Direct evidence for cation non-stoichiometry and Cottrell atmospheres around dislocation cores in functional oxide interfaces

Long-range strain fields associated with dislocation cores at an oxide interface are shown to be sufficient enough to create significant variations in the chemical composition around the core (Cottrell atmospheres). Such stress-assisted diffusion of cations towards the cores is proposed to significantly impact the properties of nanoscale functional devices. The figure shows a Z-contrast image of a single dislocation core at an oxide interface.

Influence of the cation on the solubility of CO2 and H 2 in ionic liquids based on the bis(trifluoromethylsulfonyl)imide anion

Experimental values for the solubility of carbon dioxide and hydrogen in three room temperature ionic liquids based on the same anion- (bistrifluoromethylsulfonyl)imide [Ntf2]-and three different cations-1-butyl-3-methylimidazolium, [C4mim], 1-ethyl-3- methylimidazolium, [C2mim] and trimethyl-butylammonium, [N 4111]-are reported between 283 and 343 K and close to atmospheric pressure. Carbon dioxide, with a mole-fraction solubility of the order of 10-2, is two orders of magnitude more soluble than hydrogen. The solubility of CO2 is very similar in the three ionic liquids although slightly lower in the presence of the [C2mim] cation. In the case of H2, noticeable differences were observed with larger mole fraction solubilities in the presence of [N4111] followed by [C 4mim]. All of the mole-fraction solubilities decrease with increasing temperature. From the variation of Henry's law constants with temperature, the thermodynamic functions of solvation were calculated. The precision of the experimental data, considered as the average absolute deviation of the Henry's law constants from appropriate smoothing equations, is always better than ±1%. © Springer Science+Business Media, LLC 2007.

Binding site of AMPA-receptor allosteric modulator

The computer molecular docking of piperonyl acid piperidide (BDP) and some its analogs already known as ampakins was conducted for estimating their possible binding with AMPA-receptor glutamate domains in cyclothiazide binding area and for further design of new structures maximally complimentary to the receptor. On the base of the conducted docking it can be suggested that the binding site of BDP (amides of benzodioxane-6-carboxylic and piperonyl acids) analogs is located in AMPA-receptor cyclothiazide binding pocket. It is shown that formation of protein-ligand complexes of AMPA-receptor with benzodioxane-6-carboxylic and piperonyl acid derivatives, similarly to cyclothiazide, proceeds with interaction with Ser497, Leu751, which significance is confirmed by site-specific mutagenesis.

CoMFA and homology-based models of the glycine binding site of N-methyl-D-aspartate receptor

Homology modeling was used to build 3D models of the N-methyl-D-aspartate (NMDA) receptor glycine binding site on the basis of an X-ray structure of the water-soluble AMPA-sensitive receptor. The docking of agonists and antagonists to these models was used to reveal binding modes of ligands and to explain known structure-activity relationships. Two types of quantitative models, 3D-QSAR/CoMFA and a regression model based on docking energies, were built for antagonists (derivatives of 4-hydroxy-2-quinolone, quinoxaline-2,3-dione, and related compounds). The CoMFA steric and electrostatic maps were superimposed on the homology-based model, and a close correspondence was marked. The derived computational models have permitted the evaluation of the structural features crucial for high glycine binding site affinity and are important for the design of new ligands.

Structural basis for understanding structure-activity relationships for the glutamate binding site of the NMDA receptor

We present new homology-based models of the glutamate binding site (in closed and open forms) of the NMDA receptor NR2B subunit derived from X-ray structures of the water soluble AMPA sensitive glutamate receptor. The models were used for revealing binding modes of agonists and competitive antagonists, as well as for rationalizing known experimental facts concerning structure-activity relationships: (i) the switching between the agonist and the antagonist modes of action upon lengthening the chain between the distal acidic group and the amino acid moiety, (ii) the preference for the methyl group attached to the a-amino group of ligands, (iii) the preference for the D-configuration of agonists and antagonists, and (iv) the existence of "superacidic" agonists.

Identification of Galanin and Its Receptor GalR1 as Novel Determinants of Resistance to Chemotherapy and Potential Biomarkers in Colorectal Cancer

Purpose: A major factor limiting the effective clinical management of colorectal cancer (CRC) is resistance to chemotherapy. Therefore, the identification of novel, therapeutically targetable mediators of resistance is vital.Experimental design: We used a CRC disease-focused microarray platform to transcriptionally profile chemotherapy-responsive and nonresponsive pretreatment metastatic CRC liver biopsies and in vitro samples, both sensitive and resistant to clinically relevant chemotherapeutic drugs (5-FU and oxaliplatin). Pathway and gene set enrichment analyses identified candidate genes within key pathways mediating drug resistance. Functional RNAi screening identified regulators of drug resistance.

Results: Mitogen-activated protein kinase signaling, focal adhesion, cell cycle, insulin signaling, and apoptosis were identified as key pathways involved in mediating drug resistance. The G-protein-coupled receptor galanin receptor 1 (GalR1) was identified as a novel regulator of drug resistance. Notably, silencing either GalR1 or its ligand galanin induced apoptosis in drug-sensitive and resistant cell lines and synergistically enhanced the effects of chemotherapy. Mechanistically, GalR1/galanin silencing resulted in downregulation of the endogenous caspase-8 inhibitor FLIP(L), resulting in induction of caspase-8-dependent apoptosis. Galanin mRNA was found to be overexpressed in colorectal tumors, and importantly, high galanin expression correlated with poor disease-free survival of patients with early-stage CRC.

Conclusion: This study shows the power of systems biology approaches to identify key pathways and genes that are functionally involved in mediating chemotherapy resistance. Moreover, we have identified a novel role for the GalR1/galanin receptor-ligand axis in chemoresistance, providing evidence to support its further evaluation as a potential therapeutic target and biomarker in CRC. Clin Cancer Res; 18(19); 5412–26. © 2012 AACR.

Improving multi-site benefit functions via Bayesian model averaging: A new approach to benefit transfer

A benefit function transfer obtains estimates of willingness-to-pay (WTP) for the evaluation of a given policy at a site by combining existing information from different study sites. This has the advantage that more efficient estimates are obtained, but it relies on the assumption that the heterogeneity between sites is appropriately captured in the benefit transfer model. A more expensive alternative to estimate WTP is to analyze only data from the policy site in question while ignoring information from other sites. We make use of the fact that these two choices can be viewed as a model selection problem and extend the set of models to allow for the hypothesis that the benefit function is only applicable to a subset of sites. We show how Bayesian model averaging (BMA) techniques can be used to optimally combine information from all models. The Bayesian algorithm searches for the set of sites that can form the basis for estimating a benefit function and reveals whether such information can be transferred to new sites for which only a small data set is available. We illustrate the method with a sample of 42 forests from U.K. and Ireland. We find that BMA benefit function transfer produces reliable estimates and can increase about 8 times the information content of a small sample when the forest is 'poolable'. © 2008 Elsevier Inc. All rights reserved.

A field study assessing the impact of on-site wastewater treatment systems on surface water quality in a Co. Monaghan catchment

Poorly functioning on-site wastewater treatment systems (OSWTS) can be among the many sources of pollution to groundwater and surface water, which are of critical concern owing to potential human and ecological health risks. An investigation into the effects of on-site wastewater treatment systems (OSWTS) on surface water quality has been undertaken at several sites within a catchment in Co. Monaghan. The study sites were located in areas of 'low’ permeability, suggesting that run-off usually dominates over infiltration. Poor treatment performance of OSWTS within the catchment were found to be the result of several factors, including location in areas with unsuitable soil and site characteristics, incorrect installation, poor maintenance and inappropriate operation by the home owner.