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.     

Detecting and characterising returns in a pulsed ladar system

A new multi-spectral laser radar (ladar) system based on the time-correlated single photon counting, time-of-flight technique has been designed to detect and characterise distributed targets at ranges of several kilometres. The system uses six separated laser channels in the visible and near infrared part of the electromagnetic spectrum. The authors present a method to detect the numbers, positions, heights and shape parameters of returns from this system, used for range profiling and target classification. The algorithm has two principal stages: non-parametric bump hunting based on an analysis of the smoothed derivatives of the photon count histogram in scale space, and maximum likelihood estimation using Poisson statistics. The approach is demonstrated on simulated and real data from a multi-spectral ladar system, showing that the return parameters can be estimated to a high degree of accuracy.     

Radical entry mechanisms in redox-initiated emulsion polymerizations

The mechanisms and kinetics of radical entry in emulsion polymerizations utilizing redox initiation are investigated using polymerization rate data obtained by reaction calorimetry and electrospray mass spectroscopy analysis of initiator-derived aqueous-phase products. These data have been used to evaluate an initiation scheme for redox-initiated emulsion polymerizations of common monomers such as styrene and methyl methacrylate based around the oxidant, tert-butyl hydroperoxide. Redox initiators are broadly classed by the solubility of their radical products: Hydrophilic radicals enter by propagating to a critical degree of polymerization to become surface-active whilst more hydrophobic radicals may enter particles directly. When direct entry is applicable (the hydrophobic case), initiation efficiency will always be very high.     

Characterization and use of an optical fiber interferometer for measurement of the electric wind

An optical fiber interferometer of the Mach-Zehnder type has proved to be a convenient and accurate method for measuring the electric wind in the active region of a corona discharge. The technique relies on the cooling effect of the wind on a small heated region of one arm of the interferometer, which has been remotely heated with an infrared CO(2) laser beam. Wind speeds of up to 5.5 m s(-1) have been measured near the generation region, and by the use of a mesh electrode, the wind has been detected on the axis up to 0.5 m away from the gap. A number of characterization experiments that show the interferometer to be a useful diagnostic tool in the quantitative analysis of the CO(2) laser beam have also been carried out, and good agreement between experimental results and theoretical calculations based on a simple heat-power balance equation for the fiber exists.     

Functional and metabolic evaluation of the hypertrophied heart using MRI and31P-MRS

4. Conclusions Diastolic LV function and myocardial HEP metabolism are impaired only when LVH is caused by permanent pressure or volume overload, and not by a temporary increase in cardiac workload during part of the day as in elite athletes. Therefore, training-induced and pressure/volume-overload-induced LVH seem to represent different phenotypes of LVH, possibly related to genetic reprogramming which only occurs during permanent cardiac overload [17]. Moreover, there is an association between impaired LV diastolic function and altered myocardial HEP metabolism in patients with hypertension and in patients with aortic valve disease. Finally we did not find a correlation between myocardial HEP metabolism and LV mass in any of the groups studied. The latter indicates that LVH should be regarded as an epiphenomenon to cardiac overload, and not as a primary factor causing abnormal HEP metabolism.     

Reliability-based design optimization with confidence level under input model uncertainty due to limited test data

For obtaining a correct reliability-based optimum design, the input statistical model, which includes marginal and joint distributions of input random variables, needs to be accurately estimated. However, in most engineering applications, only limited data on input variables are available due to expensive testing costs. The input statistical model estimated from the insufficient data will be inaccurate, which leads to an unreliable optimum design. In this paper, reliability-based design optimization (RBDO) with the confidence level for input normal random variables is proposed to offset the inaccurate estimation of the input statistical model by using adjusted standard deviation and correlation coefficient that include the effect of inaccurate estimation of mean, standard deviation, and correlation coefficient.     

Multi-spectral fusion for surveillance systems

Surveillance systems such as object tracking and abandoned object detection systems typically rely on a single modality of colour video for their input. These systems work well in controlled conditions but often fail when low lighting, shadowing, smoke, dust or unstable backgrounds are present, or when the objects of interest are a similar colour to the background. Thermal images are not affected by lighting changes or shadowing, and are not overtly affected by smoke, dust or unstable backgrounds. However, thermal images lack colour information which makes distinguishing between different people or objects of interest within the same scene difficult.By using modalities from both the visible and thermal infrared spectra, we are able to obtain more information from a scene and overcome the problems associated with using either modality individually. We evaluate four approaches for fusing visual and thermal images for use in a person tracking system (two early fusion methods, one mid fusion and one late fusion method), in order to determine the most appropriate method for fusing multiple modalities. We also evaluate two of these approaches for use in abandoned object detection, and propose an abandoned object detection routine that utilises multiple modalities. To aid in the tracking and fusion of the modalities we propose a modified condensation filter that can dynamically change the particle count and features used according to the needs of the system.We compare tracking and abandoned object detection performance for the proposed fusion schemes and the visual and thermal domains on their own. Testing is conducted using the OTCBVS database to evaluate object tracking, and data captured in-house to evaluate the abandoned object detection. Our results show that significant improvement can be achieved, and that a middle fusion scheme is most effective.     

Evidence for transient composition variations at GaAs/Ga1−xAlxAs heterostructure interfaces prepared by metal-organic chemical vapour deposition

The composition profiles of GaAs/Ga_1?xAl_xAs heterostructures prepared in two different Metal-Organic Chemical Vapour Deposition (MOCVD) reactors have been studied. Transmission electron microscopy (TEM). and Auger and secondary ion mass spectrometry (SIMS) sputter profiling results are in good agreement and interface widths below 20 å have been achieved. Significant new results on transient phenomena have been obtained. showing that large and sometimes very sharp excursions in composition can be associated with valve switching actions. Direct evidence is presented that gas pressure or flow transients can occur during valve operations. and it is suggested that such instabilities are the cause of the effects observed.     

The development of sibling relationships in infancy: a short-term longitudinal study

24 infants and their preschool-aged siblings were observed in a laboratory playroom in the presence of their parents. Observations took place when the infants were 12 months old and again 6 months later. Analysis of the social behavior revealed that, at both ages, the children assumed differentiable roles in their interactions: The infants "followed" by observing and imitating while the preschoolers "led" by drawing the infants' attention and by assertive dominance. Over time, infants became increasingly willing to direct social behaviors toward their siblings. There was remarkable behavioral stability across time, with the infants' early propensities seemingly causally related to later pre-schoolers' behavior. Older girls directed more social behaviors to siblings than boys did. The amount of parent-directed behavior was affected by the number of adults present, whereas the amount of sibling-directed behavior was unaffected.