Discovery of selective, small-molecule inhibitors of RNA complexes--I. The Tat protein/TAR RNA complexes required for HIV-1 transcription

We have developed a therapeutic program focusing on the inhibition of a human immunodeficiency virus-1 specific protein-RNA interaction. This program begins with a search for small organic molecules that would interfere with the binding of Tat protein to TAR RNA. The methodologies chosen to study the HIV-1 Tat-TAR interaction and inhibition include gel mobility shift assays, scintillation proximity assays, filtration assays, and mass spectrometry. These methods helped establish in vitro high-throughput screening assays which rapidly identified Tat-TAR inhibitors from our corporate compound library. Tat-activated reporter gene assays were then used to investigate the cellular activities of the Tat-TAR inhibitors. The cellular activity, selectivity, and toxicity data for select Tat-TAR inhibitors were determined. Evaluation of both the cellular data and the Tat-TAR inhibition results led to further testing in anti-HIV-1 infection assays.     

The Dentin Disc surface: a plausible model for dentin physiology and dentin sensitivity evaluation

Dentin sensitivity (DS) is a painful clinical condition which may affect 8-35% of the population. Various treatment modalities have claimed success in relieving DS, although at present there does not appear to be a universally accepted desensitizing agent. Current opinion based on Br?nnstr?m's Hydrodynamic Theory would suggest that following exposure of the dentin surface (through attrition, abrasion, or erosion), the presence of open dentinal tubules, patent to the pulp, may be a prerequisite for DS. The concept of tubule occlusion as a method of dentin desensitization, therefore, is a logical conclusion from the hydrodynamic theory. The fact that many of the agents used clinically to desensitize dentin are also effective in reducing dentin permeability tends to support the hydrodynamic theory. This paper reviews the in vitro evaluation of desensitizing agents, the techniques used to characterize their effects on the prepared dentin surface, and the ability of these agents to reduce permeability through tubule occlusion, and presents recent findings from ongoing research based on the Pashley Dentin Disc model. It can be concluded that the use of this model to determine surface characteristics, and reductions in dentin permeability through tubule narrowing or occlusion, provides a useful screening method for evaluating potential desensitizing agents. Interpreting changes observed in vitro is difficult, and extrapolation to the clinical situation must be tempered with caution.     

The influences of technological conditions and Au cluster islands on morphology of Ga<Subscript>2</Subscript>O<Subscript>3</Subscript> nanowires grown by VLS method on GaAs substrate

The synthesis of semiconductor nanowires is more and more interested to the applications for building blocks of the innovative nano-sized devices and circuits, but the research and fabrication of these nanowires are also holding a number of difficulties and challenges. Among many different kinds of semiconductor nanowires, Ga₂O₃ is increasingly grown for many promising applications in nano-device production, namely nanowire LED and Laser. So far there are many synthesizing methods of semiconductor nanowires, among them the vapor–liquid–solid (VLS) method is simple, cheap and popular. However, when we use the VLS method for nanowire growth, various technological problems exist. This paper aims at investigating some influences of the growth technological conditions and Au metal catalyst on the morphology of Ga₂O₃ nanowire grown by VLS on GaAs substrate. The main considering factors include the different growing temperatures and times, the effects of Au diffusion, Au droplets formation, Au cluster islands formation, and gas volume of the growing tube/ampoule at the 10⁻¹ torr low air pressure. The obtained experimental results regarding the structural properties of nanowires under these effects investigated by scanning electron microscopy, field emission scanning electron microscopy, high angle annular dark field and bright field, scanning transmission electron microscopy, energy-dispersive X-ray techniques, and focus ion beam are presented and discussed.     

High-yield biohydrogen production from biodiesel manufacturing waste by Thermotoga neapolitana

Efficient conversion of glycerol waste from biodiesel manufacturing processes into biohydrogen by the hyperthermophilic eubacterium Thermotoga neapolitana DSM 4359 was investigated. Biohydrogen production by T. neapolitana was examined using the batch cultivation mode in culture medium containing pure glycerol or glycerol waste as the sole substrate. Pre-treated glycerol waste showed higher hydrogen (H₂) production than untreated waste. Nitrogen (N₂) sparging and pH control were successfully implemented to maintain the culture pH and to reduce H₂ partial pressure in the headspace for optimal growth rate and to enhance hydrogen production from the glycerol waste. It was found that hydrogen production increased from 1.24 ± 0.06 to 1.98 ± 0.1 mol-H₂ mol⁻¹ glycerol_consumed by optimising N₂ sparging and pH control. We observed that in medium containing 0.05 M HEPES, with three cycles of N₂ sparging, the H₂ yield increased to 2.73 ± 0.14 mol-H₂ mol⁻¹ glycerol_consumed, which was 2.22-fold higher than the non-N₂ sparged H₂ yield (1.23 ± 0.06 mol-H₂ mol⁻¹ glycerol_consumed).     

Weakly Binding Molecules-Based Fast Charging Li-Ion Batteries

Fast charging of Li-ion batteries (LIBs) beyond standard 0.3 C (charged in 3.3 h) are desperately pursued but hindered by sluggish desolvation kinetics of ethylene carbonate-based traditional electrolyte, and Li-plating and dendrites growth at graphite anode and fire hazard. Herein, a new class of weakly binding all linear molecules-based nonflammable electrolyte (WNLE) is reported, comprising 1 m LiPF₆ in ethyl methyl carbonate and 2,2,2-trifluoroethyl acetate with additives for 10–20 times faster charging LIBs than traditional ones. The critical benefits of WNLE are 44% lower viscosity, 62% higher Li⁺ diffusion coefficient, 20% higher Li⁺ transference number, and 17% lower desolvation energy, which promotes diffusion kinetics and desolvation kinetics of Li⁺ in the vicinity of graphite anode enabling dendrites-free LIB, along with nonflammability. Under 3 C (charged in 20 min), WNLE-based industrial 800 mAh graphite//LiNi_0.8Mn_0.1Co_0.1O₂ (high active mass 13 mg cm⁻²) Li-ion pouch battery achieves outstanding 700 cycles, delivering 82% capacity retention and high Coulombic efficiencies ≈100%. Robust solid electrolyte interphase layers formed at the anode and cathode mitigate interfacial failures, making fast charge to 7 C and longer cycle-life. This new class of electrolyte formulation is a promising solution and a new opportunity to realize safe and long operation of fast-charging LIBs for practical applications.     

Formation polarity dependent improved resistive switching memory characteristics using nanoscale (1.3 nm) core-shell IrOx nano-dots

ABSTRACT: Improved resistive switching memory characteristics by controlling the formation polarity in an IrOx/Al2O3/IrOx-ND/Al2O3/WOx/W structure have been investigated. High density of 1 × 1013/cm2 and small size of 1.3 nm in diameter of the IrOx nano-dots (NDs) have been observed by high-resolution transmission electron microscopy. The IrOx-NDs, Al2O3, and WOx layers are confirmed by X-ray photo-electron spectroscopy. Capacitance-voltage hysteresis characteristics show higher charge-trapping density in the IrOx-ND memory as compared to the pure Al2O3 devices. This suggests that the IrOx-ND device has more defect sites than that of the pure Al2O3 devices. Stable resistive switching characteristics under positive formation polarity on the IrOx electrode are observed, and the conducting filament is controlled by oxygen ion migration toward the Al2O3/IrOx top electrode interface. The switching mechanism is explained schematically based on our resistive switching parameters. The resistive switching random access memory (ReRAM) devices under positive formation polarity have an applicable resistance ratio of > 10 after extrapolation of 10 years data retention at 85°C and a long read endurance of 105 cycles. A large memory size of > 60 Tbit/sq in. can be realized in future for ReRAM device application. This study is not only important for improving the resistive switching memory performance but also help design other nanoscale high-density nonvolatile memory in future.     

The thermal diffusivity and conductivity of transformation-toughened solid solutions of alumina and chromia

The thermal diffusivity of a series of solid solutions of alumina and chromia transformation toughened with a dispersed phase of unstabilized zirconia was measured by means of the laser-flash method from room temperature to 1400° C. It was found, in general, that the thermal diffusivity could be decreased significantly by the combined effects of solid solution alloying, microcracking and by the presence of the low conductivity dispersed phase of zirconia. The decrease in thermal diffusivity by microcracking was found to be present in the solid solution with low chromia content which underwent extensive grain growth. The effectiveness of solid solution formation and microcracking on thermal diffusivity was found to be greatest at the lower and intermediate ranges of temperature. The decrease in the thermal diffusivity due to the zirconia inclusions was found to be effective over the total temperature range. A numerical example is presented for the thermal conductivity calculated from the thermal diffusivity multiplied by the volumetric heat capacity.     

Natural killer cell-mediated eradication of neuroblastoma metastases to bone marrow by targeted interleukin-2 therapy

Targeted interleukin-2 (IL-2) therapy with a genetically engineered antidisialoganglioside GD2 antibody-IL-2 fusion protein induced a cell-mediated antitumor response that effectively eradicated established bone marrow and liver metastases in a syngeneic model of neuroblastoma. The mechanism involved is exclusively natural killer (NK) cell-dependent, because NK-cell deficiency abrogated the antitumor effect. In contrast, the fusion protein remained completely effective in the T-cell-deficient mice or immunocompetent mice depleted of CD8+ T cells in vivo. A strong stimulation of NK-cell activity was also shown in vitro. Immunohistology of the leukocytic infiltrate of livers from treated mice revealed a strong staining for NK cells but not for CD8+ T cells. The therapeutic effect of the fusion protein was increased when combined with NK-cell-stimulating agents, such as poly I:C or recombinant mouse interferon-gamma. In conclusion, these data show that targeted delivery of cytokines to the tumor microenvironment offers a new strategy to elicit an effective cellular immune response mediated by NK cells against metastatic neuroblastoma. This therapeutic effect may have general clinical implications for the treatment of patients with minimal residual disease who suffer from T-cell suppression after high-dose chemotherapy but are not deficient in NK cells.     

On the effects of a spacecraft subcarrier unbalanced modulator

This paper presents mathematical models with associated analysis of the deleterious effects which a spacecraft's subcarrier unbalanced modulator has on the performance of a phase-modulated residual carrier communications link. The undesired spectral components produced by the phase and amplitude imbalances in the subcarrier modulator can cause (1) potential interference to the carrier tracking and (2) degradation in the telemetry bit signal-to-noise ratio (SNR). A suitable model for the unbalanced modulator is developed and the threshold levels of undesired components that fall into the carrier tracking loop are determined. The distribution of the carrier phase error caused by the additive White Gaussian noise (AWGN) and undesired component at the residual RF carrier is derived for the limiting cases. Further, this paper analyses the telemetry bit signal-to-noise ratio degradations due to undesirable spectral components as well as the carrier tracking phase error induced by phase and amplitude imbalances. Numerical results which indicate the sensitivity of the carrier tracking loop and the telemetry symbol-error rate (SER) to various parameters of the models are also provided as a tool in the design of the subcarrier balanced modulator.