Identification and characterisation of transcriptional regulatory proteins that modulate estrogen receptor α activity

Breast cancer is the most common malignancy in women in the Western world, accounting for 18% of all female cancers. Two-thirds of breast cancers express Estrogen receptor-α (ERα) and ERα is a predictive and positive prognostic marker. Estrogens stimulate breast cancer growth, primarily through activation of ERα and hormonal therapies used in breast cancer treatment either inhibit estrogen synthesis to prevent ERα activation or bind to ERα to inhibit its activation. Unfortunately resistance to these drugs is a common clinical problem. Altered phosphorylation of ERα has been proposed as one of the mechanisms of resistance to endocrine therapy. Phosphorylation of ERα can result in its activation, both in the presence and absence of ligand. The key phosphorylation sites have been mapped to transcription activation function AF1. In particular, phosphorylation of serine residues at amino acid positions 104, 106 and 118 in AF1 results in stimulation of ERα activity. A wealth of evidence demonstrates an important role for the ERK1/2 MAPK signal transduction pathway in non-responsiveness to endocrine therapies. However, it remains unclear as to how phosphorylation potentiates the activity of AF1. It is likely that phosphorylation of AF1 stimulates the recruitment of transcriptional coactivators that mediate the transcriptional activity of AF1. Identification and characterisation of such coactivators would further our understanding of the role of phosphorylation in the molecular mechanism of transcriptional regulation by ER α Two approaches were used to identify coactivators that may mediate the effects of ERα phosphorylation on its activity. In the first approach, bacterial two-hybrid system was used to screen a breast cDNA expression library. In the second, p68 and p72 RNA helicases, two known transcriptional coregulators, previously reported to interact with AF1 of ERα, were characterised as coactivators of ERα. Both proteins stimulated activity of ERα and show synergism with the well-characterised nuclear receptor coactivator, SRC-1. Surprisingly, reporter gene assays showed that phosphorylation of ERα is not essential for the coactivator function of p68. Importantly, RNA interference studies revealed complex effects of p68 and p72 on ERα activity and consequently on estrogen-regulated gene expression. p72 knockdown reduced the expression of the estrogen-regulated genes, pS2, Cathepsin D and GREB1, and inhibited the growth of the ERα-dependent MCF-7 breast cancer cell line. Surprisingly, p68 knockdown did not affect ER signalling. Data are also presented to suggest that the balance and interplay between p68 and p72 may be responsible for the previously described regulation of ERα activity by p68. Collectively, the data presented show that p72 may be more important than p68 in modulating transcriptional responses of ERα in breast cancer cells

Security in Pervasive Computing: Current Status and Open Issues

Million of wireless device users are ever on the move, becoming more dependent on their PDAs, smart phones, and other handheld devices. With the advancement of pervasive computing, new and unique capabilities are available to aid mobile societies. The wireless nature of these devices has fostered a new era of mobility. Thousands of pervasive devices are able to arbitrarily join and leave a network, creating a nomadic environment known as a pervasive ad hoc network. However, mobile devices have vulnerabilities, and some are proving to be challenging. Security in pervasive computing is the most critical challenge. Security is needed to ensure exact and accurate confidentiality, integrity, authentication, and access control, to name a few. Security for mobile devices, though still in its infancy, has drawn the attention of various researchers. As pervasive devices become incorporated in our day-to-day lives, security will increasingly becoming a common concern for all users - - though for most it will be an afterthought, like many other computing functions. The usability and expansion of pervasive computing applications depends greatly on the security and reliability provided by the applications. At this critical juncture, security research is growing. This paper examines the recent trends and forward thinking investigation in several fields of security, along with a brief history of previous accomplishments in the corresponding areas. Some open issues have been discussed for further investigation

Why rare-earth ferromagnets are so rare: insights from the p-wave Kondo model

Magnetic exchange in Kondo lattice systems is of the Ruderman-Kittel-Kasuya-Yosida type, whose sign depends on the Fermi wave vector, $k_F$ . In the simplest setting, for small $k_F$ , the interaction is predominately ferromagnetic, whereas it turns more antiferromagnetic with growing $k_F$. It is remarkable that even though $k_F$ varies vastly among the rare-earth systems, an overwhelming majority of lanthanide magnets are in fact antiferromagnets. To address this puzzle, we investigate the effects of a p-wave form factor for the Kondo coupling pertinent to nearly all rare-earth intermetallics. We show that this leads to interference effects which for small kF are destructive, greatly reducing the size of the RKKY interaction in the cases where ferromagnetism would otherwise be strongest. By contrast, for large $k_F$, constructive interference can enhance antiferromagnetic exchange. Based on this, we propose a new route for designing ferromagnetic rare-earth magnets.Comment: 9 pages, 4 figure

ETS (Efficient, Transparent, and Secured) Self-healing Service for Pervasive Computing Applications

To ensure smooth functioning of numerous handheld devices anywhere anytime, the importance of self-healing mechanism cannot be overlooked. Incorporation of efficient fault detection and recovery in device itself is the quest for long but there is no existing self-healing scheme for devices running in pervasive computing environments that can be claimed as the ultimate solution. Moreover, the highest degree of transparency, security and privacy attainability should also be maintained. ETS Self-healing service, an integral part of our developing middleware named MARKS (Middleware Adaptability for Resource discovery, Knowledge usability, and Self-healing), holds promise for offering all of those functionalities