Structural and functional properties of human multidrug resistance protein 1 (MRP1/ABCC1)

Multidrug ABC transporters such as P-glycoprotein (P-gp/MDR1/ABCB1) and multidrug resistance protein 1 (MRP1/ABCC1) play an important role in the extrusion of drugs from the cell and their overexpression can be a cause of failure of anticancer and antimicrobial chemotherapy. Recently, the mouse P-gp/Abcb1a structure has been determined and this has significantly enhanced our understanding of the structure-activity relationship (SAR) of mammalian ABC transporters. This paper highlights our current knowledge on the structural and functional properties and the SAR of human MRP1/ABCC1. Although the crystal structure of MRP1/ABCC1 has yet to be resolved, the current topological model of MRP1/ABCC1 contains two transmembrane domains (TMD1 and TMD2) each followed by a nucleotide binding domain (NBD) plus a third NH2-terminal TMD0. MRP1/ABCC1 is expressed in the liver, kidney, intestine, brain and other tissues. MRP1/ABCC1 transports a structurally diverse array of important endogenous substances (e.g. leukotrienes and estrogen conjugates) and xenobiotics and their metabolites, including various conjugates, anticancer drugs, heavy metals, organic anions and lipids. Cells that highly express MRP1/ABCC1 confer resistance to a variety of natural product anticancer drugs such as vinca alkaloids (e.g. vincristine), anthracyclines (e.g. etoposide) and epipodophyllotoxins (e.g. doxorubicin and mitoxantrone). MRP1/ABCC1 is associated with tumor resistance which is often caused by an increased efflux and decreased intracellular accumulation of natural product anticancer drugs and other anticancer agents. However, most compounds that efficiently reverse P-gp/ABCB1-mediated multidrug resistance have only low affinity for MRP1/ABCC1 and there are only a few effective and relatively specific MRP1/ABCC1 inhibitors available. A number of site-directed mutagenesis studies, biophysical and photolabeling studies, SAR and QSAR, molecular docking and homology modeling studies have documented the role of multiple residues in determining the substrate specificity and inhibitor selectivity of MRP1/ABCC1. Most of these residues are located in the TMs of TMD1 and TMD2, in particular TMs 4, 6, 7, 8, 10, 11, 14, 16, and 17, or in close proximity to the membrane/cytosol interface of MRP1/ABCC1. The exact transporting mechanism of MRP1/ABCC1 is unclear. MRP1/ABCC1 and other multidrug transporters are front-line mediators of drug resistance in cancers and represent important therapeutic targets in future chemotherapy. The crystal structure of human MRP1/ABCC1 is expected to be resolved in the near future and this will provide an insight into the SAR of MRP1/ABCC1 and allow for rational design of anticancer drugs and potent and selective MRP1/ABCC1 inhibitors.

Building trust in cross-sector R&D collaborations : the role of credible commitments

This paper reports selected findings from a study of one form of cross-boundary relationship: cross-sector R&D collaboration under the Australian Cooperative Research Centre (CRC) Programme. The study sought to explain project partners’ collaboration experience using a theoretical model which was empirically tested with a survey of CRC project leaders. It was hypothesised (H1) that the higher the level of relational trust (measured, following Sako, in terms of contractual, competence, and goodwill trust) amongst the partners in a collaborative project team, the more positive would be the partners’ experience of the project. The construct of credible commitments (the making of pledges, or the economic equivalent of the taking of hostages, which bind partners to a relationship) was posed in the model as an antecedent of relational trust. Accordingly it was hypothesised (H2) that the more that credible commitments are made by the project partners, the higher would be the level of relational trust between them. Data from the achieved sample (n = 156, 51% response rate) were analysed using PLS Graph. The results of the analysis provided support for hypothesis 1 but not for hypothesis 2. It was concluded that this latter finding could be due to the specific context of the study (cross-sector R&D collaborations under the CRC Programme differ markedly from inter-firm strategic alliances), or it could be due to the complex nature of credible commitments which was not adequately captured by our measure of this construct. Further research is required in this area to clarify the nature credible commitments, and the circumstances under which they contribute to a spiral of rising trust, in different cross-boundary contexts.

"Rare Earth" texture development in extruded Mg-based alloys

This data collection addresses the problem of low ductility in magnesium alloys, preventing their wider use. It examines a series of dilute alloys in order to determine the effect of composition on the extrusion behaviour and texture, and on the room temperature tensile ductility.

An analysis of side chain interactions and pair correlations within antiparallel β-sheets : the differences between backbone hydrogen-bonded and non-hydrogen-bonded residue pairs

Cross-strand pair correlations are calculated for residue pairs in antiparallel β-sheet for two cases: pairs whose backbone atoms are hydrogen bonded together (H-bonded site) and pairs which are not (non-H-bonded site). The statistics show that this distinction is important. When glycine is located on the edge of a sheet, it shows a 3:1 preference for the H-bonded site. Thestrongest observed correlations are for pairs of disulfide-bonded cystines, many of which adopt a close-packed conformation with each cystine in a spiral conformation of opposite chirality to its partner. It is likely that these pairs are a signature for the family of small, cystine-rich proteins. Most other strong positive and negative correlations involve charged and polar residues. It appears that electrostatic compatibility is the strongest factor affecting pair correlation. Significant correlations are observed for β- and γ-branched residues inthe non-H-bonded site. An examination of the structures showsa directionality in side chain packing. There is a correlation between (1) the directionality in the packing interactions of non-H-bonded β- and γ-branched residue pairs, (2) the handedness of the observed enantiomers of chiral β-branched side chains, and (3) the handedness of the twist of β-sheet. These findings have implications for the formation of β-sheets during protein folding and the mechanism by which the sheet becomes twisted

Procedural modeling facilities for hierarchical object generation

We modify a selection of interactive modeling tools for use in a procedural modeling environment. These tools are selection, extrusion, subdivision and curve shaping. We create human models to demonstrate that these tools are appropriate for use on hierarchical objects. Our tools support the main benefits of procedural modeling, which are: the use of parameterisation to control and very a model, varying levels of detail, increased model complexity, base shape independence and database amplification. We demonstrate scripts which provide each of these benefits.

Performance evaluation of different ultrafiltration membranes for the reclamation and reuse of secondary effluent

This study investigates and compares the performance of two different types of ultrafiltration (UF) membranes in the recovery of water from secondary treated wastewater. Filtration experiments were carried out on a pilot scale cross-flow unit using synthetic wastewater similar to the quality of secondary treated wastewater by varying the operating parameters such as transmembrane pressure (TMP), feed composition and membrane configuration. The filtration experiments demonstrated that the flux recovery through spiral polymeric UF membrane was more sensitive to the variation in TMP compared to the tubular ceramic UF membrane over the range of TMP studied. The resistance in series model was used for the evaluation of the resistance to the permeate flux. The fouling resistance, particularly irreversible resistance compared to reversible resistance plays a major role in the total resistance for the tubular ceramic membrane. In contrast clean membrane resistance is the major contributor for the total resistance of the spiral polymeric membrane. Finally, the effectiveness of the filtration treatment was determined by evaluating the rejection coefficients for various pollution indices of the wastewater. Significant differences in the performance of the membrane types were observed which are likely to impact on the selection, operation and maintenance of the membrane system.

Solute segregation and texture modification in an extruded magnesium alloy containing gadolinium

The alloy Mg-1.5Gd has been extruded at different temperatures to produce two significantly different textures. At lower extrusion temperatures there was significant solute clustering in the matrix, coupled with segregation of solute to the grain boundaries. At higher temperatures these two phenomena were both less pronounced. It is suggested here that segregation of solute to the grain boundaries plays a significant role in the texture modification effect that rare earth elements have in magnesium alloys.

Design of a miniature UHF PIFA for DBS implants

This paper presents design and simulation of a miniature rectangular spiral planar inverted-F antenna (PIFA) at UHF RFID band (902.75 - 927.25 MHz) for integration in batteryless deep brain stimulation implants. Operation in the UHF band offers small antenna size and longer transmission range. The proposed antenna has the dimensions of 10 mm × 11.5 mm × 1.6 mm, resonance frequency of 920 MHz with a bandwidth of 18 MHz at return loss of -10 dB. A dielectric substrate of FR-4 of εr = 4.5 and δ = 0.018 with thickness of 1.5644 mm is used in this design. The resonance, radiation characteristics as well as the specific absorption rate distribution induced by the designed antenna within a four layer spherical head model is evaluated by using electromagnetic modeling software which employs the finite element method.

Grain refinement of an extruded Mg alloy via na microalloying

The effect of 0.3 wt pct Na on the microstructure of extruded alloy Mg-2Sn-1Zn is examined. We report that Na stabilizes the Mg2Sn phase, resulting in its precipitation during extrusion under conditions where a solid solution is otherwise expected. This effect appears to be thermodynamic in nature and is different from the kinetic enhancement of low- temperature aging reported by Mendis et al. [Phil. Mag. Letters, 86 (2006), 443]. The precipitates of the current study enable useful refinement of the grain size.

Compositional effects on the restoration behaviour in Mg-Zn-Re alloys

Additions of rare earth elements to magnesium alloys are qualitatively reported in the literature to retard recrystallisation. However, their effect in the presence of other (non-rare earth) alloy additions has not been systematically shown nor has the effect been quantified. The microstructural restoration following the hot deformation of Mg-xZn-yRE (x = 2.5 and 5 wt.%, y = 0 and 1 wt.%, and RE = Gd and Y) alloys has been studied using double hit compression testing and microscopy. It was found that, in the absence of rare earth additions, increases in zinc level had a negligible influence on the kinetics of restoration and the microstructure developed both during extrusion and throughout double hit testing. Adding rare earth elements to Mg-Zn alloys was found to retard restoration of the microstructure and maintain finer recrystallised grains. However, in the Mg-Zn-RE alloys, increasing the zinc concentration from 2.5 wt.% to 5 wt.% accelerated the restoration process, most likely due to a depletion of rare earth elements from solid solution and modification of the particles present in the matrix.

Na partitioning during thermomechanical processing of an Mg-Sn-Zn-Na alloy

Microstructural characterization was used to examine the changes that occur in an Mg-6Sn-5Zn-0.3Na alloy from casting to extrusion at either 623 K or 723 K (350 _C or 450 _C) followed by artificial aging at 473 K (200 _C). In particular, the partitioning of Na was examined at each step using STEM-EDS mapping. Na atoms were found to preferentially partition to the Mg-Zn phase when present. After extrusion, when no Mg-Zn was observed, the spherical Mg2Sn particles were found to be enriched in Na, particularly at the higher extrusion temperature. Artificial aging following extrusion resulted in a change in Na partitioning, and a coarse distribution of Mg-Zn precipitate rods. Na microadditions led to a high as-extruded hardness, but a significant tension–compression yield asymmetry was still observed at room temperature. The compressive yield strength was found to decrease significantly after 1000 hours of aging.