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.     

Simultaneous optimisation of multiple performance characteristics in micro-EDM drilling of titanium alloy

Micro-electrical discharge machining (micro-EDM) has become a widely accepted non-traditional material removal process for machining conductive and difficult-to-cut materials effectively and economically. Being a difficult-to-cut material, titanium alloy suffers poor machinability for most cutting processes, especially the drilling of micro-holes using traditional machining methods. Although EDM is suitable for machining titanium alloys, selection of machining parameters for higher machining rate and accuracy is a challenging task in machining micro-holes. In this study, an attempt has been made for simultaneous optimization of the process performances like, metal removal rate, tool wear rate and overcut based on Taguchi methodology. Thus, the optimal micro-EDM process parameter settings have been found out for a set of desired performances. The process parameters considered in the study were pulse-on time, frequency, voltage and current while tungsten carbide electrode was used as a tool. Verification experiments have been carried out and the results have been provided to illustrate the effectiveness of this approach.     

Weighted label propagation based on Local Edge Betweenness

The Journal of Supercomputing - In complex networks, especially social networks, networks could be divided into disjoint partitions. However, nodes could be partitioned such that the number of...     

An accurate model for the DC-side voltage control of the neutral point diode clamped converter

This paper presents an in depth analysis to show that the conventional power balance model for the dc-side control of the Neutral Point Diode Clamped (NPC) converter is not adequately accurate for all operating conditions. The inaccuracy is due to the fact that the instantaneous power of the ac-side inductors is assumed to be negligible in the power balance equation. This paper shows that this assumption obscures (i) the impact of operating point which is a direct consequence of the inherent nonlinear nature of the problem and (ii) the nonminimum-phase property of the plant in the rectifying mode of operation. Thus, the conventional dc-side control model may lead to unsatisfactory performance or even instability. To overcome the shortcoming, this paper also develops accurate nonlinear and linearized models for the dc-side controller design, including the impact of the ac-side interface reactors. The analytical results and the conclusions are validated by digital time-domain simulation of a study system in the PSCAD/EMTDC environment. The mathematical developments and conclusions of the paper are equally applicable to the conventional two-level VSC.     

Synthesis of BaZrO3 by a solid-state reaction technique using nitrate precursors

High phase purity barium metazirconate powders have been synthesized from a modified solid-state reaction. Reactive powders consisting of submicron particles and narrow particle size distribution were obtained by heating a 1:1 molar mixture of barium nitrate and zirconyl nitrate at 800°C up to 8 h. Simultaneous thermal analysis (TG-DTA) assisted in elucidating the probable reaction pathways leading to the formation of the target compound in the BaO-ZrO₂ system. Systematic structural and microstructural characterization on the green powders and the compacts sintered up to 1700°C were carried out. A two-stage sintering schedule consisting of a 6 h soak at 1600°C followed by slow heating up to 1700°C with no dwell, led to highly dense microstructural features.     

Compatibilizers based on polypropylene grafted with itaconic acid derivatives. Effect on polypropylene/polyethylene terephthalate blends

New types of compatibilizers based on functionalized polypropylene (PP) were synthesized by radical melt grafting either with monomethyl itaconate or dimethyl itaconate. The effect of these new modified PP compounds were tested as compatibilizers in PP/polyethylene terephthalate (PET) blends. Blends with compositions 15/85 and 30/70 by weight of PP and PET were prepared in a single‐screw extruder. Morphology of the compatibilized blends revealed a very fine and uniform dispersion of the PP phase as compared with that of noncompatibilized blends of the same composition, leading to improved adhesion between the two phases. Whereas dimethyl itaconate derived agent showed less activity, the monomethyl itaconate parent compound showed an increase of the impact resistance of PET in PP/PET blend. This was attributed to the hydrophilic nature of the monomethyl itaconate part of this compatibilizer. The tensile strength of PET in noncompatibilized blends gradually decreases as the PP content increases, while blends containing functionalized PP exhibited higher values.     

RNA secondary structured logic gates for profiling the microRNA cancer biomarkers

Deregulation of microRNAs expression is symptomatic of cancer disease and occurs before the awareness of cancer signs. Early detection of cancer disease can improve or drop the disease entirely. DNA computing is an emerging field of detecting microRNAs based on toehold‐mediated strand displacement reactions, which is a more efficient method than the commonly used method like real‐time PCR. Accuracy and cost of diagnostic applications are essential criteria that are achieved by using the DNA logic gates based on the DNA computing method. In this study, the authors proposed the multi‐input liver cancer biosensor with the RNA secondary structure motifs as the computational module and two approaches are suggested.Inspec keywords: cancer, biocomputing, biochemistry, DNA, RNA, biosensors, logic gates, liver, macromolecules, genetics, molecular biophysics, diseasesOther keywords: RNA secondary structured logic gates, microRNA cancer biomarkers, microRNAs expression, cancer disease, cancer signs, detecting microRNAs, toehold‐mediated strand displacement reactions, DNA logic gates, DNA computing method, multiinput liver cancer biosensor, RNA secondary structure motifs     

Simulation and exergy‐method analysis of an industrial refrigeration cycle used in NGL recovery units

The behaviour of an industrial refrigeration cycle with refrigerant propane has been investigated by the exergy method. An natural gas liquid recovery unit with its refrigeration cycle has been simulated to prepare the exergy analysis. Using a typical actual work input value; the exergetic efficiency of the refrigeration cycle is determined to be 26.51% indicating a great potential for improvements. The obtained simulation results reveal that the exergetic efficiencies of the air cooler(s) and chilling sections get the lowest rank among the other compartments of refrigeration cycle. Refrigeration calculations have been carried out through the analysis of T–S and P–H diagrams where coefficient of performance (COP) was obtained as 1.8. The novelty of this article include the suggestions for increasing efficiencies, along with the discussion about the reasons for deviation from ideal cycles and also the effect and sensitivity analysis of pressure drops on the coefficient of performance of the cycle. Copyright © 2006 John Wiley & Sons, Ltd.     

Novel Structural Modulation in Ceramic Sensors Via Redox Processing in Gas Buffers

High selectivity, enhanced sensitivity, short response time, and long shelf-life are some of the key features sought in the solid-state ceramic-based chemical sensors. As the sensing mechanism and catalytic activity are predominantly surface-dominated, benign surface features in terms of small grain size, large surface area, high aspect ratio and, open and connected porosity, are required to realize a successful material. In order to incorporate these morphological features, a technique based on rigorous thermodynamic consideration of the metal/metal oxide coexistence is described. By modulating the oxygen partial pressure across the equilibrium M/MO proximity line, formation and growth of new oxide surface on an atomic/submolecular level under conditions of "oxygen deprivation," with exotic morphological features, has been achieved in potential sensor materials. This paper describes the methodology and discusses the results obtained in the case of potential semiconducting ceramic oxide-based carbon monoxide and hydrogen sensors with enhanced characteristics.