Abstract

Rapid and direct imaging of microscopic tissue morphology and pathology can be achieved by multiphoton imaging of intrinsic tissue fluorophores and second harmonic signals. Engineering parameters for developing this technology for clinical applications include excitation levels and collection efficiencies required to obtain diagnostic quality images from different tissue types and whether these levels are mutagenic. Here we provide data on typical average powers required for high signal-to-noise in vivo tissue imaging and assess the risk potential of these irradiance levels using a mammalian cell gene mutation assay. Exposure times of ~16 milliseconds per cell to 760 nm, ~200 fs raster-scanned laser irradiation delivered through a 0.75 NA objective produced negligible mutagenicity at powers up to about 50 mW.

© 2010 OSA

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2010

J. C. Vryghem, T. Devogelaere, and P. Stodulka, “Efficacy, safety, and flap dimensions of a new femtosecond laser for laser in situ keratomileusis,” J. Cataract Refract. Surg. 36(3), 442–448 (2010).
[CrossRef] [PubMed]

R. M. Williams, A. Flesken-Nikitin, L. H. Ellenson, D. C. Connolly, T. C. Hamilton, A. Y. Nikitin, and W. R. Zipfel, “Strategies for high-resolution imaging of epithelial ovarian cancer by laparoscopic nonlinear microscopy,” Transl Oncol 3(3), 181–194 (2010).
[PubMed]

C. Lohr, N. Raquet, and D. Schrenk, “Application of the concept of relative photomutagenic potencies to selected furocoumarins in V79 cells,” Toxicol. In Vitro 24(2), 558–566 (2010).
[CrossRef] [PubMed]

H. Bao, A. Boussioutas, R. Jeremy, S. Russell, and M. Gu, “Second harmonic generation imaging via nonlinear endomicroscopy,” Opt. Express 18(2), 1255–1260 (2010).
[CrossRef] [PubMed]

2009

P. P. Provenzano, K. W. Eliceiri, and P. J. Keely, “Multiphoton microscopy and fluorescence lifetime imaging microscopy (FLIM) to monitor metastasis and the tumor microenvironment,” Clin. Exp. Metastasis 26(4), 357–370 (2009).
[CrossRef] [PubMed]

R. Brem, F. Li, and P. Karran, “Reactive oxygen species generated by thiopurine/UVA cause irreparable transcription-blocking DNA lesions,” in Nucleic Acids Res. 37, 1951–1961 (2009).

2008

J. N. Rogart, J. Nagata, C. S. Loeser, R. D. Roorda, H. Aslanian, M. E. Robert, W. R. Zipfel, and M. H. Nathanson, “Multiphoton imaging can be used for microscopic examination of intact human gastrointestinal mucosa ex vivo,” Clin. Gastroenterol. Hepatol. 6(1), 95–101 (2008).
[CrossRef] [PubMed]

2007

S. Yoshida, S. Tanaka, M. Hirata, R. Mouri, I. Kaneko, S. Oka, M. Yoshihara, and K. Chayama, “Optical biopsy of GI lesions by reflectance-type laser-scanning confocal microscopy,” Gastrointest. Endosc. 66(1), 144–149 (2007).
[CrossRef] [PubMed]

L. Fu and M. Gu, “Fibre-optic nonlinear optical microscopy and endoscopy,” J. Microsc. 226(3), 195–206 (2007).
[CrossRef] [PubMed]

K. König, A. Ehlers, I. Riemann, S. Schenkl, R. Bückle, and M. Kaatz, “Clinical two-photon microendoscopy,” Microsc. Res. Tech. 70(5), 398–402 (2007).
[CrossRef] [PubMed]

2006

L. Fu, A. Jain, H. Xie, C. Cranfield, and M. Gu, “Nonlinear optical endoscopy based on a double-clad photonic crystal fiber and a MEMS mirror,” Opt. Express 14(3), 1027–1032 (2006).
[CrossRef] [PubMed]

U. P. Kappes, D. Luo, M. Potter, K. Schulmeister, and T. M. Rünger, “Short- and long-wave UV light (UVB and UVA) induce similar mutations in human skin cells,” J. Invest. Dermatol. 126(3), 667–675 (2006).
[CrossRef] [PubMed]

2005

G. P. Pfeifer, Y. H. You, and A. Besaratinia, “Mutations induced by ultraviolet light,” Mutat. Res. 571(1-2), 19–31 (2005).
[CrossRef] [PubMed]

A. L. Polglase, W. J. McLaren, S. A. Skinner, R. Kiesslich, M. F. Neurath, and P. M. Delaney, “A fluorescence confocal endomicroscope for in vivo microscopy of the upper- and the lower-GI tract,” Gastrointest. Endosc. 62(5), 686–695 (2005).
[CrossRef] [PubMed]

B. A. Flusberg, E. D. Cocker, W. Piyawattanametha, J. C. Jung, E. L. Cheung, and M. J. Schnitzer, “Fiber-optic fluorescence imaging,” Nat. Methods 2(12), 941–950 (2005).
[CrossRef] [PubMed]

2004

A. D. Mehta, J. C. Jung, B. A. Flusberg, and M. J. Schnitzer, “Fiber optic in vivo imaging in the mammalian nervous system,” Curr. Opin. Neurobiol. 14(5), 617–628 (2004).
[CrossRef] [PubMed]

C. Macaulay, P. Lane, and R. Richards-Kortum, “In vivo pathology: microendoscopy as a new endoscopic imaging modality,” Gastrointest. Endosc. Clin. N. Am. 14(3), 595–620, xi (2004).
[CrossRef] [PubMed]

2003

R. A. Meldrum, S. W. Botchway, C. W. Wharton, and G. J. Hirst, “Nanoscale spatial induction of ultraviolet photoproducts in cellular DNA by three-photon near-infrared absorption,” EMBO Rep. 4(12), 1144–1149 (2003).
[CrossRef] [PubMed]

J. Dahle and E. Kvam, “Induction of delayed mutations and chromosomal instability in fibroblasts after UVA-, UVB-, and X-radiation,” in Cancer Res. 63, 1464–1469 (2003).

W. R. Zipfel, R. M. Williams, R. Christie, A. Y. Nikitin, B. T. Hyman, and W. W. Webb, “Live tissue intrinsic emission microscopy using multiphoton-excited native fluorescence and second harmonic generation,” Proc. Natl. Acad. Sci. U.S.A. 100(12), 7075–7080 (2003).
[CrossRef] [PubMed]

E. Brown, T. McKee, E. diTomaso, A. Pluen, B. Seed, Y. Boucher, and R. K. Jain, “Dynamic imaging of collagen and its modulation in tumors in vivo using second-harmonic generation,” Nat. Med. 9(6), 796–801 (2003).
[CrossRef] [PubMed]

2002

1999

T. Douki, D. Perdiz, P. Gróf, Z. Kuluncsics, E. Moustacchi, J. Cadet, and E. Sage, “Oxidation of guanine in cellular DNA by solar UV radiation: biological role,” Photochem. Photobiol. 70(2), 184–190 (1999).
[CrossRef] [PubMed]

1997

J. Leavitt, M. Fatone, C. Hestdalen, J. W. Obringer, and H. S. Tillinghast, “Mutagenic activity of high-energy 532 nm ultra-short laser pulses,” in Radiation Res. 147, 490–494 (1997).

Y. Sako, A. Sekihata, Y. Yanagisawa, M. Yamamoto, Y. Shimada, K. Ozaki, and A. Kusumi, “Comparison of two-photon excitation laser scanning microscopy with UV-confocal laser scanning microscopy in three-dimensional calcium imaging using the fluorescence indicator Indo-1,” J. Microsc. 185(1), 9–20 (1997).
[CrossRef] [PubMed]

1993

D. Papadopoulo, A. Laquerbe, C. Guillouf, and E. Moustacchi, “Molecular spectrum of mutations induced at the HPRT locus by a cross-linking agent in human cell lines with different repair capacities,” Mutat. Res. 294(2), 167–177 (1993).
[PubMed]

1991

J. H. Li and T. G. Rossman, “Comutagenesis of sodium arsenite with ultraviolet radiation in Chinese hamster V79 cells,” Biol. Met. 4(4), 197–200 (1991).
[CrossRef] [PubMed]

1990

A. Skandalis and B. W. Glickman, “Endogenous gene systems for the study of mutational specificity in mammalian cells,” Cancer Cells 2(3), 79–83 (1990).
[PubMed]

1989

R. M. Tyrrell and M. Pidoux, “Singlet oxygen involvement in the inactivation of cultured human-fibroblasts by UVA (334 nm, 365 nm) and near-visible (405 nm) radiations,” in Photochem. Photobiol. 49,407–412 (1989).

1981

A. W. Hsie, D. A. Casciano, D. B. Couch, D. F. Krahn, J. P. O’Neill, and B. L. Whitfield, “The use of Chinese hamster ovary cells to quantify specific locus mutation and to determine mutagenicity of chemicals. A report of the gene-tox program,” Mutat. Res. 86(2), 193–214 (1981).
[PubMed]

1963

M. Lipkin, B. Bell, and P. Sherlock, “Cell Proliferation Kinetics in the Gastrointestinal Tract Of Man: Cell Renewal In Colon and Rectum,” J. Clin. Invest. 42(6), 767–776 (1963).
[CrossRef] [PubMed]

Aslanian, H.

J. N. Rogart, J. Nagata, C. S. Loeser, R. D. Roorda, H. Aslanian, M. E. Robert, W. R. Zipfel, and M. H. Nathanson, “Multiphoton imaging can be used for microscopic examination of intact human gastrointestinal mucosa ex vivo,” Clin. Gastroenterol. Hepatol. 6(1), 95–101 (2008).
[CrossRef] [PubMed]

Bao, H.

Bell, B.

M. Lipkin, B. Bell, and P. Sherlock, “Cell Proliferation Kinetics in the Gastrointestinal Tract Of Man: Cell Renewal In Colon and Rectum,” J. Clin. Invest. 42(6), 767–776 (1963).
[CrossRef] [PubMed]

Besaratinia, A.

G. P. Pfeifer, Y. H. You, and A. Besaratinia, “Mutations induced by ultraviolet light,” Mutat. Res. 571(1-2), 19–31 (2005).
[CrossRef] [PubMed]

Botchway, S. W.

R. A. Meldrum, S. W. Botchway, C. W. Wharton, and G. J. Hirst, “Nanoscale spatial induction of ultraviolet photoproducts in cellular DNA by three-photon near-infrared absorption,” EMBO Rep. 4(12), 1144–1149 (2003).
[CrossRef] [PubMed]

Boucher, Y.

E. Brown, T. McKee, E. diTomaso, A. Pluen, B. Seed, Y. Boucher, and R. K. Jain, “Dynamic imaging of collagen and its modulation in tumors in vivo using second-harmonic generation,” Nat. Med. 9(6), 796–801 (2003).
[CrossRef] [PubMed]

Boussioutas, A.

Brem, R.

R. Brem, F. Li, and P. Karran, “Reactive oxygen species generated by thiopurine/UVA cause irreparable transcription-blocking DNA lesions,” in Nucleic Acids Res. 37, 1951–1961 (2009).

Brown, E.

E. Brown, T. McKee, E. diTomaso, A. Pluen, B. Seed, Y. Boucher, and R. K. Jain, “Dynamic imaging of collagen and its modulation in tumors in vivo using second-harmonic generation,” Nat. Med. 9(6), 796–801 (2003).
[CrossRef] [PubMed]

Bückle, R.

K. König, A. Ehlers, I. Riemann, S. Schenkl, R. Bückle, and M. Kaatz, “Clinical two-photon microendoscopy,” Microsc. Res. Tech. 70(5), 398–402 (2007).
[CrossRef] [PubMed]

Cadet, J.

T. Douki, D. Perdiz, P. Gróf, Z. Kuluncsics, E. Moustacchi, J. Cadet, and E. Sage, “Oxidation of guanine in cellular DNA by solar UV radiation: biological role,” Photochem. Photobiol. 70(2), 184–190 (1999).
[CrossRef] [PubMed]

Casciano, D. A.

A. W. Hsie, D. A. Casciano, D. B. Couch, D. F. Krahn, J. P. O’Neill, and B. L. Whitfield, “The use of Chinese hamster ovary cells to quantify specific locus mutation and to determine mutagenicity of chemicals. A report of the gene-tox program,” Mutat. Res. 86(2), 193–214 (1981).
[PubMed]

Chayama, K.

S. Yoshida, S. Tanaka, M. Hirata, R. Mouri, I. Kaneko, S. Oka, M. Yoshihara, and K. Chayama, “Optical biopsy of GI lesions by reflectance-type laser-scanning confocal microscopy,” Gastrointest. Endosc. 66(1), 144–149 (2007).
[CrossRef] [PubMed]

Cheung, E. L.

B. A. Flusberg, E. D. Cocker, W. Piyawattanametha, J. C. Jung, E. L. Cheung, and M. J. Schnitzer, “Fiber-optic fluorescence imaging,” Nat. Methods 2(12), 941–950 (2005).
[CrossRef] [PubMed]

Christie, R.

W. R. Zipfel, R. M. Williams, R. Christie, A. Y. Nikitin, B. T. Hyman, and W. W. Webb, “Live tissue intrinsic emission microscopy using multiphoton-excited native fluorescence and second harmonic generation,” Proc. Natl. Acad. Sci. U.S.A. 100(12), 7075–7080 (2003).
[CrossRef] [PubMed]

Cocker, E. D.

B. A. Flusberg, E. D. Cocker, W. Piyawattanametha, J. C. Jung, E. L. Cheung, and M. J. Schnitzer, “Fiber-optic fluorescence imaging,” Nat. Methods 2(12), 941–950 (2005).
[CrossRef] [PubMed]

Connolly, D. C.

R. M. Williams, A. Flesken-Nikitin, L. H. Ellenson, D. C. Connolly, T. C. Hamilton, A. Y. Nikitin, and W. R. Zipfel, “Strategies for high-resolution imaging of epithelial ovarian cancer by laparoscopic nonlinear microscopy,” Transl Oncol 3(3), 181–194 (2010).
[PubMed]

Couch, D. B.

A. W. Hsie, D. A. Casciano, D. B. Couch, D. F. Krahn, J. P. O’Neill, and B. L. Whitfield, “The use of Chinese hamster ovary cells to quantify specific locus mutation and to determine mutagenicity of chemicals. A report of the gene-tox program,” Mutat. Res. 86(2), 193–214 (1981).
[PubMed]

Cranfield, C.

Dahle, J.

J. Dahle and E. Kvam, “Induction of delayed mutations and chromosomal instability in fibroblasts after UVA-, UVB-, and X-radiation,” in Cancer Res. 63, 1464–1469 (2003).

Delaney, P. M.

A. L. Polglase, W. J. McLaren, S. A. Skinner, R. Kiesslich, M. F. Neurath, and P. M. Delaney, “A fluorescence confocal endomicroscope for in vivo microscopy of the upper- and the lower-GI tract,” Gastrointest. Endosc. 62(5), 686–695 (2005).
[CrossRef] [PubMed]

Devogelaere, T.

J. C. Vryghem, T. Devogelaere, and P. Stodulka, “Efficacy, safety, and flap dimensions of a new femtosecond laser for laser in situ keratomileusis,” J. Cataract Refract. Surg. 36(3), 442–448 (2010).
[CrossRef] [PubMed]

diTomaso, E.

E. Brown, T. McKee, E. diTomaso, A. Pluen, B. Seed, Y. Boucher, and R. K. Jain, “Dynamic imaging of collagen and its modulation in tumors in vivo using second-harmonic generation,” Nat. Med. 9(6), 796–801 (2003).
[CrossRef] [PubMed]

Douki, T.

T. Douki, D. Perdiz, P. Gróf, Z. Kuluncsics, E. Moustacchi, J. Cadet, and E. Sage, “Oxidation of guanine in cellular DNA by solar UV radiation: biological role,” Photochem. Photobiol. 70(2), 184–190 (1999).
[CrossRef] [PubMed]

Ehlers, A.

K. König, A. Ehlers, I. Riemann, S. Schenkl, R. Bückle, and M. Kaatz, “Clinical two-photon microendoscopy,” Microsc. Res. Tech. 70(5), 398–402 (2007).
[CrossRef] [PubMed]

Eliceiri, K. W.

P. P. Provenzano, K. W. Eliceiri, and P. J. Keely, “Multiphoton microscopy and fluorescence lifetime imaging microscopy (FLIM) to monitor metastasis and the tumor microenvironment,” Clin. Exp. Metastasis 26(4), 357–370 (2009).
[CrossRef] [PubMed]

Ellenson, L. H.

R. M. Williams, A. Flesken-Nikitin, L. H. Ellenson, D. C. Connolly, T. C. Hamilton, A. Y. Nikitin, and W. R. Zipfel, “Strategies for high-resolution imaging of epithelial ovarian cancer by laparoscopic nonlinear microscopy,” Transl Oncol 3(3), 181–194 (2010).
[PubMed]

Fatone, M.

J. Leavitt, M. Fatone, C. Hestdalen, J. W. Obringer, and H. S. Tillinghast, “Mutagenic activity of high-energy 532 nm ultra-short laser pulses,” in Radiation Res. 147, 490–494 (1997).

Flesken-Nikitin, A.

R. M. Williams, A. Flesken-Nikitin, L. H. Ellenson, D. C. Connolly, T. C. Hamilton, A. Y. Nikitin, and W. R. Zipfel, “Strategies for high-resolution imaging of epithelial ovarian cancer by laparoscopic nonlinear microscopy,” Transl Oncol 3(3), 181–194 (2010).
[PubMed]

Flusberg, B. A.

B. A. Flusberg, E. D. Cocker, W. Piyawattanametha, J. C. Jung, E. L. Cheung, and M. J. Schnitzer, “Fiber-optic fluorescence imaging,” Nat. Methods 2(12), 941–950 (2005).
[CrossRef] [PubMed]

A. D. Mehta, J. C. Jung, B. A. Flusberg, and M. J. Schnitzer, “Fiber optic in vivo imaging in the mammalian nervous system,” Curr. Opin. Neurobiol. 14(5), 617–628 (2004).
[CrossRef] [PubMed]

Foster, M. A.

Fu, L.

Gaeta, A. L.

Glickman, B. W.

A. Skandalis and B. W. Glickman, “Endogenous gene systems for the study of mutational specificity in mammalian cells,” Cancer Cells 2(3), 79–83 (1990).
[PubMed]

Gróf, P.

T. Douki, D. Perdiz, P. Gróf, Z. Kuluncsics, E. Moustacchi, J. Cadet, and E. Sage, “Oxidation of guanine in cellular DNA by solar UV radiation: biological role,” Photochem. Photobiol. 70(2), 184–190 (1999).
[CrossRef] [PubMed]

Gu, M.

Guillouf, C.

D. Papadopoulo, A. Laquerbe, C. Guillouf, and E. Moustacchi, “Molecular spectrum of mutations induced at the HPRT locus by a cross-linking agent in human cell lines with different repair capacities,” Mutat. Res. 294(2), 167–177 (1993).
[PubMed]

Hamilton, T. C.

R. M. Williams, A. Flesken-Nikitin, L. H. Ellenson, D. C. Connolly, T. C. Hamilton, A. Y. Nikitin, and W. R. Zipfel, “Strategies for high-resolution imaging of epithelial ovarian cancer by laparoscopic nonlinear microscopy,” Transl Oncol 3(3), 181–194 (2010).
[PubMed]

Helmchen, F.

F. Helmchen, “Miniaturization of fluorescence microscopes using fibre optics,” Exp. Physiol. 87(6), 737–745 (2002).
[CrossRef] [PubMed]

Hestdalen, C.

J. Leavitt, M. Fatone, C. Hestdalen, J. W. Obringer, and H. S. Tillinghast, “Mutagenic activity of high-energy 532 nm ultra-short laser pulses,” in Radiation Res. 147, 490–494 (1997).

Hirata, M.

S. Yoshida, S. Tanaka, M. Hirata, R. Mouri, I. Kaneko, S. Oka, M. Yoshihara, and K. Chayama, “Optical biopsy of GI lesions by reflectance-type laser-scanning confocal microscopy,” Gastrointest. Endosc. 66(1), 144–149 (2007).
[CrossRef] [PubMed]

Hirst, G. J.

R. A. Meldrum, S. W. Botchway, C. W. Wharton, and G. J. Hirst, “Nanoscale spatial induction of ultraviolet photoproducts in cellular DNA by three-photon near-infrared absorption,” EMBO Rep. 4(12), 1144–1149 (2003).
[CrossRef] [PubMed]

Hsie, A. W.

A. W. Hsie, D. A. Casciano, D. B. Couch, D. F. Krahn, J. P. O’Neill, and B. L. Whitfield, “The use of Chinese hamster ovary cells to quantify specific locus mutation and to determine mutagenicity of chemicals. A report of the gene-tox program,” Mutat. Res. 86(2), 193–214 (1981).
[PubMed]

Hyman, B. T.

W. R. Zipfel, R. M. Williams, R. Christie, A. Y. Nikitin, B. T. Hyman, and W. W. Webb, “Live tissue intrinsic emission microscopy using multiphoton-excited native fluorescence and second harmonic generation,” Proc. Natl. Acad. Sci. U.S.A. 100(12), 7075–7080 (2003).
[CrossRef] [PubMed]

Jain, A.

Jain, R. K.

E. Brown, T. McKee, E. diTomaso, A. Pluen, B. Seed, Y. Boucher, and R. K. Jain, “Dynamic imaging of collagen and its modulation in tumors in vivo using second-harmonic generation,” Nat. Med. 9(6), 796–801 (2003).
[CrossRef] [PubMed]

Jeremy, R.

Jung, J. C.

B. A. Flusberg, E. D. Cocker, W. Piyawattanametha, J. C. Jung, E. L. Cheung, and M. J. Schnitzer, “Fiber-optic fluorescence imaging,” Nat. Methods 2(12), 941–950 (2005).
[CrossRef] [PubMed]

A. D. Mehta, J. C. Jung, B. A. Flusberg, and M. J. Schnitzer, “Fiber optic in vivo imaging in the mammalian nervous system,” Curr. Opin. Neurobiol. 14(5), 617–628 (2004).
[CrossRef] [PubMed]

Kaatz, M.

K. König, A. Ehlers, I. Riemann, S. Schenkl, R. Bückle, and M. Kaatz, “Clinical two-photon microendoscopy,” Microsc. Res. Tech. 70(5), 398–402 (2007).
[CrossRef] [PubMed]

Kaneko, I.

S. Yoshida, S. Tanaka, M. Hirata, R. Mouri, I. Kaneko, S. Oka, M. Yoshihara, and K. Chayama, “Optical biopsy of GI lesions by reflectance-type laser-scanning confocal microscopy,” Gastrointest. Endosc. 66(1), 144–149 (2007).
[CrossRef] [PubMed]

Kappes, U. P.

U. P. Kappes, D. Luo, M. Potter, K. Schulmeister, and T. M. Rünger, “Short- and long-wave UV light (UVB and UVA) induce similar mutations in human skin cells,” J. Invest. Dermatol. 126(3), 667–675 (2006).
[CrossRef] [PubMed]

Karran, P.

R. Brem, F. Li, and P. Karran, “Reactive oxygen species generated by thiopurine/UVA cause irreparable transcription-blocking DNA lesions,” in Nucleic Acids Res. 37, 1951–1961 (2009).

Keely, P. J.

P. P. Provenzano, K. W. Eliceiri, and P. J. Keely, “Multiphoton microscopy and fluorescence lifetime imaging microscopy (FLIM) to monitor metastasis and the tumor microenvironment,” Clin. Exp. Metastasis 26(4), 357–370 (2009).
[CrossRef] [PubMed]

Kiesslich, R.

A. L. Polglase, W. J. McLaren, S. A. Skinner, R. Kiesslich, M. F. Neurath, and P. M. Delaney, “A fluorescence confocal endomicroscope for in vivo microscopy of the upper- and the lower-GI tract,” Gastrointest. Endosc. 62(5), 686–695 (2005).
[CrossRef] [PubMed]

König, K.

K. König, A. Ehlers, I. Riemann, S. Schenkl, R. Bückle, and M. Kaatz, “Clinical two-photon microendoscopy,” Microsc. Res. Tech. 70(5), 398–402 (2007).
[CrossRef] [PubMed]

Krahn, D. F.

A. W. Hsie, D. A. Casciano, D. B. Couch, D. F. Krahn, J. P. O’Neill, and B. L. Whitfield, “The use of Chinese hamster ovary cells to quantify specific locus mutation and to determine mutagenicity of chemicals. A report of the gene-tox program,” Mutat. Res. 86(2), 193–214 (1981).
[PubMed]

Kuluncsics, Z.

T. Douki, D. Perdiz, P. Gróf, Z. Kuluncsics, E. Moustacchi, J. Cadet, and E. Sage, “Oxidation of guanine in cellular DNA by solar UV radiation: biological role,” Photochem. Photobiol. 70(2), 184–190 (1999).
[CrossRef] [PubMed]

Kusumi, A.

Y. Sako, A. Sekihata, Y. Yanagisawa, M. Yamamoto, Y. Shimada, K. Ozaki, and A. Kusumi, “Comparison of two-photon excitation laser scanning microscopy with UV-confocal laser scanning microscopy in three-dimensional calcium imaging using the fluorescence indicator Indo-1,” J. Microsc. 185(1), 9–20 (1997).
[CrossRef] [PubMed]

Kvam, E.

J. Dahle and E. Kvam, “Induction of delayed mutations and chromosomal instability in fibroblasts after UVA-, UVB-, and X-radiation,” in Cancer Res. 63, 1464–1469 (2003).

Lane, P.

C. Macaulay, P. Lane, and R. Richards-Kortum, “In vivo pathology: microendoscopy as a new endoscopic imaging modality,” Gastrointest. Endosc. Clin. N. Am. 14(3), 595–620, xi (2004).
[CrossRef] [PubMed]

Laquerbe, A.

D. Papadopoulo, A. Laquerbe, C. Guillouf, and E. Moustacchi, “Molecular spectrum of mutations induced at the HPRT locus by a cross-linking agent in human cell lines with different repair capacities,” Mutat. Res. 294(2), 167–177 (1993).
[PubMed]

Leavitt, J.

J. Leavitt, M. Fatone, C. Hestdalen, J. W. Obringer, and H. S. Tillinghast, “Mutagenic activity of high-energy 532 nm ultra-short laser pulses,” in Radiation Res. 147, 490–494 (1997).

Li, F.

R. Brem, F. Li, and P. Karran, “Reactive oxygen species generated by thiopurine/UVA cause irreparable transcription-blocking DNA lesions,” in Nucleic Acids Res. 37, 1951–1961 (2009).

Li, J. H.

J. H. Li and T. G. Rossman, “Comutagenesis of sodium arsenite with ultraviolet radiation in Chinese hamster V79 cells,” Biol. Met. 4(4), 197–200 (1991).
[CrossRef] [PubMed]

Lipkin, M.

M. Lipkin, B. Bell, and P. Sherlock, “Cell Proliferation Kinetics in the Gastrointestinal Tract Of Man: Cell Renewal In Colon and Rectum,” J. Clin. Invest. 42(6), 767–776 (1963).
[CrossRef] [PubMed]

Loeser, C. S.

J. N. Rogart, J. Nagata, C. S. Loeser, R. D. Roorda, H. Aslanian, M. E. Robert, W. R. Zipfel, and M. H. Nathanson, “Multiphoton imaging can be used for microscopic examination of intact human gastrointestinal mucosa ex vivo,” Clin. Gastroenterol. Hepatol. 6(1), 95–101 (2008).
[CrossRef] [PubMed]

Lohr, C.

C. Lohr, N. Raquet, and D. Schrenk, “Application of the concept of relative photomutagenic potencies to selected furocoumarins in V79 cells,” Toxicol. In Vitro 24(2), 558–566 (2010).
[CrossRef] [PubMed]

Luo, D.

U. P. Kappes, D. Luo, M. Potter, K. Schulmeister, and T. M. Rünger, “Short- and long-wave UV light (UVB and UVA) induce similar mutations in human skin cells,” J. Invest. Dermatol. 126(3), 667–675 (2006).
[CrossRef] [PubMed]

Macaulay, C.

C. Macaulay, P. Lane, and R. Richards-Kortum, “In vivo pathology: microendoscopy as a new endoscopic imaging modality,” Gastrointest. Endosc. Clin. N. Am. 14(3), 595–620, xi (2004).
[CrossRef] [PubMed]

McKee, T.

E. Brown, T. McKee, E. diTomaso, A. Pluen, B. Seed, Y. Boucher, and R. K. Jain, “Dynamic imaging of collagen and its modulation in tumors in vivo using second-harmonic generation,” Nat. Med. 9(6), 796–801 (2003).
[CrossRef] [PubMed]

McLaren, W. J.

A. L. Polglase, W. J. McLaren, S. A. Skinner, R. Kiesslich, M. F. Neurath, and P. M. Delaney, “A fluorescence confocal endomicroscope for in vivo microscopy of the upper- and the lower-GI tract,” Gastrointest. Endosc. 62(5), 686–695 (2005).
[CrossRef] [PubMed]

Mehta, A. D.

A. D. Mehta, J. C. Jung, B. A. Flusberg, and M. J. Schnitzer, “Fiber optic in vivo imaging in the mammalian nervous system,” Curr. Opin. Neurobiol. 14(5), 617–628 (2004).
[CrossRef] [PubMed]

Meldrum, R. A.

R. A. Meldrum, S. W. Botchway, C. W. Wharton, and G. J. Hirst, “Nanoscale spatial induction of ultraviolet photoproducts in cellular DNA by three-photon near-infrared absorption,” EMBO Rep. 4(12), 1144–1149 (2003).
[CrossRef] [PubMed]

Moll, K. D.

Mouri, R.

S. Yoshida, S. Tanaka, M. Hirata, R. Mouri, I. Kaneko, S. Oka, M. Yoshihara, and K. Chayama, “Optical biopsy of GI lesions by reflectance-type laser-scanning confocal microscopy,” Gastrointest. Endosc. 66(1), 144–149 (2007).
[CrossRef] [PubMed]

Moustacchi, E.

T. Douki, D. Perdiz, P. Gróf, Z. Kuluncsics, E. Moustacchi, J. Cadet, and E. Sage, “Oxidation of guanine in cellular DNA by solar UV radiation: biological role,” Photochem. Photobiol. 70(2), 184–190 (1999).
[CrossRef] [PubMed]

D. Papadopoulo, A. Laquerbe, C. Guillouf, and E. Moustacchi, “Molecular spectrum of mutations induced at the HPRT locus by a cross-linking agent in human cell lines with different repair capacities,” Mutat. Res. 294(2), 167–177 (1993).
[PubMed]

Nagata, J.

J. N. Rogart, J. Nagata, C. S. Loeser, R. D. Roorda, H. Aslanian, M. E. Robert, W. R. Zipfel, and M. H. Nathanson, “Multiphoton imaging can be used for microscopic examination of intact human gastrointestinal mucosa ex vivo,” Clin. Gastroenterol. Hepatol. 6(1), 95–101 (2008).
[CrossRef] [PubMed]

Nathanson, M. H.

J. N. Rogart, J. Nagata, C. S. Loeser, R. D. Roorda, H. Aslanian, M. E. Robert, W. R. Zipfel, and M. H. Nathanson, “Multiphoton imaging can be used for microscopic examination of intact human gastrointestinal mucosa ex vivo,” Clin. Gastroenterol. Hepatol. 6(1), 95–101 (2008).
[CrossRef] [PubMed]

Neurath, M. F.

A. L. Polglase, W. J. McLaren, S. A. Skinner, R. Kiesslich, M. F. Neurath, and P. M. Delaney, “A fluorescence confocal endomicroscope for in vivo microscopy of the upper- and the lower-GI tract,” Gastrointest. Endosc. 62(5), 686–695 (2005).
[CrossRef] [PubMed]

Nikitin, A. Y.

R. M. Williams, A. Flesken-Nikitin, L. H. Ellenson, D. C. Connolly, T. C. Hamilton, A. Y. Nikitin, and W. R. Zipfel, “Strategies for high-resolution imaging of epithelial ovarian cancer by laparoscopic nonlinear microscopy,” Transl Oncol 3(3), 181–194 (2010).
[PubMed]

W. R. Zipfel, R. M. Williams, R. Christie, A. Y. Nikitin, B. T. Hyman, and W. W. Webb, “Live tissue intrinsic emission microscopy using multiphoton-excited native fluorescence and second harmonic generation,” Proc. Natl. Acad. Sci. U.S.A. 100(12), 7075–7080 (2003).
[CrossRef] [PubMed]

O’Neill, J. P.

A. W. Hsie, D. A. Casciano, D. B. Couch, D. F. Krahn, J. P. O’Neill, and B. L. Whitfield, “The use of Chinese hamster ovary cells to quantify specific locus mutation and to determine mutagenicity of chemicals. A report of the gene-tox program,” Mutat. Res. 86(2), 193–214 (1981).
[PubMed]

Obringer, J. W.

J. Leavitt, M. Fatone, C. Hestdalen, J. W. Obringer, and H. S. Tillinghast, “Mutagenic activity of high-energy 532 nm ultra-short laser pulses,” in Radiation Res. 147, 490–494 (1997).

Oka, S.

S. Yoshida, S. Tanaka, M. Hirata, R. Mouri, I. Kaneko, S. Oka, M. Yoshihara, and K. Chayama, “Optical biopsy of GI lesions by reflectance-type laser-scanning confocal microscopy,” Gastrointest. Endosc. 66(1), 144–149 (2007).
[CrossRef] [PubMed]

Ouzounov, D. G.

Ozaki, K.

Y. Sako, A. Sekihata, Y. Yanagisawa, M. Yamamoto, Y. Shimada, K. Ozaki, and A. Kusumi, “Comparison of two-photon excitation laser scanning microscopy with UV-confocal laser scanning microscopy in three-dimensional calcium imaging using the fluorescence indicator Indo-1,” J. Microsc. 185(1), 9–20 (1997).
[CrossRef] [PubMed]

Papadopoulo, D.

D. Papadopoulo, A. Laquerbe, C. Guillouf, and E. Moustacchi, “Molecular spectrum of mutations induced at the HPRT locus by a cross-linking agent in human cell lines with different repair capacities,” Mutat. Res. 294(2), 167–177 (1993).
[PubMed]

Perdiz, D.

T. Douki, D. Perdiz, P. Gróf, Z. Kuluncsics, E. Moustacchi, J. Cadet, and E. Sage, “Oxidation of guanine in cellular DNA by solar UV radiation: biological role,” Photochem. Photobiol. 70(2), 184–190 (1999).
[CrossRef] [PubMed]

Pfeifer, G. P.

G. P. Pfeifer, Y. H. You, and A. Besaratinia, “Mutations induced by ultraviolet light,” Mutat. Res. 571(1-2), 19–31 (2005).
[CrossRef] [PubMed]

Pidoux, M.

R. M. Tyrrell and M. Pidoux, “Singlet oxygen involvement in the inactivation of cultured human-fibroblasts by UVA (334 nm, 365 nm) and near-visible (405 nm) radiations,” in Photochem. Photobiol. 49,407–412 (1989).

Piyawattanametha, W.

B. A. Flusberg, E. D. Cocker, W. Piyawattanametha, J. C. Jung, E. L. Cheung, and M. J. Schnitzer, “Fiber-optic fluorescence imaging,” Nat. Methods 2(12), 941–950 (2005).
[CrossRef] [PubMed]

Pluen, A.

E. Brown, T. McKee, E. diTomaso, A. Pluen, B. Seed, Y. Boucher, and R. K. Jain, “Dynamic imaging of collagen and its modulation in tumors in vivo using second-harmonic generation,” Nat. Med. 9(6), 796–801 (2003).
[CrossRef] [PubMed]

Polglase, A. L.

A. L. Polglase, W. J. McLaren, S. A. Skinner, R. Kiesslich, M. F. Neurath, and P. M. Delaney, “A fluorescence confocal endomicroscope for in vivo microscopy of the upper- and the lower-GI tract,” Gastrointest. Endosc. 62(5), 686–695 (2005).
[CrossRef] [PubMed]

Potter, M.

U. P. Kappes, D. Luo, M. Potter, K. Schulmeister, and T. M. Rünger, “Short- and long-wave UV light (UVB and UVA) induce similar mutations in human skin cells,” J. Invest. Dermatol. 126(3), 667–675 (2006).
[CrossRef] [PubMed]

Provenzano, P. P.

P. P. Provenzano, K. W. Eliceiri, and P. J. Keely, “Multiphoton microscopy and fluorescence lifetime imaging microscopy (FLIM) to monitor metastasis and the tumor microenvironment,” Clin. Exp. Metastasis 26(4), 357–370 (2009).
[CrossRef] [PubMed]

Raquet, N.

C. Lohr, N. Raquet, and D. Schrenk, “Application of the concept of relative photomutagenic potencies to selected furocoumarins in V79 cells,” Toxicol. In Vitro 24(2), 558–566 (2010).
[CrossRef] [PubMed]

Richards-Kortum, R.

C. Macaulay, P. Lane, and R. Richards-Kortum, “In vivo pathology: microendoscopy as a new endoscopic imaging modality,” Gastrointest. Endosc. Clin. N. Am. 14(3), 595–620, xi (2004).
[CrossRef] [PubMed]

Riemann, I.

K. König, A. Ehlers, I. Riemann, S. Schenkl, R. Bückle, and M. Kaatz, “Clinical two-photon microendoscopy,” Microsc. Res. Tech. 70(5), 398–402 (2007).
[CrossRef] [PubMed]

Robert, M. E.

J. N. Rogart, J. Nagata, C. S. Loeser, R. D. Roorda, H. Aslanian, M. E. Robert, W. R. Zipfel, and M. H. Nathanson, “Multiphoton imaging can be used for microscopic examination of intact human gastrointestinal mucosa ex vivo,” Clin. Gastroenterol. Hepatol. 6(1), 95–101 (2008).
[CrossRef] [PubMed]

Rogart, J. N.

J. N. Rogart, J. Nagata, C. S. Loeser, R. D. Roorda, H. Aslanian, M. E. Robert, W. R. Zipfel, and M. H. Nathanson, “Multiphoton imaging can be used for microscopic examination of intact human gastrointestinal mucosa ex vivo,” Clin. Gastroenterol. Hepatol. 6(1), 95–101 (2008).
[CrossRef] [PubMed]

Roorda, R. D.

J. N. Rogart, J. Nagata, C. S. Loeser, R. D. Roorda, H. Aslanian, M. E. Robert, W. R. Zipfel, and M. H. Nathanson, “Multiphoton imaging can be used for microscopic examination of intact human gastrointestinal mucosa ex vivo,” Clin. Gastroenterol. Hepatol. 6(1), 95–101 (2008).
[CrossRef] [PubMed]

Rossman, T. G.

J. H. Li and T. G. Rossman, “Comutagenesis of sodium arsenite with ultraviolet radiation in Chinese hamster V79 cells,” Biol. Met. 4(4), 197–200 (1991).
[CrossRef] [PubMed]

Rünger, T. M.

U. P. Kappes, D. Luo, M. Potter, K. Schulmeister, and T. M. Rünger, “Short- and long-wave UV light (UVB and UVA) induce similar mutations in human skin cells,” J. Invest. Dermatol. 126(3), 667–675 (2006).
[CrossRef] [PubMed]

Russell, S.

Sage, E.

T. Douki, D. Perdiz, P. Gróf, Z. Kuluncsics, E. Moustacchi, J. Cadet, and E. Sage, “Oxidation of guanine in cellular DNA by solar UV radiation: biological role,” Photochem. Photobiol. 70(2), 184–190 (1999).
[CrossRef] [PubMed]

Sako, Y.

Y. Sako, A. Sekihata, Y. Yanagisawa, M. Yamamoto, Y. Shimada, K. Ozaki, and A. Kusumi, “Comparison of two-photon excitation laser scanning microscopy with UV-confocal laser scanning microscopy in three-dimensional calcium imaging using the fluorescence indicator Indo-1,” J. Microsc. 185(1), 9–20 (1997).
[CrossRef] [PubMed]

Schenkl, S.

K. König, A. Ehlers, I. Riemann, S. Schenkl, R. Bückle, and M. Kaatz, “Clinical two-photon microendoscopy,” Microsc. Res. Tech. 70(5), 398–402 (2007).
[CrossRef] [PubMed]

Schnitzer, M. J.

B. A. Flusberg, E. D. Cocker, W. Piyawattanametha, J. C. Jung, E. L. Cheung, and M. J. Schnitzer, “Fiber-optic fluorescence imaging,” Nat. Methods 2(12), 941–950 (2005).
[CrossRef] [PubMed]

A. D. Mehta, J. C. Jung, B. A. Flusberg, and M. J. Schnitzer, “Fiber optic in vivo imaging in the mammalian nervous system,” Curr. Opin. Neurobiol. 14(5), 617–628 (2004).
[CrossRef] [PubMed]

Schrenk, D.

C. Lohr, N. Raquet, and D. Schrenk, “Application of the concept of relative photomutagenic potencies to selected furocoumarins in V79 cells,” Toxicol. In Vitro 24(2), 558–566 (2010).
[CrossRef] [PubMed]

Schulmeister, K.

U. P. Kappes, D. Luo, M. Potter, K. Schulmeister, and T. M. Rünger, “Short- and long-wave UV light (UVB and UVA) induce similar mutations in human skin cells,” J. Invest. Dermatol. 126(3), 667–675 (2006).
[CrossRef] [PubMed]

Seed, B.

E. Brown, T. McKee, E. diTomaso, A. Pluen, B. Seed, Y. Boucher, and R. K. Jain, “Dynamic imaging of collagen and its modulation in tumors in vivo using second-harmonic generation,” Nat. Med. 9(6), 796–801 (2003).
[CrossRef] [PubMed]

Sekihata, A.

Y. Sako, A. Sekihata, Y. Yanagisawa, M. Yamamoto, Y. Shimada, K. Ozaki, and A. Kusumi, “Comparison of two-photon excitation laser scanning microscopy with UV-confocal laser scanning microscopy in three-dimensional calcium imaging using the fluorescence indicator Indo-1,” J. Microsc. 185(1), 9–20 (1997).
[CrossRef] [PubMed]

Sherlock, P.

M. Lipkin, B. Bell, and P. Sherlock, “Cell Proliferation Kinetics in the Gastrointestinal Tract Of Man: Cell Renewal In Colon and Rectum,” J. Clin. Invest. 42(6), 767–776 (1963).
[CrossRef] [PubMed]

Shimada, Y.

Y. Sako, A. Sekihata, Y. Yanagisawa, M. Yamamoto, Y. Shimada, K. Ozaki, and A. Kusumi, “Comparison of two-photon excitation laser scanning microscopy with UV-confocal laser scanning microscopy in three-dimensional calcium imaging using the fluorescence indicator Indo-1,” J. Microsc. 185(1), 9–20 (1997).
[CrossRef] [PubMed]

Skandalis, A.

A. Skandalis and B. W. Glickman, “Endogenous gene systems for the study of mutational specificity in mammalian cells,” Cancer Cells 2(3), 79–83 (1990).
[PubMed]

Skinner, S. A.

A. L. Polglase, W. J. McLaren, S. A. Skinner, R. Kiesslich, M. F. Neurath, and P. M. Delaney, “A fluorescence confocal endomicroscope for in vivo microscopy of the upper- and the lower-GI tract,” Gastrointest. Endosc. 62(5), 686–695 (2005).
[CrossRef] [PubMed]

Stodulka, P.

J. C. Vryghem, T. Devogelaere, and P. Stodulka, “Efficacy, safety, and flap dimensions of a new femtosecond laser for laser in situ keratomileusis,” J. Cataract Refract. Surg. 36(3), 442–448 (2010).
[CrossRef] [PubMed]

Tanaka, S.

S. Yoshida, S. Tanaka, M. Hirata, R. Mouri, I. Kaneko, S. Oka, M. Yoshihara, and K. Chayama, “Optical biopsy of GI lesions by reflectance-type laser-scanning confocal microscopy,” Gastrointest. Endosc. 66(1), 144–149 (2007).
[CrossRef] [PubMed]

Tillinghast, H. S.

J. Leavitt, M. Fatone, C. Hestdalen, J. W. Obringer, and H. S. Tillinghast, “Mutagenic activity of high-energy 532 nm ultra-short laser pulses,” in Radiation Res. 147, 490–494 (1997).

Tyrrell, R. M.

R. M. Tyrrell and M. Pidoux, “Singlet oxygen involvement in the inactivation of cultured human-fibroblasts by UVA (334 nm, 365 nm) and near-visible (405 nm) radiations,” in Photochem. Photobiol. 49,407–412 (1989).

Vryghem, J. C.

J. C. Vryghem, T. Devogelaere, and P. Stodulka, “Efficacy, safety, and flap dimensions of a new femtosecond laser for laser in situ keratomileusis,” J. Cataract Refract. Surg. 36(3), 442–448 (2010).
[CrossRef] [PubMed]

Webb, W. W.

W. R. Zipfel, R. M. Williams, R. Christie, A. Y. Nikitin, B. T. Hyman, and W. W. Webb, “Live tissue intrinsic emission microscopy using multiphoton-excited native fluorescence and second harmonic generation,” Proc. Natl. Acad. Sci. U.S.A. 100(12), 7075–7080 (2003).
[CrossRef] [PubMed]

D. G. Ouzounov, K. D. Moll, M. A. Foster, W. R. Zipfel, W. W. Webb, and A. L. Gaeta, “Delivery of nanojoule femtosecond pulses through large-core microstructured fibers,” Opt. Lett. 27(17), 1513–1515 (2002).
[CrossRef] [PubMed]

Wharton, C. W.

R. A. Meldrum, S. W. Botchway, C. W. Wharton, and G. J. Hirst, “Nanoscale spatial induction of ultraviolet photoproducts in cellular DNA by three-photon near-infrared absorption,” EMBO Rep. 4(12), 1144–1149 (2003).
[CrossRef] [PubMed]

Whitfield, B. L.

A. W. Hsie, D. A. Casciano, D. B. Couch, D. F. Krahn, J. P. O’Neill, and B. L. Whitfield, “The use of Chinese hamster ovary cells to quantify specific locus mutation and to determine mutagenicity of chemicals. A report of the gene-tox program,” Mutat. Res. 86(2), 193–214 (1981).
[PubMed]

Williams, R. M.

R. M. Williams, A. Flesken-Nikitin, L. H. Ellenson, D. C. Connolly, T. C. Hamilton, A. Y. Nikitin, and W. R. Zipfel, “Strategies for high-resolution imaging of epithelial ovarian cancer by laparoscopic nonlinear microscopy,” Transl Oncol 3(3), 181–194 (2010).
[PubMed]

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Figures (3)

Fig. 1
Fig. 1

Comparison of epithelial layer 2P fluorescence at 760 nm. A. Olympus microprobe lens. B. Power dependence of mouse colon, ovarian and bladder epithelial layers. Solid lines: αP2 fit (over data points that exhibit P2 dependence). Photons/pixel values are averages of cytosolic signal. C. Colon surface image acquired at 20mW (~26 photons/pixel). D. Bladder epithelia image acquired at 24mW (1-2 photons/pixel). A standard histogram equalization algorithm was applied to D to adjust contrast. E. Merged autofluorescence and collagen SHG images of colon at 40 µm deep (40 mW, 37 photons/pixel). F. Merged image of bladder taken at 120 mW (20 photons/pixel). G. Colon at 80 µm deep (50 mW and 47 photons/pixel). H. Ovarian surface epithelia images at 40 mW (24 photons/pixel). All images were acquired with 760 nm delivered through a 0.7NA 27x microprobe objective lens; emission collected from 420 to 520 nm. 384 x 384 pixels; pixel time: 3µs (~0.7 sec/frame; 0.44s illumination time) with no frame averaging, a 20 µm dia. cell is irradiated for ~4 ms total. All scale bars are 40 µm.

Fig. 2
Fig. 2

Mutation assay and autofluorescence bleaching during irradiation. A. Typical field of V79 cells used in the mutation assay imaged via cellular autofluorescence. B. Loss of cellular autofluorescence during illumination as a function of laser power. Solid lines are fits to a simple model assuming an exponential decrease (see text). C. Exponential bleaching constant (β) as a function of laser power (solid line is cubic-spline of data to help visualize the bleaching response).

Fig. 3
Fig. 3

Cell survival and mutation frequency as a function of femtosecond laser illumination. A. Cell death after irradiation (plating efficiency) as a function of laser power. B. Increase in Mutation Frequency (MF) (defined as mutants per 106 cells) normalized to the control MF value (0.35 ± 0.24, n = 5) as a function of laser power. Dashed line is a fit to aP2; solid line to aP2 + bP3. Plotted values are mean ± SEM, n = 5 for all points.

Tables (1)

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Table 1 Reported HPRT mutation frequencies in V79 cells under 760 nm femtosecond irradiation doses compared to UV illumination

Equations (1)

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F ( t ) N n b + N b exp [ β t ] ;    β = a 2 P 2 + a 3 P 3  and   a n = ϕ b , n σ n η n V p s f n d V

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