Using a Fragment‐Based Approach To Target Protein–Protein Interactions

The ability to identify inhibitors of protein–protein interactions represents a major challenge in modern drug discovery and in the development of tools for chemical biology. In recent years, fragment‐based approaches have emerged as a new methodology in drug discovery; however, few examples of small molecules that are active against chemotherapeutic targets have been published. Herein, we describe the fragment‐based approach of targeting the interaction between the tumour suppressor BRCA2 and the recombination enzyme RAD51; it makes use of a screening pipeline of biophysical techniques that we expect to be more generally applicable to similar targets. Disruption of this interaction in vivo is hypothesised to give rise to cellular hypersensitivity to radiation and genotoxic drugs. We have used protein engineering to create a monomeric form of RAD51 by humanising a thermostable archaeal orthologue, RadA, and used this protein for fragment screening. The initial fragment hits were thoroughly validated biophysically by isothermal titration calorimetry (ITC) and NMR techniques and observed by X‐ray crystallography to bind in a shallow surface pocket that is occupied in the native complex by the side chain of a phenylalanine from the conserved FxxA interaction motif found in BRCA2. This represents the first report of fragments or any small molecule binding at this protein–protein interaction site.     

Modeling Oxidation of Soot Particles Within a Laminar Aerosol Flow Reactor Using Computational Fluid Dynamics

This work examines the measurement of surface specific soot oxidation rates with the High Temperature Oxidation-Tandem Differential Mobility Analyzer (HTO-TDMA) method. The Computational Fluid Dynamics package CFD-ACE⁺ is used to understand particle flow, oxidation and size dependent particle losses in the laminar aerosol flow reactor using an Eulerian-Lagrangian framework. Decrease of DMA selected mono-disperse particle size distribution due to oxidation within the aerosol tube is modeled using fitted kinetic soot oxidation parameters. The effects of Brownian diffusion and thermophoresis on particle flow and loss to the reactor walls are evaluated. The position of peak particle diameter, which is used as an indicator to determine oxidation rate, is found to be independent of diffusion, thermophoresis and secondary flow effects, thus validating its use in deriving kinetic soot oxidation parameters. Diffusion does not affect the evolution of particle size distribution within the reactor. However, thermophoresis is found to be the dominant mechanism influencing both shape of particle size distribution and particle loss to the walls of the aerosol reactor. Simulations show reduced effects of secondary recirculating flows on the particle flow trajectories in a vertical furnace as compared to horizontal furnace orientation. This work highlights the importance of making accurate measurements of temperature within the modeling domain. Since gas temperature within the flow tube could not be measured with high radial resolution using radiation shielded thermocouple, the derived soot oxidation rate may be uncertain by a factor of 2. Importantly, CFD simulations suggest that a distribution of temperature and size-dependent particle reactivities may be present in the reactor, requiring further theoretical and experimental investigation.     

Review of specialty PVC resins

World consumption of PVC was around 25 MM MT (55 billion pounds) in year 2001, second only to that of low density polyethylene. Only 10% of the PVC produced is classified as specialty PVC resins, while the other 90% is referred to as general purpose (GP) commodity resins. This paper tries to define what specialty PVC resins are, how they are produced, and their markets, applications, fabrication processes, and compounding as compared to those of GP resins.     

Antimicrobial and anticoagulation activity of silver nanoparticles synthesized from the culture supernatant of Pseudomonas aeruginosa

Here, we describe biosynthesis of silver nanoparticles by reduction of aqueous Ag⁺ ions with the culture supernatant of Pseudomonas aeruginosa. The morphological, physiological, biochemical and molecular level identification of the strain GS1 resembles P. aeruginosa. The nanoparticles synthesized by P. aeruginosa were characterized by UV–vis spectroscopy, dynamic light scattering (DLS) and scanning electron microscopy (SEM). The size-distribution of nanoparticles was determined using a particle-size analyzer and the average particle-size was found to be 80 nm. The biological activities of the synthesized silver nanoparticles like antimicrobial activity were confirmed against Escherichia coli and Staphylococcus aureus and it have stable anti-coagulant effect.     

New observations in micro-pop-in issues in nanoindentation of coarse grain alumina

The present experiments were focused on nanoindentation behaviour and the attendant “micro-pop-in” in a dense (～95% of theoretical) coarse-grain (～20 μm) alumina ceramic as a function of loading rate variations at three constant peak loads in the range of 10⁵–10⁶ μN. Based on the experimental results here we report for the first time, to the best of our knowledge, an increase in intrinsic nano scale contact resistance as well as the nanohardness with the loading rate. These observations were explained in terms of the correlation between the nanoscale plasticity and shear stress active just underneath the nanoindenter.     

Investigation of CL‐20 and RDX Nanocomposites

Nanocrystalline explosives offer a number of advantages in comparison to conventional energetics including reduced sensitivity and improved mechanical properties. In this study, formulations consisting of 90 % hexanitro‐hexaazaisowurtzitane (CL‐20) or cyclotrimethylene trinitramine (RDX) and 10 % polyvinyl alcohol (PVOH) were prepared with mean crystal sizes ranging from 200 nm to 2 μm. The process to create these materials used a combination of aqueous mechanical crystal size reduction and spray drying. The basic physical characteristics of these formulations were determined using a variety of techniques, including scanning electron microscopy, X‐ray diffraction, and Raman spectroscopy. Compressive stress‐strain tests on pressed pellets revealed that the mechanical properties of the compositions improved with decreasing crystal size, consistent with Hall‐Petch mechanics. In the most extreme case (involving CL‐20/PVOH formulations), crystal size reduction from 2 μm to 300 nm improved compressive strength and Young’s modulus by 126 % and 61 %, respectively. These results serve to highlight the relevance of structure‐property relationships in explosive compositions, and particularly elucidate the substantial benefits of reducing the high explosive crystal size to nanoscale dimensions.     

Solution of mass transfer in step growth polymerization in films with bulk in equilibrium

We have analyzed step growth polymerization in a flat film with finite mass transfer resistance. We have shown rigorously that the molecular weight distribution (MWD) at equilibrium is given by the Flory distribution, and under reaction the form of the MWD does not change if the feed is either pure monomer or in equilibrium initially. Extensive computations have shown that it is possible to split the film into growing interfacial and shrinking bulk regions. It is possible to obtain similarity transformations of concentrations of condensation product, and polymer as time invariant profiles. Based on this finding, we have determined a solution for step growth polymerization with finite mass transfer in films. The results lie within 5% of the “exact” numerical computations, for all possible variations of parameters.     

Ultra‐selective epoxidation of styrene on pure Cu{111} and the effects of Cs promotion

Styrene undergoes efficient epoxidation to styrene epoxide on the Cu{111} surface. At the optimum condition (Θ_o = 0.03 ML) ∼20% of the styrene is converted to the epoxide with almost 100% selectivity. Comparison with Ag{111} shows that the epoxidation activity and selectivity of Cu greatly exceed those of Ag. Incipient oxidation of the Cu{111} surface does not suppress the adsorption of styrene, but the oxidised metal is catalytically inert. Submonolayer amounts of Cs enhance styrene uptake and increase conversion to the epoxide without adversely affecting epoxidation selectivity. This effect is due to inhibition of Cu oxidation by Cs. Our findings are discussed in the light of current understanding of Ag‐catalysed alkene epoxidation. This revised version was published online in July 2006 with corrections to the Cover Date.     

Formation and characterization of polyurethane—vermiculite clay nanocomposite foams

Nanocomposites of rigid polyurethane foam with unmodified vermiculite clay are synthesized. The clay is dispersed either in polyol or isocyanate before blending. The viscosity of the polyol is found to increase slightly on the addition of clay up to 5 pphp (parts per hundred parts of polyol by weight). The gel time and rise time are significantly reduced by the addition of clay, indicating that the clay acts as a heterogeneous catalyst for the foaming and polymerization reactions. X‐ray diffraction and transmission electron microscopy of the polyurethane composite foams indicate that the clay is partially exfoliated in the polymer matrix. The clay is found to induce gas bubble nucleation resulting in smaller cells with a narrower size distribution in the cured foam. The closed cell content of the clay nanocomposite foams increases slightly with clay concentration. The mechanical properties are found to be the best at 2.3 wt% of clay when the clay is dispersed in the isocyanate; the compressive strength and modulus normalized to a density of 40 kg/m³ are 40% and 34% higher than the foam without clay, respectively. The thermal conductivity is found to be 10% lower than the foam without clay. POLYM. ENG. SCI., 2008. © 2008 Society of Plastics Engineers     

Structural drivers controlling sulfur solubility in alkali aluminoborosilicate glasses

If the direct feed approach to vitrify the Hanford's tank waste is implemented, the low activity waste (LAW) will comprise higher concentrations of alkali/alkaline-earth sulfates than expected under the previously proposed vitrification scheme. To ensure a minimal impact of higher sulfate concentrations on the downstream operations and overall cost of vitrification, advanced glass formulations with enhanced sulfate loadings (solubility) are needed. While, the current sulfate solubility predictive models have been successful in designing LAW glasses with sulfate loadings <2 wt.%, it will be difficult for them to design glass compositions with enhanced loadings due to our limited understanding of the fundamental science governing these processes. In this pursuit, this article unearths the underlying compositional and structural drivers controlling the sulfate solubility in model LAW glasses. It has been shown that the preferentially removes non-framework cations from the modifier sites in the silicate network, thus, leading to the polymerization in the glass network via the formation of ring-structured borosilicate units. Furthermore, though the sulfate solubility slightly decreases with increasing Li⁺/Na⁺ in the glasses, the prefers to be charge compensated by Na⁺, as it is easier for to break Na–O bonds instead of Li–O bonds.