Abstract

Upon excitation with different wavelengths of light, biological tissues emit distinct but related autofluorescence signals. We used non-negative matrix factorization (NMF) to simultaneously decompose co-registered hyperspectral emission data from human retinal pigment epithelium/Bruch’s membrane specimens illuminated with 436 and 480 nm light. NMF analysis was initialized with Gaussian mixture model fits and constrained to provide identical abundance images for the two excitation wavelengths. Spectra recovered this way were smoother than those obtained separately; fluorophore abundances more clearly localized within tissue compartments. These studies provide evidence that leveraging multiple co-registered hyperspectral emission data sets is preferential for identifying biologically relevant fluorophore information.

© 2014 Optical Society of America

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References

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    [Crossref] [PubMed]
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    [Crossref] [PubMed]
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    [Crossref] [PubMed]
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    [Crossref] [PubMed]

2014 (2)

Z. Ablonczy, N. Smith, D. M. Anderson, A. C. Grey, J. Spraggins, Y. Koutalos, K. L. Schey, and R. K. Crouch, “The utilization of fluorescence to identify the components of lipofuscin by imaging mass spectrometry,” Proteomics 14(7-8), 936–944 (2014).
[Crossref] [PubMed]

T. Ach, C. Huisingh, G. McGwin, J. D. Messinger, T. Zhang, M. J. Bentley, D. B. Gutierrez, Z. Ablonczy, R. T. Smith, K. R. Sloan, and C. A. Curcio, “Quantitative autofluorescence and cell density maps of the human retinal pigment epithelium,” Invest. Ophthalmol. Vis. Sci. 55(8), 4832–4841 (2014).
[Crossref] [PubMed]

2013 (4)

Z. Ablonczy, D. Higbee, A. C. Grey, Y. Koutalos, K. L. Schey, and R. K. Crouch, “Similar molecules spatially correlate with lipofuscin and N-retinylidene-N-retinylethanolamine in the mouse but not in the human retinal pigment epithelium,” Arch. Biochem. Biophys. 539(2), 196–202 (2013).
[Crossref] [PubMed]

T. Pengo, A. Muñoz-Barrutia, I. Zudaire, and C. Ortiz-de-Solorzano, “Efficient blind spectral unmixing of fluorescently labeled samples using multi-layer non-negative matrix factorization,” PLoS ONE 8(11), e78504 (2013).
[Crossref] [PubMed]

P. H. Tang, M. Kono, Y. Koutalos, Z. Ablonczy, and R. K. Crouch, “New insights into retinoid metabolism and cycling within the retina,” Prog. Retin. Eye Res. 32, 48–63 (2013).
[Crossref] [PubMed]

Z. Ablonczy, D. Higbee, D. M. Anderson, M. Dahrouj, A. C. Grey, D. Gutierrez, Y. Koutalos, K. L. Schey, A. Hanneken, and R. K. Crouch, “Lack of correlation between the spatial distribution of A2E and lipofuscin fluorescence in the human retinal pigment epithelium,” Invest. Ophthalmol. Vis. Sci. 54(8), 5535–5542 (2013).
[Crossref] [PubMed]

2012 (2)

J. R. Sparrow, E. Gregory-Roberts, K. Yamamoto, A. Blonska, S. K. Ghosh, K. Ueda, and J. Zhou, “The bisretinoids of retinal pigment epithelium,” Prog. Retin. Eye Res. 31(2), 121–135 (2012).
[Crossref] [PubMed]

T. Ach, G. Best, S. Rossberger, R. Heintzmann, C. Cremer, and S. Dithmar, “Autofluorescence imaging of human RPE cell granules using structured illumination microscopy,” Br. J. Ophthalmol. 96(8), 1141–1144 (2012).
[Crossref] [PubMed]

2011 (1)

K. Yamamoto, K. D. Yoon, K. Ueda, M. Hashimoto, and J. R. Sparrow, “A novel bisretinoid of retina is an adduct on glycerophosphoethanolamine,” Invest. Ophthalmol. Vis. Sci. 52(12), 9084–9090 (2011).
[Crossref] [PubMed]

2010 (1)

J. R. Sparrow, Y. Wu, C. Y. Kim, and J. Zhou, “Phospholipid meets all-trans-retinal: the making of RPE bisretinoids,” J. Lipid Res. 51(2), 247–261 (2010).
[Crossref] [PubMed]

2009 (2)

R. A. Neher, M. Mitkovski, F. Kirchhoff, E. Neher, F. J. Theis, and A. Zeug, “Blind source separation techniques for the decomposition of multiply labeled fluorescence images,” Biophys. J. 96(9), 3791–3800 (2009).
[Crossref] [PubMed]

Y. Wu, N. E. Fishkin, A. Pande, J. Pande, and J. R. Sparrow, “Novel lipofuscin bisretinoids prominent in human retina and in a model of recessive Stargardt disease,” J. Biol. Chem. 284(30), 20155–20166 (2009).
[Crossref] [PubMed]

2008 (1)

K. P. Ng, B. Gugiu, K. Renganathan, M. W. Davies, X. Gu, J. S. Crabb, S. R. Kim, M. B. Rózanowska, V. L. Bonilha, M. E. Rayborn, R. G. Salomon, J. R. Sparrow, M. E. Boulton, J. G. Hollyfield, and J. W. Crabb, “Retinal pigment epithelium lipofuscin proteomics,” Mol. Cell. Proteomics 7(7), 1397–1405 (2008).
[Crossref] [PubMed]

2007 (1)

S. R. Kim, Y. P. Jang, S. Jockusch, N. E. Fishkin, N. J. Turro, and J. R. Sparrow, “The all-trans-retinal dimer series of lipofuscin pigments in retinal pigment epithelial cells in a recessive Stargardt disease model,” Proc. Natl. Acad. Sci. U.S.A. 104(49), 19273–19278 (2007).
[Crossref] [PubMed]

2006 (2)

P. Sajda, “Machine learning for detection and diagnosis of disease,” Annu. Rev. Biomed. Eng. 8(1), 537–565 (2006).
[Crossref] [PubMed]

J. C. Hwang, J. W. Chan, S. Chang, and R. T. Smith, “Predictive value of fundus autofluorescence for development of geographic atrophy in age-related macular degeneration,” Invest. Ophthalmol. Vis. Sci. 47(6), 2655–2661 (2006).
[Crossref] [PubMed]

2005 (2)

Y. P. Jang, H. Matsuda, Y. Itagaki, K. Nakanishi, and J. R. Sparrow, “Characterization of peroxy-A2E and furan-A2E photooxidation products and detection in human and mouse retinal pigment epithelial cell lipofuscin,” J. Biol. Chem. 280(48), 39732–39739 (2005).
[Crossref] [PubMed]

O. Strauss, “The retinal pigment epithelium in visual function,” Physiol. Rev. 85(3), 845–881 (2005).
[Crossref] [PubMed]

2004 (1)

P. Sajda, S. Du, T. R. Brown, R. Stoyanova, D. C. Shungu, X. Mao, and L. C. Parra, “Nonnegative matrix factorization for rapid recovery of constituent spectra in magnetic resonance chemical shift imaging of the brain,” IEEE Trans. Med. Imaging 23(12), 1453–1465 (2004).
[Crossref] [PubMed]

2003 (1)

J. R. Sparrow, N. Fishkin, J. Zhou, B. Cai, Y. P. Jang, S. Krane, Y. Itagaki, and K. Nakanishi, “A2E, a byproduct of the visual cycle,” Vision Res. 43(28), 2983–2990 (2003).
[Crossref] [PubMed]

1988 (1)

G. E. Eldred and M. L. Katz, “Fluorophores of the human retinal pigment epithelium: separation and spectral characterization,” Exp. Eye Res. 47(1), 71–86 (1988).
[Crossref] [PubMed]

1986 (1)

J. J. Weiter, F. C. Delori, G. L. Wing, and K. A. Fitch, “Retinal pigment epithelial lipofuscin and melanin and choroidal melanin in human eyes,” Invest. Ophthalmol. Vis. Sci. 27(2), 145–152 (1986).
[PubMed]

1980 (1)

L. Feeney-Burns, E. R. Berman, and H. Rothman, “Lipofuscin of human retinal pigment epithelium,” Am. J. Ophthalmol. 90(6), 783–791 (1980).
[Crossref] [PubMed]

1978 (1)

L. Feeney, “Lipofuscin and melanin of human retinal pigment epithelium. Fluorescence, enzyme cytochemical, and ultrastructural studies,” Invest. Ophthalmol. Vis. Sci. 17(7), 583–600 (1978).
[PubMed]

1967 (1)

M. O. Ts’o and E. Friedman, “The retinal pigment epithelium. I. Comparative histology,” Arch. Ophthalmol. 78(5), 641–649 (1967).
[Crossref] [PubMed]

Ablonczy, Z.

Z. Ablonczy, N. Smith, D. M. Anderson, A. C. Grey, J. Spraggins, Y. Koutalos, K. L. Schey, and R. K. Crouch, “The utilization of fluorescence to identify the components of lipofuscin by imaging mass spectrometry,” Proteomics 14(7-8), 936–944 (2014).
[Crossref] [PubMed]

T. Ach, C. Huisingh, G. McGwin, J. D. Messinger, T. Zhang, M. J. Bentley, D. B. Gutierrez, Z. Ablonczy, R. T. Smith, K. R. Sloan, and C. A. Curcio, “Quantitative autofluorescence and cell density maps of the human retinal pigment epithelium,” Invest. Ophthalmol. Vis. Sci. 55(8), 4832–4841 (2014).
[Crossref] [PubMed]

Z. Ablonczy, D. Higbee, A. C. Grey, Y. Koutalos, K. L. Schey, and R. K. Crouch, “Similar molecules spatially correlate with lipofuscin and N-retinylidene-N-retinylethanolamine in the mouse but not in the human retinal pigment epithelium,” Arch. Biochem. Biophys. 539(2), 196–202 (2013).
[Crossref] [PubMed]

P. H. Tang, M. Kono, Y. Koutalos, Z. Ablonczy, and R. K. Crouch, “New insights into retinoid metabolism and cycling within the retina,” Prog. Retin. Eye Res. 32, 48–63 (2013).
[Crossref] [PubMed]

Z. Ablonczy, D. Higbee, D. M. Anderson, M. Dahrouj, A. C. Grey, D. Gutierrez, Y. Koutalos, K. L. Schey, A. Hanneken, and R. K. Crouch, “Lack of correlation between the spatial distribution of A2E and lipofuscin fluorescence in the human retinal pigment epithelium,” Invest. Ophthalmol. Vis. Sci. 54(8), 5535–5542 (2013).
[Crossref] [PubMed]

Ach, T.

T. Ach, C. Huisingh, G. McGwin, J. D. Messinger, T. Zhang, M. J. Bentley, D. B. Gutierrez, Z. Ablonczy, R. T. Smith, K. R. Sloan, and C. A. Curcio, “Quantitative autofluorescence and cell density maps of the human retinal pigment epithelium,” Invest. Ophthalmol. Vis. Sci. 55(8), 4832–4841 (2014).
[Crossref] [PubMed]

T. Ach, G. Best, S. Rossberger, R. Heintzmann, C. Cremer, and S. Dithmar, “Autofluorescence imaging of human RPE cell granules using structured illumination microscopy,” Br. J. Ophthalmol. 96(8), 1141–1144 (2012).
[Crossref] [PubMed]

Anderson, D. M.

Z. Ablonczy, N. Smith, D. M. Anderson, A. C. Grey, J. Spraggins, Y. Koutalos, K. L. Schey, and R. K. Crouch, “The utilization of fluorescence to identify the components of lipofuscin by imaging mass spectrometry,” Proteomics 14(7-8), 936–944 (2014).
[Crossref] [PubMed]

Z. Ablonczy, D. Higbee, D. M. Anderson, M. Dahrouj, A. C. Grey, D. Gutierrez, Y. Koutalos, K. L. Schey, A. Hanneken, and R. K. Crouch, “Lack of correlation between the spatial distribution of A2E and lipofuscin fluorescence in the human retinal pigment epithelium,” Invest. Ophthalmol. Vis. Sci. 54(8), 5535–5542 (2013).
[Crossref] [PubMed]

Bentley, M. J.

T. Ach, C. Huisingh, G. McGwin, J. D. Messinger, T. Zhang, M. J. Bentley, D. B. Gutierrez, Z. Ablonczy, R. T. Smith, K. R. Sloan, and C. A. Curcio, “Quantitative autofluorescence and cell density maps of the human retinal pigment epithelium,” Invest. Ophthalmol. Vis. Sci. 55(8), 4832–4841 (2014).
[Crossref] [PubMed]

Berman, E. R.

L. Feeney-Burns, E. R. Berman, and H. Rothman, “Lipofuscin of human retinal pigment epithelium,” Am. J. Ophthalmol. 90(6), 783–791 (1980).
[Crossref] [PubMed]

Best, G.

T. Ach, G. Best, S. Rossberger, R. Heintzmann, C. Cremer, and S. Dithmar, “Autofluorescence imaging of human RPE cell granules using structured illumination microscopy,” Br. J. Ophthalmol. 96(8), 1141–1144 (2012).
[Crossref] [PubMed]

Blonska, A.

J. R. Sparrow, E. Gregory-Roberts, K. Yamamoto, A. Blonska, S. K. Ghosh, K. Ueda, and J. Zhou, “The bisretinoids of retinal pigment epithelium,” Prog. Retin. Eye Res. 31(2), 121–135 (2012).
[Crossref] [PubMed]

Bonilha, V. L.

K. P. Ng, B. Gugiu, K. Renganathan, M. W. Davies, X. Gu, J. S. Crabb, S. R. Kim, M. B. Rózanowska, V. L. Bonilha, M. E. Rayborn, R. G. Salomon, J. R. Sparrow, M. E. Boulton, J. G. Hollyfield, and J. W. Crabb, “Retinal pigment epithelium lipofuscin proteomics,” Mol. Cell. Proteomics 7(7), 1397–1405 (2008).
[Crossref] [PubMed]

Boulton, M. E.

K. P. Ng, B. Gugiu, K. Renganathan, M. W. Davies, X. Gu, J. S. Crabb, S. R. Kim, M. B. Rózanowska, V. L. Bonilha, M. E. Rayborn, R. G. Salomon, J. R. Sparrow, M. E. Boulton, J. G. Hollyfield, and J. W. Crabb, “Retinal pigment epithelium lipofuscin proteomics,” Mol. Cell. Proteomics 7(7), 1397–1405 (2008).
[Crossref] [PubMed]

Brown, T. R.

P. Sajda, S. Du, T. R. Brown, R. Stoyanova, D. C. Shungu, X. Mao, and L. C. Parra, “Nonnegative matrix factorization for rapid recovery of constituent spectra in magnetic resonance chemical shift imaging of the brain,” IEEE Trans. Med. Imaging 23(12), 1453–1465 (2004).
[Crossref] [PubMed]

Cai, B.

J. R. Sparrow, N. Fishkin, J. Zhou, B. Cai, Y. P. Jang, S. Krane, Y. Itagaki, and K. Nakanishi, “A2E, a byproduct of the visual cycle,” Vision Res. 43(28), 2983–2990 (2003).
[Crossref] [PubMed]

Chan, J. W.

J. C. Hwang, J. W. Chan, S. Chang, and R. T. Smith, “Predictive value of fundus autofluorescence for development of geographic atrophy in age-related macular degeneration,” Invest. Ophthalmol. Vis. Sci. 47(6), 2655–2661 (2006).
[Crossref] [PubMed]

Chang, S.

J. C. Hwang, J. W. Chan, S. Chang, and R. T. Smith, “Predictive value of fundus autofluorescence for development of geographic atrophy in age-related macular degeneration,” Invest. Ophthalmol. Vis. Sci. 47(6), 2655–2661 (2006).
[Crossref] [PubMed]

Crabb, J. S.

K. P. Ng, B. Gugiu, K. Renganathan, M. W. Davies, X. Gu, J. S. Crabb, S. R. Kim, M. B. Rózanowska, V. L. Bonilha, M. E. Rayborn, R. G. Salomon, J. R. Sparrow, M. E. Boulton, J. G. Hollyfield, and J. W. Crabb, “Retinal pigment epithelium lipofuscin proteomics,” Mol. Cell. Proteomics 7(7), 1397–1405 (2008).
[Crossref] [PubMed]

Crabb, J. W.

K. P. Ng, B. Gugiu, K. Renganathan, M. W. Davies, X. Gu, J. S. Crabb, S. R. Kim, M. B. Rózanowska, V. L. Bonilha, M. E. Rayborn, R. G. Salomon, J. R. Sparrow, M. E. Boulton, J. G. Hollyfield, and J. W. Crabb, “Retinal pigment epithelium lipofuscin proteomics,” Mol. Cell. Proteomics 7(7), 1397–1405 (2008).
[Crossref] [PubMed]

Cremer, C.

T. Ach, G. Best, S. Rossberger, R. Heintzmann, C. Cremer, and S. Dithmar, “Autofluorescence imaging of human RPE cell granules using structured illumination microscopy,” Br. J. Ophthalmol. 96(8), 1141–1144 (2012).
[Crossref] [PubMed]

Crouch, R. K.

Z. Ablonczy, N. Smith, D. M. Anderson, A. C. Grey, J. Spraggins, Y. Koutalos, K. L. Schey, and R. K. Crouch, “The utilization of fluorescence to identify the components of lipofuscin by imaging mass spectrometry,” Proteomics 14(7-8), 936–944 (2014).
[Crossref] [PubMed]

Z. Ablonczy, D. Higbee, A. C. Grey, Y. Koutalos, K. L. Schey, and R. K. Crouch, “Similar molecules spatially correlate with lipofuscin and N-retinylidene-N-retinylethanolamine in the mouse but not in the human retinal pigment epithelium,” Arch. Biochem. Biophys. 539(2), 196–202 (2013).
[Crossref] [PubMed]

Z. Ablonczy, D. Higbee, D. M. Anderson, M. Dahrouj, A. C. Grey, D. Gutierrez, Y. Koutalos, K. L. Schey, A. Hanneken, and R. K. Crouch, “Lack of correlation between the spatial distribution of A2E and lipofuscin fluorescence in the human retinal pigment epithelium,” Invest. Ophthalmol. Vis. Sci. 54(8), 5535–5542 (2013).
[Crossref] [PubMed]

P. H. Tang, M. Kono, Y. Koutalos, Z. Ablonczy, and R. K. Crouch, “New insights into retinoid metabolism and cycling within the retina,” Prog. Retin. Eye Res. 32, 48–63 (2013).
[Crossref] [PubMed]

Curcio, C. A.

T. Ach, C. Huisingh, G. McGwin, J. D. Messinger, T. Zhang, M. J. Bentley, D. B. Gutierrez, Z. Ablonczy, R. T. Smith, K. R. Sloan, and C. A. Curcio, “Quantitative autofluorescence and cell density maps of the human retinal pigment epithelium,” Invest. Ophthalmol. Vis. Sci. 55(8), 4832–4841 (2014).
[Crossref] [PubMed]

Dahrouj, M.

Z. Ablonczy, D. Higbee, D. M. Anderson, M. Dahrouj, A. C. Grey, D. Gutierrez, Y. Koutalos, K. L. Schey, A. Hanneken, and R. K. Crouch, “Lack of correlation between the spatial distribution of A2E and lipofuscin fluorescence in the human retinal pigment epithelium,” Invest. Ophthalmol. Vis. Sci. 54(8), 5535–5542 (2013).
[Crossref] [PubMed]

Davies, M. W.

K. P. Ng, B. Gugiu, K. Renganathan, M. W. Davies, X. Gu, J. S. Crabb, S. R. Kim, M. B. Rózanowska, V. L. Bonilha, M. E. Rayborn, R. G. Salomon, J. R. Sparrow, M. E. Boulton, J. G. Hollyfield, and J. W. Crabb, “Retinal pigment epithelium lipofuscin proteomics,” Mol. Cell. Proteomics 7(7), 1397–1405 (2008).
[Crossref] [PubMed]

Delori, F. C.

J. J. Weiter, F. C. Delori, G. L. Wing, and K. A. Fitch, “Retinal pigment epithelial lipofuscin and melanin and choroidal melanin in human eyes,” Invest. Ophthalmol. Vis. Sci. 27(2), 145–152 (1986).
[PubMed]

Dithmar, S.

T. Ach, G. Best, S. Rossberger, R. Heintzmann, C. Cremer, and S. Dithmar, “Autofluorescence imaging of human RPE cell granules using structured illumination microscopy,” Br. J. Ophthalmol. 96(8), 1141–1144 (2012).
[Crossref] [PubMed]

Du, S.

P. Sajda, S. Du, T. R. Brown, R. Stoyanova, D. C. Shungu, X. Mao, and L. C. Parra, “Nonnegative matrix factorization for rapid recovery of constituent spectra in magnetic resonance chemical shift imaging of the brain,” IEEE Trans. Med. Imaging 23(12), 1453–1465 (2004).
[Crossref] [PubMed]

Eldred, G. E.

G. E. Eldred and M. L. Katz, “Fluorophores of the human retinal pigment epithelium: separation and spectral characterization,” Exp. Eye Res. 47(1), 71–86 (1988).
[Crossref] [PubMed]

Feeney, L.

L. Feeney, “Lipofuscin and melanin of human retinal pigment epithelium. Fluorescence, enzyme cytochemical, and ultrastructural studies,” Invest. Ophthalmol. Vis. Sci. 17(7), 583–600 (1978).
[PubMed]

Feeney-Burns, L.

L. Feeney-Burns, E. R. Berman, and H. Rothman, “Lipofuscin of human retinal pigment epithelium,” Am. J. Ophthalmol. 90(6), 783–791 (1980).
[Crossref] [PubMed]

Fishkin, N.

J. R. Sparrow, N. Fishkin, J. Zhou, B. Cai, Y. P. Jang, S. Krane, Y. Itagaki, and K. Nakanishi, “A2E, a byproduct of the visual cycle,” Vision Res. 43(28), 2983–2990 (2003).
[Crossref] [PubMed]

Fishkin, N. E.

Y. Wu, N. E. Fishkin, A. Pande, J. Pande, and J. R. Sparrow, “Novel lipofuscin bisretinoids prominent in human retina and in a model of recessive Stargardt disease,” J. Biol. Chem. 284(30), 20155–20166 (2009).
[Crossref] [PubMed]

S. R. Kim, Y. P. Jang, S. Jockusch, N. E. Fishkin, N. J. Turro, and J. R. Sparrow, “The all-trans-retinal dimer series of lipofuscin pigments in retinal pigment epithelial cells in a recessive Stargardt disease model,” Proc. Natl. Acad. Sci. U.S.A. 104(49), 19273–19278 (2007).
[Crossref] [PubMed]

Fitch, K. A.

J. J. Weiter, F. C. Delori, G. L. Wing, and K. A. Fitch, “Retinal pigment epithelial lipofuscin and melanin and choroidal melanin in human eyes,” Invest. Ophthalmol. Vis. Sci. 27(2), 145–152 (1986).
[PubMed]

Friedman, E.

M. O. Ts’o and E. Friedman, “The retinal pigment epithelium. I. Comparative histology,” Arch. Ophthalmol. 78(5), 641–649 (1967).
[Crossref] [PubMed]

Ghosh, S. K.

J. R. Sparrow, E. Gregory-Roberts, K. Yamamoto, A. Blonska, S. K. Ghosh, K. Ueda, and J. Zhou, “The bisretinoids of retinal pigment epithelium,” Prog. Retin. Eye Res. 31(2), 121–135 (2012).
[Crossref] [PubMed]

Gregory-Roberts, E.

J. R. Sparrow, E. Gregory-Roberts, K. Yamamoto, A. Blonska, S. K. Ghosh, K. Ueda, and J. Zhou, “The bisretinoids of retinal pigment epithelium,” Prog. Retin. Eye Res. 31(2), 121–135 (2012).
[Crossref] [PubMed]

Grey, A. C.

Z. Ablonczy, N. Smith, D. M. Anderson, A. C. Grey, J. Spraggins, Y. Koutalos, K. L. Schey, and R. K. Crouch, “The utilization of fluorescence to identify the components of lipofuscin by imaging mass spectrometry,” Proteomics 14(7-8), 936–944 (2014).
[Crossref] [PubMed]

Z. Ablonczy, D. Higbee, A. C. Grey, Y. Koutalos, K. L. Schey, and R. K. Crouch, “Similar molecules spatially correlate with lipofuscin and N-retinylidene-N-retinylethanolamine in the mouse but not in the human retinal pigment epithelium,” Arch. Biochem. Biophys. 539(2), 196–202 (2013).
[Crossref] [PubMed]

Z. Ablonczy, D. Higbee, D. M. Anderson, M. Dahrouj, A. C. Grey, D. Gutierrez, Y. Koutalos, K. L. Schey, A. Hanneken, and R. K. Crouch, “Lack of correlation between the spatial distribution of A2E and lipofuscin fluorescence in the human retinal pigment epithelium,” Invest. Ophthalmol. Vis. Sci. 54(8), 5535–5542 (2013).
[Crossref] [PubMed]

Gu, X.

K. P. Ng, B. Gugiu, K. Renganathan, M. W. Davies, X. Gu, J. S. Crabb, S. R. Kim, M. B. Rózanowska, V. L. Bonilha, M. E. Rayborn, R. G. Salomon, J. R. Sparrow, M. E. Boulton, J. G. Hollyfield, and J. W. Crabb, “Retinal pigment epithelium lipofuscin proteomics,” Mol. Cell. Proteomics 7(7), 1397–1405 (2008).
[Crossref] [PubMed]

Gugiu, B.

K. P. Ng, B. Gugiu, K. Renganathan, M. W. Davies, X. Gu, J. S. Crabb, S. R. Kim, M. B. Rózanowska, V. L. Bonilha, M. E. Rayborn, R. G. Salomon, J. R. Sparrow, M. E. Boulton, J. G. Hollyfield, and J. W. Crabb, “Retinal pigment epithelium lipofuscin proteomics,” Mol. Cell. Proteomics 7(7), 1397–1405 (2008).
[Crossref] [PubMed]

Gutierrez, D.

Z. Ablonczy, D. Higbee, D. M. Anderson, M. Dahrouj, A. C. Grey, D. Gutierrez, Y. Koutalos, K. L. Schey, A. Hanneken, and R. K. Crouch, “Lack of correlation between the spatial distribution of A2E and lipofuscin fluorescence in the human retinal pigment epithelium,” Invest. Ophthalmol. Vis. Sci. 54(8), 5535–5542 (2013).
[Crossref] [PubMed]

Gutierrez, D. B.

T. Ach, C. Huisingh, G. McGwin, J. D. Messinger, T. Zhang, M. J. Bentley, D. B. Gutierrez, Z. Ablonczy, R. T. Smith, K. R. Sloan, and C. A. Curcio, “Quantitative autofluorescence and cell density maps of the human retinal pigment epithelium,” Invest. Ophthalmol. Vis. Sci. 55(8), 4832–4841 (2014).
[Crossref] [PubMed]

Hanneken, A.

Z. Ablonczy, D. Higbee, D. M. Anderson, M. Dahrouj, A. C. Grey, D. Gutierrez, Y. Koutalos, K. L. Schey, A. Hanneken, and R. K. Crouch, “Lack of correlation between the spatial distribution of A2E and lipofuscin fluorescence in the human retinal pigment epithelium,” Invest. Ophthalmol. Vis. Sci. 54(8), 5535–5542 (2013).
[Crossref] [PubMed]

Hashimoto, M.

K. Yamamoto, K. D. Yoon, K. Ueda, M. Hashimoto, and J. R. Sparrow, “A novel bisretinoid of retina is an adduct on glycerophosphoethanolamine,” Invest. Ophthalmol. Vis. Sci. 52(12), 9084–9090 (2011).
[Crossref] [PubMed]

Hazan, T.

A. Shashua and T. Hazan, “Non-negative tensor factorization with applications to statistics and computer vision,” in Proceedings of the 22nd International Conference on Machine Learning (ACM, 2005), pp. 792–799.
[Crossref]

Heintzmann, R.

T. Ach, G. Best, S. Rossberger, R. Heintzmann, C. Cremer, and S. Dithmar, “Autofluorescence imaging of human RPE cell granules using structured illumination microscopy,” Br. J. Ophthalmol. 96(8), 1141–1144 (2012).
[Crossref] [PubMed]

Higbee, D.

Z. Ablonczy, D. Higbee, A. C. Grey, Y. Koutalos, K. L. Schey, and R. K. Crouch, “Similar molecules spatially correlate with lipofuscin and N-retinylidene-N-retinylethanolamine in the mouse but not in the human retinal pigment epithelium,” Arch. Biochem. Biophys. 539(2), 196–202 (2013).
[Crossref] [PubMed]

Z. Ablonczy, D. Higbee, D. M. Anderson, M. Dahrouj, A. C. Grey, D. Gutierrez, Y. Koutalos, K. L. Schey, A. Hanneken, and R. K. Crouch, “Lack of correlation between the spatial distribution of A2E and lipofuscin fluorescence in the human retinal pigment epithelium,” Invest. Ophthalmol. Vis. Sci. 54(8), 5535–5542 (2013).
[Crossref] [PubMed]

Hollyfield, J. G.

K. P. Ng, B. Gugiu, K. Renganathan, M. W. Davies, X. Gu, J. S. Crabb, S. R. Kim, M. B. Rózanowska, V. L. Bonilha, M. E. Rayborn, R. G. Salomon, J. R. Sparrow, M. E. Boulton, J. G. Hollyfield, and J. W. Crabb, “Retinal pigment epithelium lipofuscin proteomics,” Mol. Cell. Proteomics 7(7), 1397–1405 (2008).
[Crossref] [PubMed]

Huisingh, C.

T. Ach, C. Huisingh, G. McGwin, J. D. Messinger, T. Zhang, M. J. Bentley, D. B. Gutierrez, Z. Ablonczy, R. T. Smith, K. R. Sloan, and C. A. Curcio, “Quantitative autofluorescence and cell density maps of the human retinal pigment epithelium,” Invest. Ophthalmol. Vis. Sci. 55(8), 4832–4841 (2014).
[Crossref] [PubMed]

Hwang, J. C.

J. C. Hwang, J. W. Chan, S. Chang, and R. T. Smith, “Predictive value of fundus autofluorescence for development of geographic atrophy in age-related macular degeneration,” Invest. Ophthalmol. Vis. Sci. 47(6), 2655–2661 (2006).
[Crossref] [PubMed]

Itagaki, Y.

Y. P. Jang, H. Matsuda, Y. Itagaki, K. Nakanishi, and J. R. Sparrow, “Characterization of peroxy-A2E and furan-A2E photooxidation products and detection in human and mouse retinal pigment epithelial cell lipofuscin,” J. Biol. Chem. 280(48), 39732–39739 (2005).
[Crossref] [PubMed]

J. R. Sparrow, N. Fishkin, J. Zhou, B. Cai, Y. P. Jang, S. Krane, Y. Itagaki, and K. Nakanishi, “A2E, a byproduct of the visual cycle,” Vision Res. 43(28), 2983–2990 (2003).
[Crossref] [PubMed]

Jang, Y. P.

S. R. Kim, Y. P. Jang, S. Jockusch, N. E. Fishkin, N. J. Turro, and J. R. Sparrow, “The all-trans-retinal dimer series of lipofuscin pigments in retinal pigment epithelial cells in a recessive Stargardt disease model,” Proc. Natl. Acad. Sci. U.S.A. 104(49), 19273–19278 (2007).
[Crossref] [PubMed]

Y. P. Jang, H. Matsuda, Y. Itagaki, K. Nakanishi, and J. R. Sparrow, “Characterization of peroxy-A2E and furan-A2E photooxidation products and detection in human and mouse retinal pigment epithelial cell lipofuscin,” J. Biol. Chem. 280(48), 39732–39739 (2005).
[Crossref] [PubMed]

J. R. Sparrow, N. Fishkin, J. Zhou, B. Cai, Y. P. Jang, S. Krane, Y. Itagaki, and K. Nakanishi, “A2E, a byproduct of the visual cycle,” Vision Res. 43(28), 2983–2990 (2003).
[Crossref] [PubMed]

Jockusch, S.

S. R. Kim, Y. P. Jang, S. Jockusch, N. E. Fishkin, N. J. Turro, and J. R. Sparrow, “The all-trans-retinal dimer series of lipofuscin pigments in retinal pigment epithelial cells in a recessive Stargardt disease model,” Proc. Natl. Acad. Sci. U.S.A. 104(49), 19273–19278 (2007).
[Crossref] [PubMed]

Katz, M. L.

G. E. Eldred and M. L. Katz, “Fluorophores of the human retinal pigment epithelium: separation and spectral characterization,” Exp. Eye Res. 47(1), 71–86 (1988).
[Crossref] [PubMed]

Kim, C. Y.

J. R. Sparrow, Y. Wu, C. Y. Kim, and J. Zhou, “Phospholipid meets all-trans-retinal: the making of RPE bisretinoids,” J. Lipid Res. 51(2), 247–261 (2010).
[Crossref] [PubMed]

Kim, S. R.

K. P. Ng, B. Gugiu, K. Renganathan, M. W. Davies, X. Gu, J. S. Crabb, S. R. Kim, M. B. Rózanowska, V. L. Bonilha, M. E. Rayborn, R. G. Salomon, J. R. Sparrow, M. E. Boulton, J. G. Hollyfield, and J. W. Crabb, “Retinal pigment epithelium lipofuscin proteomics,” Mol. Cell. Proteomics 7(7), 1397–1405 (2008).
[Crossref] [PubMed]

S. R. Kim, Y. P. Jang, S. Jockusch, N. E. Fishkin, N. J. Turro, and J. R. Sparrow, “The all-trans-retinal dimer series of lipofuscin pigments in retinal pigment epithelial cells in a recessive Stargardt disease model,” Proc. Natl. Acad. Sci. U.S.A. 104(49), 19273–19278 (2007).
[Crossref] [PubMed]

Kirchhoff, F.

R. A. Neher, M. Mitkovski, F. Kirchhoff, E. Neher, F. J. Theis, and A. Zeug, “Blind source separation techniques for the decomposition of multiply labeled fluorescence images,” Biophys. J. 96(9), 3791–3800 (2009).
[Crossref] [PubMed]

Kono, M.

P. H. Tang, M. Kono, Y. Koutalos, Z. Ablonczy, and R. K. Crouch, “New insights into retinoid metabolism and cycling within the retina,” Prog. Retin. Eye Res. 32, 48–63 (2013).
[Crossref] [PubMed]

Koutalos, Y.

Z. Ablonczy, N. Smith, D. M. Anderson, A. C. Grey, J. Spraggins, Y. Koutalos, K. L. Schey, and R. K. Crouch, “The utilization of fluorescence to identify the components of lipofuscin by imaging mass spectrometry,” Proteomics 14(7-8), 936–944 (2014).
[Crossref] [PubMed]

Z. Ablonczy, D. Higbee, A. C. Grey, Y. Koutalos, K. L. Schey, and R. K. Crouch, “Similar molecules spatially correlate with lipofuscin and N-retinylidene-N-retinylethanolamine in the mouse but not in the human retinal pigment epithelium,” Arch. Biochem. Biophys. 539(2), 196–202 (2013).
[Crossref] [PubMed]

P. H. Tang, M. Kono, Y. Koutalos, Z. Ablonczy, and R. K. Crouch, “New insights into retinoid metabolism and cycling within the retina,” Prog. Retin. Eye Res. 32, 48–63 (2013).
[Crossref] [PubMed]

Z. Ablonczy, D. Higbee, D. M. Anderson, M. Dahrouj, A. C. Grey, D. Gutierrez, Y. Koutalos, K. L. Schey, A. Hanneken, and R. K. Crouch, “Lack of correlation between the spatial distribution of A2E and lipofuscin fluorescence in the human retinal pigment epithelium,” Invest. Ophthalmol. Vis. Sci. 54(8), 5535–5542 (2013).
[Crossref] [PubMed]

Krane, S.

J. R. Sparrow, N. Fishkin, J. Zhou, B. Cai, Y. P. Jang, S. Krane, Y. Itagaki, and K. Nakanishi, “A2E, a byproduct of the visual cycle,” Vision Res. 43(28), 2983–2990 (2003).
[Crossref] [PubMed]

Mao, X.

P. Sajda, S. Du, T. R. Brown, R. Stoyanova, D. C. Shungu, X. Mao, and L. C. Parra, “Nonnegative matrix factorization for rapid recovery of constituent spectra in magnetic resonance chemical shift imaging of the brain,” IEEE Trans. Med. Imaging 23(12), 1453–1465 (2004).
[Crossref] [PubMed]

Matsuda, H.

Y. P. Jang, H. Matsuda, Y. Itagaki, K. Nakanishi, and J. R. Sparrow, “Characterization of peroxy-A2E and furan-A2E photooxidation products and detection in human and mouse retinal pigment epithelial cell lipofuscin,” J. Biol. Chem. 280(48), 39732–39739 (2005).
[Crossref] [PubMed]

McGwin, G.

T. Ach, C. Huisingh, G. McGwin, J. D. Messinger, T. Zhang, M. J. Bentley, D. B. Gutierrez, Z. Ablonczy, R. T. Smith, K. R. Sloan, and C. A. Curcio, “Quantitative autofluorescence and cell density maps of the human retinal pigment epithelium,” Invest. Ophthalmol. Vis. Sci. 55(8), 4832–4841 (2014).
[Crossref] [PubMed]

Messinger, J. D.

T. Ach, C. Huisingh, G. McGwin, J. D. Messinger, T. Zhang, M. J. Bentley, D. B. Gutierrez, Z. Ablonczy, R. T. Smith, K. R. Sloan, and C. A. Curcio, “Quantitative autofluorescence and cell density maps of the human retinal pigment epithelium,” Invest. Ophthalmol. Vis. Sci. 55(8), 4832–4841 (2014).
[Crossref] [PubMed]

Mitkovski, M.

R. A. Neher, M. Mitkovski, F. Kirchhoff, E. Neher, F. J. Theis, and A. Zeug, “Blind source separation techniques for the decomposition of multiply labeled fluorescence images,” Biophys. J. 96(9), 3791–3800 (2009).
[Crossref] [PubMed]

Muñoz-Barrutia, A.

T. Pengo, A. Muñoz-Barrutia, I. Zudaire, and C. Ortiz-de-Solorzano, “Efficient blind spectral unmixing of fluorescently labeled samples using multi-layer non-negative matrix factorization,” PLoS ONE 8(11), e78504 (2013).
[Crossref] [PubMed]

Nakanishi, K.

Y. P. Jang, H. Matsuda, Y. Itagaki, K. Nakanishi, and J. R. Sparrow, “Characterization of peroxy-A2E and furan-A2E photooxidation products and detection in human and mouse retinal pigment epithelial cell lipofuscin,” J. Biol. Chem. 280(48), 39732–39739 (2005).
[Crossref] [PubMed]

J. R. Sparrow, N. Fishkin, J. Zhou, B. Cai, Y. P. Jang, S. Krane, Y. Itagaki, and K. Nakanishi, “A2E, a byproduct of the visual cycle,” Vision Res. 43(28), 2983–2990 (2003).
[Crossref] [PubMed]

Neher, E.

R. A. Neher, M. Mitkovski, F. Kirchhoff, E. Neher, F. J. Theis, and A. Zeug, “Blind source separation techniques for the decomposition of multiply labeled fluorescence images,” Biophys. J. 96(9), 3791–3800 (2009).
[Crossref] [PubMed]

Neher, R. A.

R. A. Neher, M. Mitkovski, F. Kirchhoff, E. Neher, F. J. Theis, and A. Zeug, “Blind source separation techniques for the decomposition of multiply labeled fluorescence images,” Biophys. J. 96(9), 3791–3800 (2009).
[Crossref] [PubMed]

Ng, K. P.

K. P. Ng, B. Gugiu, K. Renganathan, M. W. Davies, X. Gu, J. S. Crabb, S. R. Kim, M. B. Rózanowska, V. L. Bonilha, M. E. Rayborn, R. G. Salomon, J. R. Sparrow, M. E. Boulton, J. G. Hollyfield, and J. W. Crabb, “Retinal pigment epithelium lipofuscin proteomics,” Mol. Cell. Proteomics 7(7), 1397–1405 (2008).
[Crossref] [PubMed]

Ortiz-de-Solorzano, C.

T. Pengo, A. Muñoz-Barrutia, I. Zudaire, and C. Ortiz-de-Solorzano, “Efficient blind spectral unmixing of fluorescently labeled samples using multi-layer non-negative matrix factorization,” PLoS ONE 8(11), e78504 (2013).
[Crossref] [PubMed]

Pande, A.

Y. Wu, N. E. Fishkin, A. Pande, J. Pande, and J. R. Sparrow, “Novel lipofuscin bisretinoids prominent in human retina and in a model of recessive Stargardt disease,” J. Biol. Chem. 284(30), 20155–20166 (2009).
[Crossref] [PubMed]

Pande, J.

Y. Wu, N. E. Fishkin, A. Pande, J. Pande, and J. R. Sparrow, “Novel lipofuscin bisretinoids prominent in human retina and in a model of recessive Stargardt disease,” J. Biol. Chem. 284(30), 20155–20166 (2009).
[Crossref] [PubMed]

Parra, L. C.

P. Sajda, S. Du, T. R. Brown, R. Stoyanova, D. C. Shungu, X. Mao, and L. C. Parra, “Nonnegative matrix factorization for rapid recovery of constituent spectra in magnetic resonance chemical shift imaging of the brain,” IEEE Trans. Med. Imaging 23(12), 1453–1465 (2004).
[Crossref] [PubMed]

Pengo, T.

T. Pengo, A. Muñoz-Barrutia, I. Zudaire, and C. Ortiz-de-Solorzano, “Efficient blind spectral unmixing of fluorescently labeled samples using multi-layer non-negative matrix factorization,” PLoS ONE 8(11), e78504 (2013).
[Crossref] [PubMed]

Rayborn, M. E.

K. P. Ng, B. Gugiu, K. Renganathan, M. W. Davies, X. Gu, J. S. Crabb, S. R. Kim, M. B. Rózanowska, V. L. Bonilha, M. E. Rayborn, R. G. Salomon, J. R. Sparrow, M. E. Boulton, J. G. Hollyfield, and J. W. Crabb, “Retinal pigment epithelium lipofuscin proteomics,” Mol. Cell. Proteomics 7(7), 1397–1405 (2008).
[Crossref] [PubMed]

Renganathan, K.

K. P. Ng, B. Gugiu, K. Renganathan, M. W. Davies, X. Gu, J. S. Crabb, S. R. Kim, M. B. Rózanowska, V. L. Bonilha, M. E. Rayborn, R. G. Salomon, J. R. Sparrow, M. E. Boulton, J. G. Hollyfield, and J. W. Crabb, “Retinal pigment epithelium lipofuscin proteomics,” Mol. Cell. Proteomics 7(7), 1397–1405 (2008).
[Crossref] [PubMed]

Rossberger, S.

T. Ach, G. Best, S. Rossberger, R. Heintzmann, C. Cremer, and S. Dithmar, “Autofluorescence imaging of human RPE cell granules using structured illumination microscopy,” Br. J. Ophthalmol. 96(8), 1141–1144 (2012).
[Crossref] [PubMed]

Rothman, H.

L. Feeney-Burns, E. R. Berman, and H. Rothman, “Lipofuscin of human retinal pigment epithelium,” Am. J. Ophthalmol. 90(6), 783–791 (1980).
[Crossref] [PubMed]

Rózanowska, M. B.

K. P. Ng, B. Gugiu, K. Renganathan, M. W. Davies, X. Gu, J. S. Crabb, S. R. Kim, M. B. Rózanowska, V. L. Bonilha, M. E. Rayborn, R. G. Salomon, J. R. Sparrow, M. E. Boulton, J. G. Hollyfield, and J. W. Crabb, “Retinal pigment epithelium lipofuscin proteomics,” Mol. Cell. Proteomics 7(7), 1397–1405 (2008).
[Crossref] [PubMed]

Sajda, P.

P. Sajda, “Machine learning for detection and diagnosis of disease,” Annu. Rev. Biomed. Eng. 8(1), 537–565 (2006).
[Crossref] [PubMed]

P. Sajda, S. Du, T. R. Brown, R. Stoyanova, D. C. Shungu, X. Mao, and L. C. Parra, “Nonnegative matrix factorization for rapid recovery of constituent spectra in magnetic resonance chemical shift imaging of the brain,” IEEE Trans. Med. Imaging 23(12), 1453–1465 (2004).
[Crossref] [PubMed]

Salomon, R. G.

K. P. Ng, B. Gugiu, K. Renganathan, M. W. Davies, X. Gu, J. S. Crabb, S. R. Kim, M. B. Rózanowska, V. L. Bonilha, M. E. Rayborn, R. G. Salomon, J. R. Sparrow, M. E. Boulton, J. G. Hollyfield, and J. W. Crabb, “Retinal pigment epithelium lipofuscin proteomics,” Mol. Cell. Proteomics 7(7), 1397–1405 (2008).
[Crossref] [PubMed]

Schey, K. L.

Z. Ablonczy, N. Smith, D. M. Anderson, A. C. Grey, J. Spraggins, Y. Koutalos, K. L. Schey, and R. K. Crouch, “The utilization of fluorescence to identify the components of lipofuscin by imaging mass spectrometry,” Proteomics 14(7-8), 936–944 (2014).
[Crossref] [PubMed]

Z. Ablonczy, D. Higbee, A. C. Grey, Y. Koutalos, K. L. Schey, and R. K. Crouch, “Similar molecules spatially correlate with lipofuscin and N-retinylidene-N-retinylethanolamine in the mouse but not in the human retinal pigment epithelium,” Arch. Biochem. Biophys. 539(2), 196–202 (2013).
[Crossref] [PubMed]

Z. Ablonczy, D. Higbee, D. M. Anderson, M. Dahrouj, A. C. Grey, D. Gutierrez, Y. Koutalos, K. L. Schey, A. Hanneken, and R. K. Crouch, “Lack of correlation between the spatial distribution of A2E and lipofuscin fluorescence in the human retinal pigment epithelium,” Invest. Ophthalmol. Vis. Sci. 54(8), 5535–5542 (2013).
[Crossref] [PubMed]

Shashua, A.

A. Shashua and T. Hazan, “Non-negative tensor factorization with applications to statistics and computer vision,” in Proceedings of the 22nd International Conference on Machine Learning (ACM, 2005), pp. 792–799.
[Crossref]

Shungu, D. C.

P. Sajda, S. Du, T. R. Brown, R. Stoyanova, D. C. Shungu, X. Mao, and L. C. Parra, “Nonnegative matrix factorization for rapid recovery of constituent spectra in magnetic resonance chemical shift imaging of the brain,” IEEE Trans. Med. Imaging 23(12), 1453–1465 (2004).
[Crossref] [PubMed]

Sloan, K. R.

T. Ach, C. Huisingh, G. McGwin, J. D. Messinger, T. Zhang, M. J. Bentley, D. B. Gutierrez, Z. Ablonczy, R. T. Smith, K. R. Sloan, and C. A. Curcio, “Quantitative autofluorescence and cell density maps of the human retinal pigment epithelium,” Invest. Ophthalmol. Vis. Sci. 55(8), 4832–4841 (2014).
[Crossref] [PubMed]

Smith, N.

Z. Ablonczy, N. Smith, D. M. Anderson, A. C. Grey, J. Spraggins, Y. Koutalos, K. L. Schey, and R. K. Crouch, “The utilization of fluorescence to identify the components of lipofuscin by imaging mass spectrometry,” Proteomics 14(7-8), 936–944 (2014).
[Crossref] [PubMed]

Smith, R. T.

T. Ach, C. Huisingh, G. McGwin, J. D. Messinger, T. Zhang, M. J. Bentley, D. B. Gutierrez, Z. Ablonczy, R. T. Smith, K. R. Sloan, and C. A. Curcio, “Quantitative autofluorescence and cell density maps of the human retinal pigment epithelium,” Invest. Ophthalmol. Vis. Sci. 55(8), 4832–4841 (2014).
[Crossref] [PubMed]

J. C. Hwang, J. W. Chan, S. Chang, and R. T. Smith, “Predictive value of fundus autofluorescence for development of geographic atrophy in age-related macular degeneration,” Invest. Ophthalmol. Vis. Sci. 47(6), 2655–2661 (2006).
[Crossref] [PubMed]

Sparrow, J. R.

J. R. Sparrow, E. Gregory-Roberts, K. Yamamoto, A. Blonska, S. K. Ghosh, K. Ueda, and J. Zhou, “The bisretinoids of retinal pigment epithelium,” Prog. Retin. Eye Res. 31(2), 121–135 (2012).
[Crossref] [PubMed]

K. Yamamoto, K. D. Yoon, K. Ueda, M. Hashimoto, and J. R. Sparrow, “A novel bisretinoid of retina is an adduct on glycerophosphoethanolamine,” Invest. Ophthalmol. Vis. Sci. 52(12), 9084–9090 (2011).
[Crossref] [PubMed]

J. R. Sparrow, Y. Wu, C. Y. Kim, and J. Zhou, “Phospholipid meets all-trans-retinal: the making of RPE bisretinoids,” J. Lipid Res. 51(2), 247–261 (2010).
[Crossref] [PubMed]

Y. Wu, N. E. Fishkin, A. Pande, J. Pande, and J. R. Sparrow, “Novel lipofuscin bisretinoids prominent in human retina and in a model of recessive Stargardt disease,” J. Biol. Chem. 284(30), 20155–20166 (2009).
[Crossref] [PubMed]

K. P. Ng, B. Gugiu, K. Renganathan, M. W. Davies, X. Gu, J. S. Crabb, S. R. Kim, M. B. Rózanowska, V. L. Bonilha, M. E. Rayborn, R. G. Salomon, J. R. Sparrow, M. E. Boulton, J. G. Hollyfield, and J. W. Crabb, “Retinal pigment epithelium lipofuscin proteomics,” Mol. Cell. Proteomics 7(7), 1397–1405 (2008).
[Crossref] [PubMed]

S. R. Kim, Y. P. Jang, S. Jockusch, N. E. Fishkin, N. J. Turro, and J. R. Sparrow, “The all-trans-retinal dimer series of lipofuscin pigments in retinal pigment epithelial cells in a recessive Stargardt disease model,” Proc. Natl. Acad. Sci. U.S.A. 104(49), 19273–19278 (2007).
[Crossref] [PubMed]

Y. P. Jang, H. Matsuda, Y. Itagaki, K. Nakanishi, and J. R. Sparrow, “Characterization of peroxy-A2E and furan-A2E photooxidation products and detection in human and mouse retinal pigment epithelial cell lipofuscin,” J. Biol. Chem. 280(48), 39732–39739 (2005).
[Crossref] [PubMed]

J. R. Sparrow, N. Fishkin, J. Zhou, B. Cai, Y. P. Jang, S. Krane, Y. Itagaki, and K. Nakanishi, “A2E, a byproduct of the visual cycle,” Vision Res. 43(28), 2983–2990 (2003).
[Crossref] [PubMed]

Spraggins, J.

Z. Ablonczy, N. Smith, D. M. Anderson, A. C. Grey, J. Spraggins, Y. Koutalos, K. L. Schey, and R. K. Crouch, “The utilization of fluorescence to identify the components of lipofuscin by imaging mass spectrometry,” Proteomics 14(7-8), 936–944 (2014).
[Crossref] [PubMed]

Stoyanova, R.

P. Sajda, S. Du, T. R. Brown, R. Stoyanova, D. C. Shungu, X. Mao, and L. C. Parra, “Nonnegative matrix factorization for rapid recovery of constituent spectra in magnetic resonance chemical shift imaging of the brain,” IEEE Trans. Med. Imaging 23(12), 1453–1465 (2004).
[Crossref] [PubMed]

Strauss, O.

O. Strauss, “The retinal pigment epithelium in visual function,” Physiol. Rev. 85(3), 845–881 (2005).
[Crossref] [PubMed]

Tang, P. H.

P. H. Tang, M. Kono, Y. Koutalos, Z. Ablonczy, and R. K. Crouch, “New insights into retinoid metabolism and cycling within the retina,” Prog. Retin. Eye Res. 32, 48–63 (2013).
[Crossref] [PubMed]

Theis, F. J.

R. A. Neher, M. Mitkovski, F. Kirchhoff, E. Neher, F. J. Theis, and A. Zeug, “Blind source separation techniques for the decomposition of multiply labeled fluorescence images,” Biophys. J. 96(9), 3791–3800 (2009).
[Crossref] [PubMed]

Ts’o, M. O.

M. O. Ts’o and E. Friedman, “The retinal pigment epithelium. I. Comparative histology,” Arch. Ophthalmol. 78(5), 641–649 (1967).
[Crossref] [PubMed]

Turro, N. J.

S. R. Kim, Y. P. Jang, S. Jockusch, N. E. Fishkin, N. J. Turro, and J. R. Sparrow, “The all-trans-retinal dimer series of lipofuscin pigments in retinal pigment epithelial cells in a recessive Stargardt disease model,” Proc. Natl. Acad. Sci. U.S.A. 104(49), 19273–19278 (2007).
[Crossref] [PubMed]

Ueda, K.

J. R. Sparrow, E. Gregory-Roberts, K. Yamamoto, A. Blonska, S. K. Ghosh, K. Ueda, and J. Zhou, “The bisretinoids of retinal pigment epithelium,” Prog. Retin. Eye Res. 31(2), 121–135 (2012).
[Crossref] [PubMed]

K. Yamamoto, K. D. Yoon, K. Ueda, M. Hashimoto, and J. R. Sparrow, “A novel bisretinoid of retina is an adduct on glycerophosphoethanolamine,” Invest. Ophthalmol. Vis. Sci. 52(12), 9084–9090 (2011).
[Crossref] [PubMed]

Weiter, J. J.

J. J. Weiter, F. C. Delori, G. L. Wing, and K. A. Fitch, “Retinal pigment epithelial lipofuscin and melanin and choroidal melanin in human eyes,” Invest. Ophthalmol. Vis. Sci. 27(2), 145–152 (1986).
[PubMed]

Wing, G. L.

J. J. Weiter, F. C. Delori, G. L. Wing, and K. A. Fitch, “Retinal pigment epithelial lipofuscin and melanin and choroidal melanin in human eyes,” Invest. Ophthalmol. Vis. Sci. 27(2), 145–152 (1986).
[PubMed]

Wu, Y.

J. R. Sparrow, Y. Wu, C. Y. Kim, and J. Zhou, “Phospholipid meets all-trans-retinal: the making of RPE bisretinoids,” J. Lipid Res. 51(2), 247–261 (2010).
[Crossref] [PubMed]

Y. Wu, N. E. Fishkin, A. Pande, J. Pande, and J. R. Sparrow, “Novel lipofuscin bisretinoids prominent in human retina and in a model of recessive Stargardt disease,” J. Biol. Chem. 284(30), 20155–20166 (2009).
[Crossref] [PubMed]

Yamamoto, K.

J. R. Sparrow, E. Gregory-Roberts, K. Yamamoto, A. Blonska, S. K. Ghosh, K. Ueda, and J. Zhou, “The bisretinoids of retinal pigment epithelium,” Prog. Retin. Eye Res. 31(2), 121–135 (2012).
[Crossref] [PubMed]

K. Yamamoto, K. D. Yoon, K. Ueda, M. Hashimoto, and J. R. Sparrow, “A novel bisretinoid of retina is an adduct on glycerophosphoethanolamine,” Invest. Ophthalmol. Vis. Sci. 52(12), 9084–9090 (2011).
[Crossref] [PubMed]

Yoon, K. D.

K. Yamamoto, K. D. Yoon, K. Ueda, M. Hashimoto, and J. R. Sparrow, “A novel bisretinoid of retina is an adduct on glycerophosphoethanolamine,” Invest. Ophthalmol. Vis. Sci. 52(12), 9084–9090 (2011).
[Crossref] [PubMed]

Zeug, A.

R. A. Neher, M. Mitkovski, F. Kirchhoff, E. Neher, F. J. Theis, and A. Zeug, “Blind source separation techniques for the decomposition of multiply labeled fluorescence images,” Biophys. J. 96(9), 3791–3800 (2009).
[Crossref] [PubMed]

Zhang, T.

T. Ach, C. Huisingh, G. McGwin, J. D. Messinger, T. Zhang, M. J. Bentley, D. B. Gutierrez, Z. Ablonczy, R. T. Smith, K. R. Sloan, and C. A. Curcio, “Quantitative autofluorescence and cell density maps of the human retinal pigment epithelium,” Invest. Ophthalmol. Vis. Sci. 55(8), 4832–4841 (2014).
[Crossref] [PubMed]

Zhou, J.

J. R. Sparrow, E. Gregory-Roberts, K. Yamamoto, A. Blonska, S. K. Ghosh, K. Ueda, and J. Zhou, “The bisretinoids of retinal pigment epithelium,” Prog. Retin. Eye Res. 31(2), 121–135 (2012).
[Crossref] [PubMed]

J. R. Sparrow, Y. Wu, C. Y. Kim, and J. Zhou, “Phospholipid meets all-trans-retinal: the making of RPE bisretinoids,” J. Lipid Res. 51(2), 247–261 (2010).
[Crossref] [PubMed]

J. R. Sparrow, N. Fishkin, J. Zhou, B. Cai, Y. P. Jang, S. Krane, Y. Itagaki, and K. Nakanishi, “A2E, a byproduct of the visual cycle,” Vision Res. 43(28), 2983–2990 (2003).
[Crossref] [PubMed]

Zudaire, I.

T. Pengo, A. Muñoz-Barrutia, I. Zudaire, and C. Ortiz-de-Solorzano, “Efficient blind spectral unmixing of fluorescently labeled samples using multi-layer non-negative matrix factorization,” PLoS ONE 8(11), e78504 (2013).
[Crossref] [PubMed]

Am. J. Ophthalmol. (1)

L. Feeney-Burns, E. R. Berman, and H. Rothman, “Lipofuscin of human retinal pigment epithelium,” Am. J. Ophthalmol. 90(6), 783–791 (1980).
[Crossref] [PubMed]

Annu. Rev. Biomed. Eng. (1)

P. Sajda, “Machine learning for detection and diagnosis of disease,” Annu. Rev. Biomed. Eng. 8(1), 537–565 (2006).
[Crossref] [PubMed]

Arch. Biochem. Biophys. (1)

Z. Ablonczy, D. Higbee, A. C. Grey, Y. Koutalos, K. L. Schey, and R. K. Crouch, “Similar molecules spatially correlate with lipofuscin and N-retinylidene-N-retinylethanolamine in the mouse but not in the human retinal pigment epithelium,” Arch. Biochem. Biophys. 539(2), 196–202 (2013).
[Crossref] [PubMed]

Arch. Ophthalmol. (1)

M. O. Ts’o and E. Friedman, “The retinal pigment epithelium. I. Comparative histology,” Arch. Ophthalmol. 78(5), 641–649 (1967).
[Crossref] [PubMed]

Biophys. J. (1)

R. A. Neher, M. Mitkovski, F. Kirchhoff, E. Neher, F. J. Theis, and A. Zeug, “Blind source separation techniques for the decomposition of multiply labeled fluorescence images,” Biophys. J. 96(9), 3791–3800 (2009).
[Crossref] [PubMed]

Br. J. Ophthalmol. (1)

T. Ach, G. Best, S. Rossberger, R. Heintzmann, C. Cremer, and S. Dithmar, “Autofluorescence imaging of human RPE cell granules using structured illumination microscopy,” Br. J. Ophthalmol. 96(8), 1141–1144 (2012).
[Crossref] [PubMed]

Exp. Eye Res. (1)

G. E. Eldred and M. L. Katz, “Fluorophores of the human retinal pigment epithelium: separation and spectral characterization,” Exp. Eye Res. 47(1), 71–86 (1988).
[Crossref] [PubMed]

IEEE Trans. Med. Imaging (1)

P. Sajda, S. Du, T. R. Brown, R. Stoyanova, D. C. Shungu, X. Mao, and L. C. Parra, “Nonnegative matrix factorization for rapid recovery of constituent spectra in magnetic resonance chemical shift imaging of the brain,” IEEE Trans. Med. Imaging 23(12), 1453–1465 (2004).
[Crossref] [PubMed]

Invest. Ophthalmol. Vis. Sci. (6)

L. Feeney, “Lipofuscin and melanin of human retinal pigment epithelium. Fluorescence, enzyme cytochemical, and ultrastructural studies,” Invest. Ophthalmol. Vis. Sci. 17(7), 583–600 (1978).
[PubMed]

J. C. Hwang, J. W. Chan, S. Chang, and R. T. Smith, “Predictive value of fundus autofluorescence for development of geographic atrophy in age-related macular degeneration,” Invest. Ophthalmol. Vis. Sci. 47(6), 2655–2661 (2006).
[Crossref] [PubMed]

Z. Ablonczy, D. Higbee, D. M. Anderson, M. Dahrouj, A. C. Grey, D. Gutierrez, Y. Koutalos, K. L. Schey, A. Hanneken, and R. K. Crouch, “Lack of correlation between the spatial distribution of A2E and lipofuscin fluorescence in the human retinal pigment epithelium,” Invest. Ophthalmol. Vis. Sci. 54(8), 5535–5542 (2013).
[Crossref] [PubMed]

T. Ach, C. Huisingh, G. McGwin, J. D. Messinger, T. Zhang, M. J. Bentley, D. B. Gutierrez, Z. Ablonczy, R. T. Smith, K. R. Sloan, and C. A. Curcio, “Quantitative autofluorescence and cell density maps of the human retinal pigment epithelium,” Invest. Ophthalmol. Vis. Sci. 55(8), 4832–4841 (2014).
[Crossref] [PubMed]

J. J. Weiter, F. C. Delori, G. L. Wing, and K. A. Fitch, “Retinal pigment epithelial lipofuscin and melanin and choroidal melanin in human eyes,” Invest. Ophthalmol. Vis. Sci. 27(2), 145–152 (1986).
[PubMed]

K. Yamamoto, K. D. Yoon, K. Ueda, M. Hashimoto, and J. R. Sparrow, “A novel bisretinoid of retina is an adduct on glycerophosphoethanolamine,” Invest. Ophthalmol. Vis. Sci. 52(12), 9084–9090 (2011).
[Crossref] [PubMed]

J. Biol. Chem. (2)

Y. P. Jang, H. Matsuda, Y. Itagaki, K. Nakanishi, and J. R. Sparrow, “Characterization of peroxy-A2E and furan-A2E photooxidation products and detection in human and mouse retinal pigment epithelial cell lipofuscin,” J. Biol. Chem. 280(48), 39732–39739 (2005).
[Crossref] [PubMed]

Y. Wu, N. E. Fishkin, A. Pande, J. Pande, and J. R. Sparrow, “Novel lipofuscin bisretinoids prominent in human retina and in a model of recessive Stargardt disease,” J. Biol. Chem. 284(30), 20155–20166 (2009).
[Crossref] [PubMed]

J. Lipid Res. (1)

J. R. Sparrow, Y. Wu, C. Y. Kim, and J. Zhou, “Phospholipid meets all-trans-retinal: the making of RPE bisretinoids,” J. Lipid Res. 51(2), 247–261 (2010).
[Crossref] [PubMed]

Mol. Cell. Proteomics (1)

K. P. Ng, B. Gugiu, K. Renganathan, M. W. Davies, X. Gu, J. S. Crabb, S. R. Kim, M. B. Rózanowska, V. L. Bonilha, M. E. Rayborn, R. G. Salomon, J. R. Sparrow, M. E. Boulton, J. G. Hollyfield, and J. W. Crabb, “Retinal pigment epithelium lipofuscin proteomics,” Mol. Cell. Proteomics 7(7), 1397–1405 (2008).
[Crossref] [PubMed]

Physiol. Rev. (1)

O. Strauss, “The retinal pigment epithelium in visual function,” Physiol. Rev. 85(3), 845–881 (2005).
[Crossref] [PubMed]

PLoS ONE (1)

T. Pengo, A. Muñoz-Barrutia, I. Zudaire, and C. Ortiz-de-Solorzano, “Efficient blind spectral unmixing of fluorescently labeled samples using multi-layer non-negative matrix factorization,” PLoS ONE 8(11), e78504 (2013).
[Crossref] [PubMed]

Proc. Natl. Acad. Sci. U.S.A. (1)

S. R. Kim, Y. P. Jang, S. Jockusch, N. E. Fishkin, N. J. Turro, and J. R. Sparrow, “The all-trans-retinal dimer series of lipofuscin pigments in retinal pigment epithelial cells in a recessive Stargardt disease model,” Proc. Natl. Acad. Sci. U.S.A. 104(49), 19273–19278 (2007).
[Crossref] [PubMed]

Prog. Retin. Eye Res. (2)

P. H. Tang, M. Kono, Y. Koutalos, Z. Ablonczy, and R. K. Crouch, “New insights into retinoid metabolism and cycling within the retina,” Prog. Retin. Eye Res. 32, 48–63 (2013).
[Crossref] [PubMed]

J. R. Sparrow, E. Gregory-Roberts, K. Yamamoto, A. Blonska, S. K. Ghosh, K. Ueda, and J. Zhou, “The bisretinoids of retinal pigment epithelium,” Prog. Retin. Eye Res. 31(2), 121–135 (2012).
[Crossref] [PubMed]

Proteomics (1)

Z. Ablonczy, N. Smith, D. M. Anderson, A. C. Grey, J. Spraggins, Y. Koutalos, K. L. Schey, and R. K. Crouch, “The utilization of fluorescence to identify the components of lipofuscin by imaging mass spectrometry,” Proteomics 14(7-8), 936–944 (2014).
[Crossref] [PubMed]

Vision Res. (1)

J. R. Sparrow, N. Fishkin, J. Zhou, B. Cai, Y. P. Jang, S. Krane, Y. Itagaki, and K. Nakanishi, “A2E, a byproduct of the visual cycle,” Vision Res. 43(28), 2983–2990 (2003).
[Crossref] [PubMed]

Other (6)

N. Lee, J. Wielaard, A. A. Fawzi, P. Sajda, A. F. Laine, G. Martin, M. S. Humayun, and R. T. Smith, “In vivo snapshot hyperspectral image analysis of age-related macular degeneration,” in Engineering in Medicine and Biology Society (EMBC),2010Annual International Conference of the IEEE (IEEE, 2010), pp. 5363–5366.
[Crossref]

A. Cichocki, R. Zdunek, A. H. Phan, and S. Amari, Nonnegative Matrix and Tensor Factorizations: Applications to Exploratory Multi-Way Data Analysis and Blind Source Separation (John Wiley & Sons, 2009).

P. Sajda, S. Du, and L. C. Parra, “Recovery of constituent spectra using non-negative matrix factorization,” in Proceedings of SPIEVol. 5207, Wavelets: Applications in Signal and Image Processing X, M. A. Unser, A. Aldroubi, and A. F. Laine, eds. (SPIE, 2003), pp. 321–331.

C. A. Curcio and M. Johnson, “Structure, function, and pathology of Bruch's membrane,” in Retina Vol. 1, Fifth ed., S. J. Ryan, A. P. Schachat, C. P. Wilkinson, D. R. Hinton, S. Sadda, and P. Wiedemann, eds. (Elsevier, 2013).

A. Shashua and T. Hazan, “Non-negative tensor factorization with applications to statistics and computer vision,” in Proceedings of the 22nd International Conference on Machine Learning (ACM, 2005), pp. 792–799.
[Crossref]

V. P. Gabel, R. Birngruber, and F. Hillenkamp, “Visible and near infrared light absorption in pigment epithelium and choroid,” in Proceedings of the 23rd International Congress of Ophthalmology, K. Shimizu and J. A. Oosterhuis, eds. (Exerpta Medica, 1979), pp. 658–662.

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Figures (7)

Fig. 1
Fig. 1 Quantum efficiency (QE) of the Nuance camera spectral detector (arbitrary units) supplied by the manufacturer (Caliper Life Sciences). The QE is approximately linear from 400 to 700 nm, with some small shoulders, and then drops at 700 nm. Since both RPE and BrM have intrinsic autofluorescence properties, and RPE anatomically overlies BrM, the hyperspectral data cubes captured the sum of the RPE signal and a portion of that from the underlying BrM. Hence, to assist in identifying the pure RPE spectrum at each location, a pure BrM signal without overlying RPE cells was also recorded separately from areas where a few RPE cells were dislodged during preparation. For locations at which the RPE monolayer was completely intact, a pure BrM signal was separately imaged at an adjacent area.
Fig. 2
Fig. 2 The pure spectrum of the RPE. Left: RGB composite AF image from a 47-year-old female donor, excitation 480 nm, perifovea. Sample raw spectral data (photon counts) were acquired in regions marked. Green mark: BrM in isolation. Red marks: RPE cells containing lipofuscin overlying BrM. Right: Separated emission curves. Green: isolated BrM. Red: RPE overlying BrM, which includes 25% of the pure BrM signal. Magenta: pure RPE signal (after subtraction of 25% of the BrM signal).
Fig. 3
Fig. 3 Gaussian fits to a sample RPE spectrum. The pure RPE hyperspectral data from Fig. 2 (black line) were calibrated to the acquisition time of 18 ms and instrument gain of 3 to yield spectral intensity in units of photons/sec and then fit to the four Gaussian components of the mixture model. The arrows indicate two peaks and two slight shoulders in the original spectrum. The mixture model (sum of four Gaussians) is the solid magenta line and largely overlies the original RPE data (an overall excellent fit). Note that the centers of the Gaussians, especially Gaussian 3 (red), do not necessarily coincide with the original peaks in the RPE data. The dotted magenta lines are the 95% confidence prediction bounds of the model under the assumption of 5% random error in the original RPE spectrum.
Fig. 4
Fig. 4 RPE flatmount, 90-year-old female donor, perifovea. A, (B), spectra recovered from 436 nm excitation; (C), (D), spectra recovered from 480 nm excitation. (A), (C), decomposed spectra from individual excitation data sets; (B), (D), spectra from simultaneous solution of both excitation data sets. The tissue image is a full 40X field. The five individual spectra in each set are labeled C1 to C5. The corresponding abundance images are also labeled C1 to C5, with false coloring to indicate the relative signal intensities. The spectra in (A), (C) have multiple subsidiary peaks, suggesting contributions from multiple sources. Those from 480 nm excitation are particularly jagged, while two signals from 436 nm excitation are nearly degenerate (C4, C5). The spectra in (B), (D) are all broad, as expected from known fluorophore data, and can be paired by shape and location. In particular, there are no degenerate solutions in the simultaneous solutions. The recovered paired spectra are smoother than either spectrum recovered separately, with more congruent shapes. The lower right element of each panel is the composite RGB image from the total AF signal for that excitation. The constrained identical abundance images on the right for each pair of spectra show precise anatomic detail and are more clearly defined than the abundances recovered individually; hence they are more consistent with well-defined species of emitter. For example, C3 is more specifically localized to isolated BrM than its counterparts in the individual cases, at both excitation wavelengths. Signals from RPE cells (C1, C2, C4, and C5) can be distinguished from each other by the relative size of the signal-poor region (blue) in the center of each hexagonal RPE cell in the concatenated solutions, whereas such distinctions between the abundances in the individual solutions are slight. C1-436 and C2-480, similarly shaped, are linked, initialized with Gaussians at 600 nm; C3 is BrM in each; C4 and C5 are linked in each; C1-480 is linked to, and red-shifted from, C2-436.
Fig. 5
Fig. 5 Graded improvement in spectral recovery. Top: Moderate improvement in spectral recovery with concatenated NMF. Jagged C2 and C3 are replaced by smoother C3 and C4, both significantly improved. The other signals are not improved. NTF improvement is graded moderate. Bottom: No improvement. C5, almost degenerate, regains amplitude with NTF, but C4 changes from a single peak to two. Net improvement is graded none.
Fig. 6
Fig. 6 BrM total emission spectra; perifovea of a 78-year-old female donor; excitations at 436 and 480 nm. Each signal was fit with three approximately evenly spaced Gaussians (not shown) in a manner similar to that in Fig. 3.
Fig. 7
Fig. 7 Isolated BrM; perifovea of 78-year-old female donor. (A), (B), spectra recovered from 436 nm excitation; (C), (D), spectra recovered from 480 nm excitation. (A), (C), decomposed spectra from individual excitation data sets; (B), (D), spectra from NTF, simultaneous solution of all three concatenated excitation data sets. Three abundant signals are recovered with NMF decomposition of each individual excitation data set and with the concatenated solution. The corresponding abundance images are C1, C2, and C3 in each set. False coloring indicates the relative intensities of the signals. The lower right panel in each set is the composite RGB image from the total AF signal for that excitation.

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