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.     

Estimation of the Stress-Strength Reliability for Exponentiated Pareto Distribution Using Median and Ranked Set Sampling Methods

In reliability analysis, the stress-strength model is often used to describe the life of a component which has a random strength (X) and is subjected to a random stress (Y). In this paper, we considered the problem of estimating the reliability R=P [Y<X] when the distributions of both stress and strength are independent and follow exponentiated Pareto distribution. The maximum likelihood estimator of the stress strength reliability is calculated under simple random sample, ranked set sampling and median ranked set sampling methods. Four different reliability estimators under median ranked set sampling are derived. Two estimators are obtained when both strength and stress have an odd or an even set size. The two other estimators are obtained when the strength has an odd size and the stress has an even set size and vice versa. The performances of the suggested estimators are compared with their competitors under simple random sample via a simulation study. The simulation study revealed that the stress strength reliability estimates based on ranked set sampling and median ranked set sampling are more efficient than their competitors via simple random sample. In general, the stress strength reliability estimates based on median ranked set sampling are smaller than the corresponding estimates under ranked set sampling and simple random sample methods.     

Physical and chemical characteristics of butterfat fractions obtained by crystallization from molten fat

Both summer and winter butterfats were fractionated using a laboratory procedure which was designed to simulate a commercial fractionation process. The process is based on a slow, controlled cooling of the melted fat, a short stabilization time at the fractionation temperature, and separation of the crystals from the liquid oil by vacuum filtration using a stainless steel perforated disc. Fractionation temperatures of 29, 26, 23 and 19 C for winter butterfat and 29 and 19 C for summer butterfat were used to obtain solid and liquid fractions at each temperature. Three replications at each temperature showed good reproducibility of results. The fractions were characterized by their fatty acid and triglyceride compositions, melting and crystallization behavior, iodine value, peroxide value and melting point. Presented at the AOCS meeting in Philadelphia in May 1985.     

Interfacial hybridization kinetics of oligonucleotides immobilized onto fused silica surfaces

Fused silica optical fibers have been used in an intrinsic mode optical configuration as biosensors for fluorescence based detection of hybridization of nucleic acids. In this work, the kinetics of hybridization of single-stranded oligonucleotides that were covalently immobilized were studied. The probe DNA was dT₂₀, and the target was Fluorescein-labeled non-complementary (dT₂₀) or complementary (dA₂₀) oligonucleotide. Chronofluorimetric monitoring of the adsorption and hybridization processes was used to investigate oligonucleotide films of different density, in different salt concentrations, at temperatures of 25 and 40 °C, with the concentration of the target DNA being 0.005–0.1 μM. Mathematical models based on first- and second-order Langmuir adsorption have been examined to describe both the adsorption and the hybridization processes. Experimental data were processed using the models, and the hybridization kinetics were calculated. Hybridization kinetics on these optical fiber DNA sensors was found to be up to three orders faster than results presented for a number of other experiments using different immobilization chemistries.     

Stress Heterogeneity Effect on the Strength of Silicon Nitride

The experiments reported in this paper demonstrate the causes of the failure of monolithic ceramics. The specimens are made of silicon nitride and tested at room temperature. The stress field within the specimen is different for each of four series of tests that have been conducted. Fractographic observations have also been made to identify the causes of the failures. A size effect analysis is performed.     

A 90-nm Wideband Merged CMOS LNA and Mixer Exploiting Noise Cancellation

This paper describes the design and implementation of a wideband merged LNA and mixer chip covering the frequency range from 0.1 to 3.85 GHz using 90-nm CMOS technology. Its high level of integration as well as its low power consumption makes it suitable for the rapidly growing software defined radio RF receivers. The chip performance achieves S11 below -10 dB along the entire band and a minimum single side band noise figure of 8.4 dB at IF frequency of 70 MHz. Power conversion gain is measured to be 12.1 dB while the input referred 1 dB compression point is measured to be -12.8 dBm. The chip core consumes only 9.8 mW from a 1.2 V supply with a die area, including the pads, of 0.88 mm²     

Cross-sectional study of the isokinetic muscle trunk strength among school children

Our surveys have shown lifetime prevalence of L.BP. over 30% among schoolchildren. The purpose of this study was to evaluate the relationship between back and isokinetic trunk strength, anthropometric parameters, and sports activities. One hundred and seventeen healthy children aged 10-16 years were included. All these volunteers had semi-structured interview, anthropometric and dynamic strength measurements. Lifetime prevalence of back pain was 44.5% and point prevalence was 13%. In this cross-sectional study, anthropometric and strength profiles were significantly related to age and gender. Non specific low back pain was not correlated to trunk muscle strength and/or sports activities.     

Thermal induced transformations in glassy chalcogenides SixTe60−xAs30Ge10

Temperature-induced transformations are considered to be interesting characteristic properties of amorphous materials including the Si _x Te_60–x As₃₀Ge₁₀ system, withx=5, 10, 12 and 20. Density (), X-ray diffraction and differential thermal analysis (DTA) were used to characterize the compositions. DTA traces of each glass composition at different heating rates from 5 to 30° C min^–1 were obtained and interpreted. Fast and slow cooling cycles were used to determine the rate of structure formation. Cycling studies of materials show no memory effect but only ovonic switching action. The compositional dependence of the crystallization activation energy (E) and the coefficient of glass-forming tendency (K _gl) have been calculated. The thermal transition temperatures and associated changes in specific heat have been examined as a function of the Te/Si ratio by differential scanning calorimetry. It was found that andE increase linearly with increasing tellurium content, while the heat capacity (c _p) andK _gl, decrease with increasing tellurium content.E=1.54 eV andc _p=0.246 J g^–1 K^–1 forx=20 whileE=2.74eV andc _p=0.22 J g^–1 K^–1 forx=5.     

Effect of the Te/Si ratio on the electrical characteristics of the amorphous chalcogenide switches

The effect of composition on amorphous chalcogenide threshold switches of the system Si _x Te_60-x As₃₀Ge₁₀, wherex = 5, 10, 12 and 20, has been studied. The compositionx = 5 shows the best switching characteristics, e.g. the smallest holding voltage (V _h = 0.4V), the highest ON state current (I _h = 45A) and smallest threshold voltage (V _s = 1.5V). Applying the three mechanisms of conductance of Mottet al. (Phil. Mag. 37 (1975) 961), it is found that for a particular composition ₂ < ₁ < ₀ (the pre-exponential factors) andW ₂ < (E _a –E ₁ +W ₁) < (E _c –E _f) (whereE _a,E _c andE _e = activation energies at band edge, fermi level and conduction band;W ₁ andW ₂ = activation energy for hopping). It was found that the density of states at the fermi levelN(E _f) increases with the decrease of silicon content. The results provided further evidence against thermal interpretations and thereby support electronic models of threshold switching for these glass systems.