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.     

Impact of non‐solvent on regeneration of cellulose dissolved in 1‐(carboxymethyl)pyridinium chloride ionic liquid

Cellulose dissolved in ionic liquid (1‐(carboxymethyl)pyridinium chloride)/water (60/40 w/w) mixture is regenerated in various non‐solvents, namely water, ethanol, methanol and acetone, to gain more insight into the contribution of non‐solvent medium to the morphology of regenerated cellulose. To this end, the initial and regenerated celluloses were characterized with respect to crystallinity, thermal stability, chemical structure and surface morphology using wide‐angle X‐ray diffraction, thermogravimetric analysis, Fourier transform infrared spectroscopy and scanning electron microscopy. According to the results, regardless of non‐solvent type, all regenerated samples have the same chemical structure and lower crystallinity in comparison to the initial cellulose, making them a promising candidate for efficient biofuel production based on enzymatic hydrolysis of cellulose. The reduction in crystallinity of regenerated samples is explained based on the potential of the non‐solvent to break the hydrogen bonds between cellulose chains and ionic liquid molecules as well as the affinity of water and non‐solvent which can be evaluated based on Hansen solubility parameter. The latter also determines the phase‐separation mechanism during the regeneration process, which in turn affects surface morphology of the regenerated cellulose. The pivotal effect of regenerated cellulose crystallinity on its thermal stability is also demonstrated. Regenerated cellulose with lower crystallinity is more susceptible to molecular rearrangement during heating and hence exhibits enhanced thermal stability. © 2019 Society of Chemical Industry     

IMPACCT: Methodology and Tools for Power-Aware Embedded Systems

Power-aware systems are those that must exploit a widerange of power/performance trade-offs in order to adapt to the power availabilityand application requirements. They require the integration of many novel powermanagement techniques, ranging from voltage scaling to subsystem shutdown.However, those techniques do not always compose synergistically with eachother; in fact, they can combine subtractively and often yield counterintuitive,and sometimes incorrect, results in the context of a complete system. Thiscan become a serious problem as more of these power aware systems are beingdeployed in mission critical applications.To address the problem of technique integration for power-aware embedded systems, we propose a new design tool framework called IMPACCT and the associated design methodology. The system modeling methodology includes application model for capturing timing/powerconstraints and mode dependencies at the system level. The tool performs power-awarescheduling and mode selection to ensure that all timing/power constraintsare satisfied and that all overhead is taken into account. IMPACCT then synthesizesthe implementation targeting a symmetric multiprocessor platform. Experimentalresults show that the increased dynamic range of power/performance settingsenabled a Mars rover to achieve significant acceleration while using lessenergy. More importantly, our tool correctly combines the state-of-the-arttechniques at the system level, thereby saving even experienced designersfrom many pitfalls of system-level power management.     

Quasi-static and dynamic crushing behaviors of aluminum and steel tubes with a cutout

Tubular members are commonly used as an energy absorber in engineering structures and many such members have a cutout. In this study, the crushing behaviors of tubes with a cutout are characterized and the effects of cutout on the energy absorption capabilities of these tubes are quantified. Systematic parametric studies were carried out to study the effect of material properties, including yield and ultimate strength of material, strain rate effect, location of cutout, tube length and impact speed on the crushing behaviors and energy absorption capacity of aluminum and steel tubes. First, a numerical model was constructed with a commercial explicit finite element code. It will be first proven that the numerical simulation can produce sufficiently accurate results in an economic manner. Subsequently, the crushing behavior of aluminum and steel tubes with a cutout was experimentally characterized and their energy absorption capacity was evaluated in terms of mean crushing force, peak crushing force and specific energy absorption (SEA). Tubes of various lengths with a cutout located at different locations, subject to both quasi-static and dynamic impact loadings were considered. For steel tubes, the numerical simulation investigated the influence of the strain rate effect and variation in strain hardening ratio of the material. Empirical equations describing the mean and peak crushing forces of aluminum and steel tubes with a cutout were developed using linear and nonlinear regression methods applied to the results obtained from the numerical and experimental studies.     

The renal and hepatic distribution of Bence Jones proteins depends on glycosylation: a scintigraphic study in rats

The aim of the present study was to evaluate renal and liver distribution of two monoclonal immunoglobulin light chains. The chains were purified individually from the urine of patients with multiple myeloma and characterized as lambda light chains with a molecular mass of 28 kDa. They were named BJg (high amount of galactose residues exposed) and BJs (sialic acid residues exposed) on the basis of carbohydrate content. A scintigraphic study was performed on male Wistar rats weighing 250 g for 60 min after i.v. administration of 1 mg of each protein (7.4 MBq), as the intact proteins and also after carbohydrate oxidation. Images were obtained with a Siemens gamma camera with a high-resolution collimator and processed with a MicroDelta system. Hepatic and renal distribution were established and are reported as percent of injected dose. Liver uptake of BJg was significantly higher than liver uptake of BJs (94.3 vs 81.4%) (P < 0.05). This contributed to its greater removal from the intravascular compartment, and consequently lower kidney accumulation of BJg in comparison to BJs (5.7 vs 18.6%) (P < 0.05). After carbohydrate oxidation, there was a decrease in hepatic accumulation of both proteins and consequently a higher renal overload. The tissue distribution of periodate-treated BJg was similar to that of native BJs: 82.7 vs 81.4% in the liver and 17.3 vs 18.6% in the kidneys. These observations indicate the important role of sugar residues of Bence Jones proteins for their recognition by specific membrane receptors, which leads to differential tissue accumulation and possible toxicity.     

Real-time processing and compression of DNA microarray images.

In this paper, we present a pipeline architecture specifically designed to process and compress DNA microarray images. Many of the pixilated image generation methods produce one row of the image at a time. This property is fully exploited by the proposed pipeline that takes in one row of the produced image at each clock pulse and performs the necessary image processing steps on it. This will remove the present need for sluggish software routines that are considered a major bottleneck in the microarray technology. Moreover, two different structures are proposed for compressing DNA microarray images. The proposed architecture is proved to be highly modular, scalable, and suited for a standard cell VLSI implementation.     

THEORETICAL STUDY OF NONUNIFORM DROPLETS CONCENTRATION DISTRIBUTION ON VENTURI SCRUBBER PERFORMANCE

A new three-dimensional dispersion model has been developed and was used to study particulate removal operations in a venturi type scrubber. The model takes into account the effect of nonuniform droplets concentration distribution on the particulate removal efficiency of the scrubber of Brink and Contant (1958). Experimental data was used to test the results of the mathematical model. The results from the model are in good agreement with the experimental data. After validating the model, it was used to predict the effect of parameters such as liquid to gas flow rate ratio, gas throat velocity, and angle of the divergent section and nozzle diameter on the extent of nonuniformity of drops. Removal efficiency will increase with increasing uniformity of droplets concentration distribution. Thus, any factor that increases removal efficiency increases uniformity and vice versa. The factors affecting uniformity are: droplet diameter, liquid jet penetration length and size of scrubber.     

Influence of thermal boundary conditions on natural convection in a square enclosure partially heated from below

Natural convection in air-filled 2D square enclosure heated with a constant source from below and cooled from above is studied numerically for a variety of thermal boundary conditions at the top and sidewalls. Simulations are performed for two kinds of lengths of the heated source, i.e., a small and a large source corresponding to 20% and 80% of the total length of the bottom wall, respectively. The Rayleigh number varied from 10³ to 10⁷. Results are presented in the form of streamline and isotherm plots as well as the variation of the Nusselt number and maximum temperature at the heat source surface. Comparisons among the different thermal configurations considered are reported.     

Bayesian estimation based on vague lifetime data

In Classical Bayesian approach, estimation of lifetime data usually is dealing with precise information. However, in real world, some informations about an underlying system might be imprecise and represented in the form of vague quantities. In these situations, we need to generalize classical methods to vague environment for studying and analyzing the systems of interest. In this paper, we propose the Bayesian estimation of failure rate and mean time to failure based on vague set theory in the case of complete and censored data sets. To employ the Bayesian approach, model parameters are assumed to be vague random variables with vague prior distributions. This approach will be used to induce the vague Bayes estimate of failure rate and mean time to failure by introducing and applying a theorem called “Resolution Identity” for vague sets. In order to evaluate the membership degrees of vague Bayesian estimate for these quantities, a computational procedure is investigated. In the proposed method, the original problem is transformed into a nonlinear programming problem which is then divided into eight subproblems to simplifying computations.