Our laboratory is focusing on a family of proteins called phospholipid scramblases. We originally cloned phospholipid scramblase 1 (PLSCR1), a Ca2+-binding, endofacial plasma membrane protein, based on its capacity to promote rapid transbilayer movement of phospholipids in response to elevated Ca2+. Such redistribution of phospholipids is normally observed upon platelet activation, and in injured or apoptotic cells. We subsequently identified three additional members of this gene family. Recent data from our laboratory suggest a considerably more complex biology for these proteins than their putative role in mediating transbilayer lipid movement. PLSCR1 -- and possibly other members of the PLSCR gene family -- plays a role in modulating the signal transduction through multiple growth factor receptors, and is itself transcriptionally upregulated through these same growth factor receptor pathways. We also discovered that when transcriptionally induced, a portion of the newly synthesized PLSCR1 translocates to the nucleus, in addition to its usual location at the plasma membrane, where it can increase gene transcription. One such gene identified to be upregulated in presence of PLSCR1 is the IP3-receptor type 1. Our current efforts are aimed at elucidating the role of PLSCRs in diverse signaling pathways underlying proliferation, differentiation, and apoptosis.

• Li D, Yang H, Nan H, Liu P, Pang S, Zhao Q, Karni R, Kamps MP, Xu Y, Zhou J, Wiedmer T, Sims PJ, Wang F. Identification of key regulatory pathways of myeloid differentiation using an mESC-based karyotypically normal cell model. Blood. 2012 Dec 6; 120(24):4712-9.
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• Chen CW, Sowden M, Zhao Q, Wiedmer T, Sims PJ. Nuclear phospholipid scramblase 1 prolongs the mitotic expansion of granulocyte precursors during G-CSF-induced granulopoiesis. J Leukoc Biol. 2011 Aug; 90(2):221-33.
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• Bateman A, Finn RD, Sims PJ, Wiedmer T, Biegert A, Söding J. Phospholipid scramblases and Tubby-like proteins belong to a new superfamily of membrane tethered transcription factors. Bioinformatics. 2009 Jan 15; 25(2):159-62.
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• Lu B, Sims PJ, Wiedmer T, Moser AH, Shigenaga JK, Grunfeld C, Feingold KR. Expression of the phospholipid scramblase (PLSCR) gene family during the acute phase response. Biochim Biophys Acta. 2007 Sep; 1771(9):1177-85.
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• Mutch DM, O'Maille G, Wikoff WR, Wiedmer T, Sims PJ, Siuzdak G. Mobilization of pro-inflammatory lipids in obese Plscr3-deficient mice. Genome Biol. 2007; 8(3):R38.
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• Huang Y, Zhao Q, Zhou CX, Gu ZM, Li D, Xu HZ, Wiedmer T, Sims PJ, Zhao KW, Chen GQ. Antileukemic roles of human phospholipid scramblase 1 gene, evidence from inducible PLSCR1-expressing leukemic cells. Oncogene. 2006 Oct 26; 25(50):6618-27.
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• Zhou Q, Ben-Efraim I, Bigcas JL, Junqueira D, Wiedmer T, Sims PJ. Phospholipid scramblase 1 binds to the promoter region of the inositol 1,4,5-triphosphate receptor type 1 gene to enhance its expression. J Biol Chem. 2005 Oct 14; 280(41):35062-8.
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• Dong B, Zhou Q, Zhao J, Zhou A, Harty RN, Bose S, Banerjee A, Slee R, Guenther J, Williams BR, Wiedmer T, Sims PJ, Silverman RH. Phospholipid scramblase 1 potentiates the antiviral activity of interferon. J Virol. 2004 Sep; 78(17):8983-93.
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• Wiedmer T, Zhao J, Li L, Zhou Q, Hevener A, Olefsky JM, Curtiss LK, Sims PJ. Adiposity, dyslipidemia, and insulin resistance in mice with targeted deletion of phospholipid scramblase 3 (PLSCR3). Proc Natl Acad Sci U S A. 2004 Sep 7; 101(36):13296-301.
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• Zhao KW, Li X, Zhao Q, Huang Y, Li D, Peng ZG, Shen WZ, Zhao J, Zhou Q, Chen Z, Sims PJ, Wiedmer T, Chen GQ. Protein kinase Cdelta mediates retinoic acid and phorbol myristate acetate-induced phospholipid scramblase 1 gene expression: its role in leukemic cell differentiation. Blood. 2004 Dec 1; 104(12):3731-8.
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• Ben-Efraim I, Zhou Q, Wiedmer T, Gerace L, Sims PJ. Phospholipid scramblase 1 is imported into the nucleus by a receptor-mediated pathway and interacts with DNA. Biochemistry. 2004 Mar 30; 43(12):3518-26.
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• Nanjundan M, Sun J, Zhao J, Zhou Q, Sims PJ, Wiedmer T. Plasma membrane phospholipid scramblase 1 promotes EGF-dependent activation of c-Src through the epidermal growth factor receptor. J Biol Chem. 2003 Sep 26; 278(39):37413-8.
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• Wiedmer T, Zhao J, Nanjundan M, Sims PJ. Palmitoylation of phospholipid scramblase 1 controls its distribution between nucleus and plasma membrane. Biochemistry. 2003 Feb 11; 42(5):1227-33.
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• de Vries KJ, Wiedmer T, Sims PJ, Gadella BM. Caspase-independent exposure of aminophospholipids and tyrosine phosphorylation in bicarbonate responsive human sperm cells. Biol Reprod. 2003 Jun; 68(6):2122-34.
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• Zhou Q, Zhao J, Wiedmer T, Sims PJ. Normal hemostasis but defective hematopoietic response to growth factors in mice deficient in phospholipid scramblase 1. Blood. 2002 Jun 1; 99(11):4030-8.
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• Sun J, Nanjundan M, Pike LJ, Wiedmer T, Sims PJ. Plasma membrane phospholipid scramblase 1 is enriched in lipid rafts and interacts with the epidermal growth factor receptor. Biochemistry. 2002 May 21; 41(20):6338-45.
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• Silverman RH, Halloum A, Zhou A, Dong B, Al-Zoghaibi F, Kushner D, Zhou Q, Zhao J, Wiedmer T, Sims PJ. Suppression of ovarian carcinoma cell growth in vivo by the interferon-inducible plasma membrane protein, phospholipid scramblase 1. Cancer Res. 2002 Jan 15; 62(2):397-402.
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• Sims PJ, Wiedmer T. Unraveling the mysteries of phospholipid scrambling. Thromb Haemost. 2001 Jul; 86(1):266-75.
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• Sun J, Zhao J, Schwartz MA, Wang JY, Wiedmer T, Sims PJ. c-Abl tyrosine kinase binds and phosphorylates phospholipid scramblase 1. J Biol Chem. 2001 Aug 3; 276(31):28984-90.
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• Wiedmer T, Zhou Q, Kwoh DY, Sims PJ. Identification of three new members of the phospholipid scramblase gene family. Biochim Biophys Acta. 2000 Jul 31; 1467(1):244-53.
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• Tepper AD, Ruurs P, Wiedmer T, Sims PJ, Borst J, van Blitterswijk WJ. Sphingomyelin hydrolysis to ceramide during the execution phase of apoptosis results from phospholipid scrambling and alters cell-surface morphology. J Cell Biol. 2000 Jul 10; 150(1):155-64.
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• Zhou Q, Zhao J, Al-Zoghaibi F, Zhou A, Wiedmer T, Silverman RH, Sims PJ. Transcriptional control of the human plasma membrane phospholipid scramblase 1 gene is mediated by interferon-alpha. Blood. 2000 Apr 15; 95(8):2593-9.
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• Fadeel B, Gleiss B, Högstrand K, Chandra J, Wiedmer T, Sims PJ, Henter JI, Orrenius S, Samali A. Phosphatidylserine exposure during apoptosis is a cell-type-specific event and does not correlate with plasma membrane phospholipid scramblase expression. Biochem Biophys Res Commun. 1999 Dec 20; 266(2):504-11.
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• Stout JG, Zhou Q, Wiedmer T, Sims PJ. Change in conformation of plasma membrane phospholipid scramblase induced by occupancy of its Ca2+ binding site. Biochemistry. 1998 Oct 20; 37(42):14860-6.
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• Zhou Q, Sims PJ, Wiedmer T. Expression of proteins controlling transbilayer movement of plasma membrane phospholipids in the B lymphocytes from a patient with Scott syndrome. Blood. 1998 Sep 1; 92(5):1707-12.
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• Zhao J, Zhou Q, Wiedmer T, Sims PJ. Palmitoylation of phospholipid scramblase is required for normal function in promoting Ca2+-activated transbilayer movement of membrane phospholipids. Biochemistry. 1998 May 5; 37(18):6361-6.
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• Zhao J, Zhou Q, Wiedmer T, Sims PJ. Level of expression of phospholipid scramblase regulates induced movement of phosphatidylserine to the cell surface. J Biol Chem. 1998 Mar 20; 273(12):6603-6.
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• Zhou Q, Sims PJ, Wiedmer T. Identity of a conserved motif in phospholipid scramblase that is required for Ca2+-accelerated transbilayer movement of membrane phospholipids. Biochemistry. 1998 Feb 24; 37(8):2356-60.
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• Zhou Q, Zhao J, Stout JG, Luhm RA, Wiedmer T, Sims PJ. Molecular cloning of human plasma membrane phospholipid scramblase. A protein mediating transbilayer movement of plasma membrane phospholipids. J Biol Chem. 1997 Jul 18; 272(29):18240-4.
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• Zhao J, Sims PJ, Wiedmer T. Production and characterization of a mutant cell line defective in aminophospholipid translocase. Biochim Biophys Acta. 1997 Jun 5; 1357(1):57-64.
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• Stout JG, Bassé F, Luhm RA, Weiss HJ, Wiedmer T, Sims PJ. Scott syndrome erythrocytes contain a membrane protein capable of mediating Ca2+-dependent transbilayer migration of membrane phospholipids. J Clin Invest. 1997 May 1; 99(9):2232-8.
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• Bassé F, Stout JG, Sims PJ, Wiedmer T. Isolation of an erythrocyte membrane protein that mediates Ca2+-dependent transbilayer movement of phospholipid. J Biol Chem. 1996 Jul 19; 271(29):17205-10.
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• Sims PJ, Wiedmer T. Induction of cellular procoagulant activity by the membrane attack complex of complement. Semin Cell Biol. 1995 Oct; 6(5):275-82.
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• Bevers EM, Wiedmer T, Comfurius P, Zhao J, Smeets EF, Schlegel RA, Schroit AJ, Weiss HJ, Williamson P, Zwaal RF, Sims PJ. The complex of phosphatidylinositol 4,5-bisphosphate and calcium ions is not responsible for Ca2+-induced loss of phospholipid asymmetry in the human erythrocyte: a study in Scott syndrome, a disorder of calcium-induced phospholipid scrambling. Blood. 1995 Sep 1; 86(5):1983-91.
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• Kojima H, Newton-Nash D, Weiss HJ, Zhao J, Sims PJ, Wiedmer T. Production and characterization of transformed B-lymphocytes expressing the membrane defect of Scott syndrome. J Clin Invest. 1994 Dec; 94(6):2237-44.
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• Chang CP, Hüsler T, Zhao J, Wiedmer T, Sims PJ. Identity of a peptide domain of human C9 that is bound by the cell-surface complement inhibitor, CD59. J Biol Chem. 1994 Oct 21; 269(42):26424-30.
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• Wiedmer T, Hall SE, Ortel TL, Kane WH, Rosse WF, Sims PJ. Complement-induced vesiculation and exposure of membrane prothrombinase sites in platelets of paroxysmal nocturnal hemoglobinuria. Blood. 1993 Aug 15; 82(4):1192-6.
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• Chang CP, Zhao J, Wiedmer T, Sims PJ. Contribution of platelet microparticle formation and granule secretion to the transmembrane migration of phosphatidylserine. J Biol Chem. 1993 Apr 5; 268(10):7171-8.
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• Dahlbäck B, Wiedmer T, Sims PJ. Binding of anticoagulant vitamin K-dependent protein S to platelet-derived microparticles. Biochemistry. 1992 Dec 29; 31(51):12769-77.
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• Shattil SJ, Cunningham M, Wiedmer T, Zhao J, Sims PJ, Brass LF. Regulation of glycoprotein IIb-IIIa receptor function studied with platelets permeabilized by the pore-forming complement proteins C5b-9. J Biol Chem. 1992 Sep 15; 267(26):18424-31.
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• Braga LL, Ninomiya H, McCoy JJ, Eacker S, Wiedmer T, Pham C, Wood S, Sims PJ, Petri WA. Inhibition of the complement membrane attack complex by the galactose-specific adhesion of Entamoeba histolytica. J Clin Invest. 1992 Sep; 90(3):1131-7.
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• Bevers EM, Wiedmer T, Comfurius P, Shattil SJ, Weiss HJ, Zwaal RF, Sims PJ. Defective Ca(2+)-induced microvesiculation and deficient expression of procoagulant activity in erythrocytes from a patient with a bleeding disorder: a study of the red blood cells of Scott syndrome. Blood. 1992 Jan 15; 79(2):380-8.
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• Braga LL, Ninomiya H, McCoy JJ, Adal K, Wiedmer T, Pham C, Sims PJ, Petri WA. Inhibition of the complement membrane attack complex by the galactose-specific adhesin of Entamoeba histolytica. Arch Med Res. 1992; 23(2):133.
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• Wiedmer T, Sims PJ. Participation of protein kinases in complement C5b-9-induced shedding of platelet plasma membrane vesicles. Blood. 1991 Dec 1; 78(11):2880-6.
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• Gilbert GE, Sims PJ, Wiedmer T, Furie B, Furie BC, Shattil SJ. Platelet-derived microparticles express high affinity receptors for factor VIII. J Biol Chem. 1991 Sep 15; 266(26):17261-8.
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• Sims PJ, Wiedmer T. The response of human platelets to activated components of the complement system. Immunol Today. 1991 Sep; 12(9):338-42.
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• Gerrard JM, Lint D, Sims PJ, Wiedmer T, Fugate RD, McMillan E, Robertson C, Israels SJ. Identification of a platelet dense granule membrane protein that is deficient in a patient with the Hermansky-Pudlak syndrome. Blood. 1991 Jan 1; 77(1):101-12.
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• Wiedmer T, Shattil SJ, Cunningham M, Sims PJ. Role of calcium and calpain in complement-induced vesiculation of the platelet plasma membrane and in the exposure of the platelet factor Va receptor. Biochemistry. 1990 Jan 23; 29(3):623-32.
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• Sims PJ, Rollins SA, Wiedmer T. Regulatory control of complement on blood platelets. Modulation of platelet procoagulant responses by a membrane inhibitor of the C5b-9 complex. J Biol Chem. 1989 Nov 15; 264(32):19228-35.
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• Sims PJ, Wiedmer T, Esmon CT, Weiss HJ, Shattil SJ. Assembly of the platelet prothrombinase complex is linked to vesiculation of the platelet plasma membrane. Studies in Scott syndrome: an isolated defect in platelet procoagulant activity. J Biol Chem. 1989 Oct 15; 264(29):17049-57.
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• Ando B, Wiedmer T, Sims PJ. The secretory release reaction initiated by complement proteins C5b-9 occurs without platelet aggregation through glycoprotein IIb-IIIa. Blood. 1989 Feb; 73(2):462-7.
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• Sims PJ, Faioni EM, Wiedmer T, Shattil SJ. Complement proteins C5b-9 cause release of membrane vesicles from the platelet surface that are enriched in the membrane receptor for coagulation factor Va and express prothrombinase activity. J Biol Chem. 1988 Dec 5; 263(34):18205-12.
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• Ando B, Wiedmer T, Hamilton KK, Sims PJ. Complement proteins C5b-9 initiate secretion of platelet storage granules without increased binding of fibrinogen or von Willebrand factor to newly expressed cell surface GPIIb-IIIa. J Biol Chem. 1988 Aug 25; 263(24):11907-14.
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• Wiedmer T, Ando B, Sims PJ. Complement C5b-9-stimulated platelet secretion is associated with a Ca2+-initiated activation of cellular protein kinases. J Biol Chem. 1987 Oct 5; 262(28):13674-81.
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• Wiedmer T, Esmon CT, Sims PJ. On the mechanism by which complement proteins C5b-9 increase platelet prothrombinase activity. J Biol Chem. 1986 Nov 5; 261(31):14587-92.
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• Wiedmer T, Esmon CT, Sims PJ. Complement proteins C5b-9 stimulate procoagulant activity through platelet prothrombinase. Blood. 1986 Oct; 68(4):875-80.
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• Sims PJ, Wiedmer T. Repolarization of the membrane potential of blood platelets after complement damage: evidence for a Ca++ -dependent exocytotic elimination of C5b-9 pores. Blood. 1986 Aug; 68(2):556-61.
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• Benz R, Schmid A, Wiedmer T, Sims PJ. Single-channel analysis of the conductance fluctuations induced in lipid bilayer membranes by complement proteins C5b-9. J Membr Biol. 1986; 94(1):37-45.
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• Wiedmer T, Sims PJ. Effect of complement proteins C5b-9 on blood platelets. Evidence for reversible depolarization of membrane potential. J Biol Chem. 1985 Jul 5; 260(13):8014-9.
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• Cheng KH, Wiedmer T, Sims PJ. Fluorescence resonance energy transfer study of the associative state of membrane-bound complexes of complement proteins C5b-8. J Immunol. 1985 Jul; 135(1):459-64.
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• Parker CJ, Wiedmer T, Sims PJ, Rosse WF. Characterization of the complement sensitivity of paroxysmal nocturnal hemoglobinuria erythrocytes. J Clin Invest. 1985 Jun; 75(6):2074-84.
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• Wiedmer T, Sims PJ. Cyanine dye fluorescence used to measure membrane potential changes due to the assembly of complement proteins C5b-9. J Membr Biol. 1985; 84(3):249-58.
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• Pink DA, Chapman D, Laidlaw DJ, Wiedmer T. Electron spin resonance and steady-state fluorescence polarization studies of lipid bilayers containing integral proteins. Biochemistry. 1984 Aug 28; 23(18):4051-8.
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• Sims PJ, Wiedmer T. Kinetics of polymerization of a fluoresceinated derivative of complement protein C9 by the membrane-bound complex of complement proteins C5b-8. Biochemistry. 1984 Jul 3; 23(14):3260-7.
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• Sims PJ, Wiedmer T. The influence of electrochemical gradients of Na+ and K+ upon the membrane binding and pore forming activity of the terminal complement proteins. J Membr Biol. 1984; 78(2):169-76.
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• Wiedmer T, Lauf PK. Properties of the M antigen solubilized from genetically high potassium sheep red cells. Membr Biochem. 1981; 4(1):31-47.
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• Wiedmer T, Di Francesco C, Brodbeck U. Effects of amphiphiles on structure and activity of human erythrocyte membrane acetylcholinesterase. Eur J Biochem. 1979 Dec; 102(1):59-64.
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• Wiedmer T, Brodbeck U, Zahler P, Fulpius BW. Interactions of acetylcholine receptor and acetylcholinesterase with lipid monolayers. Biochim Biophys Acta. 1978 Jan 19; 506(2):161-72.
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• Wiedmer T, Gentinetta R, Brodbeck U. Binding of acetylcholinesterases to concanavalin A. FEBS Lett. 1974 Oct 15; 47(2):260-3.
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