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The key nuclear export protein CRM1/XPO1 may represent a promising novel therapeutic target in human multiple myeloma (MM). Here we showed that chromosome region maintenance 1 (CRM1) is highly expressed in patients with MM, plasma cell leukemia cells and increased in patient cells resistant to bortezomib treatment. CRM1 expression also correlates with increased lytic bone and shorter survival. Importantly, CRM1 knockdown inhibits MM cell viability. Novel, oral, irreversible selective inhibitors of nuclear export (SINEs) targeting CRM1 (KPT-185, KPT-330) induce cytotoxicity against MM cells (ED 50 <200 n M ), alone and cocultured with bone marrow stromal cells (BMSCs) or osteoclasts (OC). SINEs trigger nuclear accumulation of multiple CRM1 cargo tumor suppressor proteins followed by growth arrest and apoptosis in MM cells. They further block c-myc, Mcl-1, and nuclear factor κB (NF-κB) activity. SINEs induce proteasome-dependent CRM1 protein degradation; concurrently, they upregulate CRM1, p53-targeted, apoptosis-related, anti-inflammatory and stress-related gene transcripts in MM cells. In SCID mice with diffuse human MM bone lesions, SINEs show strong anti-MM activity, inhibit MM-induced bone lysis and prolong survival. Moreover, SINEs directly impair osteoclastogenesis and bone resorption via blockade of RANKL-induced NF-κB and NFATc1, with minimal impact on osteoblasts and BMSCs. These results support clinical development of SINE CRM1 antagonists to improve patient outcome in MM.

Grain refinement plays a crucial role in improving characteristics and properties of cast and wrought aluminium alloys. Generally Al-Ti and Al-Ti-B master alloys are added to the aluminium alloys to grain refine the solidified product. The mechanism of grain refinement is of considerable controversy in the scientific literature. The nucleant effects i.e. which particle and its characteristics nucleate α-Al, has been the subject of intensive research. Lately the solute effect i.e. the effect of dissolved titanium on grain refinement, has come into forefront of grain refinement research. The present paper attempts to review the literature on the nucleant effects and solute effects on grain refinement and addresses the importance of dissolved titanium in promoting nucleation of α-Al on nucleant particles.

Grain structure is an important and readily observable feature in aluminum alloy castings. Depending on the constitutional and heat-flow conditions in a solidified aluminum alloy, various morphologies are possible. Grain refining is one of the predominant techniques in controlling the quality of castings. It plays a vital role in improving metallurgical characteristics and mechanical properties of aluminum alloys. Fine equiaxed grains ensure remarkable benefits. There are a number of techniques to achieve fine equiaxed grain structure, but grain refinement by the addition of grain refiners referred to as inoculation is the most popular due to its simplicity. Grain refinement has been studied extensively by researchers for several decades, not only for developing efficient grain refiners but also for achieving an understanding of the mechanism of grain refinement. In spite of its commercial importance, benefits and numerous scientific studies in this area, the grain refinement of aluminum and its alloys is still a controversial subject. Solute elements like titanium segregate to the inoculants/melt interface affecting the dendrites and also affect the constitutional undercooling at the solid–liquid interface. This segregating power of an element is quantified by the growth restricting factor (GRF). In the present investigation, the effect of GRF on grain refinement of aluminum-silicon alloys was studied by the addition of Al-5Ti-1B master alloy. It is evident from this investigation that the growth rate of grains is inversely proportional to the GRF.

Carbon nanotubes (CNTs) were discovered by Iijima in 1991 as the fourth form of carbon. Carbon nanotubes are the ultimate carbon fibres because of their high Young’s modulus of ≈ 1 TPa which is very useful for load transfer in nanocomposites. In the present work, CNT/Al nanocomposites were fabricated by the powder metallurgy technique and after extrusion of the nanocomposites bright field transmission electron microscopic (TEM) studies were carried out. From the TEM images so obtained, a novel method of ascertaining the Young’s modulus of multi-walled carbon nanotubes is worked out in the present paper which turns out to be 0·9 TPa which is consistent with the experimental results.

Rigorous Mullins and Sekerka perturbation theory has been applied to two solidification interfaces. The results indicate that as the distance between the two interfaces decreases, the rate of amplitude growth of perturbations on the planar solid–liquid interface becomes negative, which is a further verification of the stability of a planar interface due to soft impingement of diffusion fields during solidification. This work conclusively shows that spheroidal grains form due to grain refinement of Mg alloys by Zr addition because of the high density of nucleation.

Discontinuous precipitation (DP) is associated with grain boundary migration in the wake of which alternate plates of the precipitate and the depleted matrix form. Some copper base alloys show DP while others do not. In this paper the misfit strain parameter, η , has been calculated and predicted that if 100 η > ± 0·1, DP is observed. This criterion points to diffusional coherency strain theory to be the operative mechanism for DP.

Cube texture is a sharp recrystallization texture component infcc metals like aluminium, copper, etc. It is described by an ideal orientation i.e. (100) (100). The subject of cube texture nucleation i.e. cube grain nucleation, from the deformed state of aluminium and copper is of scientific curiosity with concurrent technological implications. There are essentially two models currently in dispute over the mechanism of cube grain nucleation i.e. the differential stored energy model founded on the hypothesis proposed by Ridha and Hutchinson and the micro-growth selection model of Dugganet al. In this paper, calculations are made on the proposal of Ridha and Hutchinson model and the results are obtained in favour of the differential stored energy model. It is also shown that there is no need for the micro-growth model.

It has been well established that spheroidal grain morphology in the microstructure forms during stir casting (rheocasting) and grain refinement of magnesium alloys by zirconium addition. This curious microstructure has been of interest both commercially from enhanced mechanical properties and also scientific interest in explaining the mechanism of spheroidal grain formation. Vogel and Doherty proposed a model describing the fracturing of dendrite arms during stir casting to produce a high density of nuclei which they presume to give rise to spheroidal grains. They proposed that there is soft impingement of diffusion fields of neighbouring nuclei, which reduces the concentration gradient ahead of the planar solid and liquid interface, which in turn negates shape instability. In this paper, the Vogel and Doherty model is pursued by quantitative modeling of soft impingement problem and related to shape instability by constitutional supercooling theory. This analysis correctly predicts the spheroidal grain formation during stir casting or rheocasting. This model can also be used to explain the grain refinement of magnesium alloys by zirconium addition wherein spheroidal grains are formed.

In the present work, Cu-Ni phase diagram is evaluated and assessed using the CALPHAD method for the accurate prediction of liquidus and solidus curves. Phase diagrams were plotted for both bulk and nanoalloys. Phase diagrams for nanoparticles are significantly different from that of the bulk because the melting point of the nanoparticle is a function of particle size. The melting point of the nanoparticle is determined using two different models, Surface Energy model and Enthalpy and Entropy model. Phase diagrams were plotted using both models for Copper-Nickel binary isomorphous system and were compared with the experimental data. It was found that the Enthalpy and Entropy model is in good agreement with the experimental data compared to the Surface Energy model. This is because the Enthalpy and Entropy model considers the thermal interactions at various temperatures whereas the surface energy model only considers the surface free energy of the particle. Also, Enthalpy and Entropy model is a dynamic model because it can predict the melting enthalpy and entropy of the nanoparticles for various particle sizes which result in accurate free energies predictions. Hence, phase diagrams that are predicted using Enthalpy and Entropy model tend to be more accurate than that of the surface energy model.

It is well known that Guinier Preston (GP) zones form in Al-Cu alloys upon solutionizing and artificial aging, which are extensively used in commercial practice. It is well established that GP zones are discshaped precipitates, i.e. disks of clusters of copper atoms in the FCC aluminium matrix. These disks have coherency strain fields in aluminium that give the alloy its high yield strength. The formation of GP zones in the supersaturated aluminium matrix is thought to be heterogeneous nucleation and growth. Some authors have believed that the formation of GP zones is by spinodal decomposition of the supersaturated Al-Cu solid solution. The main objective of the present work is to test whether spinodal decomposition is responsible for the formation of GP zones in Al-Cu alloy. The experimental alloy AA2219 was selected for its high copper content (Al-6%Cu-0·2%Zr). After solutionizing and artificial aging, the aging curve was plotted and small-angle scattering experiments were carried on the powdered samples as a function of time during artificial aging. Small-angle scattering data were analysed, and evidence has been obtained for the occurrence of spinodal decomposition as the mechanism responsible in the early stages of formation of GP zones.