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.     

Supramolecular Tuning Enables Selective Oxygen Reduction Catalyzed by Cobalt Porphyrins for Direct Electrosynthesis of Hydrogen Peroxide

We report a supramolecular strategy for promoting the selective reduction of O₂ for direct electrosynthesis of H₂O₂. We utilized cobalt tetraphenylporphyrin (Co-TPP), an oxygen reduction reaction (ORR) catalyst with highly variable product selectivity, as a building block to assemble the permanently porous supramolecular cage Co-PB-1(6) bearing six Co-TPP subunits connected through twenty-four imine bonds. Reduction of these imine linkers to amines yields the more flexible cage Co-rPB-1(6). Both Co-PB-1(6) and Co-rPB-1(6) cages produce 90–100 % H₂O₂ from electrochemical ORR catalysis in neutral pH water, whereas the Co-TPP monomer gives a 50 % mixture of H₂O₂ and H₂O. Bimolecular pathways have been implicated in facilitating H₂O formation, therefore, we attribute this high H₂O₂ selectivity to site isolation of the discrete molecular units in each supramolecule. The ability to control reaction selectivity in supramolecular structures beyond traditional host–guest interactions offers new opportunities for designing such architectures for a broader range of catalytic applications.     

Measurements of small-scale fading and path loss for long range RF tags

RF modulated backscatter (RFMB), also known as modulated radar cross section or sigma modulation, is a RF transmission technique useful for short-range, low-data-rate applications, such as nonstop toll collection, electronic shelf tags, freight container identification and chassis identification in automobile manufacturing, that are constrained to have extremely low power requirements. The small-scale fading observed on the backscattered signal has deeper fades than the signal from a traditional one-way link of the same range in the same environment because the fading on the backscattered signal is the product of the fading on the off-board-generated carrier times the fading on the reflected signal. This paper considers the continuous wave (CW) type of RFMB, in which the interrogator transmitter and receiver antennas are different. This two-way link also doubles the path loss exponent of the one-way link. This paper presents the cumulative distribution functions for the measured small-scale fading and the measured path loss for short ranges in an indoor environment at 2.4 GHz over this type of link.     

1/f noise in large-area Hg<Subscript>1−x</Subscript>Cd<Subscript>x</Subscript>Te photodiodes

The 1/f noise in photovoltaic (PV) molecular-beam epitaxy (MBE)-grown Hg_1−xCd_xTe double-layer planar heterostructure (DLPH) large-area detectors is a critical noise component with the potential to limit sensitivity of the cross-track infrared sounder (CrIS) instrument. Therefore, an understanding of the origins and mechanisms of noise currents in these PV detectors is of great importance. Excess low-frequency noise has been measured on a number of 1000-μm-diameter active-area detectors of varying “quality” (i.e., having a wide range of I-V characteristics at 78 K). The 1/f noise was measured as a function of cut-off wavelength under illuminated conditions. For short-wave infrared (SWIR) detectors at 98 K, minimal 1/f noise was measured when the total current was dominated by diffusion with white noise spectral density in the mid-10⁻¹⁵A/Hz^1/2 range. For SWIR detectors dominated by other than diffusion current, the ratio, α, of the noise current in unit bandwidth i_n(f = 1 Hz, V_d = −60 mV, and Δf = 1 Hz) to dark current I_d(V_d = −60 mV) was α_SW-d = i_n/I_d ∼ 1 × 10⁻³. The SWIR detectors measured at 0 mV under illuminated conditions had median α_SW-P = i_n/I_ph ∼ 7 × 10⁻⁶. For mid-wave infrared (MWIR) detectors, α_MW-d = i_n/I_d ∼ 2 × 10⁻⁴, due to tunneling current contributions to the 1/f noise. Measurements on forty-nine 1000-μm-diameter MWIR detectors under illuminated conditions at 98 K and −60 mV bias resulted in α_MW-P = i_n/I_ph = 4.16 ± 1.69 × 10⁻⁶. A significant point to note is that the photo-induced noise spectra are nearly identical at 0 mV and 100 mV reverse bias, with a noise-current-to-photocurrent ratio, α_MW-P, in the mid 10⁻⁶ range. For long-wave infrared (LWIR) detectors measured at 78 K, the ratio, α_LW-d = i_n/I_d ∼ 6 × 10⁻⁶, for the best performers. The majority of the LWIR detectors exhibited α_LW-d on the order of 2 × 10⁻⁵. The photo-induced 1/f noise had α_LW-P = i_n/I_ph ∼ 5 × 10⁻⁶. The value of the noise-current-to-dark-current ratio, α appears to increase with increasing bandgap. It is not clear if this is due to different current mechanisms impacting 1/f noise performance. Measurements on detectors of different bandgaps are needed at temperatures where diffusion current is the dominant current. Excess low-frequency noise measurements made as a function of detector reverse bias indicate 1/f noise may result primarily from the dominant current mechanism at each particular bias. The 1/f noise was not a direct function of the applied bias.     

Securing Mobile Ad hoc Networks — A Motivational Approach

Mobile ad hoc networks rely on the co-operation of devices that route for each other. This immediately presents security problems. Each device's data passes through the not so friendly hands of other devices. Forwarding devices must use their processing power and battery power to route packets for others. When bandwidth is limited they must also use bandwidth that they might want to use for themselves. These are not great issues with the first incarnations of ad hoc networks — military systems or others where all the devices are owned by a single organisation. However, if ad hoc networks are to be generally deployed and become an alternative or adjunct to future cellular systems, then ways to encourage co-operation are required. This revised version was published online in July 2006 with corrections to the Cover Date.     

A Language for Teaching Discrete-event Simulation

Courses which teach discrete-event simulation are based on many different simulation languages. The requirements for a language to support teaching simulation are discussed. In particular, it is recommended that such languages separate into distinct modules those aspects of simulation which are taught as separate topics. Implementation of the separation is discussed. The SEESIM language, developed as a teaching aid, is described, and examples of its use are given. Straightforward use of SEESIM can be learned quickly, yet the language provides facilities for a staged introduction to advanced concepts of simulation.