Articles de revues : « PI4K »

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Klima, Martin, Adriana Baumlova, Dominika Chalupska, Hubert Hřebabecký, Milan Dejmek, Radim Nencka et Evzen Boura. « The high-resolution crystal structure of phosphatidylinositol 4-kinase IIβ and the crystal structure of phosphatidylinositol 4-kinase IIα containing a nucleoside analogue provide a structural basis for isoform-specific inhibitor design ». Acta Crystallographica Section D Biological Crystallography 71, n^o 7 (30 juin 2015) : 1555–63. http://dx.doi.org/10.1107/s1399004715009505.

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Phosphatidylinositol 4-phosphate (PI4P) is the most abundant monophosphoinositide in eukaryotic cells. Humans have four phosphatidylinositol 4-kinases (PI4Ks) that synthesize PI4P, among which are PI4K IIβ and PI4K IIα. In this study, two crystal structures are presented: the structure of human PI4K IIβ and the structure of PI4K IIα containing a nucleoside analogue. The former, a complex with ATP, is the first high-resolution (1.9 Å) structure of a PI4K. These structures reveal new details such as high conformational heterogeneity of the lateral hydrophobic pocket of the C-lobe and together provide a structural basis for isoform-specific inhibitor design.

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Wu, Liujie, Ayan Sadhukhan, Yuriko Kobayashi, Naohisa Ogo, Mutsutomo Tokizawa, Raj Kishan Agrahari, Hiroki Ito et al. « Involvement of phosphatidylinositol metabolism in aluminum-induced malate secretion in Arabidopsis ». Journal of Experimental Botany 70, n^o 12 (12 avril 2019) : 3329–42. http://dx.doi.org/10.1093/jxb/erz179.

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Abstract To identify the upstream signaling of aluminum-induced malate secretion through aluminum-activated malate transporter 1 (AtALMT1), a pharmacological assay using inhibitors of human signal transduction pathways was performed. Early aluminum-induced transcription of AtALMT1 and other aluminum-responsive genes was significantly suppressed by phosphatidylinositol 4-kinase (PI4K) and phospholipase C (PLC) inhibitors, indicating that the PI4K–PLC metabolic pathway activates early aluminum signaling. Inhibitors of phosphatidylinositol 3-kinase (PI3K) and PI4K reduced aluminum-activated malate transport by AtALMT1, suggesting that both the PI3K and PI4K metabolic pathways regulate this process. These results were validated using T-DNA insertion mutants of PI4K and PI3K-RNAi lines. A human protein kinase inhibitor, putatively inhibiting homologous calcineurin B-like protein-interacting protein kinase and/or Ca-dependent protein kinase in Arabidopsis, suppressed late-phase aluminum-induced expression of AtALMT1, which was concomitant with the induction of an AtALMT1 repressor, WRKY46, and suppression of an AtALMT1 activator, Calmodulin-binding transcription activator 2 (CAMTA2). In addition, a human deubiquitinase inhibitor suppressed aluminum-activated malate transport, suggesting that deubiquitinases can regulate this process. We also found a reduction of aluminum-induced citrate secretion in tobacco by applying inhibitors of PI3K and PI4K. Taken together, our results indicated that phosphatidylinositol metabolism regulates organic acid secretion in plants under aluminum stress.

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WAUGH, Mark G., Shane MINOGUE, J. Simon ANDERSON, Adam BALINGER, Deena BLUMENKRANTZ, Denis P. CALNAN, Rainer CRAMER et J. Justin HSUAN. « Localization of a highly active pool of type II phosphatidylinositol 4-kinase in a p97/valosin-containing-protein-rich fraction of the endoplasmic reticulum ». Biochemical Journal 373, n^o 1 (1 juillet 2003) : 57–63. http://dx.doi.org/10.1042/bj20030089.

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Different phosphoinositides are synthesized in cell membranes in order to perform a variety of functions. One of the most abundant of these lipids is phosphatidylinositol (PI) 4-phosphate (PI4P), which is formed in human eukaryotes by type II and type III phosphatidylinositol 4-kinase (PI4K II and III) activities. PI4K II activity occurs in many different subcellular membranes, although no detailed analysis of the distribution of this activity has been reported. Using density gradient ultracentrifugation, we have previously found that in A431 cells the predominant PI4K activity arises from a type IIα enzyme that is localized to a buoyant membrane fraction of unknown origin [Waugh, Lawson, Tan and Hsuan (1998) J. Biol. Chem. 273, 17115–17121]. We show here that these buoyant membranes contain an activated form of PI4K IIα that can be separated from the bulk of the PI4K IIα protein in A431 and COS-7 cells. Proteomic analysis revealed that the buoyant membrane fraction contains numerous endoplasmic reticulum (ER)-marker proteins, although it was separated from the bulk of the ER, ER–Golgi intermediate compartment, transitional ER, Golgi and other major subcellular membranes. Furthermore, the majority of the cytoplasmic valosin-containing protein (VCP), an AAA+ATPase implicated in various ER, transitional ER, Golgi and nuclear functions, was almost completely localized to the same buoyant membrane fraction. Co-localization of VCP and PI4K activity was confirmed by co-immunoprecipitation. These results suggest the previously unsuspected existence of an ER-related domain in which the bulk of the cellular PI4P synthesis and VCP are localized.

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Balla, Andras, Yeun Ju Kim, Peter Varnai, Zsofia Szentpetery, Zachary Knight, Kevan M. Shokat et Tamas Balla. « Maintenance of Hormone-sensitive Phosphoinositide Pools in the Plasma Membrane Requires Phosphatidylinositol 4-Kinase IIIα ». Molecular Biology of the Cell 19, n^o 2 (février 2008) : 711–21. http://dx.doi.org/10.1091/mbc.e07-07-0713.

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Type III phosphatidylinositol (PtdIns) 4-kinases (PI4Ks) have been previously shown to support plasma membrane phosphoinositide synthesis during phospholipase C activation and Ca2+ signaling. Here, we use biochemical and imaging tools to monitor phosphoinositide changes in the plasma membrane in combination with pharmacological and genetic approaches to determine which of the type III PI4Ks (α or β) is responsible for supplying phosphoinositides during agonist-induced Ca2+ signaling. Using inhibitors that discriminate between the α- and β-isoforms of type III PI4Ks, PI4KIIIα was found indispensable for the production of phosphatidylinositol 4-phosphate (PtdIns4P), phosphatidylinositol 4,5-bisphosphate [PtdIns(4,5)P2], and Ca2+ signaling in angiotensin II (AngII)-stimulated cells. Down-regulation of either the type II or type III PI4K enzymes by small interfering RNA (siRNA) had small but significant effects on basal PtdIns4P and PtdIns(4,5)P2 levels in 32P-labeled cells, but only PI4KIIIα down-regulation caused a slight impairment of PtdIns4P and PtdIns(4,5)P2 resynthesis in AngII-stimulated cells. None of the PI4K siRNA treatments had a measurable effect on AngII-induced Ca2+ signaling. These results indicate that a small fraction of the cellular PI4K activity is sufficient to maintain plasma membrane phosphoinositide pools, and they demonstrate the value of the pharmacological approach in revealing the pivotal role of PI4KIIIα enzyme in maintaining plasma membrane phosphoinositides.

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Hammond, Gerald R. V., Giampietro Schiavo et Robin F. Irvine. « Immunocytochemical techniques reveal multiple, distinct cellular pools of PtdIns4P and PtdIns(4,5)P2 ». Biochemical Journal 422, n^o 1 (29 juillet 2009) : 23–35. http://dx.doi.org/10.1042/bj20090428.

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PtdIns4P is the major precursor for the synthesis of the multifunctional plasma membrane lipid, PtdIns(4,5)P2. Yet PtdIns4P also functions as a regulatory lipid in its own right, particularly at the Golgi apparatus. In the present study we define specific conditions that enable preservation of several organellar membranes for the immunocytochemical detection of PtdIns4P. We report distinct pools of this lipid in both Golgi and plasma membranes, which are synthesized by different PI4K (phosphatidylinositol 4-kinase) activities, and also the presence of PtdIns4P in cytoplasmic vesicles, which are not readily identifiable as PI4K containing trafficking intermediates. In addition, we present evidence that the majority of PtdIns4P resides in the plasma membrane, where it is metabolically distinct from the steady-state plasma membrane pool of PtdIns(4,5)P2.

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Dembele, Laurent, Yaw Aniweh, Nouhoum Diallo, Fanta Sogore, Cheick Papa Oumar Sangare, Aboubecrin Sedhigh Haidara, Aliou Traore et al. « Plasmodium malariae and Plasmodium falciparum comparative susceptibility to antimalarial drugs in Mali ». Journal of Antimicrobial Chemotherapy 76, n^o 8 (22 mai 2021) : 2079–87. http://dx.doi.org/10.1093/jac/dkab133.

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Abstract Objectives To evaluate Plasmodium malariae susceptibility to current and lead candidate antimalarial drugs. Methods We conducted cross-sectional screening and detection of all Plasmodium species malaria cases, which were nested within a longitudinal prospective study, and an ex vivo assessment of efficacy of a panel of antimalarials against P. malariae and Plasmodium falciparum, both PCR-confirmed mono-infections. Reference compounds tested included chloroquine, lumefantrine, artemether and piperaquine, while candidate antimalarials included the imidazolopiperazine GNF179, a close analogue of KAF156, and the Plasmodium phosphatidylinositol-4-OH kinase (PI4K)-specific inhibitor KDU691. Results We report a high frequency (3%–15%) of P. malariae infections with a significant reduction in ex vivo susceptibility to chloroquine, lumefantrine and artemether, which are the current frontline drugs against P. malariae infections. Unlike these compounds, potent inhibition of P. malariae and P. falciparum was observed with piperaquine exposure. Furthermore, we evaluated advanced lead antimalarial compounds. In this regard, we identified strong inhibition of P. malariae using GNF179, a close analogue of KAF156 imidazolopiperazines, which is a novel class of antimalarial drug currently in clinical Phase IIb testing. Finally, in addition to GNF179, we demonstrated that the Plasmodium PI4K-specific inhibitor KDU691 is highly inhibitory against P. malariae and P. falciparum. Conclusions Our data indicated that chloroquine, lumefantrine and artemether may not be suitable for the treatment of P. malariae infections and the potential of piperaquine, as well as new antimalarials imidazolopiperazines and PI4K-specific inhibitor, for P. malariae cure.

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Bar-Lev, Tali H., Dagan Harris, Melanija Tomić, Stanko Stojilkovic, Zeev Blumenfeld, Pamela Brown, Rony Seger et Zvi Naor. « Role of PI4K and PI3K-AKT in ERK1/2 activation by GnRH in the pituitary gonadotropes ». Molecular and Cellular Endocrinology 415 (novembre 2015) : 12–23. http://dx.doi.org/10.1016/j.mce.2015.07.029.

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Galvão, Rafaelo M., Uma Kota, Erik J. Soderblom, Michael B. Goshe et Wendy F. Boss. « Characterization of a new family of protein kinases from Arabidopsis containing phosphoinositide 3/4-kinase and ubiquitin-like domains ». Biochemical Journal 409, n^o 1 (11 décembre 2007) : 117–27. http://dx.doi.org/10.1042/bj20070959.

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At least two of the genes predicted to encode type II PI4K (phosphoinositide 4-kinase) in Arabidopsis thaliana (thale cress), namely AtPI4Kγ4 and AtPI4Kγ7, encode enzymes with catalytic properties similar to those of members of the PIKK (phosphoinositide kinase-related kinase) family. AtPI4Kγ4 and AtPI4Kγ7 undergo autophosphorylation and phosphorylate serine/threonine residues of protein substrates, but have no detectable lipid kinase activity. AtPI4Kγ4 and AtPI4Kγ7 are members of a subset of five putative AtPI4Ks that contain N-terminal UBL (ubiquitin-like) domains. In vitro analysis of AtPI4Kγ4 indicates that it interacts directly with, and phosphorylates, two proteins involved in the ubiquitin–proteasome system, namely UFD1 (ubiquitin fusion degradation 1) and RPN10 (regulatory particle non-ATPase 10). On the basis of the present results, we propose that AtPI4Kγ4 and AtPI4Kγ7 should be designated UbDKγ4 and UbDKγ7 (ubiquitin-like domain kinases γ4 and γ7). These UBL-domain-containing AtPI4Ks correspond to a new PIKK subfamily of protein kinases. Furthermore, UFD1 and RPN10 phosphorylation represents an additional mechanism by which their function can be regulated.

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Kim, I. A., J. Kwon, Y. H. Park, D. H. Kim et J. M. Park. « Targeting PI4K for Radiosensitization : A Potential Model of Drug Repositioning ». International Journal of Radiation Oncology*Biology*Physics 96, n^o 2 (octobre 2016) : E558. http://dx.doi.org/10.1016/j.ijrobp.2016.06.2025.

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Banerji, Sangeeta, Mike Ngo, Ciaran F. Lane, Carolyn-Ann Robinson, Shane Minogue et Neale D. Ridgway. « Oxysterol Binding Protein-dependent Activation of Sphingomyelin Synthesis in the Golgi Apparatus Requires Phosphatidylinositol 4-Kinase IIα ». Molecular Biology of the Cell 21, n^o 23 (décembre 2010) : 4141–50. http://dx.doi.org/10.1091/mbc.e10-05-0424.

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Cholesterol and sphingomyelin (SM) associate in raft domains and are metabolically coregulated. One aspect of coordinate regulation occurs in the Golgi apparatus where oxysterol binding protein (OSBP) mediates sterol-dependent activation of ceramide transport protein (CERT) activity and SM synthesis. Because CERT transfer activity is dependent on its phosphatidylinositol 4 phosphate [PtdIns(4)P]-specific pleckstrin homology domain, we investigated whether OSBP activation of CERT involved a Golgi-associated PtdIns 4-kinase (PI4K). Cell fractionation experiments revealed that Golgi/endosome-enriched membranes from 25-hydroxycholesterol-treated Chinese hamster ovary cells had increased activity of a sterol-sensitive PI4K that was blocked by small interfering RNA silencing of OSBP. Consistent with this sterol-requirement, OSBP silencing also reduced the cholesterol content of endosome/trans-Golgi network (TGN) fractions containing PI4KIIα. PI4KIIα, but not PI4KIIIβ, was required for oxysterol-activation of SM synthesis and recruitment of CERT to the Golgi apparatus. However, neither PI4KIIα nor PI4KIIIβ expression was required for 25-hydroxycholesterol–dependent translocation of OSBP to the Golgi apparatus. The presence of OSBP, CERT, and PI4KIIα in the TGN of oxysterol-stimulated cells suggests that OSBP couples sterol binding or transfer activity with regulation of PI4KIIα activity, leading to CERT recruitment to the TGN and increased SM synthesis.

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Balla, Andras, Galina Tuymetova, Arnold Tsiomenko, Péter Várnai et Tamas Balla. « A Plasma Membrane Pool of Phosphatidylinositol 4-Phosphate Is Generated by Phosphatidylinositol 4-Kinase Type-III Alpha : Studies with the PH Domains of the Oxysterol Binding Protein and FAPP1 ». Molecular Biology of the Cell 16, n^o 3 (mars 2005) : 1282–95. http://dx.doi.org/10.1091/mbc.e04-07-0578.

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The PH domains of OSBP and FAPP1 fused to GFP were used to monitor PI(4)P distribution in COS-7 cells during manipulations of PI 4-kinase (PI4K) activities. Both domains were associated with the Golgi and small cytoplasmic vesicles, and a small fraction of OSBP-PH was found at the plasma membrane (PM). Inhibition of type-III PI4Ks with 10 μM wortmannin (Wm) significantly reduced but did not abolish Golgi localization of either PH domains. Downregulation of PI4KIIα or PI4KIIIβ by siRNA reduced the localization of the PH domains to the Golgi and in the former case any remaining Golgi localization was eliminated by Wm treatment. PLC activation by Ca2+ ionophores dissociated the domains from all membranes, but after Ca2+ chelation, they rapidly reassociated with the Golgi, the intracellular vesicles and with the PM. PM association of the domains was significantly higher after the Ca2+ transient and was abolished by Wm pretreatment. PM relocalization was not affected by down-regulation of PI4KIIIβ or -IIα, but was inhibited by down-regulation of PI4KIIIα, or by 10 μM PAO, which also inhibits PI4KIIIα. Our data suggest that these PH domains detect PI(4)P formation in extra-Golgi compartments under dynamic conditions and that various PI4Ks regulate PI(4)P synthesis in distinct cellular compartments.

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Kim, I. A., J. Kwon, Y. Park, D. Kim et J. Park. « PV-0426 : Targeting PI4K for radiosensitisation : a viable model of drug repositioning ». Radiotherapy and Oncology 119 (avril 2016) : S198—S199. http://dx.doi.org/10.1016/s0167-8140(16)31675-9.

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Wood, Christopher S., Chia-Sui Hung, Yu-San Huoh, Carl J. Mousley, Christopher J. Stefan, Vytas Bankaitis, Kathryn M. Ferguson et Christopher G. Burd. « Local control of phosphatidylinositol 4-phosphate signaling in the Golgi apparatus by Vps74 and Sac1 phosphoinositide phosphatase ». Molecular Biology of the Cell 23, n^o 13 (juillet 2012) : 2527–36. http://dx.doi.org/10.1091/mbc.e12-01-0077.

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In the Golgi apparatus, lipid homeostasis pathways are coordinated with the biogenesis of cargo transport vesicles by phosphatidylinositol 4-kinases (PI4Ks) that produce phosphatidylinositol 4-phosphate (PtdIns4P), a signaling molecule that is recognized by downstream effector proteins. Quantitative analysis of the intra-Golgi distribution of a PtdIns4P reporter protein confirms that PtdIns4P is enriched on the trans-Golgi cisterna, but surprisingly, Vps74 (the orthologue of human GOLPH3), a PI4K effector required to maintain residence of a subset of Golgi proteins, is distributed with the opposite polarity, being most abundant on cis and medial cisternae. Vps74 binds directly to the catalytic domain of Sac1 (KD = 3.8 μM), the major PtdIns4P phosphatase in the cell, and PtdIns4P is elevated on medial Golgi cisternae in cells lacking Vps74 or Sac1, suggesting that Vps74 is a sensor of PtdIns4P level on medial Golgi cisternae that directs Sac1-mediated dephosphosphorylation of this pool of PtdIns4P. Consistent with the established role of Sac1 in the regulation of sphingolipid biosynthesis, complex sphingolipid homeostasis is perturbed in vps74Δ cells. Mutant cells lacking complex sphingolipid biosynthetic enzymes fail to properly maintain residence of a medial Golgi enzyme, and cells lacking Vps74 depend critically on complex sphingolipid biosynthesis for growth. The results establish additive roles of Vps74-mediated and sphingolipid-dependent sorting of Golgi residents.

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Walsh, Ciara M., Michael Chvanov, Lee P. Haynes, Ole H. Petersen, Alexei V. Tepikin et Robert D. Burgoyne. « Role of phosphoinositides in STIM1 dynamics and store-operated calcium entry ». Biochemical Journal 425, n^o 1 (14 décembre 2009) : 159–68. http://dx.doi.org/10.1042/bj20090884.

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Ca2+ entry through store-operated Ca2+ channels involves the interaction at ER–PM (endoplasmic reticulum–plasma membrane) junctions of STIM (stromal interaction molecule) and Orai. STIM proteins are sensors of the luminal ER Ca2+ concentration and, following depletion of ER Ca2+, they oligomerize and translocate to ER–PM junctions where they form STIM puncta. Direct binding to Orai proteins activates their Ca2+ channel function. It has been suggested that an additional interaction of the C-terminal polybasic domain of STIM1 with PM phosphoinositides could contribute to STIM1 puncta formation prior to binding to Orai. In the present study, we investigated the role of phosphoinositides in the formation of STIM1 puncta and SOCE (store-operated Ca2+ entry) in response to store depletion. Treatment of HeLa cells with inhibitors of PI3K (phosphatidylinositol 3-kinase) and PI4K (phosphatidylinositol 4-kinase) (wortmannin and LY294002) partially inhibited formation of STIM1 puncta. Additional rapid depletion of PtdIns(4,5)P2 resulted in more substantial inhibition of the translocation of STIM1–EYFP (enhanced yellow fluorescent protein) into puncta. The inhibition was extensive at a concentration of LY294002 (50 μM) that should primarily inhibit PI3K, consistent with a major role for PtdIns(4,5)P2 and PtdIns(3,4,5)P3 in puncta formation. Depletion of phosphoinositides also inhibited SOCE based on measurement of the rise in intracellular Ca2+ concentration after store depletion. Overexpression of Orai1 resulted in a recovery of translocation of STMI1 into puncta following phosphoinositide depletion and, under these conditions, SOCE was increased to above control levels. These observations support the idea that phosphoinositides are not essential but contribute to STIM1 accumulation at ER–PM junctions with a second translocation mechanism involving direct STIM1–Orai interactions.

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Highland, Carolyn M., et J. Christopher Fromme. « Arf1 directly recruits the Pik1-Frq1 PI4K complex to regulate the final stages of Golgi maturation ». Molecular Biology of the Cell 32, n^o 10 (1 mai 2021) : 1064–80. http://dx.doi.org/10.1091/mbc.e21-02-0069.

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Arf1 oversees a myriad of conserved processes at the Golgi complex. This work provides new insight into the relationship between Arf1 activity and PI4P synthesis in budding yeast by demonstrating that Arf1 directly recruits the Pik1-Frq1 PI 4-kinase complex to the Golgi. PI4P then primes the Golgi for the final stages of Golgi maturation.

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Park, Younghee, Ji Min Park, Dan Hyo Kim, Jeanny Kwon et In Ah Kim. « Inhibition of PI4K IIIα radiosensitizes in human tumor xenograft and immune-competent syngeneic murine tumor model ». Oncotarget 8, n^o 66 (30 novembre 2017) : 110392–405. http://dx.doi.org/10.18632/oncotarget.22778.

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Zeeman, Anne-Marie, Suresh B. Lakshminarayana, Nicole van der Werff, Els J. Klooster, Annemarie Voorberg-van der Wel, Ravinder R. Kondreddi, Christophe Bodenreider et al. « PI4 Kinase Is a Prophylactic but Not Radical Curative Target in Plasmodium vivax-Type Malaria Parasites ». Antimicrobial Agents and Chemotherapy 60, n^o 5 (29 février 2016) : 2858–63. http://dx.doi.org/10.1128/aac.03080-15.

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ABSTRACTTwoPlasmodiumPI4 kinase (PI4K) inhibitors, KDU691 and LMV599, were selected forin vivotesting as causal prophylactic and radical-cure agents forPlasmodium cynomolgisporozoite-infected rhesus macaques, based on theirin vitroactivity against liver stages. Animals were infected withP. cynomolgisporozoites, and compounds were dosed orally. Both the KDU691 and LMV599 compounds were fully protective when administered prophylactically, and the more potent compound LMV599 achieved protection as a single oral dose of 25 mg/kg of body weight. In contrast, when tested for radical cure, five daily doses of 20 mg/kg of KDU691 or 25 mg/kg of LMV599 did not prevent relapse, as all animals experienced a secondary infection due to the reactivation of hypnozoites in the liver. Pharmacokinetic data show that LMV599 achieved plasma exposure that was sufficient to achieve efficacy based on ourin vitrodata. These findings indicate thatPlasmodiumPI4K is a potential drug target for malaria prophylaxis but not radical cure. Longerin vitroculture systems will be required to assess these compounds' activity on established hypnozoites and predict radical curein vivo.

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Liu, Pei, Zhao-Shi Xu, Lu Pan-Pan, Di Hu, Ming Chen, Lian-Cheng Li et You-Zhi Ma. « A wheat PI4K gene whose product possesses threonine autophophorylation activity confers tolerance to drought and salt in Arabidopsis ». Journal of Experimental Botany 64, n^o 10 (16 mai 2013) : 2915–27. http://dx.doi.org/10.1093/jxb/ert133.

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Chang, Guan Jun, Yi Xu, Hong Ju Hu, Li Dong Wei, Shang Fei Sun, Hai Yan Sun, Chang Liu et al. « Building of Poly(Imino Ketone) Chains Model via Molecular Simulation ». Applied Mechanics and Materials 117-119 (octobre 2011) : 1306–9. http://dx.doi.org/10.4028/www.scientific.net/amm.117-119.1306.

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Based on different aromatic dibromides and diamines, using Material Studio software and molecular simulation method, Poly(imino ketone) (PIK), Poly(imino ketone ketone) (PIKK), Poly(imino imino ketone) (PIIK), Poly(imino imino ketone ketone) (PIIKK), Flourene-PIIK and Naphthyl-PIIK, respectively, were designed as six different structures of polymers. And through the method of molecular mechanics and molecular dynamics the single-molecule polymer chain model and the aggregation-state model with three-dimensional periodic boundary conditions would be built. Theoretically, the established model has been verified availably after optimization based on molecular mechanics and molecular dynamics.

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Liu, Hui, Fen-Fen Wang, Xian-Jun Peng, Jian-Hui Huang et Shi-Hua Shen. « Global Phosphoproteomic Analysis Reveals the Defense and Response Mechanisms of Jatropha Curcas Seedling under Chilling Stress ». International Journal of Molecular Sciences 20, n^o 1 (8 janvier 2019) : 208. http://dx.doi.org/10.3390/ijms20010208.

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As a promising energy plant for biodiesel, Jatropha curcas is a tropical and subtropical shrub and its growth is affected by one of major abiotic stress, chilling. Therefore, we adopt the phosphoproteomic analysis, physiological measurement and ultrastructure observation to illustrate the responsive mechanism of J. curcas seedling under chilling (4 °C) stress. After chilling for 6 h, 308 significantly changed phosphoproteins were detected. Prolonged the chilling treatment for 24 h, obvious physiological injury can be observed and a total of 332 phosphoproteins were examined to be significantly changed. After recovery (28 °C) for 24 h, 291 phosphoproteins were varied at the phosphorylation level. GO analysis showed that significantly changed phosphoproteins were mainly responsible for cellular protein modification process, transport, cellular component organization and signal transduction at the chilling and recovery periods. On the basis of protein-protein interaction network analysis, phosphorylation of several protein kinases, such as SnRK2, MEKK1, EDR1, CDPK, EIN2, EIN4, PI4K and 14-3-3 were possibly responsible for cross-talk between ABA, Ca2+, ethylene and phosphoinositide mediated signaling pathways. We also highlighted the phosphorylation of HOS1, APX and PIP2 might be associated with response to chilling stress in J. curcas seedling. These results will be valuable for further study from the molecular breeding perspective.

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Mello, Chris, Esmeralda Aguayo, Madeleine Rodriguez, Gary Lee, Robert Jordan, Tomas Cihlar et Gabriel Birkus. « Multiple Classes of Antiviral Agents ExhibitIn VitroActivity against Human Rhinovirus Type C ». Antimicrobial Agents and Chemotherapy 58, n^o 3 (23 décembre 2013) : 1546–55. http://dx.doi.org/10.1128/aac.01746-13.

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ABSTRACTHuman rhinovirus type C (HRV-C) is a newly discovered enterovirus species frequently associated with exacerbation of asthma and other acute respiratory conditions. Until recently, HRV-C could not be propagatedin vitro, hampering in-depth characterization of the virus replication cycle and preventing efficient testing of antiviral agents. Herein we describe several subgenomic RNA replicon systems and a cell culture infectious model for HRV-C that can be used for antiviral screening. The replicon constructs consist of genome sequences from HRVc15, HRVc11, HRVc24, and HRVc25 strains, with the P1 capsid region replaced by aRenillaluciferase coding sequence. Following transfection of the replicon RNA into HeLa cells, the constructs produced time-dependent increases in luciferase signal that can be inhibited in a dose-dependent manner by known inhibitors of HRV replication, including the 3C protease inhibitor rupintrivir, the nucleoside analog inhibitor MK-0608, and the phosphatidylinositol 4-kinase IIIβ (PI4K-IIIβ) kinase inhibitor PIK93. Furthermore, with the exception of pleconaril and pirodavir, the other tested classes of HRV inhibitors blocked the replication of full-length HRVc15 and HRVc11 in human airway epithelial cells (HAEs) that were differentiated in the air-liquid interface, exhibiting antiviral activities similar to those observed with HRV-16. In summary, this study is the first comprehensive profiling of multiple classes of antivirals against HRV-C, and the set of newly developed quantitative HRV-C antiviral assays represent indispensable tools for the identification and evaluation of novel panserotype HRV inhibitors.

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Jung, Gwanghyun, Jing Wang, Pawel Wlodarski, Barbara Barylko, Derk D. Binns, Hongjun Shu, Helen L. Yin et Joseph P. Albanesi. « Molecular determinants of activation and membrane targeting of phosphoinositol 4-kinase IIβ ». Biochemical Journal 409, n^o 2 (21 décembre 2007) : 501–9. http://dx.doi.org/10.1042/bj20070821.

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Mammalian cells contain two isoforms of the type II PI4K (phosphoinositol 4-kinase), PI4KIIα and β. These 55 kDa proteins have highly diverse N-terminal regions (approximately residues 1–90) but conserved catalytic domains (approximately from residue 91 to the C-termini). Nearly the entire pool of PI4KIIα behaves as an integral membrane protein, in spite of a lack of a transmembrane domain. This integral association with membranes is due to palmitoylation of a cysteine-rich motif, CCPCC, located within the catalytic domain. Although the CCPCC motif is conserved in PI4KIIβ, only 50% of PI4KIIβ is membrane-associated, and approximately half of this pool is only peripherally attached to the membranes. Growth factor stimulation or overexpression of a constitutively active Rac mutant induces the translocation of a portion of cytosolic PI4KIIβ to plasma membrane ruffles and stimulates its activity. Here, we demonstrate that membrane-associated PI4KIIβ undergoes two modifications, palmitoylation and phosphorylation. The cytosolic pool of PI4KIIβ is not palmitoylated and has much lower lipid kinase activity than the membrane-associated kinase. Although only membrane-associated PI4KIIβ is phosphorylated in the unique N-terminal region, this modification apparently does not influence its membrane binding or activity. A series of truncation mutants and α/β chimaeras were generated to identify regions responsible for the isoform-specific behaviour of the kinases. Surprisingly, the C-terminal approx. 160 residues, and not the diverse N-terminal regions, contain the sites that are most important in determining the different solubilities, palmitoylation states and stimulus-dependent redistributions of PI4KIIα and β.

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Jeong, Jun Yeong, Yeon Joo Lee, Jeong Hoon Han, Sun Young Park, Kwang Woo Hwang et Uy Dong Sohn. « The Inhibitory Effect of PIK-75 on Inflammatory Mediator Response Induced by Hydrogen Peroxide in Feline Esophageal Epithelial Cells ». Mediators of Inflammation 2014 (2014) : 1–9. http://dx.doi.org/10.1155/2014/178049.

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Isoform-selective inhibitors of phosphoinositide 3-kinase (PI3K) activation have an anti-inflammatory effect by reducing proinflammatory cytokines. Cultured feline esophageal epithelial cells (EEC) of passages 3~4 were treated with hydrogen peroxide and PIK-75. The cell viability was measured by a MTT incorporation assay. The distribution of PI3K isoforms, p-Akt, IL-1β, and IL-8 was inferred from Western blots. The release of IL-6 was determined by ELISA. The cell morphology was not considerably different from nontreated cells if the cells were pretreated with PIK-75 and treated with 300 μM hydrogen peroxide. The density of p110α of PI3K was increased, but that of other types was not affected after the treatment with hydrogen peroxide. The density of p-Akt, when the cells were exposed to PIK-75 and hydrogen peroxide, was diminished dose dependently more than that of hydrogen peroxide treatment only. The decrease of p-Akt showed an inhibition of PI3K by PIK-75. PIK-75 dose dependently reduced the expression of IL-1β, IL-8, and the level of IL-6 compared with hydrogen peroxide treatment only. These results suggest evidence that p110α mediates esophageal inflammation and that PIK-75 has an anti-inflammatory effect by reducing proinflammatory cytokines on feline esophageal epithelial cultured cells.

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Borawski, Jason, Philip Troke, Xiaoling Puyang, Veronica Gibaja, ShanChaun Zhao, Craig Mickanin, Juliet Leighton-Davies et al. « Class III Phosphatidylinositol 4-Kinase Alpha and Beta Are Novel Host Factor Regulators of Hepatitis C Virus Replication ». Journal of Virology 83, n^o 19 (15 juillet 2009) : 10058–74. http://dx.doi.org/10.1128/jvi.02418-08.

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ABSTRACT Host factor pathways are known to be essential for hepatitis C virus (HCV) infection and replication in human liver cells. To search for novel host factor proteins required for HCV replication, we screened a subgenomic genotype 1b replicon cell line (Luc-1b) with a kinome and druggable collection of 20,779 siRNAs. We identified and validated several enzymes required for HCV replication, including class III phosphatidylinositol 4-kinases (PI4KA and PI4KB), carbamoyl-phosphate synthetase 2, aspartate transcarbamylase, and dihydroorotase (CAD), and mevalonate (diphospho) decarboxylase. Knockdown of PI4KA could inhibit the replication and/or HCV RNA levels of the two subgenomic genotype 1b clones (SG-1b and Luc-1b), two subgenomic genotype 1a clones (SG-1a and Luc-1a), JFH-1 genotype 2a infectious virus (JFH1-2a), and the genomic genotype 1a (FL-1a) replicon. In contrast, PI4KB knockdown inhibited replication and/or HCV RNA levels of Luc-1b, SG-1b, and Luc-1a replicons. The small molecule inhibitor, PIK93, was found to block subgenomic genotype 1b (Luc-1b), subgenomic genotype 1a (Luc-1a), and genomic genotype 2a (JFH1-2a) infectious virus replication in the nanomolar range. PIK93 was characterized by using quantitative chemical proteomics and in vitro biochemical assays to demonstrate PIK93 is a bone fide PI4KA and PI4KB inhibitor. Our data demonstrate that genetic or pharmacological modulation of PI4KA and PI4KB inhibits multiple genotypes of HCV and represents a novel druggable class of therapeutic targets for HCV infection.

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Dornan, Gillian L., Jacob A. McPhail et John E. Burke. « Type III phosphatidylinositol 4 kinases : structure, function, regulation, signalling and involvement in disease ». Biochemical Society Transactions 44, n^o 1 (9 février 2016) : 260–66. http://dx.doi.org/10.1042/bst20150219.

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Many important cellular functions are regulated by the selective recruitment of proteins to intracellular membranes mediated by specific interactions with lipid phosphoinositides. The enzymes that generate lipid phosphoinositides therefore must be properly positioned and regulated at their correct cellular locations. Phosphatidylinositol 4 kinases (PI4Ks) are key lipid signalling enzymes, and they generate the lipid species phosphatidylinositol 4-phosphate (PI4P), which plays important roles in regulating physiological processes including membrane trafficking, cytokinesis and organelle identity. PI4P also acts as the substrate for the generation of the signalling phosphoinositides phosphatidylinositol 4,5-bisphosphate (PIP2) and phosphatidylinositol 3,4,5-trisphosphate (PIP3). PI4Ks also play critical roles in a number of pathological processes including mediating replication of a number of pathogenic RNA viruses, and in the development of the parasite responsible for malaria. Key to the regulation of PI4Ks is their regulation by a variety of both host and viral protein-binding partners. We review herein our current understanding of the structure, regulatory interactions and role in disease of the type III PI4Ks.

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Dagia, Nilesh M., Gautam Agarwal, Divya V. Kamath, Anshu Chetrapal-Kunwar, Ravindra D. Gupte, Mahesh G. Jadhav, Shruta S. Dadarkar et al. « A preferential p110α/γ PI3K inhibitor attenuates experimental inflammation by suppressing the production of proinflammatory mediators in a NF-κB-dependent manner ». American Journal of Physiology-Cell Physiology 298, n^o 4 (avril 2010) : C929—C941. http://dx.doi.org/10.1152/ajpcell.00461.2009.

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A promising therapeutic approach to diminish pathological inflammation is to inhibit the increased production and/or biological activity of proinflammatory cytokines (e.g., TNF-α, IL-6). The production of proinflammatory cytokines is controlled at the gene level by the activity of transcription factors, such as NF-κB. Phosphatidylinositol 3-kinase (PI3K), a lipid kinase, is known to induce the activation of NF-κB. Given this, we hypothesized that inhibitors of PI3K activation would demonstrate anti-inflammatory potential. Accordingly, we studied the effects of a preferential p110α/γ PI3K inhibitor (compound 8C; PIK-75) in inflammation-based assays. Mechanism-based assays utilizing human cells revealed that PIK-75-mediated inhibition of PI3K activation is associated with dramatic suppression of downstream signaling events, including AKT phosphorylation, IKK activation, and NF-κB transcription. Cell-based assays revealed that PIK-75 potently and dose dependently inhibits in vitro and in vivo production of TNF-α and IL-6, diminishes the induced expression of human endothelial cell adhesion molecules (E-selectin, ICAM-1, and VCAM-1), and blocks human monocyte-endothelial cell adhesion. Most importantly, PIK-75, when administered orally in a therapeutic regimen, significantly suppresses the macroscopic and histological abnormalities associated with dextran sulfate sodium-induced murine colitis. The efficacy of PIK-75 in attenuating experimental inflammation is mediated, at least in part, due to the downregulation of pertinent inflammatory mediators in the colon. Collectively, these results provide first evidence that PIK-75 possesses anti-inflammatory potential. Given that PIK-75 is known to exhibit anti-cancer activity, the findings from this study thus reinforce the cross-therapeutic functionality of potential drugs.

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Reinecke, Maria, Benjamin Ruprecht, Sandra Poser, Svenja Wiechmann, Mathias Wilhelm, Stephanie Heinzlmeir, Bernhard Kuster et Guillaume Médard. « Chemoproteomic Selectivity Profiling of PIKK and PI3K Kinase Inhibitors ». ACS Chemical Biology 14, n^o 4 (22 mars 2019) : 655–64. http://dx.doi.org/10.1021/acschembio.8b01020.

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Evans, William B., Peter M. Hudson et Keri L. Paridon. « MISSISSIPPI HAND-HARVEST, FRESH-MARKET SOUTHERNPEA TRIAL : A THREE-YEAR REVIEW ». HortScience 41, n^o 3 (juin 2006) : 517A—517. http://dx.doi.org/10.21273/hortsci.41.3.517a.

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In 2005, fifteen southernpea (Vigna unguiculata L.) Walp. subsp. unguiculata (L.) cultivars were evaluated for yield and quality at Crystal Springs, Miss. Pods were hand-harvested at the green-shell stage on three dates in August and early September 2005. In-shell fresh weights, shelled seed weight, and percent shell-out were recorded. Data was compared with that from similar trials in 2003 and 2004. Little disease or insect pressure has been seen in any year. Most peas evaluated have been in the pink-eye class. In 2005, all pink-eye types produced statistically similar fresh seed yield. Top Pick Brown Crowder produced higher seed yield than all other entries. Cream peas tested were generally lower yielding than the pink-eye types, with the lone black-eye cultivar tested, California Blackeye No. 5, intermediate in seed yield. Weighted average days to midharvest was not different among pink-eye cultivars evaluated but was slightly longer for several cream entries and for California Blackeye No. 5. Percent shell-out was highest in Top Pick Brown Crowder and lowest in Mississippi Cream. Over 3 years, more than thirty cultivars have been evaluated in the trials. Overall, most peas within a seed type have produced similar yields with few exceptions. Some lodging of the top-setting peas has been seen. The top-setting peas may offer advantages of ease of picking for hand-harvest in pick-your-own, small farm, and home garden situations. This trial does not address performance for machine harvest.

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Naga Prasad, Sathyamangla V., Stéphane A. Laporte, Dean Chamberlain, Marc G. Caron, Larry Barak et Howard A. Rockman. « Phosphoinositide 3-kinase regulates β2-adrenergic receptor endocytosis by AP-2 recruitment to the receptor/β-arrestin complex ». Journal of Cell Biology 158, n^o 3 (5 août 2002) : 563–75. http://dx.doi.org/10.1083/jcb.200202113.

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Internalization of β-adrenergic receptors (βARs) occurs by the sequential binding of β-arrestin, the clathrin adaptor AP-2, and clathrin. D-3 phosphoinositides, generated by the action of phosphoinositide 3-kinase (PI3K) may regulate the endocytic process; however, the precise molecular mechanism is unknown. Here we demonstrate that βARKinase1 directly interacts with the PIK domain of PI3K to form a cytosolic complex. Overexpression of the PIK domain displaces endogenous PI3K from βARK1 and prevents βARK1-mediated translocation of PI3K to activated β2ARs. Furthermore, disruption of the βARK1/PI3K interaction inhibits agonist-stimulated AP-2 adaptor protein recruitment to the β2AR and receptor endocytosis without affecting the internalization of other clathrin dependent processes such as internalization of the transferrin receptor. In contrast, AP-2 recruitment is enhanced in the presence of D-3 phospholipids, and receptor internalization is blocked in presence of the specific phosphatidylinositol-3,4,5-trisphosphate lipid phosphatase PTEN. These findings provide a molecular mechanism for the agonist-dependent recruitment of PI3K to βARs, and support a role for the localized generation of D-3 phosphoinositides in regulating the recruitment of the receptor/cargo to clathrin-coated pits.

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Thomas, Daniel, Jason A. Powell, Francois Vergez, David H. Segal, Nhu-Y. N. Nguyen, Adele Baker, Tse-Chieh Teh et al. « Targeting acute myeloid leukemia by dual inhibition of PI3K signaling and Cdk9-mediated Mcl-1 transcription ». Blood 122, n^o 5 (1 août 2013) : 738–48. http://dx.doi.org/10.1182/blood-2012-08-447441.

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Key Points Simultaneous inhibition of Cdk9 and PI3K in human AML cells liberates Bak from both Mcl-1 and Bcl-xL, inducing Bak-dependent apoptosis. Dual inhibitors of Cdk9 and PI3K, such as PIK-75, have broad activity against malignant cells including human AML cells.

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Sharma, Sanjeev, Swarna Mathre, Avishek Ghosh, Dhananjay Shinde et Padinjat Raghu. « Drosophila PIP4K activity regulates Insulin/PI3K signalling in cellular growth ». Mechanisms of Development 145 (juillet 2017) : S132. http://dx.doi.org/10.1016/j.mod.2017.04.365.

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Curcio, Antonio, Takahisa Noma, Sathyamangla V. Naga Prasad, Matthew J. Wolf, Anthony Lemaire, Cinzia Perrino, Lan Mao et Howard A. Rockman. « Competitive displacement of phosphoinositide 3-kinase from β-adrenergic receptor kinase-1 improves postinfarction adverse myocardial remodeling ». American Journal of Physiology-Heart and Circulatory Physiology 291, n^o 4 (octobre 2006) : H1754—H1760. http://dx.doi.org/10.1152/ajpheart.01199.2005.

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Adverse remodeling after myocardial infarction (MI) determines the progression of heart failure. Failing hearts are characterized by downregulation of β-adrenergic receptor (β-AR) signaling in part because of increased β-AR kinase 1 activity. Our previous studies have shown that overexpression of the phosphoinositide kinase (PIK) domain of phosphoinositide 3-kinase (PI3K), prevents β-AR downregulation and enhances adrenergic agonist responsiveness by inhibiting the targeting of PI3K to the β-AR complex. To investigate whether preventing β-AR downregulation in the heart ameliorates cardiac function post-MI, transgenic mice with cardiac-specific overexpression of the PIK domain peptide (TgPIK) underwent left coronary artery ligation and were subsequently followed by serial echocardiography at 4, 8, 12, 16, and 20 wk. Despite having similar infarction sizes, TgPIK mice showed better systolic function, less cardiac dilatation, and improved hemodynamic response to dobutamine compared with littermate controls after MI. To test that displacement of PI3K from the β-AR complex, but not the total loss of PI3K-γ, is critical for amelioration of cardiac function, mice lacking the PI3K-γ (PI3K-γ-KO) underwent MI, and their cardiac function was assessed 20 wk post-MI. Serial echocardiographic measurements showed severe reduction in contractile performance in PI3K-γ-KO compared with TgPIK mice. Furthermore, significant β-AR downregulation and desensitization were only seen in infarcted wild-type and PI3K-γ-KO mice and not in TgPIK mice. Together, these results demonstrate that adverse remodeling of the ventricle after MI can be attenuated by a strategy that prevents recruitment of PI3K to the plasma membrane and restores normal β-AR function.

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Burrows, Natalie, Joseph Williams, Brian A. Telfer, Julia Resch, Helen R. Valentine, Richard J. Fitzmaurice, Amanda Eustace et al. « Phosphatidylinositide 3-kinase (PI3K) and PI3K-related kinase (PIKK) activity contributes to radioresistance in thyroid carcinomas ». Oncotarget 7, n^o 39 (4 août 2016) : 63106–23. http://dx.doi.org/10.18632/oncotarget.11056.

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Sohn, Mira, Pavlina Ivanova, H. Alex Brown, Daniel J. Toth, Peter Varnai, Yeun Ju Kim et Tamas Balla. « Lenz-Majewski mutations in PTDSS1 affect phosphatidylinositol 4-phosphate metabolism at ER-PM and ER-Golgi junctions ». Proceedings of the National Academy of Sciences 113, n^o 16 (4 avril 2016) : 4314–19. http://dx.doi.org/10.1073/pnas.1525719113.

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Lenz-Majewski syndrome (LMS) is a rare disease characterized by complex craniofacial, dental, cutaneous, and limb abnormalities combined with intellectual disability. Mutations in the PTDSS1 gene coding one of the phosphatidylserine (PS) synthase enzymes, PSS1, were described as causative in LMS patients. Such mutations render PSS1 insensitive to feedback inhibition by PS levels. Here we show that expression of mutant PSS1 enzymes decreased phosphatidylinositol 4-phosphate (PI4P) levels both in the Golgi and the plasma membrane (PM) by activating the Sac1 phosphatase and altered PI4P cycling at the PM. Conversely, inhibitors of PI4KA, the enzyme that makes PI4P in the PM, blocked PS synthesis and reduced PS levels by 50% in normal cells. However, mutant PSS1 enzymes alleviated the PI4P dependence of PS synthesis. Oxysterol-binding protein–related protein 8, which was recently identified as a PI4P-PS exchanger between the ER and PM, showed PI4P-dependent membrane association that was significantly decreased by expression of PSS1 mutant enzymes. Our studies reveal that PS synthesis is tightly coupled to PI4P-dependent PS transport from the ER. Consequently, PSS1 mutations not only affect cellular PS levels and distribution but also lead to a more complex imbalance in lipid homeostasis by disturbing PI4P metabolism.

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Poli, Alessandro, Shidqiyyah Abdul-Hamid, Antonio Enrico Zaurito, Francesca Campagnoli, Valeria Bevilacqua, Bhavwanti Sheth, Roberta Fiume, Massimiliano Pagani, Sergio Abrignani et Nullin Divecha. « PIP4Ks impact on PI3K, FOXP3, and UHRF1 signaling and modulate human regulatory T cell proliferation and immunosuppressive activity ». Proceedings of the National Academy of Sciences 118, n^o 31 (26 juillet 2021) : e2010053118. http://dx.doi.org/10.1073/pnas.2010053118.

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Regulatory T cells (Tregs) play fundamental roles in maintaining peripheral tolerance to prevent autoimmunity and limit legitimate immune responses, a feature hijacked in tumor microenvironments in which the recruitment of Tregs often extinguishes immune surveillance through suppression of T-effector cell signaling and tumor cell killing. The pharmacological tuning of Treg activity without impacting on T conventional (Tconv) cell activity would likely be beneficial in the treatment of various human pathologies. PIP4K2A, 2B, and 2C constitute a family of lipid kinases that phosphorylate PtdIns5P to PtdIns(4,5)P2. They are involved in stress signaling, act as synthetic lethal targets in p53-null tumors, and in mice, the loss of PIP4K2C leads to late onset hyperinflammation. Accordingly, a human single nucleotide polymorphism (SNP) near the PIP4K2C gene is linked with susceptibility to autoimmune diseases. How PIP4Ks impact on human T cell signaling is not known. Using ex vivo human primary T cells, we found that PIP4K activity is required for Treg cell signaling and immunosuppressive activity. Genetic and pharmacological inhibition of PIP4K in Tregs reduces signaling through the PI3K, mTORC1/S6, and MAPK pathways, impairs cell proliferation, and increases activation-induced cell death while sparing Tconv. PIP4K and PI3K signaling regulate the expression of the Treg master transcriptional activator FOXP3 and the epigenetic signaling protein Ubiquitin-like containing PHD and RING finger domains 1 (UHRF1). Our studies suggest that the pharmacological inhibition of PIP4K can reprogram human Treg identity while leaving Tconv cell signaling and T-helper differentiation to largely intact potentially enhancing overall immunological activity.

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Yang, Guang, Xia Liu, Yangsheng Zhou, Lian Xu, Yang Cao, Robert Manning, Christopher Patterson et al. « PI3K/AKT Pathway Is Activated By MYD88 L265P and Use Of PI3K-Delta Inhibitors Induces Robust Tumor Cell Killing In Waldenstrom’s Macroglobulinemia ». Blood 122, n^o 21 (15 novembre 2013) : 4255. http://dx.doi.org/10.1182/blood.v122.21.4255.4255.

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Abstract Background MYD88 L265P is a somatic mutation present in >90% of Waldenstrom's Macroglobulinemia (WM) patients. The downstream signaling pathways that promote malignant cell growth and survival remain to be fully clarified but include IRAK 1/4 and BTK (Treon et al, NEJM 2012; Yang et al, Blood 2013). Methods To further clarify the downstream signaling associated with MYD88 L265P in WM cells, we employed Phospho Explorer Antibody Arrays in MYD88 L265P expressing BCWM.1 and MCWL-1 WM cells following lentiviral mediated knockdown of MYD88, or over-expression of MYD88 wild type or L265P; or the use of MYD88 homodimerization inhibitor that block MYD88 signaling. Arrays were scanned by Axon GenePix Microarray Scanner and data analyzed by Ingenuity Pathway Analysis. Western blot analysis was performed using total and phospho-specific antibodies in WM cells. CellTiter-Glo® Luminescent cell viability assay (Promega) was used to assess cell survival following treatment with the PI3K-delta inhibitors, CAL101 and PIK-294 (Selleck Chemicals). Results Ingenuity pathway analysis demonstrated significant enrichment for B-Cell Receptor, PI3K/AKT, LPS-stimulated MAPK and ERK/MAPK signaling following MYD88 modulation in both BCWM.1 and MWCL-1 WM cells. Signal proteins that demonstrated the greatest changes in phosphorylation following MYD88 modulation are shown in Table 1. Western blot analysis confirmed the activation of ATK as downstream of PI3K in WM cells. Use of a MYD88 inhibitor significantly decreased phosphorylation of ATK-pS473 and AKT-pY308 in both BCWM.1 and MCWL-1 WM cells. Cell viability analysis demonstrated robust tumor cell killing (EC50 30-50nM) in BCWM.1 and MWCL-1 WM cells following treatment with both PI3K-delta inhibitors (CAL-101 and PIK-294). Conclusion In addition to activation of NF-kB through IRAK and BTK signaling, MYD88 L265P promotes survival of WM cells by activation of PI3K/AKT signaling. Inhibition of PI3K-delta is associated with robust killing of WM cells. These studies provide the framework for the investigation of PI3K-delta inhibitors in WM. Disclosures: No relevant conflicts of interest to declare.

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Liang, Xiaofei, Zongru Jiang, Zhenghui Huang, Feng Li, Cheng Chen, Chen Hu, Wenliang Wang et al. « Discovery of 6′-chloro-N-methyl-5’-(phenylsulfonamido)-[3,3′-bipyridine]-5-carboxamide (CHMFL-PI4K-127) as a novel Plasmodium falciparum PI(4)K inhibitor with potent antimalarial activity against both blood and liver stages of Plasmodium ». European Journal of Medicinal Chemistry 188 (février 2020) : 112012. http://dx.doi.org/10.1016/j.ejmech.2019.112012.

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Everton, Kathryn L., David R. Abbott, David K. Crockett, Kojo S. J. Elenitoba-Johnson et Megan S. Lim. « Proteome Changes Induced by Rituximab : Significance for Monoclonal Antibody Therapy of B-Cell Lymphoproliferative Disorders. » Blood 104, n^o 11 (16 novembre 2004) : 2292. http://dx.doi.org/10.1182/blood.v104.11.2292.2292.

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Abstract Rituximab is a human chimeric monoclonal antibody that targets the CD20 receptor uniquely expressed on normal and malignant B-cells. While it is particularly useful for follicular lymphoma, Rituximab has recently been used for other types of B-cell proliferative disorders. Four major mechanisms have been proposed to account for the activity of Rituximab in B-cell lymphoproliferative disorders: 1) apoptosis and proliferation inhibition via intracellular signaling, 2) increased sensitivity to other chemotherapeutic drugs, 3) complement-dependent cytotoxicity (CDC), and 4) antibody-dependent cellular cytotoxicity (ADCC). A combination of all four mechanisms has also been proposed as the mechanism of action. However, the intracellular events that occur in B-cells in response to Rituximab are largely unknown. We have employed a global quantitative proteomic profiling approach to study the effects of Rituximab on a t(14;18)+ B cell lymphoma (SUDHL-4). A decrease in viability of 31.3 ± 2.9% was observed after treatment with 10μg/mL of Rituximab for 48 hours. We used isotope-coded affinity tagging (ICAT™) in combination with microcapillary liquid chromatography and tandem mass spectrometry (μLC-MS/MS) to quantitatively determine the proteomic differences between equal amounts of untreated and treated total cell lystates. Protein lysates were labeled with either heavy or light cleavable ICAT™ reagents, digested with trypsin, and purified using avidin affinity chromatography. The labeled peptides were then fractionated using off-line strong cation exchange (SCX) and each fraction was subjected to μLC-MS/MS analysis. Several proteins previously unknown to be expressed in B-cells were identified using this approach. Of the 123 positively identified proteins, 59 proteins were differentially expressed by greater than or less than 1.5 fold (25 upregulated, 34 downregulated). Analysis of differentially expressed proteins identified several functional groups, including integral membrane proteins (Integrin alpha-7 precursor), transcription factors (Zinc finger proteins 445 and 20), proteins involved in migration and adhesion (Astrotactin1), proteins associated with degradation and turnover (26S proteasome non-ATPase regulatory subunit 9), proteins affecting calcium-induced signaling (Tumor-associated calcium signal transducer 1 precursor), proteins associated with lipid rafts (Gemin7), and components of the phosphoinositol (PI4K-alpha) and NF-κB pathways (IKK-E). Our studies reveal the proteomic consequences of Rituximab administration to neoplastic B-cells, and provide novel insights into the mechanism of the drug’s efficacy in the treatment of susceptible B-cell lymphoproliferative disorders.

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Evans, W. B., P. Hudson et K. L. Paridon. « MISSISSIPPI HAND-HARVEST, FRESH MARKET SOUTHERNPEA TRIAL–2004 ». HortScience 40, n^o 3 (juin 2005) : 877a—877. http://dx.doi.org/10.21273/hortsci.40.3.877a.

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Twenty southernpea (Vigna unguiculata) entries were evaluated for fresh market potential in a hand-harvested trial at Crystal Springs, Miss. Ten entries in the pinkeye or black-eye categories were evaluated in an experiment with four replicates and randomized complete block design. Another ten entries in the cream or crowder category were evaluated in an adjacent observational trial with one plot per entry. In both experiments, rows were 40 inches apart and 20 ft long. Peas were seeded in May 2004. Plots were harvested on three dates in July. Pods were weighed after harvesting ten feet of row in each plot. After resting overnight in bins, the peas were shelled and weighed. Quick Pick matured earlier than other entries in the replicated trial. Lady Pea was very late in the observational trial, to the point it was not harvested. In-shell fresh weight was greatest for CT Pinkeye, Quick Pick, Mississippi Pinkeye, Knucklehull, and Top Pick. Shelled weight was greatest for CT Pinkeye, Quick Pick, and Mississippi Pinkeye in the replicated trial. Yields of the cream and crowder peas tested in a adjacent observational trial were less than those of the pink-eye and black-eyed peas.

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Švec, Alois. « On the Pick invariant ». Czechoslovak Mathematical Journal 38, n^o 3 (1988) : 493–97. http://dx.doi.org/10.21136/cmj.1988.102246.

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Huang, Hongmei, Ling Huang, Guangping Feng, Suhua Wang, Yue Wang, Jinling Liu, Nan Jiang et al. « Molecular Mapping of the New Blast Resistance Genes Pi47 and Pi48 in the Durably Resistant Local Rice Cultivar Xiangzi 3150 ». Phytopathology® 101, n^o 5 (mai 2011) : 620–26. http://dx.doi.org/10.1094/phyto-08-10-0209.

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The indica rice cultivar Xiangzi 3150 (XZ3150) confers a high level of resistance to 95% of the isolates of Magnaporthe oryzae (the agent of rice blast disease) collected in Hunan Province, China. To identify the resistance (R) gene(s) controlling the high level of resistance in this cultivar, we developed 286 F9 recombinant inbred lines (RILs) from a cross between XZ3150 and the highly susceptible cultivar CO39. Inoculation of the RILs and an F2 population from a cross between the two cultivars with the avirulent isolate 193-1-1 in the growth chamber indicated the presence of two dominant R genes in XZ3150. A linkage map with 134 polymorphic simple sequence repeat and single feature polymorphism markers was constructed with the genotype data of the 286 RILs. Composite interval mapping (CIM) using the results of 193-1-1 inoculation showed that two major R genes, designated Pi47 and Pi48, were located between RM206 and RM224 on chromosome 11, and between RM5364 and RM7102 on chromosome 12, respectively. Interestingly, the CIM analysis of the four resistant components of the RILs to the field blast population revealed that Pi47 and Pi48 were also the major genetic factors responsible for the field resistance in XZ3150. The DNA markers linked to the new R genes identified in this study should be useful for further fine mapping, gene cloning, and marker-aided breeding of blast-resistant rice cultivars.

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Marshall, Dale E. « Fifty-year History of Harvesting Pickling Cucumbers Mechanically ». HortScience 31, n^o 4 (août 1996) : 573d—573. http://dx.doi.org/10.21273/hortsci.31.4.573d.

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For 50 years, engineers, producers, processors, and manufacturers have been working on new and improved ways for mechanization of the harvest of pickling cucumbers, Cucumis sativus L. In 1957, processors investigated multiple-pick concepts. Multiple-pick harvesters were commercially manufactured in the early 1960s (Chisholm–Ryder). In the late 1950s, Stout and Ries evaluated the known multiple-pick harvesting concepts. In the early 1960s, once-over harvesting concepts were considered and evaluated by Ries and Stout. By significantly increasing the plant population and other horticultural practice and variety improvements, once-over harvest became the main thrust of mechanization from 1965 on. By 1970, at least major five commercial manufacturers sold harvesters (Blackwelder, FMC Corp., Hart Carter [later sold out to Cuke, Inc.], Porter-Way, and Wilde). In 1996 there are four commercial manufacturers (Cuke, FMC Corp., Jerry's Welding, and Pik Rite). Limited multiple-pick research and manufacturers persisted (Aero-Glide, Mac-Weld, and Powell). By 1975 over 85% of Michigan's pickling cucumbers were mechanically harvested, leading all other states. Today, about 60% of Michigan's production is harvested with machines. The information presented will be informative and an historical aid for engineers, manufacturers, horticulturists, processors, and historians, etc. to ensure that the worldwide research is known by scientists endeavoring to accomplish harvest mechanization.

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Wang, Yuan, Zhijuan Xie et Fang Xu. « Gefitinib Combined with Pemetrexed Affects Proliferation and Apoptosis of Non-Small Cell Lung Cancer Cells by Regulating PI3KAKT Pathway ». Journal of Biomaterials and Tissue Engineering 10, n^o 3 (1 mars 2020) : 379–86. http://dx.doi.org/10.1166/jbt.2020.2276.

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Dysfunction of PI3K/AKT pathway mediates EGFR-TKI resistance, which can be corrected by chemotherapy combined with EGFR-TKI. Pemetrexed mediates PI1K/AKT activity, thus modulating cell proliferation and apoptosis. This study investigated if Gefitinib combined with Pemetrexed played a role in regulating PI3K/AKT pathway and proliferation/apoptosis of non-small cell lung cancer (NSCLC). IC50 and p-AKT expression were compared between Gefitinib and Pemetrexed on PC9 or H1975 cells. H1975 cells were treated with Gefitinib and/or Pemetrexed, for assay of apoptosis and proliferation by flow cytometry. H1975 cells were infused into nude mice, which were treated with Gefitinib and/or Pemetrexed. Tumor growth was compared, along with p-AKT, Sur-vivin, and Ki67 expression. Gefitinib had 1.43 μM and 12.26 μM IC50 in PC9 and H1975 cells, whilst Pemetrexed had IC50 values of 0.81 μM and 1.32 μM. Gefitinib-resistant H1975 cells had significantly higher p-AKT than drug sensitive PC9 cells. Pemetrexed had more potent effect for anti-proliferation, pro-apoptosis, and down-regulation of p-AKT or Survivin than Gefitinib. Combined therapy remarkably weakened Gefitinib resistance in H1975 cell, and exerted more potent inhibitory effects on tumor growth in nude mice, accompanied with PI3K/ATK inactivation and Ki67 down-regulation. Pemetrexed combined with Gefitinib inhibits lung cancer cell H1975 proliferation and facilitates cell apoptosis via suppressing PI3K/AKT signal pathway, thus weakening Gefitinib resistance of lung cancer cells.

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Zhu, Jingyu, Man Wang, Yang Yu, Huixin Qi, Kunkun Han, Juan Tang, Zubin Zhang et al. « A novel PI3K inhibitor PIK-C98 displays potent preclinical activity against multiple myeloma ». Oncotarget 6, n^o 1 (2 décembre 2014) : 185–95. http://dx.doi.org/10.18632/oncotarget.2688.

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Rebeiro, Patricia, Alexander James, Nicole Caxeiro, Soon Lee, Silvia Ling et Tara Roberts. « PIKK of the pick : the role of smg1 and atm in b cell lymphoproliferative disorders ». Pathology 49 (février 2017) : S110. http://dx.doi.org/10.1016/j.pathol.2016.12.318.

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Misman, Siti Norsuha, Mohd Shahril Firdaus Ab Razak, Nur Syahirah Ahmad Sobri et Latiffah Zakaria. « Virulence Pattern of Pyricularia oryzae Pathotypes Towards Blast Monogenic Lines ». Tropical Life Sciences Research 32, n^o 3 (30 septembre 2021) : 147–60. http://dx.doi.org/10.21315/tlsr2021.32.3.8.

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Rice blast caused by Pyricularia oryzae (P. oryzae) is one of the most serious diseases infecting rice worldwide. In the present study, virulence pattern of six P. oryzae pathotypes (P0.0, P0.2, P1.0, P3.0, P7.0 and P9.0) identified from the blast pathogen collected in Peninsular Malaysia, were evaluated using a set of 22 IRRI-bred blast resistance lines (IRBL) as well as to determine the resistance genes involved. The information on the virulence of the blast pathotypes and the resistance genes involved is important for breeding of new rice variety for durable resistance against blast disease. The IRBL was established from 22 monogenic lines, harbouring 22 resistance genes [Pia, Pib, Pii, Pit, Pi3, Pi5(t), Pish, Pi1, Pik, Pik-s, Pik-m, Pik-h, Pik-p, Pi7(t), Pi9, Piz, Piz-5, Piz-t, Pi19, Pi20(t), Pita-2, and Pita=Pi4(t)]. Based on the disease severity patterns, the tested pathotypes were avirulence towards seven IRBLs [IRBLi-F5, IRBLk-Ka, IRBLkh-K3, IRBLz-Fu, IRBLsh-S, IRBLPi7 (t) and IRBL9-W] of which these IRBLs harbouring Pii, Pik, Pik-h, Piz, Pish, Pi7(t) and Pi9 resistance genes, respectively. Therefore, the results suggested that the seven IRBLs carrying seven resistance genes [Pii, Pik, Pik-h, Piz, Pish, Pi7(t) and Pi9] would be suitable candidates of resistance genes to be incorporated in new breeding lines to combat the current blast pathotypes in the field.

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Misman, Siti Norsuha, Mohd Shahril Firdaus Ab Razak, Nur Syahirah Ahmad Sobri et Latiffah Zakaria. « Virulence Pattern of Pyricularia oryzae Pathotypes Towards Blast Monogenic Lines ». Tropical Life Sciences Research 32, n^o 3 (30 septembre 2021) : 147–60. http://dx.doi.org/10.21315/tlsr2021.32.3.8.

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Rice blast caused by Pyricularia oryzae (P. oryzae) is one of the most serious diseases infecting rice worldwide. In the present study, virulence pattern of six P. oryzae pathotypes (P0.0, P0.2, P1.0, P3.0, P7.0 and P9.0) identified from the blast pathogen collected in Peninsular Malaysia, were evaluated using a set of 22 IRRI-bred blast resistance lines (IRBL) as well as to determine the resistance genes involved. The information on the virulence of the blast pathotypes and the resistance genes involved is important for breeding of new rice variety for durable resistance against blast disease. The IRBL was established from 22 monogenic lines, harbouring 22 resistance genes [Pia, Pib, Pii, Pit, Pi3, Pi5(t), Pish, Pi1, Pik, Pik-s, Pik-m, Pik-h, Pik-p, Pi7(t), Pi9, Piz, Piz-5, Piz-t, Pi19, Pi20(t), Pita-2, and Pita=Pi4(t)]. Based on the disease severity patterns, the tested pathotypes were avirulence towards seven IRBLs [IRBLi-F5, IRBLk-Ka, IRBLkh-K3, IRBLz-Fu, IRBLsh-S, IRBLPi7 (t) and IRBL9-W] of which these IRBLs harbouring Pii, Pik, Pik-h, Piz, Pish, Pi7(t) and Pi9 resistance genes, respectively. Therefore, the results suggested that the seven IRBLs carrying seven resistance genes [Pii, Pik, Pik-h, Piz, Pish, Pi7(t) and Pi9] would be suitable candidates of resistance genes to be incorporated in new breeding lines to combat the current blast pathotypes in the field.

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Shaikh, Rizwaan Areef, Ajinkya Ramesh Vadaje et Tejaswi Uttam Zagade. « Hot Disk Pick and Place Robot ». International Journal of Trend in Scientific Research and Development Volume-2, Issue-3 (30 avril 2018) : 2463–65. http://dx.doi.org/10.31142/ijtsrd12758.

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Lee, Hyun-Soo, et Byung-Ha Lee. « Influence of CrCl3in Sphene-Pink Pigments ». Journal of the Korean Ceramic Society 45, n^o 5 (31 mai 2008) : 268–75. http://dx.doi.org/10.4191/kcers.2008.45.5.268.

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Joo, In-Don, Hyun-Soo Lee et Byung-Ha Lee. « Synthesis of Sphene - pink Pigment by Rice Husk Ash ». Journal of the Korean Ceramic Society 47, n^o 3 (31 mai 2010) : 237–43. http://dx.doi.org/10.4191/kcers.2010.47.3.237.

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