CURRICULUM  VITAE

 

         Name:                                      Mark S. Schlissel

            Birth:                                       November 24, 1957

                                                            Brooklyn, New York

            Address:                                  26 Merrill Circle South

                                                            Moraga, CA, 94556

            Phone:                                     510-643-2462 (lab)

 

 

EMPLOYMENT                    

Dean of Biological Sciences (2008-present)

                                                                        College of Letters & Science

                                                            Director, Berkeley Health Sciences Initiative

Professor of Immunology (2002-present)

Professor of Biochemistry & Molecular Biology

Vice-Chair (2002-2007)

Shubert Family Assoc. Professor of Biochemistry

                                                             & Associate Professor of Immunology (1999-2002)

                                                            Department of Molecular and Cell Biology

                                                            University of California, Berkeley

                                               

Associate Professor (1995-1999)

                                                            Assistant Professor (1991-1995)

                                                            Department of Medicine

                                                            Department of Molecular Biology and Genetics

                                                            Department of Oncology

                                                            The Johns Hopkins University

                                                                        School of Medicine

 

EDUCATION

 

         Undergraduate:                        Bachelor of Arts, 1979

                                                            Princeton University

                                                            Major in Biochemical Sciences

 

            Graduate:                                 M.D. and Ph.D. (Physiological Chemistry), 1986

                                                            Johns Hopkins University

                                                            Thesis Advisor-- Dr. Donald D. Brown

                                                               

            Postgraduate:                           Medical Residency, 1986-1988

                                                            The Johns Hopkins Hospital

                                                            Postdoctoral Research Fellow, 1988-1991

                                                            Whitehead Institute for Biological Research

                                                            Research Advisor-- Dr. David Baltimore

                                                           
HONORS AND AWARDS

 

         Undergraduate:                        A.B., Summa cum laude

                                                            Elected, Phi Beta Kappa

                                                            Elected, Sigma Xi Science Honor Society

 

            Graduate:                                 Fellow: NIH Medical Scientist Training                                                                                  Program, 1979-1986

                                                            Recipient: Michael A. Shanoff Research

                                                                Award, 1984

 

            Postgraduate:                           Awardee: Bristol-Myers Cancer Research

                                                                Fellowship, 1988-1991

                                                            Diplomate: American Board of Internal

                                                                Medicine

 

            Faculty:                                   Cancer Research Institute Investigator                                                                                         Award, 1992

                                                            Culpeper Foundation Scholar, 1993

                                                            Leukemia Society Scholar, 1996-2001

                                                            Arthritis Foundation Investigator, 1997-2003

                                                            W.W. Smith Foundation Scholar, 1997

                                                            Associate Editor, Journal of Immunology

                                                                 (1995-1998)

                                                            Elected to Membership, American Society

                                                                for Clinical Investigation (1998)

                                                            Graduate Student Teaching Award (1998)

                                                            NIH Immunobiology (IMB). Study Section                                                                                           (2000-2002 member, 2002-2004 Chair)

                                                            Stohlman Scholar, Leukemia & Lymphoma                                                                                Society (2001)

                                                            NIH MERIT Award (2005-2015)

 

AD HOC REVIEWER

 

                  Cell                                          Immunity

                        Science                                    Molecular Cell

                        Nature                                     Journal of Immunology

                        J. Exp. Medicine                     Molecular & Cell Biology

                        Nucleic Acids Res.                  International Immunology

                        Embo Journal                          Nature Immunology

                        Nature Genetics                       Oncogene

                        Blood                                      PLOS

                       

 

INSTITUTIONAL RESPONSIBILITIES

 

         Teaching--       MCB 150, Molecular Immunology. (2000-2003, 2008                                                                                   teaching evaluation 6.72 / 7.0).

                                    MCB 250, Graduate Immunology. (2000, 2004; teaching                                                                   evaluation 6.58 / 7.0).

                                    MCB 251, Regulation of Immune System Development                                                                     and Function. (2000-present).

                                    Bio1A  Introductory Biology (2006- present ; teaching evaluation                                                      5.9/7.0)

 

            Administrative--           Graduate Admissions Committee 1999-2001;                                                                                     (co-chair 2000, chair 2001).

                                                Graduate Affairs Committee (2000-2002).

                                                MCB Departmental Graduate Diversity Officer                                                                                  (1999-2003).

                                                Faculty Search Committee (Immunology; 2000-2001)

Vice-Chair, Molecular & Cell Biology (2002 to 2007)

Dean of Biological Sciences (2008-present)

 

OUTSIDE ORGANIZATION RESPONSIBILITIES

 

         American Association of Immunologists (AAI) Education Committee                                                (2000-2003)

            Midwinter Conference of Immunologists Organizing Committee                                                       (2001-2006)

            Scientific Advisory Board-- Genetastix, Inc. (2000-2006)

            Scientific Advisor—Leukemia & Lymphoma Society (2001-2003)

            Chair—Immunobiology Study Section (NIH) (2002-2004)

            HHMI Board of Scientific Advisors (2005-present)

            Organizer, Cold Spring Harbor Meeting ÒSignaling and Transcription in the                                    Immune system (2008, 2010)

            Organizer, Keystone Meeting, B Cells in Health and Disease (2009)

            Expert Witness—Biogen Idec (Patent infringement case; 2006-2007)

 

INVITED LECTURES (2000-present)

 

            UCSF                                      Keystone Symposium

            University of Illinois Med.      FASEB Meeting

            University of Pennsylvania      Gordon Conference

            Emory                                     AAI Meeting

            University of Chicago             Stanford University

            University of Washington       Harvard Medical School

            University of Kentucky           Fox Chase Cancer Center

            University of Virginia              Ohio State University

            Duke University                      Cold Spring Harbor Meetings (2004, 2006)

            University of Calif. Irvine        Scripps Research Inst.

            Aegean Conference                 National Jewish Hospital

            UCLA                                     NYU Medical School

            RCAI Symp (Yokohama)        Tufts Medical School

            Yale                                         Johns Hopkins Medical

            USC                                        Erlangen Symposium (Germany)

            Columbia P&S                        University of Pittsburg

            Washington Univ                    University of Pennsylvania

            University of Toronto              La Jolla Inst. Of Allergy & Immunology

            University of Alabama University of Vermont

            University of Massachusetts

 

 

GRANT SUPPORT

 

         NIH HL48702-16       The Regulation of B Cell Development.

            NIH AI 40227-14       The Biochemistry and Regulation of V(D)J Recombination

            NIH AI 57487-05       c-Abl in B Cell Development and Leukemia

 

 

PUBLICATIONS

(peer reviewed article numbers in boldface)

 

1.         Cozzarelli, N.R., S.P. Gerrard, M. Schlissel, D.D. Brown, and D.F. Bogenhagen. 1983. Purified RNA polymerase III accurately and efficiently terminates transcription of 5S RNA genes. Cell 34:829-835.

2.         Wormington, W.M., M. Schlissel, and D.D. Brown. 1983. Developmental regulation of Xenopus 5S RNA genes. Cold Spring Harb Symp Quant Biol 47:879-884.

3.         Schlissel, M.S., and D.D. Brown. 1984. The transcriptional regulation of Xenopus 5s RNA genes in chromatin: the roles of active stable transcription complexes and histone H1. Cell 37:903-913.

4.         Brown, D.D., and M.S. Schlissel. 1985. The molecular basis of differential gene expression of two 5S RNA genes. Cold Spring Harb Symp Quant Biol 50:549-553.

5.         Brown, D.D., and M.S. Schlissel. 1985. A positive transcription factor controls the differential expression of two 5S RNA genes. Cell 42:759-767.

6.         Schlissel, M.S., and D. Baltimore. 1989. Activation of immunoglobulin kappa gene rearrangement correlates with induction of germline kappa gene transcription. Cell 58:1001-1007.

7.         Hendrickson, E.A., M.S. Schlissel, and D.T. Weaver. 1990. Wild-type V(D)J recombination in scid pre-B cells. Mol Cell Biol 10:5397-5407.

8.         Schlissel, M., A. Voronova, and D. Baltimore. 1991. Helix-loop-helix transcription factor E47 activates germ-line immunoglobulin heavy-chain gene transcription and rearrangement in a pre-T-cell line. Genes Dev 5:1367-1376.

9.         Schlissel, M.S., L.M. Corcoran, and D. Baltimore. 1991. Virus-transformed pre-B cells show ordered activation but not inactivation of immunoglobulin gene rearrangement and transcription. J Exp Med 173:711-720.

10.       Morrow, T., and M. Schlissel. 1992. The purification of B-cell precursors from mouse fetal liver. Curr Top Microbiol Immunol 182:55-64.

11.       Schatz, D.G., M.A. Oettinger, and M.S. Schlissel. 1992. V(D)J recombination: molecular biology and regulation. Annu Rev Immunol 10:359-383.

12.       Schlissel, M., A. Constantinescu, T. Morrow, M. Baxter, and A. Peng. 1993. Double-strand signal sequence breaks in V(D)J recombination are blunt, 5'-phosphorylated, RAG-dependent, and cell cycle regulated. Genes Dev 7:2520-2532.

13.       Shapiro, A.M., M.S. Schlissel, D. Baltimore, and A.L. DeFranco. 1993. Stimulation of kappa light-chain gene rearrangement by the immunoglobulin mu heavy chain in a pre-B-cell line. Mol Cell Biol 13:5679-5690.

14.       Bain, G., E.C. Maandag, D.J. Izon, D. Amsen, A.M. Kruisbeek, B.C. Weintraub, I. Krop, M.S. Schlissel, A.J. Feeney, M. van Roon, and et al. 1994. E2A proteins are required for proper B cell development and initiation of immunoglobulin gene rearrangements [see comments]. Cell 79:885-892.

15.       Schlissel, M.S., and T. Morrow. 1994. Ig heavy chain protein controls B cell development by regulating germ- line transcription and retargeting V(D)J recombination. J Immunol 153:1645-1657.

16.       Spanopoulou, E., C.A. Roman, L.M. Corcoran, M.S. Schlissel, D.P. Silver, D. Nemazee, M.C. Nussenzweig, S.A. Shinton, R.R. Hardy, and D. Baltimore. 1994. Functional immunoglobulin transgenes guide ordered B-cell differentiation in Rag-1-deficient mice. Genes Dev 8:1030-1042.

17.       Schlissel, M., and T. Morrow. 1995. Broken-ended DNA and V(D)J recombination. Curr Top Microbiol Immunol 194:381-388.

18.       Casciola-Rosen, L., A. Rosen, M. Petri, and M. Schlissel. 1996. Surface blebs on apoptotic cells are sites of enhanced procoagulant activity: implications for coagulation events and antigenic spread in systemic lupus erythematosus. Proc Natl Acad Sci U S A 93:1624-1629.

19.       Fang, W., D.L. Mueller, C.A. Pennell, J.J. Rivard, Y.S. Li, R.R. Hardy, M.S. Schlissel, and T.W. Behrens. 1996. Frequent aberrant immunoglobulin gene rearrangements in pro-B cells revealed by a bcl-xL transgene. Immunity 4:291-299.

20.       Krop, I., A.R. de Fougerolles, R.R. Hardy, M. Allison, M.S. Schlissel, and D.T. Fearon. 1996. Self-renewal of B-1 lymphocytes is dependent on CD19. Eur J Immunol 26:238-242.

21.       Krop, I., A.L. Shaffer, D.T. Fearon, and M.S. Schlissel. 1996. The signaling activity of murine CD19 is regulated during cell development. J Immunol 157:48-56.

22.       Nacht, M., A. Strasser, Y.R. Chan, A.W. Harris, M. Schlissel, R.T. Bronson, and T. Jacks. 1996. Mutations in the p53 and SCID genes cooperate in tumorigenesis. Genes Dev 10:2055-2066.

23.       Stanhope-Baker, P., K.M. Hudson, A.L. Shaffer, A. Constantinescu, and M.S. Schlissel. 1996. Cell type-specific chromatin structure determines the targeting of V(D)J recombinase activity in vitro. Cell 85:887-897.

24.       Bain, G., E.C. Robanus Maandag, H.P. te Riele, A.J. Feeney, A. Sheehy, M. Schlissel, S.A. Shinton, R.R. Hardy, and C. Murre. 1997. Both E12 and E47 allow commitment to the B cell lineage. Immunity 6:145-154.

25.       Constantinescu, A., and M.S. Schlissel. 1997. Changes in locus-specific V(D)J recombinase activity induced by immunoglobulin gene products during B cell development. J Exp Med 185:609-620.

26.       Gu, Y., K.J. Seidl, G.A. Rathbun, C. Zhu, J.P. Manis, N. van der Stoep, L. Davidson, H.L. Cheng, J.M. Sekiguchi, K. Frank, P. Stanhope-Baker, M.S. Schlissel, D.B. Roth, and F.W. Alt. 1997. Growth retardation and leaky SCID phenotype of Ku70-deficient mice. Immunity 7:653-665.

27.       Han, S., S.R. Dillon, B. Zheng, M. Shimoda, M.S. Schlissel, and G. Kelsoe. 1997. V(D)J recombinase activity in a subset of germinal center B lymphocytes [see comments]. Science 278:301-305.

28.       Schlissel, M.S., and P. Stanhope-Baker. 1997. Accessibility and the developmental regulation of V(D)J recombination. Semin Immunol 9:161-170.

29.       Shaffer, A.L., A. Peng, and M.S. Schlissel. 1997. In vivo occupancy of the kappa light chain enhancers in primary pro- and pre-B cells: a model for kappa locus activation. Immunity 6:131-143.

30.       Shaffer, A.L., and M.S. Schlissel. 1997. A truncated heavy chain protein relieves the requirement for surrogate light chains in early B cell development. J Immunol 159:1265-1275.

31.       Hempel, W.M., P. Stanhope-Baker, N. Mathieu, F. Huang, M.S. Schlissel, and P. Ferrier. 1998. Enhancer control of V(D)J recombination at the TCRbeta locus: differential effects on DNA cleavage and joining. Genes Dev 12:2305-2317.

32.       Schlissel, M.S. 1998. Structure of nonhairpin coding-end DNA breaks in cells undergoing V(D)J recombination. Mol Cell Biol 18:2029-2037.

33.       Golding, A., S. Chandler, E. Ballestar, A.P. Wolffe, and M.S. Schlissel. 1999. Nucleosome structure completely inhibits in vitro cleavage by the V(D)J recombinase. Embo J 18:3712-3723.

34.       Lauring, J., and M.S. Schlissel. 1999. Distinct factors regulate the murine RAG-2 promoter in B- and T-cell lines. Mol Cell Biol 19:2601-2612.

35.       Morrow, T.A., S.A. Muljo, J. Zhang, J.M. Hardwick, and M.S. Schlissel. 1999. Pro-B-cell-specific transcription and proapoptotic function of protein kinase ceta. Cell Biol 19:5608-5618.

36.       Sheehy, A.M., and M.S. Schlissel. 1999. Overexpression of RelA causes G1 arrest and apoptosis in a pro-B cell line. J Biol Chem 274:8708-8716.

37.       Dillon, S.R., M. Mancini, A. Rosen, and M.S. Schlissel. 2000. Annexin V binds to viable B cells and colocalizes with a marker of lipid rafts upon B cell receptor activation. J Immunol 164:1322-1332.

38.       Muljo, S.A., and M.S. Schlissel. 2000. Pre-B and pre-T-cell receptors: conservation of strategies in regulating early lymphocyte development. Immunol Rev 175:80-93.

39.       Schlissel, M.S. 2000. Perspectives: transcription. A tail of histone acetylation and DNA recombination. Science 287:438-440.

40.       Schlissel, M.S., S.D. Durum, and K. Muegge. 2000. The interleukin 7 receptor is required for T cell receptor gamma locus accessibility to the V(D)J recombinase. J Exp Med 191:1045-1050.

41.       Wang, Q.F., J. Lauring, and M.S. Schlissel. 2000. c-Myb binds to a sequence in the proximal region of the RAG-2 promoter and is essential for promoter activity in T-lineage cells. Mol Cell Biol 20:9203-9211.

42.       Whitehurst, C.E., M.S. Schlissel, and J. Chen. 2000. Deletion of germline promoter PD beta 1 from the TCR beta locus causes hypermethylation that impairs D beta 1 recombination by multiple mechanisms. Immunity 13:703-714.

43.       Cost, G.J., A. Golding, M.S. Schlissel, and J.D. Boeke. 2001. Target DNA chromatinization modulates nicking by L1 endonuclease. Nucleic Acids Res 29:573-577.

44.       Dillon, S.R., A. Constantinescu, and M.S. Schlissel. 2001. Annexin V binds to positively selected B cells. J Immunol 166:58-71.

45.       Lee, P.P., D.R. Fitzpatrick, C. Beard, H.K. Jessup, S. Lehar, K.W. Makar, M. Perez-Melgosa, M.T. Sweetser, M.S. Schlissel, S. Nguyen, S.R. Cherry, J.H. Tsai, S.M. Tucker, W.M. Weaver, A. Kelso, R. Jaenisch, and C.B. Wilson. 2001. A critical role for dnmt1 and DNA methylation in T cell development, function, and survival. Immunity 15:763-774.

46.       Lu, L., C.A. Bonham, X. Liang, Z. Chen, W. Li, L. Wang, S.C. Watkins, M.A. Nalesnik, M.S. Schlissel, A.J. Demestris, J.J. Fung, and S. Qian. 2001. Liver-derived DEC205+B220+CD19- dendritic cells regulate T cell responses. J Immunol 166:7042-7052.

48.       Dillon, S.R., and M.S. Schlissel. 2002. Partial restoration of B cell development in Jak-3(-/-) mice achieved by co-expression of IgH and E(mu)-myc transgenes. Int Immunol 14:893-904.

49.       Goldmit, M., M. Schlissel, H. Cedar, and Y. Bergman. 2002. Differential accessibility at the kappa chain locus plays a role in allelic exclusion. Embo J 21:5255-5261.

50.       Liang, H.E., L.Y. Hsu, D. Cado, L.G. Cowell, G. Kelsoe, and M.S. Schlissel. 2002. The "dispensable" portion of RAG2 is necessary for efficient V-to-DJ rearrangement during B and T cell development. Immunity 17:639-651.

51.       Muljo, S.A., and M.S. Schlissel. 2002. The variable, C(H)1, C(H)2 and C(H)3 domains of Ig heavy chain are dispensable for pre-BCR function in transgenic mice. Int Immunol 14:577-584.

52.       Schlissel, M. 2002. Allelic exclusion of immunoglobulin gene rearrangement and expression: why and how? Semin Immunol 14:207.

53.       Schlissel, M.S. 2002. Does artemis end the hunt for the hairpin-opening activity in V(D)J recombination? Cell 109:1-4.

54.       Hsu, L.Y., J. Lauring, H.E. Liang, S. Greenbaum, D. Cado, Y. Zhuang, and M.S. Schlissel. 2003. A conserved transcriptional enhancer regulates RAG gene expression in developing B cells. Immunity 19:105-117.

55.       Muljo, S.A., and M.S. Schlissel. 2003. A small molecule Abl kinase inhibitor induces differentiation of Abelson virus-transformed pre-B cell lines. Nat Immunol 4:31-37.

56.       Robey, E., and M. Schlissel. 2003. Lymphocyte development. Curr Opin Immunol 15:155-157.

57.       Schlissel, M. 2003. How pre-B cells know when they have it right. Nat Immunol 4:817-819.

58.       Schlissel, M.S. 2003. Regulating antigen-receptor gene assembly. Nat Rev Immunol 3:890-899.

59.       Borghesi, L., L.Y. Hsu, J.P. Miller, M. Anderson, L. Herzenberg, M.S. Schlissel, D. Allman, and R.M. Gerstein. 2004. B lineage-specific regulation of V(D)J recombinase activity is established in common lymphoid progenitors. J Exp Med 199:491-502.

60.       Hsu, L.Y., H.E. Liang, K. Johnson, C. Kang, and M.S. Schlissel. 2004. Pax5 activates immunoglobulin heavy chain V to DJ rearrangement in transgenic thymocytes. J Exp Med 199:825-830.

61.       Liang, H.E., L.Y. Hsu, D. Cado, and M.S. Schlissel. 2004. Variegated transcriptional activation of the immunoglobulin kappa locus in pre-b cells contributes to the allelic exclusion of light-chain expression. Cell 118:19-29.

62.       Schlissel, M. 2004. The spreading influence of chromatin modification. Nat Genet 36:438-440.

63.       Schlissel, M.S. 2004. Regulation of activation and recombination of the murine Igkappa locus. Immunol Rev 200:215-223.

64.       Amin, R.H., and M.S. Schlissel. 2005. NF-kappa B comes home. Immunity 22:401-402.

65.       Curry, J.D., J.K. Geier, and M.S. Schlissel. 2005. Single-strand recombination signal sequence nicks in vivo: evidence for a capture model of synapsis. Nat Immunol 6:1272-1279.

66.       Curry, J.D., L. Li, and M.S. Schlissel. 2005. Quantification of Jkappa signal end breaks in developing B cells by blunt-end linker ligation and qPCR. J Immunol Methods 296:19-30.

67.       Geier, J.K., and M.S. Schlissel. 2005. Pre-BCR signals and the control of Ig gene rearrangements. Semin Immunol

68.       Tze, L.E., B.R. Schram, K.P. Lam, K.A. Hogquist, K.L. Hippen, J. Liu, S.A. Shinton, K.L. Otipoby, P.R. Rodine, A.L. Vegoe, M. Kraus, R.R. Hardy, M.S. Schlissel, K. Rajewsky, and T.W. Behrens. 2005. Basal immunoglobulin signaling actively maintains developmental stage in immature B cells. PLoS Biol 3:e82.

69.       Geier, J.K., and M.S. Schlissel. 2006. Pre-BCR signals and the control of Ig gene rearrangements. Semin Immunol 18:31-39.

70.       Huang, F., Y. Kitaura, I. Jang, M. Naramura, H.H. Kole, L. Liu, H. Qin, M.S. Schlissel, and H. Gu. 2006. Establishment of the major compatibility complex-dependent development of CD4+ and CD8+ T cells by the Cbl family proteins. Immunity 25:571-581.

71.       Lazorchak, A.S., M.S. Schlissel, and Y. Zhuang. 2006. E2A and IRF-4/Pip promote chromatin modification and transcription of the immunoglobulin kappa locus in pre-B cells. Mol Cell Biol 26:810-821.

72.       Pedraza-Alva, G., M. Koulnis, C. Charland, T. Thornton, J.L. Clements, M.S. Schlissel, and M. Rincon. 2006. Activation of p38 MAP kinase by DNA double-strand breaks in V(D)J recombination induces a G2/M cell cycle checkpoint. Embo J 25:763-773.

73.       Schlissel, M.S., C.R. Kaffer, and J.D. Curry. 2006. Leukemia and lymphoma: a cost of doing business for adaptive immunity. Genes Dev 20:1539-1544.

74.       Schlissel, M.S., and T.C. Kuo. 2006. AID for innate immunity to retroviral transformation. Immunity 24:671-672.

75.       Bates, J.G., D. Cado, H. Nolla, and M.S. Schlissel. 2007. Chromosomal position of a VH gene segment determines its activation and inactivation as a substrate for V(D)J recombination. J Exp Med 204:3247-3256.

76.       Curry, J.D., D. Schulz, C.J. Guidos, J.S. Danska, L. Nutter, A. Nussenzweig, and M.S. Schlissel. 2007. Chromosomal reinsertion of broken RSS ends during T cell development. J Exp Med 204:2293-2303.

77.       Kitaura, Y., I.K. Jang, Y. Wang, Y.C. Han, T. Inazu, E.J. Cadera, M. Schlissel, R.R. Hardy, and H. Gu. 2007. Control of the B cell-intrinsic tolerance programs by ubiquitin ligases Cbl and Cbl-b. Immunity 26:567-578.

78.       Schlissel, M.S. 2007. The regulation of receptor editing. Adv Exp Med Biol 596:173-179.

79.       Amin, R.H., and M.S. Schlissel. 2008. Foxo1 directly regulates the transcription of recombination-activating genes during B cell development. Nat Immunol 9:613-622.

80.       Curry, J.D., and M.S. Schlissel. 2008. RAG2's non-core domain contributes to the ordered regulation of V(D)J recombination. Nucleic Acids Res 36:5750-5762.

81.       Hewitt, S.L., D. Farmer, K. Marszalek, E. Cadera, H.E. Liang, Y. Xu, M.S. Schlissel, and J.A. Skok. 2008. Association between the Igk and Igh immunoglobulin loci mediated by the 3' Igk enhancer induces 'decontraction' of the Igh locus in pre-B cells. Nat Immunol 9:396-404.

82.       Amin, R.H., D. Cado, H. Nolla, D. Huang, S.A. Shinton, Y. Zhou, R.R. Hardy, and M.S. 2009. Biallelic, ubiquitous transcription from the distal germline Ig{kappa} locus promoter during B cell development. Proc Natl Acad Sci U S A 106:522-527.