Native state kinetic stabilization as a strategy to ameliorate protein misfolding diseases: a focus on the transthyretin amyloidoses

Small molecule-mediated protein stabilization inside or outside of the cell is a promising strategy to treat protein misfolding/misassembly diseases. Herein we focus on the transthyretin (TTR) amyloidoses and demonstrate that preferential ligand binding to and stabilization of the native state over the dissociative transition state raises the kinetic barrier of dissociation (rate-limiting for amyloidogenesis), slowing and in many cases preventing TTR amyloid fibril formation. Since T119M-TTR subunit incorporation into tetramers otherwise composed of disease-associated subunits also imparts kinetic stability on the tetramer and ameliorates amyloidosis in humans, it is likely that small molecule-mediated native state kinetic stabilization will also alleviate TTR amyloidoses.     

Evaluation of activity,selectivity and stability of catalysts for naphtha reforming

A method to evaluate naphtha-reforming catalysts has been developed and the equipment and its operation is described here in detail. The octane number computed by chromatographic analysis is similar to the one derived using the motor method and is proportional to the total aromatic concentration. The aromatic concentration is a quick and easy method to evaluate catalyst activity. The liquid yield and selectivity were also measured chromatographically. The efficiencies of commercial and prepared catalysts were compared by plotting octane number vs liquid yield. The catalysts were Pt/Al₃O₃-Cl and the process variables were similar to those used in industry. The feed was n-heptane or C₆-C₈ naphtha. Accelerated deactivation tests at lower pressure and hydrogen : hydrocarbon ratios were performed to study stability in shorter times.     

Preparation and characterization of scleroglucan drug delivery films: The effect of freeze‐thaw cycling

This study examined the effect of the freeze‐thaw process on the physical properties of films prepared from scleroglucan (Scl) hydrogels, suitable for drug delivery applications. Films made from Scl, using glycerol as plasticizer, were prepared from hydrogels by two procedures: a room temperature drying (RTD) method and a freeze‐thaw cyclic process, before the application of RTD, which results in a reinforced physically cross‐linked network. Films were characterized by studies of water vapor transmission (WVT), swelling, tensile tests, ESEM microscopy, FTIR, and drug release measurements. These determinations showed significant differences between films obtained by both treatments. The films prepared through freeze‐thaw cycles showed an important increase of the tensile strength with respect to those corresponding to films only air dried and a decreasing swelling degree in direct relationship to the number of freeze‐thaw cycles. A model drug, Theophylline, was included in these biocompatible films for in vitro drug release measurements, using a flat Franz cell. The physical differences observed between Scl films prepared with both methods can be explained proposing that the number of crosslinking points by hydrogen bonding increase when increasing the number of freezing and thawing cycles used for film preparation. © 2009 Wiley Periodicals, Inc. J Appl Polym Sci, 2009     

Incremental Learning Framework for Mining Big Data Stream

At this current time, data stream classification plays a key role in big data analytics due to its enormous growth. Most of the existing classification methods used ensemble learning, which is trustworthy but these methods are not effective to face the issues of learning from imbalanced big data, it also supposes that all data are pre-classified. Another weakness of current methods is that it takes a long evaluation time when the target data stream contains a high number of features. The main objective of this research is to develop a new method for incremental learning based on the proposed ant lion fuzzy-generative adversarial network model. The proposed model is implemented in spark architecture. For each data stream, the class output is computed at slave nodes by training a generative adversarial network with the back propagation error based on fuzzy bound computation. This method overcomes the limitations of existing methods as it can classify data streams that are slightly or completely unlabeled data and providing high scalability and efficiency. The results show that the proposed model outperforms state-of-the-art performance in terms of accuracy (0.861) precision (0.9328) and minimal MSE (0.0416).     

Engineering DNA-Grafted Quatsomes as Stable Nucleic Acid-Responsive Fluorescent Nanovesicles

The development of artificial vesicles into responsive architectures capable of sensing the biological environment and simultaneously signaling the presence of a specific target molecule is a key challenge in a range of biomedical applications from drug delivery to diagnostic tools. Herein, the rational design of biomimetic DNA-grafted quatsome (QS) nanovesicles capable of translating the binding of a target molecule to amphiphilic DNA probes into an optical output is presented. QSs are synthetic lipid-based nanovesicles able to confine multiple organic dyes at the nanoscale, resulting in ultra-bright soft materials with attractiveness for sensing applications. Dye-loaded QS nanovesicles of different composition and surface charge are grafted with fluorescent amphiphilic nucleic acid-based probes to produce programmable FRET-active nanovesicles that operate as highly sensitive signal transducers. The photophysical properties of the DNA-grafted nanovesicles are characterized and the highly selective, ratiometric detection of clinically relevant microRNAs with sensitivity in the low nanomolar range are demonstrated. The potential applications of responsive QS nanovesicles for biosensing applications but also as functional nanodevices for targeted biomedical applications is envisaged.     

Modeling of complex interfaces: Gadolinium‐doped ceria in contact with yttria‐stabilized zirconia

Gadolinium‐doped ceria (GDC) and yttria‐stabilized zirconia (YSZ) are well‐known electrolyte materials in solid oxide fuel cells (SOFCs). Although they can be used independently, it is common to find them in combination in SOFCs, where they are used as protective layers against the formation of secondary phases or electron conduction blockers. Despite their different optimum operating temperatures, it appears that oxygen conduction is not affected by their interface. However, the intrinsic mechanisms of oxygen diffusion at these interfaces still remain unclear. One of the main difficulties when modeling the contact between different materials, or indeed different particles of the same material, is caused by the structural complexity of these systems. If we wish to evaluate the properties of the materials, we first need to obtain a model that includes the main features of the GDC/YSZ interface, such as large‐scale defects or cation interdiffusion in the contiguous phase. Since the generation of such a mixed system is complicated, we show here how the “amorphization and recrystallization” strategy can help us to obtain realistic systems. In this, the first of our papers on the structure and properties of layered GDC/YSZ materials, we discuss the structural features of the grain boundary between GDC and YSZ obtained by molecular dynamics simulations.     

The effect of surface silanol groups on the deposition of apatite onto silica surfaces: a computer simulation study

Computer modelling techniques were employed to investigate the effect of surface silanol groups on the strength of adhesion of apatite thin films to silica surfaces. To this end, we have studied a series of silica surfaces with different silanol densities and calculated their interaction with apatite thin films. Our findings indicate that apatite does not attach strongly to surface hydroxy groups, but that apatite should deposit at dehydrated silica surfaces, especially when the surface silicon and oxygen species rearrange to form O–Si–O links. Any dangling silicon and oxygen bonds at the silica surfaces are saturated by coordination to oxygen and calcium atoms in the apatite layer, but the extra reactivity afforded by these under-coordinated surface species does not necessarily lead to more favourable substrate/film interactions. The lowest energy silica/apatite interfaces are those where an undistorted apatite layer can be deposited on a regular, stable substrate surface. Our simulations support the suggestion, that in vivo surface hydroxy groups are first condensed to form O–Si–O bridges before deposition and growth of apatite.     

Quantifying the degree of disorder in micronized salbutamol sulfate using moisture sorption analysis

Salbutamol sulfate is often micronized for use in dry powder inhalers. Therefore, it is of high interest to quantify the amorphous amount. It was investigated whether moisture sorption is able to measure the amorphous content of salbutamol sulfate. Different mixtures of amorphous and crystalline salbutamol sulfate were analyzed by moisture sorption. The amorphous material was obtained by spray drying. The measurement results were used to plot a calibration curve, which was used to quantify the amorphous amount in micronized salbutamol sulfate.     

Comparative study between two different sources of n-3 poliunsaturated fatty acids and it effect on thymus and lipid profile in rats

In the present paper we analyzed the effect caused by different recovery diets enriched with n-3 polyunsaturated fatty acids (PUFA n-3) on thymus and serum lipid pattern. Severe depleted weanling Wistar rats (D) were divided in three groups that received during 10 days a 20% casein diet supplemented with EPA+DHA (group Cas), a 20% protein milk diet prepared using a commercial reduced-fat product enriched with linolenic and linoleic acids (group L) and a 20% casein diet as control group C. Cas and L gave each other 24 mg/day of PUFA n-3 being the ratio n-6/n-3 8.1/1 and 7.6/1, respectively. Thymus was removed and weighted and cell number were determined; blood was recollected and Total cholesterol, triacylglycerol, HDL and LDL-cholesterol fractions and myristic, palmitic, stearic, oleic, linoleic, linolenic, araquidonic, EPA and DHA fatty acid concentrations were measured in serum. Statistical analysis was performed using Anova test. Cell number were higher (p<0.01) in Cas (44.48+/-8.20) and in L (56.45+/-14.72) when compared to group D (1.80+/-0.70) and group C (23.70+/-4.04). L presented lower values of cholesterol, HDL and LDL-cholesterol (p<0.01) and higher values of triacylglycerol (p<0.05) when compared to Cas, being EPA (p<0.05) and DHA (p<0.01) higher in Cas. Being PUFA n-3 contribution the same in Cas and L, both diets were able to reverse the thymic athropy presenting a different hipolipemic behavior due to the different sources of PUFA n-3 used in the diets.     

Isobutene production from skeletal isomerization of 1-butene on WOx/ferrierite

Both potassium and ammonium ferrierite (FK and FA, respectively) were impregnated with tungsten species using either tungstic acid or ammonium metatungstate as precursors. The skeletal isomerization of 1-butene at 200–400°C, atmospheric pressure and 0.15 atm 1-butene partial pressure, was studied on samples with and without tungsten. Tungsten species on FK promote the isobutene formation while those species on FA generate a synergetic effect over the isobutene production. The presence of tungsten species improves the material stability and mainly, the isobutene yield. Starting the 1-butene feed over the catalytic bed at 200°C and then increasing the reaction temperature to 400°C, makes it possible to avoid the low isobutene selectivity at short times-on-stream. This revised version was published online in August 2006 with corrections to the Cover Date.