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.     

Effect of the cultivation mode on red pigments production from Monascus ruber

In submerged cultures performed in chemically defined fermentation medium containing glucose and glutamate, the growth and production of water‐soluble red pigments and citrinin by the filamentous fungus Monascus ruber were studied under various carbon/nitrogen (C/N) ratios. The specific production of the red pigments was optimal at a glucose/glutamate ratio of about 10 and then steadily decreased at higher C/N ratio. In contrast, the production of the mycotoxin increased with increased C/N with an optimum in the range of 30–45. In a fed‐batch mode, it was also found that the production of pigments was not favoured in fed‐batch mode by feeding the medium with glucose while keeping the C/N ratio lower than 10. This low production likely resulted from concurrent high accumulation of L‐malic acid that was reported to inhibit this production. In contrast, this mode of cultivation was rather favourable for the production of the mycotoxin.     

Apparent power-law distributions in animal movements can arise from intraspecific interactions

Lévy flights have gained prominence for analysis of animal movement. In a Lévy flight, step-lengths are drawn from a heavy-tailed distribution such as a power law (PL), and a large number of empirical demonstrations have been published. Others, however, have suggested that animal movement is ill fit by PL distributions or contend a state-switching process better explains apparent Lévy flight movement patterns. We used a mix of direct behavioural observations and GPS tracking to understand step-length patterns in females of two related butterflies. We initially found movement in one species (Euphydryas editha taylori) was best fit by a bounded PL, evidence of a Lévy flight, while the other (Euphydryas phaeton) was best fit by an exponential distribution. Subsequent analyses introduced additional candidate models and used behavioural observations to sort steps based on intraspecific interactions (interactions were rare in E. phaeton but common in E. e. taylori). These analyses showed a mixed-exponential is favoured over the bounded PL for E. e. taylori and that when step-lengths were sorted into states based on the influence of harassing conspecific males, both states were best fit by simple exponential distributions. The direct behavioural observations allowed us to infer the underlying behavioural mechanism is a state-switching process driven by intraspecific interactions rather than a Lévy flight.     

Phase-Structural and Electrochemical Properties of La2MgNi9 Alloys

Powder Metallurgy and Metal Ceramics - Multiphase La 2 MgNi 9 alloys are synthesized by induction melting. The crystalline structures of all phases in the alloys are determined with X-ray...