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Till 1991, there was excessive control of Government over economy with inward looking policies leading to over protection of economy leading todeterioration of trade, economic growth and large fiscal deficits financed by external borrowings. Foreign currency reserves plummeted to very low levels. Since then India has seen a steady set of reforms in LPG mode with foreign investment playing important role. In this study datahas been obtained from secondary sources, mainly government and global bodies. Literature cited has been taken with reference to India or generic in nature and problems identified. Policies needed for attracting FDI are not very different from those required for domestic investors. Preferential for FDI may act as an extra incentive. Foreign Portfolio investment is contingent upon returns expected from capital market and home country issues. Foreign direct investment has slowly moved from manufacturing to service sector probably because of easy entry and exit conditions as well as leveraging labour arbitrage. In this study we have reviewed papers on determinants, patterns and impact of FDI and FII/FPI on Indian economy for the period 1991-2012 and attempted to find out interrelation between FDI and FII/FPIinflows. [ABSTRACT FROM AUTHOR]

To understand the mechanisms of water oxidation on materials such as hematite it is important that accurate measurements and models of the interfacial fields at the semiconductor liquid junction are developed. Here we demonstrate how electric field induced second harmonic generation (EFISHG) spectroscopy can be used to monitor the electric field across the space-charge and Helmholtz layers in a hematite electrode during water oxidation. We are able to identify the occurrence of Fermi level pinning at specific applied potentials which lead to a change in the Helmholtz potential. Through combined electrochemical and optical measurements we correlate these to the presence of surface trap states and the accumulation of holes (h + ) during electrocatalysis. Despite the change in Helmholtz potential as h + accumulate we find that a population model can be used to fit the electrocatalytic water oxidation kinetics with a transition between a first and third order regime with respect to hole concentration. Within these two regimes there are no changes in the rate constants for water oxidation, indicating that the rate determining step under these conditions does not involve electron/ion transfer, in-line with it being O-O bond formation., Competing Interests: There are no conflicts of interest to declare., (This journal is © The Royal Society of Chemistry.)

We report a H 2 evolving hybrid photocathode based on Sb 2 Se 3 and a precious metal free molecular catalyst. Through the use of a high surface area TiO 2 scaffold, we successfully increased the Ni molecular catalyst loading from 7.08 ± 0.43 to 45.76 ± 0.81 nmol cm -2 , achieving photocurrents of 1.3 mA cm -2 at 0 V vs. RHE, which is 81-fold higher than the device without the TiO 2 mesoporous layer.

Herein, we present the cathodic paths of the Group-7 metal complex [Re(3,3'-DHBPY)(CO) 3 Cl] (3,3'-DHBPY = 3,3'-dihydroxy-2,2'-bipyridine) producing a moderately active catalyst of electrochemical reduction of CO 2 to CO. The combined techniques of cyclic voltammetry and IR/UV-vis spectroelectrochemistry have revealed significant differences in the chemistry of the electrochemically reduced parent complex compared to the previously published Re/4,4'-DHBPY congener. The initial irreversible cathodic step in weakly coordinating THF is shifted toward much less negative electrode potentials, reflecting facile reductive deprotonation of one hydroxyl group and strong intramolecular hydrogen bonding, O-H···O - . The latter process occurs spontaneously in basic dimethylformamide where Re/4,4'-DHBPY remains stable. The subsequent reduction of singly deprotonated [Re(3,3'-DHBPY-H + )(CO) 3 Cl] - under ambient conditions occurs at a cathodic potential close to that of the Re/4,4'-DHBPY-H + derivative. However, for the stabilized 3,3'-DHBPY-H + ligand, the latter process at the second cathodic wave is more complex and involves an overall transfer of three electrons. Rapid potential step electrolysis induces 1e - -reductive cleavage of the second O-H bond, triggering dissociation of the Cl - ligand from [Re(3,3'-DHBPY-2H + )(CO) 3 Cl] 2- . The ultimate product of the second cathodic step in THF was identified as 5-coordinate [Re(3,3'-DHBPY-2H + )(CO) 3 ] 3- , the equivalent of classical 2e - -reduced [Re(BPY)(CO) 3 ] - . Each reductive deprotonation of the DHBPY ligand results in a redshift of the IR ν(CO) absorption of the tricarbonyl complexes by ca. 10 cm -1 , facilitating the product assignment based on comparison with the literature data for corresponding Re/BPY complexes. The Cl - dissociation from [Re(3,3'-DHBPY-2H + )(CO) 3 Cl] 2- was proven in strongly coordinating butyronitrile. The latter dianion is stable at 223 K, converting at 258 K to 6-coordinate [Re(3,3'-DHBPY-2H + )(CO) 3 (PrCN)] 3- . Useful reference data were obtained with substituted parent [Re(3,3'-DHBPY)(CO) 3 (PrCN)] + that also smoothly deprotonates by the initial reduction to [Re(3,3'-DHBPY-H + )(CO) 3 (PrCN)]. The latter complex ultimately converts at the second cathodic wave to [Re(3,3'-DHBPY-2H + )(CO) 3 (PrCN)] 3- via a counterintuitive ETC step generating the 1e - radical of the parent complex, viz., [Re(3,3'-DHBPY)(CO) 3 (PrCN)]. The same alternative reduction path is also followed by [Re(3,3'-DHBPY-H + )(CO) 3 Cl] - at the onset of the second cathodic wave, where the ETC step results in the intermediate [Re(3,3'-DHBPY)(CO) 3 Cl] •- further reducible to [Re(3,3'-DHBPY-2H + )(CO) 3 ] 3- as the CO 2 catalyst.

Mediators of PI3K/AKT signaling have been implicated in chronic myeloid leukemia (CML) and acute myeloid leukemia (AML). Studies have shown that inhibitors of PI3K/AKT signaling, such as wortmannin and LY294002, are able to inhibit CML and AML cell proliferation and synergize with targeted tyrosine kinase inhibitors. We investigated the ability of BAG956, a dual PI3K/PDK-1 inhibitor, to be used in combination with inhibitors of BCR-ABL and mutant FLT3, as well as with the mTOR inhibitor, rapamycin, and the rapamycin derivative, RAD001. BAG956 was shown to block AKT phosphorylation induced by BCR-ABL-, and induce apoptosis of BCR-ABL-expressing cell lines and patient bone marrow cells at concentrations that also inhibit PI3K signaling. Enhancement of the inhibitory effects of the tyrosine kinase inhibitors, imatinib and nilotinib, by BAG956 was demonstrated against BCR-ABL expressing cells both in vitro and in vivo. We have also shown that BAG956 is effective against mutant FLT3-expressing cell lines and AML patient bone marrow cells. Enhancement of the inhibitory effects of the tyrosine kinase inhibitor, PKC412, by BAG956 was demonstrated against mutant FLT3-expressing cells. Finally, BAG956 and rapamycin/RAD001 were shown to combine in a nonantagonistic fashion against BCR-ABL- and mutant FLT3-expressing cells both in vitro and in vivo.

Drug resistance resulting from emergence of imatinib-resistant BCR-ABL point mutations is a significant problem in advanced-stage chronic myelogenous leukemia (CML). The BCR-ABL inhibitor, nilotinib (AMN107), is significantly more potent against BCR-ABL than imatinib, and is active against many imatinib-resistant BCR-ABL mutants. Phase 1/2 clinical trials show that nilotinib can induce remissions in patients who have previously failed imatinib, indicating that sequential therapy with these 2 agents has clinical value. However, simultaneous, rather than sequential, administration of 2 BCR-ABL kinase inhibitors is attractive for many reasons, including the theoretical possibility that this could reduce emergence of drug-resistant clones. Here, we show that exposure of a variety of BCR-ABL+ cell lines to imatinib and nilotinib results in additive or synergistic cytotoxicity, including testing of a large panel of cells expressing BCR-ABL point mutations causing resistance to imatinib in patients. Further, using a highly quantifiable bioluminescent in vivo model, drug combinations were at least additive in antileukemic activity, compared with each drug alone. These results suggest that despite binding to the same site in the same target kinase, the combination of imatinib and nilotinib is highly efficacious in these models, indicating that clinical testing of combinations of BCR-ABL kinase inhibitors is warranted.

Human stem cell leukemia-lymphoma syndrome usually presents itself as a myeloproliferative disorder (MPD) that evolves to acute myeloid leukemia and/or lymphoma. The syndrome associated with t(8;13)(p11;q12) results in expression of the ZNF198-fibroblast growth factor receptor (FGFR) 1 fusion tyrosine kinase. Current empirically derived cytotoxic chemotherapy is inadequate for treatment of this disease. We hypothesized that small-molecule inhibitors of the ZNF198-FGFR1 fusion would have therapeutic efficacy. We characterized the transforming activity of ZNF198-FGFR1 in hematopoietic cells in vitro and in vivo. Expression of ZNF198-FGFR1 in primary murine hematopoietic cells caused a myeloproliferative syndrome in mice that recapitulated the human MPD phenotype. Transformation in these assays, and activation of the downstream effector molecules PLC-gamma, STAT5, and phosphatidylinositol 3-kinase/AKT, required the proline-rich domains, but not the ZNF domains, of ZNF198. A small-molecule tyrosine kinase inhibitor, PKC412 (N-benzoyl-staurosporine) effectively inhibited ZNF198-FGFR1 tyrosine kinase activity and activation of downstream effector pathways, and inhibited proliferation of ZNF198-FGFR1 transformed Ba/F3 cells. Furthermore, treatment with PKC412 resulted in statistically significant prolongation of survival in the murine model of ZNF198-FGFR1-induced MPD. Based in part on these data, PKC412 was administered to a patient with t(8;13)(p11;q12) and was efficacious in treatment of progressive myeloproliferative disorder with organomegaly. Therefore, PKC412 may be a useful therapy for treatment of human stem cell leukemia-lymphoma syndrome.

Myeloid leukaemias are frequently associated with translocations and mutations of tyrosine kinase genes. The products of these oncogenes, including BCR-ABL, TEL-PDGFR, Flt3 and c-Kit, have elevated tyrosine kinase activity and transform haematopoietic cells, mainly by augmentation of proliferation and enhanced viability. Activated ABL kinases are associated with chronic myeloid leukaemia. Mutations in platelet-derived growth factor receptor beta are associated with chronic myelomonocytic leukaemia. Flt3 or c-Kit cooperate with other types of oncogenes to create fully transformed acute leukaemias. Elevated activity of these tyrosine kinases is crucial for transformation, thus making the kinase domain an ideal target for therapeutic intervention. Tyrosine kinase inhibitors for various kinases are currently being evaluated in clinical trials and are potentially useful therapeutic agents in myeloid leukaemias. Here, the authors review the signalling activities, mechanism of transformation and therapeutic targeting of several tyrosine kinase oncogenes important in myeloid leukaemias.

Cyclin D2 affects B cell proliferation and differentiation in vivo. It is rate-limiting for B cell receptor (BCR)-dependent proliferation of B cells, and cyclin D2-/- mice lack CD5+(B1) B lymphocytes. We show here that the bone marrow (BM) of cyclin D2-/- mice contains half the numbers of Sca1+B220+ B cell progenitors but normal levels of Sca1+ progenitor cells of other lineages. In addition, clonal analysis of BM from the cyclin D2-/- and cyclin D2+/+ mice confirmed that there were fewer B cell progenitors (B220+) in the cyclin D2-/- mice. In addition, the colonies from cyclin D2-/- mice were less mature (CD19lo) than those from cyclin D2+/+ mice (CD19Hi). The number of mature B2 B cells in vivo is the same in cyclin D2-/- and cyclin D2+/+ animals. Lack of cyclin D2 protein may be compensated by cyclin D3, as cyclin-dependent kinase (cdk)6 coimmunoprecipitates with cyclin D3 but not cyclin D1 from BM mononuclear cells of cyclin D2-/- mice. It is active, as endogenous retinoblastoma protein is phosphorylated at the cdk6/4-cyclin D-specific sites, S807/811. We conclude that cyclin D2 is rate-limiting for the production of B lymphoid progenitor cells whose proliferation does not depend on BCR signaling.

The p85alpha subunit of PI3-K and Btk are two crucial components of the B-cell receptor (BCR) signalling pathway. In the present study, we showed that primary splenic B cells from p85alpha null and xid (Btk-deficient) mice fail to induce cyclin D2 expression and enter early G1, but not S phase of the cell cycle in response to BCR engagement. Furthermore, these Btk or p85alpha null B cells displayed increased cell death compared with wild type following BCR engagement. These findings are further confirmed by studies showing that specific pharmacological inhibitors of Btk (LFM-A13), PI3-K (LY294002 and Wortmannin) and PLCgamma (U73122) also block cyclin D2 expression and S phase entry following BCR stimulation, as well as triggering apoptosis. Collectively, these data provide evidence for the concept that the B-cell signalosome (p85alpha, Btk, BLNK and PLCgamma) is involved in regulating cyclin D2 expression in response to BCR engagement. PKC and intracellular calcium are two major downstream effectors of the B-cell signalosome and can be activated by PMA and ionomycin, respectively. In small resting (G0) B cells, costimulation with PMA and ionomycin, but not PMA or ionomycin alone, induces cyclin D2 expression and cell-cycle progression. Consistent with this, we also showed that the BCR-mediated cyclin D2 induction could be abolished by pretreatment of resting B cells with specific inhibitors of capacitative Ca(2+) entry (SK&F 96365) or PKC (Gö6850). Our present results lead us to propose a model in which the B-cell signalosome targets cyclin D2 via the Ca(2+) and PKC-dependent signalling cascades to mediate cell-cycle progression in response to BCR engagement.

B lymphocytes from mice null for the Rho-family guanine-nucleotide exchange factor, Vav, are defective in their ability to proliferate in response to BCR cross-linking, but are able to proliferate normally in response to LPS. In addition, they have a depletion of CD5(+) (B1) lymphocytes and defective IgG class switching. This phenotype is reminiscent of that observed in mice null for the cell cycle regulatory protein, cyclin D2. We demonstrate here that the inability of vav(-/-) B cells to proliferate in response to BCR ligation is due to an inability to induce cyclin D2. In addition, we show that the proliferative defect of these cells occurs after the cells have entered early G1 phase. Analyses of potential down-stream signaling intermediates revealed differential activation of the stress-activated MAP kinases in the absence of Vav, normal activation of the ERK, MAPK, and phosphatidylinositol 3-kinase pathways, and defective intracellular calcium mobilization. We further demonstrate that intracellular calcium homeostasis is required for cyclin D2 induction, implicating a possible link with the defective calcium response of vav(-/-) B cells and their inability to induce cyclin D2.

Leukemia cells bearing the Philadelphia (Ph) chromosome express a Bcr-Abl fusion protein with deregulated protein tyrosine kinase (PTK) activity, which plays a central role in the malignant transformation. Many different signal transduction pathways are activated by Bcr-Abl, but little is known about their downstream targets in specific cell lineages. We show here that Ph-positive cell lines as well as primary cells derived from chronic myeloid leukemia (CML) in lymphoid blast crisis or from acute lymphoblastic leukemia (ALL) consistently express high levels of cyclin D2, whereas expression of this protein is low or absent in comparable Ph-negative lines and Ph-positive myeloid lines. Inhibition of Bcr-Abl with STI571 resulted in down-regulation of cyclin D2 and reduction of the number of cells in S phase, although complete G1 arrest was not induced. The expression of cyclin D2 in Ph-positive lymphoblasts was mediated via the phosphatidyl-inositol-3 kinase pathway. Analogous results were seen in murine BaF/3 cells transfected with a BCR-ABL expression vector. In contrast to the human cell lines, murine Baf/BCR-ABL cells exposed to STI571 inhibitor were all arrested in G1. This arrest could be abrogated by exogenous expression of cyclin D2 from a transfected cDNA construct. We conclude that a direct connection exists between Bcr-Abl PTK activity and cell cycle progression in which cyclin D2 plays a critical role. However, cell cycle progression in human Ph-positive lymphoid cells is not entirely dependent on Bcr-Abl PTK, and additional genetic lesions must be present.

Cross-linking of the B cell antigen receptor (BCR) on immature WEHI 231 B cells results in G1 cell cycle arrest and apoptosis. Here we investigated the molecular mechanisms that are necessary and sufficient for these changes to occur. We show that BCR stimulation of WEHI 231 cells results in down-regulation of cyclin D2 and up-regulation of p27(Kip1), which are associated with pocket protein hypophosphorylation and E2F inactivation. Ectopic expression of p27(Kip1) by TAT-fusion protein or retroviral transduction is sufficient to cause G1 cell cycle arrest, followed by apoptosis. In contrast, over-expression of cyclin D2 overcomes the cell cycle arrest and apoptosis induced by anti-IgM, indicating that down-regulation of cyclin D2 is necessary for the cell cycle arrest and apoptosis activated by BCR stimulation. Thus, cyclin D2 and p27(Kip1) have opposing roles in these pathways and our data also suggest that cyclin D2 functions upstream of p27(Kip1) and the pRB pathway and therefore plays an essential part in integrating the signals from BCR with the cell cycle machinery. We next investigated which signal transduction pathways triggered by the BCR regulate cell proliferation and apoptosis via cyclin D2 and p27(Kip1). Inhibition of PI3-K signalling by LY294002 down-regulated cyclin D2 and up-regulated p27(Kip1) expression at both protein and RNA levels, mimicking the effects of BCR-stimulation. Furthermore, ectopic expression of a constitutively active form of AKT blocked the cell cycle arrest and apoptosis triggered by anti-IgM and also abrogated down-regulation of cyclin D2 and up-regulation of p27(Kip1) expression induced by BCR-engagement. These results indicate that BCR activation targets p27(Kip1) and cyclin D2 to mediate cell cycle arrest and apoptosis and that down-regulation of PI3-K/AKT activity post BCR stimulation is necessary for these to occur.

Although it is evident that BCR-ABL can rescue cytokine-deprived hematopoietic progenitor cells from cell cycle arrest and apoptosis, the exact mechanism of action of BCR/ABL and interleukin (IL)-3 to promote proliferation and survival has not been established. Using the pro-B cell line BaF3 and a BaF3 cell line stably overexpressing BCR-ABL (BaF3-p210), we investigated the proliferative signals derived from BCR-ABL and IL-3. The results indicate that both IL-3 and BCR-ABL target the expression of cyclin Ds and down-regulation of p27(Kip1) to mediate pRB-related pocket protein phosphorylation, E2F activation, and thus S phase progression. These findings were further confirmed in a BaF3 cell line (TonB.210) where the BCR-ABL expression is inducible by doxycyclin and by using the drug STI571 to inactivate BCR-ABL activity in BaF3-p210. To establish the functional significance of cyclin D2 and p27(Kip1) expression in response to IL-3 and BCR-ABL expression, we studied the effects of ectopic expression of cyclin D2 and p27(Kip1) on cell proliferation and survival. Our results demonstrate that both cyclin D2 and p27(Kip1) have a role in BaF3 cell proliferation and survival, as ectopic expression of cyclin D2 is sufficient to abolish the cell cycle arrest and apoptosis induced by IL-3 withdrawal or by BCR-ABL inactivation, while overexpression of p27(Kip1) can cause cell cycle arrest and apoptosis in the BaF3 cells. Furthermore, our data also suggest that cyclin D2 functions upstream of p27(Kip1), cyclin E, and cyclin D3, and therefore, plays an essential part in integrating the signals from IL-3 and BCR-ABL with the pRB/E2F pathway.

This study investigated the influence of expression of proteins of the INK4 family, particularly p16, on the growth and self-renewal kinetics of hematopoietic cells. First, retrovirus-mediated gene transfer (RMGT) was used to restore p16(INK4a) expression in the p16(INK4a)-deficient lymphoid and myeloid cell lines BV173 and K562, and it was confirmed that this inhibited their growth. Second, to sequester p16(INK4a) and related INK4 proteins, cyclin-dependent kinase 4 (CDK4) was retrovirally transduced into normal human CD34(+) bone marrow cells and then cultured in myeloid colony-forming cell (CFC) assays. The growth of CDK4-transduced colonies was more rapid; the cell-doubling time was reduced; and, upon replating, the colonies produced greater yields of secondary colonies than mock-untransduced controls. Third, colony formation was compared by marrow cells from p16(INK4a-/-) mice and wild-type mice. The results from p16(INK4a-/-) marrow were similar to those from CDK4-transduced human CFCs, in terms of growth rate and replating ability, and were partially reversed by RMGT of p16(INK4a). Lines of immature granulocytic cells were raised from 15 individual colonies grown from the marrow of p16(INK4a-/-) mice. These had a high colony-forming ability (15%) and replating efficiency (96.7%). The p16(INK4a-/-) cell lines readily became growth factor-independent upon cytokine deprivation. Taken together, these results demonstrate that loss of INK4 proteins, in particular p16(INK4a), increases the growth rate of myeloid colonies in vitro and, more importantly, confers an increased ability for clonal expansion on hematopoietic progenitor cells.

Interleukin-3 (IL-3), IL-5, and granulocyte-macrophage colony-stimulating factor regulate the survival, proliferation, and differentiation of hematopoietic lineages. Phosphatidylinositol 3-kinase (PI3K) has been implicated in the regulation of these processes. Here we investigate the molecular mechanism by which PI3K regulates cytokine-mediated proliferation and survival in the murine pre-B-cell line Ba/F3. IL-3 was found to repress the expression of the cyclin-dependent kinase inhibitor p27(KIP1) through activation of PI3K, and this occurs at the level of transcription. This transcriptional regulation occurs through modulation of the forkhead transcription factor FKHR-L1, and IL-3 inhibited FKHR-L1 activity in a PI3K-dependent manner. We have generated Ba/F3 cell lines expressing a tamoxifen-inducible active FKHR-L1 mutant [FKHR-L1(A3):ER*]. Tamoxifen-mediated activation of FKHR-L1(A3):ER* resulted in a striking increase in p27(KIP1) promoter activity and mRNA and protein levels as well as induction of the apoptotic program. The level of p27(KIP1) appears to be critical in the regulation of cell survival since mere ectopic expression of p27(KIP1) was sufficient to induce Ba/F3 apoptosis. Moreover, cell survival was increased in cytokine-starved bone marrow-derived stem cells from p27(KIP1) null-mutant mice compared to that in cells from wild-type mice. Taken together, these observations indicate that inhibition of p27(KIP1) transcription through PI3K-induced FKHR-L1 phosphorylation provides a novel mechanism of regulating cytokine-mediated survival and proliferation.

Since signals via CD40 and the B cell receptor are known to synergize to induce B cell activation, we have analyzed the pocket protein/E2F complexes in mouse B lymphocytes following stimulation by anti-IgM, anti-CD40, alone or together. We find that E2F4 and DP1 form the predominant E2F heterodimers in the G0 and G1 phases of the cell cycle, complexed with hypophosphorylated p130. During late G1 and S phase this complex is replaced by at least three different E2F complexes, one of which is an E2F complex containing p107 or pRB as well as two "free" E2F complexes consisting of E2F4/DP1 and E2F1-3/DP1. These effects were mirrored by the levels and phosphorylation status of the three pocket proteins. We also observed an increase in electrophoretic mobility of DP1 and E2F4 as B cells progressed from G0 into early G1, resulting from their dephosphorylation. This is known to correlate with a decrease in DNA binding capacity of these proteins and could also be important for derepression of genes negatively regulated through E2F sites in their promoters. These results therefore indicate that the pRB/E2F pathway integrates proliferative signals emanating from the sIgM and CD40 receptors.