Antisense oligonucleotide inhibition of hepatitis C virus gene expression in transformed hepatocytes

Genetic and biochemical studies have provided convincing evidence that the 5' noncoding region (5' NCR) of hepatitis C virus (HCV) is highly conserved among viral isolates worldwide and that translation of HCV is directed by an internal ribosome entry site (IRES) located within the 5' NCR. We have investigated inhibition of HCV gene expression using antisense oligonucleotides complementary to the 5' NCR, translation initiation codon, and core protein coding sequences. Oligonucleotides were evaluated for activity after treatment of a human hepatocyte cell line expressing the HCV 5' NCR, core protein coding sequences, and the majority of the envelope gene (E1). More than 50 oligonucleotides were evaluated for inhibition of HCV RNA and protein expression. Two oligonucleotides, ISIS 6095, targeted to a stem-loop structure within the 5' NCR known to be important for IRES function, and ISIS 6547, targeted to sequences spanning the AUG used for initiation of HCV polyprotein translation, were found to be the most effective at inhibiting HCV gene expression. ISIS 6095 and 6547 caused concentration-dependent reductions in HCV RNA and protein levels, with 50% inhibitory concentrations of 0.1 to 0.2 microM. Reduction of RNA levels, and subsequently protein levels, by these phosphorothioate oligonucleotides was consistent with RNase H cleavage of RNA at the site of oligonucleotide hybridization. Chemically modified HCV antisense phosphodiester oligonucleotides were designed and evaluated for inhibition of core protein expression to identify oligonucleotides and HCV target sequences that do not require RNase H activity to inhibit expression. A uniformly modified 2'-methoxyethoxy phosphodiester antisense oligonucleotide complementary to the initiator AUG reduced HCV core protein levels as effectively as phosphorothioate oligonucleotide ISIS 6095 but without reducing HCV RNA levels. Results of our studies show that HCV gene expression is reduced by antisense oligonucleotides and demonstrate that it is feasible to design antisense oligonucleotide inhibitors of translation that do not require RNase H activation. The data demonstrate that chemically modified antisense oligonucleotides can be used as tools to identify important regulatory sequences and/or structures important for efficient translation of HCV.     

Improved bioavailability and pharmacokinetics of tea polyphenols by encapsulation into gelatin nanoparticles

The authors prepared surface modified (with polyelectrolyte layers), tea polyphenols (TPP) encapsulated, gelatin nanoparticles (TPP‐GNP) and characterised them. The size of the spherical nanoparticles was ∼50 nm. Number of polyelectrolyte layers and incubation time influenced the encapsulation efficiency (EE); highest EE was noted in nanoparticles with six polyelectrolyte layers (TPP‐GNP‐6L) incubated for 4 h. TPP released from TPP‐GNP‐6L in simulated biological fluids indicated protection and controlled release of TPP due to encapsulation. Mathematical modelling indicated anomalous type as a predominant mode of TPP release. TPP‐GNP‐6L exhibited enhanced pharmacokinetics in rabbit model compared with free TPP. The area under the concentration‐time curve and mean residence time were significantly higher in TPP‐GNP‐6L compared with free TPP which provide an evidence of higher bioavailability of TPP due to encapsulation. The authors demonstrated that encapsulation of TPP into GNPs favoured slow and sustained release of TPP with improved pharmacokinetics and bioavailability thereby can prolong the action of TPP.Inspec keywords: gelatin, nanoparticles, encapsulation, biomedical materials, nanomedicine, particle size, polymer electrolytes, polymer films, nanofabricationOther keywords: bioavailability, pharmacokinetics, gelatin nanoparticles, surface modified tea polyphenols, polyelectrolyte layers, spherical nanoparticle size, incubation time, encapsulation efficiency, TPP‐GNP‐6L, simulated biological fluids, mathematical modelling, TPP release, rabbit model, concentration‐time curve, mean residence time, time 4 h     

Predicting performance in ASEAN banks: an integrated fuzzy MCDM–neural network approach

This paper presents a performance assessment of 88 Association of Southeast Asian Nations banks from 2010 to 2013, using an integrated three‐stage approach on financial criteria that emulates the CAMELS rating system. More precisely, fuzzy analytic hierarchy process is used first to assess the relative weights of a number of criteria related to capital adequacy (C), asset quality (A), management quality (M), earnings (E), liquidity (L), and sensitivity to market risk (S) based on the opinion of 88 Association of Southeast Asian Nations experts. Then, these weights are used as technique for order of preference by similarity to ideal solution inputs to assess their relative efficiency. Lastly, neural networks are combined with technique for order of preference by similarity to ideal solution results to produce a model for banking performance with effective predictive ability. The results reveal that contextual variables have a prominent impact on efficiency. Specifically, parsimony in equity leveraging derived from Islamic finance principles may be the underlying cause in explaining higher efficiency levels.     

冷加工和时效处理顺序对6061铝合金力学性能的影响(英文)

研究不同的析出硬化和冷加工组合对6061铝合金拉伸性能的影响。结果表明,在不同的热处理过程中,在180℃单时效4h能提高合金的强度和伸长率。然而,双时效处理不能改善其力学性能。另外,预时效对随后的析出硬化有负面影响。合金力学性能的变化归因于析出硬化、应变硬化和加工软化的竞争而引起的显微组织演变。     

Applying a normalized ratio scale technique to assess influences of urban expansion on land surface temperature of the semi-arid city of Erbil

The difference between surface and air temperature within a city and its surrounding area is a result of variations in surface cover, thermal capacity, and 3-dimensional geometry. This research has examined and quantified the decreasing daytime land surface temperature (LST) in Erbil, Kurdistan region of Iraq, and the influence of rapid urban expansion on urban heat/cool island effect over a 20 year period. Land-use/land-cover change across this time period is also established using pixel samples. The current study proposes the application of the normalized ratio scale (NRS) to adjust the temperature of images acquired at different dates to the same range. Eleven satellite images acquired by Landsat 4, 5, 7, and 8 during the period 1992–2013 are used to retrieve LST. The results indicate that 55.3 km² of city land cover changed from bare soil to urban; consequently, the mean LST of the new urbanized area decreased by 2.28°C. The normalized difference vegetation index (NDVI) of Sami Abdul-Rahman (S.A.) Park increased from 0.09 ± 0.01 to 0.32 ± 0.11, resulting in a decrease of the mean LST by 7.29°C. This study shows that the NRS method is appropriate for detecting temperature trends from urbanization using remote-sensing data. It also highlights that urban expansion may lead to a decrease in daytime LST in drylands.     

Fabrication of Mn–ZnO photoanodes for photoelectrochemical water splitting applications

Journal of Materials Science: Materials in Electronics - A photoelectrochemical (PEC) water splitting ability of pure ZnO and manganese-incorporated ZnO thin films fabricated via a simple...     

Systematic multiscale models to predict the compressive strength of self-compacting concretes modified with nanosilica at different curing ages

The evolution of nanotechnology brings materials with novel performance and during last year’s much attempt has been established to include nanoparticles especially nano-silica (NS) into the concrete to improve performance and develop concrete with enhanced characteristics. Generally, NS is incorporated into the self-compacting concrete (SCC) aiming to positively influence the fresh, mechanical, microstructure, and durability properties of the composite. The most important mechanical property for all types of concrete composites is compressive strength. Therefore, developing reliable models for predicting the compressive strength of SCC is crucial regarding saving time, energy, and cost-effectiveness. Moreover, it gives valuable information for scheduling the construction work and provides information about the correct time for removing the formwork. In this study, three different models including the linear relationship model (LR), nonlinear model (NLR), and multi-logistic model (MLR) were proposed to predict the compressive strength of SCC mixtures made with or without NS. In this regard, a comprehensive data set that consists of 450 samples were collected and analyzed to develop the models. In the modeling process, the most important variables affecting the compressive strength such as NS content, cement content, water to binder ratio, curing time from 1 to 180 days, superplasticizer content, fine aggregate content, and coarse aggregate content were considered as input variables. Various statistical assessments such as Root Mean Squared Error (RMSE), Mean Absolute Error (MAE), Scatter Index (SI), OBJ value, and the coefficient of determination (R²) were used to evaluate the performance of the proposed models. The results indicated that the MLR model performed better for forecasting the compression strength of SCC mixtures modified with NS compared to other models. The SI and OBJ values of the MLR model were 18.8% and 16.7% lower than the NLR model, indicating the superior performance of the MLR model. Moreover, the sensitivity analysis demonstrated that the curing time is the most affecting variable for forecasting the compressive strength of SCC modified with NS.

     

Pre-aging time dependence of microstructure and mechanical properties in nanostructured Al-2wt%Cu alloy

This work is focused on the effect of pre-aging time on the properties of Al-2wt%Cu alloy processed by accumulative roll bonding (ARB) process. Following aged at 190 °C for 10 or 30 min, the samples were deformed up to a strain of 4.8 by the ARB process. The microstructure evolution was investigated by transmission electron microscope and electron backscattering diffraction analyzes. The results showed that the Al₂Cu precipitates were formed with different sizes due to the different pre-aging times and the finer precipitates were more effective on the formation of high angle grain boundaries during the ARB process. The grain size of Aged-10 min and Aged-30 min specimens decreased to 400 nm and 420 nm, respectively, after 6 cycles of the ARB process. Also, the final texture after 6 cycles of the ARB process, shown in the {111} pole figure, were different depending on the starting microstructures. The mechanical properties of specimens were investigated by the Vickers microhardness measurements and the tensile tests. The results showed that the mechanical properties are affected by the starting microstructure. The mechanical properties of Aged-10 min specimen were different compared to Aged-30 min specimen due to the different size of the pre-existing precipitates. Although by continuing process, the precipitates were probably dissolved due to the heavy deformation.     

Spray drying of drug-swellable dispersant suspensions for preparation of fast-dissolving,high drug-loaded,surfactant-free nanocomposites

Bioavailability of a poorly soluble drug can be improved by preparing a drug nanosuspension and subsequently drying it into nanocomposite microparticles (NCMPs). Unfortunately, drug nanoparticles aggregate during milling and drying, causing incomplete recovery and slow dissolution. The aim of this study is to investigate the impact of various classes of dispersants on drug dissolution from drug NCMPs, with the ultimate goal of enhancing the bioavailability of poorly water-soluble drugs via high drug nanoparticle loaded, surfactant-free NCMPs. Precursor suspensions of griseofulvin (GF, model drug) nanoparticles in the presence of various dispersants were prepared via wet stirred media milling and spray dried to form the NCMPs. Hydroxypropyl cellulose (HPC, polymer) alone and with sodium dodecyl sulfate (SDS, surfactant) was used as a base-line stabilizer/dispersant during milling. Two swellable crosslinked polymers, croscarmellose sodium (CCS) and sodium starch glycolate (SSG), and a conventional soluble matrix former, Mannitol, were used in addition to HPC. Besides being used as-received, CCS was also wet co-milled with GF for two different durations to examine the impact of CCS particle size. Laser diffraction, scanning electron microscopy, powder X-ray diffraction (XRD), UV spectroscopy, NCMP redispersion and dissolution tests were used for characterization. The results show that incorporation of CCS/SSG, preferably wet-milled to a wide particle size distribution, into the spray-dried NCMPs resulted in fast release and dispersion of drug nanoparticle clusters. The swellable dispersants were superior to Mannitol in dissolution enhancement, and could achieve fast release comparable to SDS, demonstrating the feasibility of spray drying to prepare high drug-loaded, surfactant-free nanocomposites.