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.     

Microscopic simulation of electronic noise in semiconductormaterials and devices

We present a microscopic interpretation of electronic noise in semiconductor materials and two-terminal devices. The theory is based on Monte Carlo simulations of the carrier motion self-consistently coupled with a Poisson solver. Current and voltage noise operations are applied and their respective representations discussed. As application we consider the cases of homogeneous materials, resistors, n⁺nn ⁺ structures, and Schottky-barrier diodes. Phenomena associated with coupling between fluctuations in carrier velocity and self-consistent electric field are quantitatively investigated for the first time. At increasing applied fields hot-carrier effects are found to be of relevant importance in all the cases considered here. As a general result, noise spectroscopy is found to be a source of valuable information to investigate and characterize transport properties of semiconductor materials and devices     

Elevated temperature performance of pseudomorphic AlGaAs/InGaAsMODFETs

Parametric DC measurements on pseudomorphic AlGaAs/InGaAs modulation-doped field-effect transistors (MODFETs) were carried out over the 300-405 K temperature range. A gradual channel device model was developed to simulate the temperature dependent behavior and assist in the interpretation of the characteristics. The simulations are shown to provide good predictive ability and confirm the physical reasons why the zero temperature coefficient point of a MODFET occurs only for gate bias voltages below the threshold voltage     

Synchronization of quadrature-quadrature phase-shift keying signals

The key synchronization aspects in the system design of a QQPSK (quadrature-quadrature phase-shift-keying) modem are addressed. The sensitivity of the data demodulator to synchronization errors is discussed, and contextually the performances of some IF and baseband carrier phase and symbol timing recovery schemes are evaluated both theoretically and by computer simulations. In particular, a fourth-power IF carrier/clock regenerator and two baseband clock recovery schemes, with and without the aid of data decisions, respectively, are taken into account. The analysis shows on the one hand the substantial robustness of QQPSK to carrier phase errors and the adequacy of the examined carrier extraction scheme. On the other hand, the remarkable sensitivity of QQPSK to symbol timing inaccuracy is stressed and the need to resort to the newly proposed decision-aided baseband clock recovery scheme is pointed out     

Expression, exon-intron organization, and chromosome mapping of the human sodium iodide symporter

The active iodide uptake of the thyroid gland in humans is mediated by the human sodium iodide symporter (hNIS). In this report, we show that hNIS expression was detected primarily in thyroid tissue, but also in breast, colon, and ovary tissues. Expression of hNIS is greatly reduced in thyroid tumors compared to normal thyroid tissue. Among tumor tissues, hNIS expression appears to be variable, consistent with the variable response to radioiodide treatment observed for thyroid carcinomas. The coding region of hNIS is interrupted by 14 introns, and the nucleotide sequence of each exon-intron junction is reported. Using this information, an alternatively spliced form of hNIS was identified. Finally, the chromosome location of the hNIS gene was mapped to chromosome 19p.     

The application of semantic classification trees to naturallanguage understanding

This article describes a new method for building a natural language understanding (NLU) system, in which the system's rules are learnt automatically from training data. The method has been applied to design of a speech understanding (SU) system. Designers of such systems rely increasingly on robust matchers to perform the task of extracting meaning from one or several word sequence hypotheses generated by a speech recognizer. We describe a new data structure, the semantic classification tree (SCT), that learns semantic rules from training data and can be a building block for robust matchers for NLU tasks. By reducing the need for handcoding and debugging a large number of rules, this approach facilitates rapid construction of an NLU system. In the case of an SU system, the rules learned by an SCT are highly resistant to errors by the speaker or by the speech recognizer because they depend on a small number of words in each utterance. Our work shows that semantic rules can be learned automatically from training data, yielding successful NLU for a realistic application     

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Ultrastructure of a bio-electrolytic methanogenic/methanotrophic granular biofilm for the complete degradation of tetrachloroethylene in contaminated groundwater.

The electrolytical methanogenic/methanotrophic coupling (eMaMoC) process was tested in a laboratory-scale single-stage reactor for the treatment of tetrachloroethene (PCE)-contaminated waters. A water electrolysis cell was placed directly in the effluent recirculation loop for the supply of both O2 and H2 to the system: H2 serving as the electron donor for both carbonate reduction into CH4 and reductive dechlorination. The concurrent presence of O2 and CH4 could be used by the methanotrophs for co-metabolically oxidising the chlorinated intermediates left over by the anaerobic transformation of PCE. At a PCE inlet of 33-52 microM and a hydraulic residence time (HRT) of 5.6 days, PCE reductive dechlorination to dichloroethene (DCE) was over 95% with a maximum DCE mineralisation of 83%. Fluorescence in situ hybridisation with 16S rRNA probes related to type I and type II methanotrophic bacteria were utilised to localise the methanotrophic communities in the anaerobic/aerobic granules. It evidenced that with operational time, along with increasing oxygenation rate, methanotrophic communities were specifically colonising onto the outermost layer of the anaerobic/aerobic granule.     

Group B rotavirus associated with an outbreak of neonatal lamb diarrhea

A 66-year-old woman was admitted because of postmenopausal vaginal bleeding. Diagnostic workup revealed a poorly differentiated endometrial adenocarcinoma. A total abdominal hysterectomy and bilateral salpingo-oophorectomy was carried out (FIGO stage Ia, G3). One and a half years later she developed a solitary humeral metastasis which was treated by local radiotherapy and progesterone acetate. Because osseous metastases in endometrial adenocarcinoma are rare, the literature is reviewed. In analogy to the treatment of pulmonary metastases the option of disarticulation of the patient's arm is discussed.