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.

FEA comparison of high and low pressure tube hydroforming of TRIP steel

The increasing application of hydroforming for the production of automotive lightweight components is mainly due to the attainable advantages regarding part properties and improving technology of the forming equipment. However, the high pressure requirements during hydroforming decreases the costs benefit and make the part expensive. Another requirement of automotive industries is weight reduction and better crash performance. Thereby steel industries developed advanced high strength steels which have high strength, good formability and better crash performance. Even though the thickness of the sheet to form the component is reduced, the pressure requirement to form the part during expansion is still high during high pressure hydroforming. This paper details the comparison between high and low pressure tube hydroforming for the square cross-section geometry. It is determined that the internal pressure and die closing force required for low pressure tube hydroforming process is much less than that of high pressure tube hydroforming process. The stress and thickness distribution of the part during tube crushing were critically analysed. Further, the stress distribution and forming mode were studied in this paper. Also friction effect on both processes was discussed.

Defect assessment procedures for high temperature applications : final report TW5-TTMS-005, D5

The objective of this task is to develop the high temperature part of a design code for fusion reactor components build from EUROFER. This development includes fracture mechanical rules for the assessment of detected defects under creep and creep–fatigue conditions. The assessment procedures R5, R6, JNC, A16, Partial Safety Factors were investigated and tested. As the most suitable procedure is chosen R5 and it is further verified by comparison with finite element simulations using the EUROFER material data. These simulations consist of evaluation of C(t) parameter for several geometries (CT specimen,cylinder with fully circumferential crack subjected to the internal pressure, cylinder with semi–elliptical circumferential crack subjected to the internal pressure and Mock-Up test blanket module (TBM) geometry). The R5 procedure provides very good accordance with FE simulations and it is suitable for lifetime assessment. Therefore the guide for R5 application is implemented in the report.

Influence of deformation conditions and texture on the high temperature flow stress of magnesium AZ31

The evolution of hot working flow stress with strain is examined in torsion, uniaxial compression and channel die compression. The flow stress was found to be strongly dependent on texture and deformation mode. At low strains this dependency accounted for a difference in flow stress of up to a factor of two. At higher strains the influence of texture and deformation mode was less marked. The stresses corresponding to an equivalent strain of 0.5 were modelled using a power law expression with an activation energy of 147 kJ/mol and a strain rate exponent of 0.15. The influence of texture and deformation mode on flow stress is rationalised in terms of the influence of prismatic slip, twinning and dynamic recrystallisation on deformation stress and structure.

Fabrication of porous TiAl intermetallic compound by self-propagating high temperature synthesis

The present paper describes processing of a lotus-structured porous Ti-Al/Ti composite by SHS with Ti powder and Al rods. Ti-Al intermetallic compound was formed in a range of 200-300μm around the pore by SHS of reaction between Ti and Al, resulting in formation of a lotus-structured porous Ti-Al/Ti composite.

21Cr - 10Ni - 3Mo duplex stainless steel high temperature deformation microstructures

Data includes EBSD orentation maps of the specimens deformed in torsion at 1200 degrees celsius to strains of 0.1, 0.5, 0.9 and 1.3. The phase ratio is about 60% austenite and 40% ferrite. The miscrostructure is dynamically recovered and there is also some dynamic recrystallisation at strains of 0.9 and 1.3. The main portion of softening can be attributed to dynamic subgrain coalescence in austenite.

Synthesis and characterization of nanocrystalline hexagonal boron carbo-nitride under high temperature and high pressure

A study of the synthesis of hexagonal boron carbo-nitride (h-BCN) compounds via a two-step high-temperature and high-pressure (HTHP) technique using melamine (C 3N 6H 6) and boron oxide (B 2O 3) as raw materials is presented. An amorphous BCN precursor was prepared at 1000K under vacuum in a resistance furnace and then single-phase h-BCN nanocrystalline was synthesized at 1600K and 5.1GPa in a multi-anvil apparatus. X-ray diffraction (XRD) and transmission electron microscopy (TEM) indicated that the final products were pure h-BCN crystals with the lattice constants a ≤ 0.2510nm and c ≤ 0.6690nm. The average grain size was about 150nm. X-ray photoelectron spectroscopy (XPS) results confirmed the occurrence of bonding between C-C, C-N, C-B and N-B atoms. Raman scattering analysis suggested that there were three strong Raman bands centered at 1359, 1596 and 1617cm -1, respectively. The band at 1617cm -1 was considered to be consistent with the characteristic Raman peak of h-BCN.