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.     

Some scientist-practitioners do.

Comments on the argument of L. T. Hoshmand and D. E. Polkinghorn (see record 1992-21300-001) that psychological practice should inform science to the same degree that science informs practice. Based on a survey of 121 faculty members in programs accredited by the American Psychological Association, 65% reported practice activity. The authors agree that the problem involves a much more complex integrative task that goes beyond simply recognizing knowledge gained in practice settings as valid. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

On the Consistency of the Normalized Eight-Point Algorithm

A recently proposed argument to explain the improved performance of the eight-point algorithm that results from using normalized data (Chojnacki, W., et al. in IEEE Trans. Pattern Anal. Mach. Intell. 25(9):1172–1177, 2003) relies upon adoption of a certain model for statistical data distribution. Under this model, the cost function that underlies the algorithm operating on the normalized data is statistically more advantageous than the cost function that underpins the algorithm using unnormalized data. Here we extend this explanation by introducing a more refined, structured model for data distribution. Under the extended model, the normalized eight-point algorithm turns out to be approximately consistent in a statistical sense. The proposed extension provides a link between the existing statistical rationalization of the normalized eight-point algorithm and the approach of Mühlich and Mester for enhancing total least squares estimation methods via equilibration. The paper forms part of a wider effort to rationalize and interrelate foundational methods in vision parameter estimation.     

Microfabricated Lamb wave device based on PZT sol-gel thin film formechanical transport of solid particles and liquids

The fabrication using silicon micromachining and characterization of an acoustic Lamb wave actuator is presented. The intended use of the device is for mass transport and sensor applications. The device consists of dual interdigitated transducers patterned on a thin-film composite membrane of silicon nitride, platinum, and a sol-gel-derived piezoelectric ceramic (PZT) thin film. The acoustic properties of the device are presented along with preliminary applications to mechanical transport and liquid delivery systems. Improved acoustic signals and improved mass transport are achieved with PZT over present Lamb wave devices utilizing ZnO or AlN as the piezoelectric transducer     

Early intervention for spelling problems: Teaching functional spelling units of varying size with a multiple-connections framework.

Poor spellers in 2nd grade (n?=?128) participated in 24 20-min sessions that included (a) direct instruction in the alphabet principle (most frequent phoneme-spelling connections); (b) modeling of different approaches, singly and in combination, for developing connections between spoken and written words for 48 words ordered by sound-spelling predictability; and (c) practice in composing. Results of this multilayered intervention showed that (a) more than 1 way of developing sound-spelling connections is effective in teaching spelling but that after training in the alphabet principle, combining whole word and onset-rime training is most effective in achieving transfer of the alphabet principle across word contexts; (b) functional spelling units of not only a single letter but also 2 or more letters are important in beginning spelling; and (c) training in spelling transfers to composition and word recognition. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Reaction steady states and stationary states in modelling semi-batch enzyme hydrolysis

Dimensionless material balance equations describing an uninhibited enzyme hydrolysis process in a semi-batch reactor (i.e. fed-batch reactor) are formulated; numerical solution of these equations provided concentration profiles of the enzyme-substrate complex by using published kinetic parameters. The unrestricted values obtained are compared with estimates based separately on the reaction steady state and stationary state assumptions. Results are discussed in terms of the enzyme/substrate inventory used and it is found that the reaction steady state is a satisfactory approximation only when this ratio is sufficiently small. The stationary state may be a better approximation at other values, particularly when enzyme is added to substrate or when an empty tank is being filled. Reaction yields from semi-batch and batch operations are compared. Processing takes longer in the semi-batch operations and complete conversions are only practical in this mode when enzyme is added to substrate.     

Impossible and ambiguous shading patterns

A smooth object depicted in a monochrome image will often exhibit brightness variation, or shading. A problem much studied in computer vision has been that of how object shape may be recovered from image shading. When the imaging conditions are such that an overhead point-source illuminates a smooth Lambertian surface, the problem may be formulated as that of finding a solution to an eikonal equation. This article will focus on the existence and uniqueness of such solutions, reporting recent results obtained. With regard to existence, shading patterns are exhibited for which there is no corresponding object shape. Specifically, a necessary and sufficient condition is presented for a circularly symmetric eikonal equation to admit exclusively unbounded solutions; additionally, a sufficient condition is given for an eikonal equation to have no solution whatsoever. In connection with uniqueness, we consider eikonal equations, defined over a disc, such that the Euclidean norm of the gradient of any solution is circularly symmetric, vanishes exactly at the disc center, and diverges to infinity as the circumference of the disc is approached. Contrary to earlier influential work, a class of such eikonal equations is shown to possess simultaneously circularly symmetric and noncircularly symmetric bounded smooth solutions.     

Validation of a specific selection criterion for dental periapical radiography

We report three children with hemidystonia in whom anti-cardiolipin (aCL) antibodies were demonstrated. Systemic lupus erythematosus was excluded on the basis of both clinical and serological criteria, and the diagnosis of primary antiphospholipid syndrome (PAPS) was made. In two cases, aCL antibodies could be causally related to a presumed immune-mediated thrombotic event involving the basal ganglia as shown by magnetic resonance imaging (MRI). In the remaining patient the finding of white matter alteration on NMR might be due to cross-reactivity of anti-phospholipid (aPL) antibodies with cerebral phospholipids, resulting in demyelination. We suggest that PAPS must always be considered when isolated or recurrent focal cerebral ischaemia, and particularly hemidystonia, occur in childhood.