Increasing the content of high-content screening: An overview

Journal of Biomolecular Screening

Volumn 19, Issue 5, 2014, Pages 640-650

  Singh, Shantanu ^a   Carpenter, Anne E ^a   Genovesio, Auguste ^a  

^a BROAD INSTITUTE OF MIT AND HARVARD   (United States)

Author keywords

Cell based assays; High content screening; Image analysis; Phenotypic drug discovery; Statistical analyses

Indexed keywords

CELL POPULATION; CELL SUBPOPULATION; CLASSIFICATION ALGORITHM; DATA ANALYSIS; DRUG ANALYSIS; HIGH CONTENT SCREENING; HIGH THROUGHPUT SCREENING; HYPOTHESIS; INFORMATION PROCESSING; MACHINE LEARNING; MOLECULAR INTERACTION; PHENOTYPE; PRIORITY JOURNAL; PUBLICATION; QUALITY CONTROL; REVIEW; SCREENING; SIGNAL NOISE RATIO; STRUCTURE ACTIVITY RELATION; SUPPORT VECTOR MACHINE; BIOASSAY; DRUG DEVELOPMENT; MEDICINAL CHEMISTRY; MULTIVARIATE ANALYSIS; NORMAL DISTRIBUTION; PROCEDURES;

BIOLOGICAL ASSAY; CHEMISTRY, PHARMACEUTICAL; DRUG DISCOVERY; HIGH-THROUGHPUT SCREENING ASSAYS; MULTIVARIATE ANALYSIS; NORMAL DISTRIBUTION; PHENOTYPE; SUPPORT VECTOR MACHINE;

EID: 84902210226     PISSN: 10870571     EISSN: 1552454X     Source Type: Journal    
DOI: 10.1177/1087057114528537     Document Type: Review

References (150)

1. Swinney, D. C.; Anthony, J. How Were New Medicines Discovered? Nat. Rev. Drug Discov. 2011, 10, 507-519
2. Perlman, Z. E.; Slack, M. D.; Feng, Y.; et al. Multidimensional Drug Profiling by Automated Microscopy. Science 2004, 306, 1194-1198
3. Loo, L.-H.; Wu, L. F.; Altschuler, S. J. Image-Based Multivariate Profiling of Drug Responses from Single Cells. Nat. Methods 2007, 4, 445-453 (Pubitemid 46901279)
4. Genovesio, A.; Kwon, Y.-J.; Windisch, M. P.; et al. Automated Genome-Wide Visual Profiling of Cellular Proteins Involved in HIV Infection. J. Biomol. Screen. 2011, 16, 945-958
5. Zhang, J.-H. A Simple Statistical Parameter for Use in Evaluation and Validation of High Throughput Screening Assays. J. Biomol. Screen. 1999, 4, 67-73
6. Kummel, A.; Gubler, H.; Gehin, P.; et al. Integration of Multiple Readouts into the Z′ Factor for Assay Quality Assessment. J. Biomol. Screen. 2010, 15, 95-101
7. Kozak, K.; Csucs, G. Kernelized Z′ Factor in Multiparametric Screening Technology. RNA Biol. 2010, 7, 615-620
8. Haney, S. A. Rapid Assessment and Visualization of Normality in High Content and Other Cell-Level Data and Its Impact on the Interpretation of Experimental Result. J. Biomol. Screen. 2014. In press
9. Wild, T.; Horvath, P.; Wyler, E.; et al. A Protein Inventory of Human Ribosome Biogenesis Reveals an Essential Function of Exportin 5 in 60S Subunit Export. PLoS Biol. 2010, 8, e1000522
10. Misselwitz, B.; Dilling, S.; Vonaesch, P.; et al. RNAi Screen of Salmonella Invasion Shows Role of COPI in Membrane Targeting of Cholesterol and Cdc42. Mol. Syst. Biol. 2011, 7, 474
11. Misselwitz, B.; Dehio, C.; Truttmann, M. C.; et al. Bartonella henselae Engages Inside-Out and Outside-In Signaling by Integrin 1 and Talin1 during Invasome-Mediated Bacterial Uptake. J. Cell Sci. 2011, 124, 3591-3602
12. Hardt, W.-D.; Chabria, M.; Misselwitz, B.; et al. Near Surface Swimming of Salmonella typhimurium Explains Target-Site Selection and Cooperative Invasion. PLoS Pathog. 2012, 8, e1002810
13. March, S.; Ng, S.; Velmurugan, S.; et al. Resource A Microscale Human Liver Platform that Supports the Hepatic Stages of Plasmodium falciparum and vivax. Cell Host Microbe 2013, 14, 104-115
14. Paul, P.; van den Hoorn, T.; Jongsma, M. L. M.; et al. A Genome-Wide Multidimensional RNAi Screen Reveals Pathways Controlling MHC Class II Antigen Presentation. Cell 2011, 145, 268-283
15. Stergiou, L.; Bauer, M.; Mair, W.; et al. Integrin-Mediated Signaling Induced by Simian Virus 40 Leads to Transient Uncoupling of Cortical Actin and the Plasma Membrane. PLoS One 2013, 8
16. Snijder, B.; Sacher, R.; Ramo, P.; et al. Single-Cell Analysis of Population Context Advances RNAi Screening at Multiple Levels. Mol. Syst. Biol. 2012, 8, 579
17. Jones, T. R.; Carpenter, A. E.; Lamprecht, M. R.; et al. Scoring Diverse Cellular Morphologies in Image-Based Screens with Iterative Feedback and Machine Learning. Proc. Natl. Acad. Sci. U. S. A. 2009, 106, 1826-1831
18. Ramo, P.; Sacher, R.; Snijder, B.; et al. CellClassifier: Supervised Learning of Cellular Phenotypes. Bioinformatics 2009, 25, 3028-3030
19. Misselwitz, B.; Strittmatter, G.; Periaswamy, B.; et al. Enhanced CellClassifier: A Multi-Class Classification Tool for Microscopy Images. BMC Bioinformatics 2010, 11, 30
20. Horvath, P.; Wild, T.; Kutay, U.; et al. Machine Learning Improves the Precision and Robustness of High-Content Screens: Using Nonlinear Multiparametric Methods to Analyze Screening Results. J. Biomol. Screen. 2011, 16, 1059-1067
21. Friedman, J.; Hastie, T.; Tibshirani, R. Additive Logistic Regression: A Statistical View of Boosting. Ann. Stat. 2000, 28, 337-407 (Pubitemid 33227445)
22. Hall, M.; Frank, E.; Holmes, G.; et al. The WEKA Data Mining Software: An Update. ACM SIGKDD Explor. Newsl. 2009, 11, 10-18
23. Held, M.; Schmitz, M. H.; Fischer, B.; et al. CellCognition: Time-Resolved Phenotype Annotation in High-Throughput Live Cell Imaging. Nat. Methods 2010, 7, 747-754
24. Adams, C. L.; Kutsyy, V.; Coleman, D.; et al. Compound Classification Using Image-Based Cellular Phenotypes. Methods Enzymol. 2006, 414, 440-468 (Pubitemid 44716236)
25. Gustafsdottir, S. M.; Ljosa, V.; Sokolnicki, K. L.; et al. Multiplex Cytological Profiling Assay to Measure Diverse Cellular States. PLoS One 2013, 8, e80999
26. Ljosa, V.; Caie, P. D.; Ter Horst, R.; et al. Comparison of Methods for Image-Based Profiling of Cellular Morphological Responses to Small-Molecule Treatment. J. Biomol. Screen. 2013, 18, 1321-1329
27. Snijder, B.; Pelkmans, L. Origins of Regulated Cell-to-Cell Variability. Nat Rev Mol Cell Biol. 2011, 12, 119-125
28. Altschuler, S. J.; Wu, L. F. Cellular Heterogeneity: Do Differences Make a Difference? Cell 2010, 141, 559-563
29. Slack, M. D.; Martinez, E. D.; Wu, L. F.; et al. Characterizing Heterogeneous Cellular Responses to Perturbations. Proc. Natl. Acad. Sci. U. S. A. 2008, 105, 19306-19311
30. Parsons, L.; Haque, E.; Liu, H. Subspace Clustering for High Dimensional Data: A Review. SIGKDD Explor. Newsl. 2004, 6, 90-105
31. Young, D. W.; Bender, A.; Hoyt, J.; et al. Integrating High- Content Screening and Ligand-Target Prediction to Identify Mechanism of Action. Nat. Chem. Biol. 2008, 4, 59-68 (Pubitemid 350273652)
32. Reisen, F.; Zhang, X.; Gabriel, D.; et al. Benchmarking of Multivariate Similarity Measures for High-Content Screening Fingerprints in Phenotypic Drug Discovery. J. Biomol. Screen. 2013, 18, 1284-1297
33. Wang, J.; Xie, X. Development of a Quantitative, Cell-Based, High-Content Screening Assay for Epidermal Growth Factor Receptor Modulators. Acta Pharmacol. Sin. 2007, 28, 1698- 1704 (Pubitemid 47493290)
34. Quintavalle, M.; Elia, L.; Price, J. H.; et al. A Cell-Based High-Content Screening Assay Reveals Activators and Inhibitors of Cancer Cell Invasion. Sci. Signal. 2011, 4, ra49
35. Kitami, T.; Spiegelman, B. M.; Logan, D. J.; et al. A Chemical Screen Probing the Relationship between Mitochondrial Content and Cell Size. PLoS One 2012, 7, e33755
36. Giddings, A. M.; Maitra, R. A disease-Relevant High-Content Screening Assay to Identify Anti-Inflammatory Compounds for Use in Cystic Fibrosis. J. Biomol. Screen. 2010, 15, 1204- 1210
37. Paul, P.; van den Hoorn, T.; Jongsma, M. L. M.; et al. A Genome-Wide Multidimensional RNAi Screen Reveals Pathways Controlling MHC Class II Antigen Presentation. Cell 2011, 145, 268-283
38. Dobbelaere, J.; Josue, F.; Suijkerbuijk, S.; et al. A Genome- Wide RNAi Screen to Dissect Centriole Duplication and Centrosome Maturation in Drosophila. PLoS Biol. 2008, 6, e224
39. Proszynski, T. J.; Klemm, R. W.; Gravert, M.; et al. A Genome-Wide Visual Screen Reveals a Role for Sphingolipids and Ergosterol in Cell Surface Delivery in Yeast. Proc. Natl. Acad. Sci. 2005, 102, 17981-17986
40. Boyd, J. D.; Glicksman, M.; El Khoury, J.; et al. A High Content Drug Screen Identifies Ursolic Acid as an Inhibitor of Amyloid Protein Interactions with Its Receptor CD36. J. Biol. Chem. 2011, 286, 34914-34922
41. Yip, K. W.; Cuddy, M.; Pinilla, C.; et al. A High-Content Screening (HCS) Assay for the Identification of Chemical Inducers of PML Oncogenic Domains (PODs). J. Biomol. Screen. 2011, 16, 251-258
42. Teusch, N.; Kiefer, C. A High-Content Screening Assay for the Nogo Receptor Based on Cellular Rho Activation. Assay Drug Dev. Technol. 2006, 4, 133-141 (Pubitemid 43810917)
43. Saydmohammed, M.; Vollmer, L. L.; Onuoha, E. O.; et al. A High-Content Screening Assay in Transgenic Zebrafish Identifies Two Novel Activators of fgf Signaling. Birth Defects Res. C. Embryo Today 2011, 93, 281-287
44. Moffat, J.; Grueneberg, D. A.; Yang, X.; et al. A Lentiviral RNAi Library for Human and Mouse Genes Applied to an Arrayed Viral High-Content Screen. Cell 2006, 124, 1283- 1298
45. Emery, A.; Sorrell, D. A.; Lawrence, S.; et al. A Novel Cell- Based, High-Content Assay for Phosphorylation of lats2 by Aurora A. J. Biomol. Screen. 2011, 16, 925-931
46. Wild, T.; Horvath, P.; Wyler, E.; et al. A Protein Inventory of Human Ribosome Biogenesis Reveals an Essential Function of Exportin 5 in 60S Subunit Export. PLoS Biol. 2010, 8, e1000522
47. Collins, C. S.; Hong, J.; Sapinoso, L.; et al. A Small Interfering RNA Screen for Modulators of Tumor Cell Motility Identifies MAP4K4 as a Promigratory Kinase. Proc. Natl. Acad. Sci. 2006, 103, 3775-3780
48. Carey, K. L.; Westwood, N. J.; Mitchison, T. J.; et al. A Small-Molecule Approach to Studying Invasive Mechanisms of Toxoplasma gondii. Proc. Natl. Acad. Sci. 2004, 101, 7433-7438
49. Wolff, M.; Kauschke, S. G.; Schmidt, S.; et al. Activation and Translocation of Glucokinase in Rat Primary Hepatocytes Monitored by High Content Image Analysis. J. Biomol. Screen. 2008, 13, 837-846
50. de Boer, J.; Post, G. F.; Hulsman, M.; et al. An Algorithm- Based Topographical Biomaterials Library to Instruct Cell Fate. Proc. Natl. Acad. Sci. 2011, 108, 16565-16570
51. Kriston-Vizi, J.; Lim, C. A.; Condron, P.; et al. An Automated High-Content Screening Image Analysis Pipeline for the Identification of Selective Autophagic Inducers in Human Cancer Cell Lines. J. Biomol. Screen. 2010, 15, 869-881
52. Kittler, R.; Putz, G.; Pelletier, L.; et al. An Endoribonuclease- Prepared siRNA Screen in Human Cells Identifies Genes Essential for Cell Division. Nature 2004, 432, 1036-1040 (Pubitemid 40052235)
53. Zanella, F.; Rosado, A.; Blanco, F.; et al. An HTS Approach to Screen for Antagonists of the Nuclear Export Machinery Using High Content Cell-Based Assays. Assay Drug Dev. Technol. 2007, 5, 333-341
54. Schultz, P. G.; Boitano, A. E.; Cooke, M. P.; et al. An Image- Based Screen Identifies a Small Molecule Regulator of Megakaryopoiesis. Proc. Natl. Acad. Sci. 2012, 109, 14019- 14023
55. Jurgeit, A.; Moese, S.; Roulin, P.; et al. An RNA Replication- Center Assay for High Content Image-Based Quantifications of Human Rhinovirus and Coxsackievirus Infections. Virol. J. 2010, 7, 264
56. Finco, O.; Frigimelica, E.; Buricchi, F.; et al. Approach to Discover T- and B-Cell Antigens of Intracellular Pathogens Applied to the Design of Chlamydia trachomatis Vaccines. Proc. Natl. Acad. Sci. 2011, 108, 9969-9974
57. Radio, N. M.; Breier, J. M.; Shafer, T. J.; et al. Assessment of Chemical Effects on Neurite Outgrowth in PC12 Cells Using High Content Screening. Toxicol. Sci. 2008, 105, 106-118
58. Hirota, T.; Kunitoku, N.; Sasayama, T.; et al. Aurora-A and an Interacting Activator, the LIM Protein Ajuba, Are Required for Mitotic Commitment in Human Cells. Cell 2003, 114, 585-598 (Pubitemid 37159255)
59. Wolff, M.; Haasen, D.; Merk, S.; et al. Automated High Content Screening for Phosphoinositide 3 Kinase Inhibition Using an AKT 1 Redistribution Assay. Comb. Chem. High Throughput Screen. 2006, 9, 339-350 (Pubitemid 43830727)
60. Norton, J. T.; Titus, S. A.; Dexter, D.; et al. Automated High- Content Screening for Compounds That Disassemble the Perinucleolar Compartment. J. Biomol. Screen. 2009, 14, 1045-1053
61. Saucerman, J. J.; Ryall, K. A. Automated Imaging Reveals a Concentration Dependent Delay in Reversibility of Cardiac Myocyte Hypertrophy. J. Mol. Cell. Cardiol. 2012, 53, 282- 290
62. Knowles, D. W.; Sudar, D.; Bator-Kelly, C.; et al. Automated Local Bright Feature Image Analysis of Nuclear Protein Distribution Identifies Changes in Tissue Phenotype. Proc. Natl. Acad. Sci. 2006, 103, 4445-4450
63. Chu, J. J. H.; Yang, P. L. c-Src Protein Kinase Inhibitors Block Assembly and Maturation of Dengue Virus. Proc. Natl. Acad. Sci. 2007, 104, 3520-3525 (Pubitemid 46364191)
64. Iniesta, A. A.; Hillson, N. J.; Shapiro, L. Cell Pole-Specific Activation of a Critical Bacterial Cell Cycle Kinase. Proc. Natl. Acad. Sci. 2010, 107, 7012-7017
65. Ghosh, R. N.; Chen, Y. T.; DeBiasio, R.; et al. Cell-Based, High- Content Screen for Receptor Internalization, Recycling and Intracellular Trafficking. Biotechniques 2000, 29, 170-175 (Pubitemid 30439431)
66. Prigozhina, N. L.; Heisel, A.; Wei, K.; et al. Characterization of a Novel Angiogenic Model Based on Stable, Fluorescently Labelled Endothelial Cell Lines Amenable to Scale-Up for High Content Screening. Biol. Cell 2011, 103, 467-481
67. Therizols, P.; Duong, T.; Dujon, B.; et al. Chromosome Arm Length and Nuclear Constraints Determine the Dynamic Relationship of Yeast Subtelomeres. Proc. Natl. Acad. Sci. 2010, 107, 2025-2030.
68. Kaltenbach, L. S.; Bolton, M. M.; Shah, B.; et al. Composite Primary Neuronal High-Content Screening Assay for Huntington's Disease Incorporating Non-Cell-Autonomous Interactions. J. Biomol. Screen. 2010, 15, 806-819
69. Piskunov, A.; Fischer, B.; Boeglin, M.; et al. Cullin 3 Mediates SRC-3 Ubiquitination and Degradation to Control the Retinoic Acid Response. Proc. Natl. Acad. Sci. 2011, 108, 20603-20608
70. Berke, J. M.; Fenistein, D.; Pauwels, F.; et al. Development of a High-Content Screening Assay to Identify Compounds Interfering with the Formation of the Hepatitis C Virus Replication Complex. J. Virol. Methods 2010, 165, 268-276
71. Kim, S.; Jun, D. H.; Kim, H. J.; et al. Development of a High- Content Screening Method for Chemicals Modulating DNA Damage Response. J. Biomol. Screen. 2011, 16, 259-265
72. Zunder, E. R.; Knight, Z. A.; Houseman, B. T.; et al. Discovery of Drug-Resistant and Drug-Sensitizing Mutations in the Oncogenic PI3K Isoform p110 Alpha. Cancer Cell 2008, 14, 180-192
73. Ricicova, M.; Hamidi, M.; Quiring, A.; et al. Dissecting Genealogy and Cell Cycle as Sources of Cell-to-Cell Variability in MAPK Signaling Using High-Throughput Lineage Tracking. Proc. Natl. Acad. Sci. 2013, 110, 11403- 11408
74. Rosales, N.; Rao, T. D.; Spriggs, D. R. Dual-Fluorescence Isogenic High-Content Screening for MUC16/CA125 Selective Agents. Mol. Cancer Ther. 2011, 10, 1939-1948
75. Taylor, R. J.; Falconnet, D.; Niemisto, A.; et al. Dynamic Analysis of MAPK Signaling Using a High-Throughput Microfluidic Single-Cell Imaging Platform. Proc. Natl. Acad. Sci. 2009, 106, 3758-3763
76. Feng, Y.; Yu, S.; Lasell, T. K. R.; et al. Exo1: A New Chemical Inhibitor of the Exocytic Pathway. Proc. Natl. Acad. Sci. 2003, 100, 6469-6474 (Pubitemid 36666605)
77. Guo, Y.; Walther, T. C.; Rao, M.; et al. Functional Genomic Screen Reveals Genes Involved in Lipid-Droplet Formation and Utilization. Nature 2008, 453, 657-661 (Pubitemid 351769298)
78. Eulalio, A.; Mano, M.; Dal Ferro, M.; et al. Functional Screening Identifies miRNAs Inducing Cardiac Regeneration. Nature 2012, 492, 376-381
79. Ko, E. C.; Rosenstein, B. S.; Kao, J.; et al. γ-H2AX Kinetics as a Novel Approach to High Content Screening for Small Molecule Radiosensitizers. PLoS One 2012, 7, e38465
80. Lindquist, R. A.; Ottina, K. A.; Wheeler, D. B.; et al. Genome-Scale RNAi on Living-Cell Microarrays Identifies Novel Regulators of Drosophila melanogaster TORC1-S6K Pathway Signaling. Genome Res. 2011, 21, 433-446
81. Pelkmans, L.; Fava, E.; Grabner, H.; et al. Genome-Wide Analysis of Human Kinases in Clathrin- and Caveolae/Raft- Mediated Endocytosis. Nature 2005, 436, 78-86 (Pubitemid 40966188)
82. O'Brien, P. J.; Irwin, W.; Diaz, D.; et al. High Concordance of Drug-Induced Human Hepatotoxicity with in Vitro Cytotoxicity Measured in a Novel Cell-Based Model Using High Content Screening. Arch. Toxicol. 2006, 80, 580-604 (Pubitemid 44214526)
83. Florean, C.; Zampese, E.; Zanese, M.; et al. High Content Analysis of Gamma-Secretase Activity Reveals Variable Dominance of Presenilin Mutations Linked to Familial Alzheimer's Disease. Biochim. Biophys. Acta 2008, 1783, 1551-1560
84. Havinga, J.; Horbach, G. J. M. J.; Schoonen, W. G. E. J.; et al. High Content Screening Analysis of Phospholipidosis: Validation of a 96-Well Assay with CHO-K1 and HepG2 Cells for the Prediction of in Vivo Based Phospholipidosis. Toxicol. Vitr. 2011, 25, 1870-1882
85. Granas, C.; Lundholt, B. K.; Heydorn, A.; et al. High Content Screening for G Protein-Coupled Receptors Using Cell-Based Protein Translocation Assays. Comb. Chem. High Throughput Screen. 2005, 8, 301-309 (Pubitemid 40694866)
86. Leuchowius, K.-J.; Jarvius, M.; Wickstrom, M.; et al. High Content Screening for Inhibitors of Protein Interactions and Post-Translational Modifications in Primary Cells by Proximity Ligation. Mol. Cell. Proteomics 2010, 9, 178-183
87. Christophe, T.; Jackson, M.; Jeon, H. K.; et al. High Content Screening Identifies Decaprenyl-Phosphoribose 2' Epimerase as a Target for Intracellular Antimycobacterial Inhibitors. PLoS Pathog. 2009, 5, e1000645
88. Blackmore, M. G.; Moore, D. L.; Smith, R. P.; et al. High Content Screening of Cortical Neurons Identifies Novel Regulators of Axon Growth. Mol. Cell. Neurosci. 2010, 44, 43-54
89. Schulte, J.; Sepp, K. J.; Wu, C.; et al. High-Content Chemical and RNAi Screens for Suppressors of Neurotoxicity in a Huntington's Disease Model. PLoS One 2011, 6, e23841
90. Au, Q.; Kanchanastit, P.; Barber, J. R.; et al. High-Content Image- Based Screening for Small-Molecule Chaperone Amplifiers in Heat Shock. J. Biomol. Screen. 2008, 13, 953-959
91. Ross, S.; Chen, T.; Yu, V.; et al. High-Content Screening Analysis of the p38 Pathway: Profiling of Structurally Related p38alpha Kinase Inhibitors Using Cell-Based Assays. Assay Drug Dev. Technol. 2006, 4, 397-409 (Pubitemid 44781631)
92. Borchert, K. M.; Galvin, R. J. S.; Frolik, C. A.; et al. High- Content Screening Assay for Activators of the Wnt/Fzd Pathway in Primary Human Cells. Assay Drug Dev. Technol. 2005, 3, 133-141 (Pubitemid 40846883)
93. Nadanaciva, S.; Dillman, K.; Gebhard, D. F.; et al. High- Content Screening for Compounds That Affect mtDNAEncoded Protein Levels in Eukaryotic Cells. J. Biomol. Screen. 2010, 15, 937-948
94. Starkuviene, V.; Liebel, U.; Simpson, J. C.; et al. High- Content Screening Microscopy Identifies Novel Proteins with a Putative Role in Secretory Membrane Traffic. Genome Res. 2004, 14, 1948-1956 (Pubitemid 39386509)
95. Andrews, P. D.; Becroft, M.; Aspegren, A.; et al. High- Content Screening of Feeder-Free Human Embryonic Stem Cells to Identify Pro-Survival Small Molecules. Biochem. J. 2010, 432, 21-33
96. Teunissen, E. A.; Mastrobattista, E.; de Raad, M.; et al. High-Content Screening of Peptide-Based Non-Viral Gene Delivery Systems. J. Control. Release 2012, 158, 433-442
97. Ibig-Rehm, Y.; Gotte, M.; Gabriel, D.; et al. High-Content Screening to Distinguish between Attachment and Post- Attachment Steps of Human Cytomegalovirus Entry into Fibroblasts and Epithelial Cells. Antiviral Res. 2011, 89, 246- 256
98. Giuliano, K. A.; Chen, Y.-T.; Taylor, D. L. High-Content Screening with siRNA Optimizes a Cell Biological Approach to Drug Discovery: Defining the Role of P53 Activation in the Cellular Response to Anticancer Drugs. J. Biomol. Screen. 2004, 9, 557-568.
99. Christen, B.; Fero, M. J.; Hillson, N. J.; et al. High- Throughput Identification of Protein Localization Dependency Networks. Proc. Natl. Acad. Sci. 2010, 107, 4681-4686
100. Rae, J.; Fontaine, F.; Salim, A. A.; et al. High-Throughput Screening of Australian Marine Organism Extracts for Bioactive Molecules Affecting the Cellular Storage of Neutral Lipids. PLoS One 2011, 6, e22868
101. Wong, S. T. C.; Xia, X.; Lipinski, M. M.; et al. Identification of Small Molecule Inhibitors of Neurite Loss Induced by A peptide using High Content Screening. J. Biol. Chem. 2012, 287, 8714-8723
102. Wilson, C. J.; Si, Y.; Thompsons, C. M.; et al. Identification of a Small Molecule That Induces Mitotic Arrest Using a Simplified High-Content Screening Assay and Data Analysis Method. J. Biomol. Screen. 2006, 11, 21-28 (Pubitemid 43255778)
103. Peltan, A.; Briggs, L.; Matthews, G.; et al. Identification of Drosophila Gene Products Required for Phagocytosis of Leishmania donovani. PLoS One 2012, 7, e51831
104. Bonilla-Santiago, R.; Wu, Z.; Zhang, L.; et al. Identification of Growth Inhibiting Compounds in a Giardia lamblia High-Throughput Screen. Mol. Biochem. Parasitol. 2008, 162, 149-154
105. Au, Q.; Zhang, Y.; Barber, J. R.; et al. Identification of Inhibitors of HSF1 Functional Activity by High-Content Target-Based Screening. J. Biomol. Screen. 2009, 14, 1165- 1175
106. Whittaker, R.; Loy, P. A.; Sisman, E.; et al. Identification of MicroRNAs That Control Lipid Droplet Formation and Growth in Hepatocytes via High-Content Screening. J. Biomol. Screen. 2010, 15, 798-805
107. Tolliday, N. J.; VerPlank, L.; Schenone, M.; et al. Identification of Regulators of Polyploidization Presents Therapeutic Targets for Treatment of AMKL. Cell 2012, 150, 575-589
108. Zhang, B.; Au, Q.; Yoon, I. S.; et al. Identification of Small- Molecule HSF1 Amplifiers by High Content Screening in Protection of Cells from Stress Induced Injury. Biochem. Biophys. Res. Commun. 2009, 390, 925-930
109. Bellomo, E. A.; Li, W.-H.; Chen, S.; et al. Imaging dynamic Insulin Release Using a Fluorescent Zinc Indicator for Monitoring Induced Exocytotic Release (ZIMIR). Proc. Natl. Acad. Sci. 2011, 108, 21063-21068
110. Vasudevan, C.; Fursov, N.; Maunder, P.; et al. Improving High-Content-Screening Assay Performance by Using Division-Arrested Cells. Assay Drug Dev. Technol. 2005, 3, 515-523 (Pubitemid 41824369)
111. Arrasate, M.; Mitra, S.; Schweitzer, E. S.; et al. Inclusion Body Formation Reduces Levels of Mutant Huntingtin and the Risk of Neuronal Death. Nature 2004, 431, 805-810 (Pubitemid 39434070)
112. Bertelsen, M.; Sanfridson, A. Inflammatory Pathway Analysis Using a High Content Screening Platform. Assay Drug Dev. Technol. 2005, 3, 261-271 (Pubitemid 41079124)
113. Nadler-Holly, M.; Breker, M.; Gruber, R.; et al. Interactions of Subunit CCT3 in the Yeast Chaperonin CCT/TRiC with Q/N-Rich Proteins Revealed by High-Throughput Microscopy Analysis. Proc. Natl. Acad. Sci. U. S. A. 2012, 109, 18833-18838
114. Kuijl, C.; Savage, N. D. L.; Marsman, M.; et al. Intracellular Bacterial Growth Is Controlled by a Kinase Network around PKB/AKT1. Nature 2007, 450, 725-730 (Pubitemid 350207691)
115. Ainscow, E. K.; Pilling, J. E.; Brown, N. M.; et al. Investigations into the Liver Effects of Ximelagatran Using High Content Screening of Primary Human Hepatocyte Cultures. Expert Opin. Drug Saf. 2008, 7, 351-365
116. Westphal, A. J.; Price, P. B.; Leighton, T. J.; et al. Kinetics of Size Changes of Individual Bacillus thuringiensis Spores in Response to Changes in Relative Humidity. Proc. Natl. Acad. Sci. 2003, 100, 3461-3466 (Pubitemid 36356606)
117. Antczak, C.; Takagi, T.; Ramirez, C. N.; et al. Live-Cell Imaging of Caspase Activation for High-Content Screening. J. Biomol. Screen. 2009, 14, 956-969
118. Hersen, P.; Batt, G.; Fages, F.; et al. Long-Term Model Predictive Control of Gene Expression at the Population and Single-Cell Levels. Proc. Natl. Acad. Sci. 2012, 109, 14271-14276
119. Danielsson, F.; Skogs, M.; Huss, M.; et al. Majority of Differentially Expressed Genes Are Down-Regulated during Malignant Transformation in a Four-Stage Model. Proc. Natl. Acad. Sci. 2013, 110, 6853-6858
120. DeBolt, S.; Gutierrez, R.; Ehrhardt, D. W.; et al. Morlin, an Inhibitor of Cortical Microtubule Dynamics and Cellulose Synthase Movement. Proc. Natl. Acad. Sci. 2007, 104, 5854-5859 (Pubitemid 47175623)
121. Ross, D. A.; Lee, S.; Reiser, V.; et al. Multiplexed Assays by High-Content Imaging for Assessment of GPCR Activity. J. Biomol. Screen. 2008, 13, 449-455 (Pubitemid 351905074)
122. Carter, C. A. Multiplexed High Content Screening Reveals That Cigarette Smoke Condensate-Altered Cell Signaling Pathways Are Accentuated through FAK Inhibition in Human Bronchial Cells. Int. J. Toxicol. 2012, 31, 257-266
123. Carter, C. A.; Hamm, J. T. Multiplexed Quantitative High Content Screening Reveals That Cigarette Smoke Condensate Induces Changes in Cell Structure and Function through Alterations in Cell Signaling Pathways in Human Bronchial Cells. Toxicology 2009, 261, 89-102
124. Hardt, W.-D.; Chabria, M.; Misselwitz, B.; et al. Near Surface Swimming of Salmonella typhimurium Explains Target-Site Selection and Cooperative Invasion. PLoS Pathog. 2012, 8, e1002810
125. Moese, S.; McDowell, R.; Schwendener, R.; et al. Niclosamide Is a Proton Carrier and Targets Acidic Endosomes with Broad Antiviral Effects. PLoS Pathog. 2012, 8, e1002976
126. Haasen, D.; Merk, S.; Seither, P.; et al. Pharmacological Profiling of Chemokine Receptor-Directed Compounds Using High-Content Screening. J. Biomol. Screen. 2008, 13, 40-53
127. Yuen, D.; Reisen, F.; Chen, L.; et al. PNAS Plus: Phenotype- Based High-Content Chemical Library Screening Identifies Statins as Inhibitors of in Vivo Lymphangiogenesis. Proc. Natl. Acad. Sci. 2012, 109, E2665-E2674
128. Neumann, B.; Walter, T.; Heriche, J.-K.; et al. Phenotypic Profiling of the Human Genome by Time-Lapse Microscopy Reveals Cell Division Genes. Nature 2010, 464, 721-727
129. Prigozhina, N. L.; Zhong, L.; Hunter, E. A.; et al. Plasma Membrane Assays and Three-Compartment Image Cytometry for High Content Screening. Assay Drug Dev. Technol. 2007, 5, 29-48 (Pubitemid 46581239)
130. Hughes, H. V.; Huitema, E.; Pritchard, S.; et al. Protein Localization and Dynamics within a Bacterial Organelle. Proc. Natl. Acad. Sci. 2010, 107, 5599-5604
131. Ghosh, R. N.; DeBiasio, R.; Hudson, C. C.; et al. Quantitative Cell-Based High-Content Screening for Vasopressin Receptor Agonists Using Transfluor Technology. J. Biomol. Screen. 2005, 10, 476-484 (Pubitemid 41233226)
132. Han, E.; Tak, Y. K.; Song, J. M.; et al. Real-Time Concurrent Monitoring of Apoptosis, Cytosolic Calcium, and Mitochondria Permeability Transition for Hypermulticolor High-Content Screening of Drug-Induced Mitochondrial Dysfunction-Mediated Hepatotoxicity. Toxicol. Lett. 2012, 214, 175-181
133. Schembri, L.; Zanese, M.; Depierre-Plinet, G.; et al. Recombinant differential Anchorage Probes That Tower over the Spatial Dimension of Intracellular Signals for High Content Screening and Analysis. Anal. Chem. 2009, 81, 9590-9598
134. Xu, Y.; Zhu, X.; Hahm, H. S.; et al. Revealing a Core Signaling Regulatory Mechanism for Pluripotent Stem Cell Survival and Self-Renewal by Small Molecules. Proc. Natl. Acad. Sci. 2010, 107, 8129-8134
135. Wu, C.-C.; Chawla, F.; Games, D.; et al. Selective Vulnerability of Dentate Granule Cells Prior to Amyloid Deposition in PDAPP Mice: Digital Morphometric Analyses. Proc. Natl. Acad. Sci. 2004, 101, 7141-7146 (Pubitemid 38596456)
136. Snijder, B.; Sacher, R.; Ramo, P.; et al. Single-Cell Analysis of Population Context Advances RNAi Screening at Multiple Levels. Mol. Syst. Biol. 2012, 8, 579
137. Tay, S.; Hughey, J. J.; Lee, T. K.; et al. Single-Cell NF-kappaB Dynamics Reveal Digital Activation and Analogue Information Processing. Nature 2010, 466, 267- 271
138. Reiter, J. F.; Arkin, M. R.; Wu, V. M.; et al. Small Molecule Inhibitors of Smoothened Ciliary Localization and Ciliogenesis. Proc. Natl. Acad. Sci. 2012, 109, 13644- 13649
139. Zhang, L.; Yu, J.; Pan, H.; et al. Small Molecule Regulators of Autophagy Identified by an Image-Based High-Throughput Screen. Proc. Natl. Acad. Sci. 2007, 104, 19023-19028
140. Xie, C.; Zhang, H.; Shimkets, L. J.; et al. Statistical Image Analysis Reveals Features Affecting Fates of Myxococcus xanthus Developmental Aggregates. Proc. Natl. Acad. Sci. 2011, 108, 5915-5920
141. Collinet, C.; Stoter, M.; Bradshaw, C. R.; et al. Systems Survey of Endocytosis by Multiparametric Image Analysis. Nature 2010, 464, 243-249
142. Guzi, T. J.; Paruch, K.; Dwyer, M. P.; et al. Targeting the Replication Checkpoint Using SCH 900776, a Potent and Functionally Selective CHK1 Inhibitor Identified via High Content Screening. Mol. Cancer Ther. 2011, 10, 591-602
143. Barabasz, A.; Foley, B.; Otto, J. C.; et al. The Use of High- Content Screening for the Discovery and Characterization of Compounds That Modulate Mitotic Index and Cell Cycle Progression by Differing Mechanisms of Action. Assay Drug Dev. Technol. 2006, 4, 153-163 (Pubitemid 43810919)
144. Lee, J.-Y.; Colinas, J.; Wang, J. Y.; et al. Transcriptional and Posttranscriptional Regulation of Transcription Factor Expression in Arabidopsis Roots. Proc. Natl. Acad. Sci. 2006, 103, 6055-6060
145. Devreotes, P. N.; Rohlfs, M.; Batsios, P.; et al. Tumor Suppressor Hippo/MST1 Kinase Mediates Chemotaxis by Regulating Spreading aAnd Adhesion. Proc. Natl. Acad. Sci. 2012, 109, 13632-13637
146. Ramirez, C. N.; Ozawa, T.; Takagi, T.; et al. Validation of a High-Content Screening Assay Using Whole-Well Imaging of Transformed Phenotypes. Assay Drug Dev. Technol. 2011, 9, 247-261
147. Kim, M. J.; Lim, C.; Lee, J. Y.; et al. Visible-to-Near IR Quantum Dot-Based Hypermulticolor High-Content Screening of Herbal Medicines for the Efficacy Monitoring of Hair Growth Promotion and Hair Loss Inhibition. J. Biomol. Screen. 2013, 18, 462-473
148. Benn, A. E.; Hopkins, A. L.; Bickle, Q. D.; et al. Whole Organism High-Content Screening by Label-Free, Image- Based Bayesian Classification for Parasitic Diseases. PLoS Negl. Trop. Dis. 2012, 6, e1762
149. Jee, J.; Jeon, H.; Hwang, D.; et al. High Content Screening for Compounds That Induce Early Stages of Human Embryonic Stem Cell Differentiation. Comb. Chem. High Throughput Screen. 2012, 15, 656-665
150. Sexton, J. Z.; He, Q.; Forsberg, L. J.; et al. High Content Screening for Non-Classical Peroxisome Proliferators. Int. J. High Throughput Screen. 2010, 2010, 127-140