrane reactor operating at 323 K and 40 bar hydrogen pressure. The reactor system was constructed as a loop of a saturation vessel and a membrane module in which the reaction mixture was resaturated with hydrogen up to 100 times. In a porous membrane made from cross-linked polyacrylic acid palladium nanoparticles were incorporated as catalysts. A well-defined residence time within the membrane was achieved due to a defined pore structure of the membrane and a convective mass flow of the reaction mixture through the membrane. The selectivity for the partially hydrogenated products was investigated as a function of the pore size of the PAA membrane and was compared to commercially available catalysts. Compared to experiments with supported catalysts (Pd/C and Pd/Al₂O₃) in a slurry and a fixed bed reactor the selectivity for the desired products could be increased by 3% (1-octyne) up to 40% (geraniol).     

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.     

Critical review of available correlations for two-phase flow heat transfer of ammonia

Although ammonia has been used for decades as a refrigerant of choice for selected large- and small-scale applications, no formal database is available on heat transfer of ammonia. A critical review of the published literature on heat transfer of ammonia is provided in this paper. The available correlations for in-tube and external boiling/evaporation and condensation heat transfer of ammonia are discussed and evaluated where possible. Supported by the findings of this effort, research areas of relevance that can contribute to expanded use of ammonia as an environmentally friendly refrigerant are suggested.     

Prediction of evaporation heat transfer coefficient and pressure drop of refrigerant mixtures

A study on the prediction of heat transfer coefficient (HTC) and pressure drop of refrigerant mixtures is reported. HTCs and pressure drops of prospective mixtures to replace R12 and R22 are predicted on the same cooling capacity basis. Results indicate that nucleate boiling is suppressed at qualities greater than 20.0% for all mixtures and evaporation becomes the main heat transfer mechanism. For the same capacity, some mixtures containing R32 and R152a show 8.0–10.0% increase in HTCs. Some mixtures with large volatility difference exhibit as much as 55.0% reduction compared with R12 and R22, caused by mass transfer resistance and property degradation due to mixing (32.0%) and reduced mass flow rates (23.0%). Other mixtures with moderate volatility difference exhibit 20.0–30.0% degradation due mainly to reduced mass flow rates. The overall impact of heat transfer degradation, however, is insignificant if major heat transfer resistance exists in the heat transfer fluid side (air system). If the resistance in the heat transfer fluid side is of the same order of magnitude as that on the refrigerant side (water system), considerable reduction in overall HTC of up to 20% is expected. A study of the effect of uncertainties in transport properties on heat transfer shows that transport properties of liquid affect heat transfer more than other properties. Uncertainty of 10.0% in transport properties causes a change of less than 6% in heat transfer prediction.     

Evaluation of rapeseed meals in broiler chicks: Effect of iodine supply and glucosinolate degradation by myrosinase or copper

In rapeseed meals (RSM) of a conventional (c) or a newly bred (n) variety 117 or 44 mmol glucosinolates and glucosinolate degradation products per kg dry matter were detected. Soaking meals in aqueous myrosinase or copper sulphate solution and subsequent drying reduced the content of antinutrients by more than 90%. Broiler chickens were fed (i) a glucosinolate-free diet, or this diet in which half the soybean meal was replaced by RSM of various origins and treatment; (ii) untreated cRSM; (iii) cRSM treated with myrosinase: (iv) cRSM treated with Cu (v) untreated nRSM; or (vi) nRSM treated with myrosinase. These diets were administered with or without supplementary iodine. Chickens receiving the iodine-deficient diets with myrosinase-treated RSM showed growth depression, incomplete feathering, leg injuries and severe goitre. In the serum T⁴ could not be detected. Giving myrosinase-treated RSM plus iodine, or giving other RSM diets irrespective of iodine administration, no growth depression was observed. RSM diets without iodine dosage markedly increased thyroid weight: there were no differences between the RSM variants. In contrast to the treatment with myrosinase, in the sera of the chickens fed on untreated RSM or RSM treated with copper T⁴ could be detected, suggesting that in iodine-deficient conditions differences in serum T⁴ concentration between RSM groups indicate a differing anti-thyroid activity. With iodine supplementation the RSM had a significant effect on thyroid weight. The largest thyroids (five-fold heavier) were in the animals with myrosinase-treated cRSM. The untreated cRSM and the nRSM trebled or doubled the thyroid weight, and the myrosinase-treated nRSM trebled it. The thyroid weight of chicks fed cRSM treated with copper did not differ significantly from the glucosinolate-free control. There was evidence that heating the myrosinase-treated RMS produced anti-thyroid compounds; these should be identified in further investigations.