Regulation of intracellular Ca2؉ mobilization has been associated with the functions of polycystin-1 (PC1) and polycystin-2 (PC2), the protein products of the PKD1 and PKD2 genes. We have now demonstrated that PC1 can activate the calcineurin/NFAT (nuclear factor of activated T-cells) signaling pathway through G␣ q -mediated activation of phospholipase C (PLC). Transient transfection of HEK293T cells with an NFAT promoterluciferase reporter demonstrated that membrane-targeted PC1 constructs containing the membrane proximal region of the C-terminal tail, which includes the heterotrimeric G protein binding and activation domain, can stimulate NFAT luciferase activity. Inhibition of glycogen synthase kinase-3␤ by LiCl treatment further increased PC1-mediated NFAT activity. PC1-mediated activation of NFAT was completely inhibited by the calcineurin inhibitor, cyclosporin A. Cotransfection of a construct expressing the G␣ q subunit augmented PC1-mediated NFAT activity, whereas the inhibitors of PLC (U73122) and the inositol trisphosphate and ryanodine receptors (xestospongin and 2-aminophenylborate) and a nonspecific Ca 2؉ channel blocker (gadolinium) diminished PC1-mediated NFAT activity. PC2 was not able to activate NFAT. An NFAT-green fluorescent protein nuclear localization assay demonstrated that PC1 constructs containing the C-tail only or the entire 11-transmembrane spanning region plus C-tail induced NFATgreen fluorescent protein nuclear translocation. NFAT expression was demonstrated in the M-1 mouse cortical collecting duct cell line and in embryonic and adult mouse kidneys by reverse transcriptase-PCR and immunolocalization. These data suggest a model in which PC1 signaling leads to a sustained elevation of intracellular Ca 2؉ mediated by PC1 activation of G␣ q followed by PLC activation, release of Ca 2؉ from intracellular stores, and activation of store-operated Ca 2؉ entry, thus activating calcineurin and NFAT.

The Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB) represent family of structurally-related eukaryotic transcription factors which regulate diverse array of cellular processes including immunological responses, inflammation, apoptosis, growth & development. Increased expression of NF-kB has often been seen in many diverse diseases, suggesting the importance of genomic deregulation to disease pathophysiology. In the present study we focused on acute kidney injury (AKI), which remains one of the major risk factor showing a high rate of mortality and morbidity. The pathology associated with it, however, remains incompletely known though inflammation has been reported to be one of the major risk factor in the disease pathophysiology. The role of NF-kB thus seemed pertinent. In the present study we show that high dose of folic acid (FA) induced acute kidney injury (AKI) characterized by elevation in levels of blood urea nitrogen & serum creatinine together with extensive tubular necrosis, loss of brush border and marked reduction in mitochondria. One of the salient observations of this study was a coupled increase in the expression of renal, relA, NF-kB2, and p53 genes and proteins during folic acid induced AKI (FA AKI). Treatment of mice with NF-kB inhibitor, pyrrolidine dithio-carbamate ammonium (PDTC) lowered the expression of these transcription factors and ameliorated the aberrant renal function by decreasing serum creatinine levels. In conclusion, our results suggested that NF-kB plays a pivotal role in maintaining renal function that also involved regulating p53 levels during FA AKI.

The present research is the first type of study, in which the application of powder mixed electrical discharge machining (PM-EDM) for the machining of β-phase titanium (β-Ti) alloy has been proposed. β-Ti alloys are new range of titanium alloys, which has wide spread application in dental, orthopaedics, shape memory, and stents. The aim of the present study is to fabricate submicro-and nano scale topography by PMEDM process to enhance the biocompatibility without affecting machining efficiency. The effect of Si powder concentration along with pulse-current and duration on the surface and machining characteristics has been investigated. A significant decrease in surface crack density on the machined surface with 4 g/l Si powder concentration was observed. When β-Ti alloy was modified at 15 A pulse-current, longer pulse interval with 8 g/l concentration of Si powder particles, the interconnected surface porosities with pore size 200-500 nm was observed. Moreover, at Si powder concentration of 2 and 4 g/l, the recast layer thickness is 8µm and 2-3 µm, respectively. Elemental mapping analysis confirmed that PMEDM also generated carbides and oxides enriched surface, a favourable surface chemistry to enhance the biocompatibility of β-Ti alloy. Furthermore, Downloaded by [George Mason University] at 06:41 22 June 2016 2 PMEDM also enhances the machining performance by improving MRR and reducing TWR.

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