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24.
Flaherty, P; Giaever, G; Kumm, J; Jordan, M I; Arkin, A P
A latent variable model for chemogenomic profiling Journal Article
In: Bioinformatics, vol. 21, no. 15, pp. 3286–3293, 2005.
@article{pmid15919724,
title = {A latent variable model for chemogenomic profiling},
author = {P Flaherty and G Giaever and J Kumm and M I Jordan and A P Arkin},
year = {2005},
date = {2005-00-01},
journal = {Bioinformatics},
volume = {21},
number = {15},
pages = {3286--3293},
abstract = {In haploinsufficiency profiling data, pleiotropic genes are often misclassified by clustering algorithms that impose the constraint that a gene or experiment belong to only one cluster. We have developed a general probabilistic model that clusters genes and experiments without requiring that a given gene or drug only appear in one cluster. The model also incorporates the functional annotation of known genes to guide the clustering procedure. We applied our model to the clustering of 79 chemogenomic experiments in yeast. Known pleiotropic genes PDR5 and MAL11 are more accurately represented by the model than by a clustering procedure that requires genes to belong to a single cluster. Drugs such as miconazole and fenpropimorph that have different targets but similar off-target genes are clustered more accurately by the model-based framework. We show that this model is useful for summarizing the relationship among treatments and genes affected by those treatments in a compendium of microarray profiles. Supplementary information and computer code at http://genomics.lbl.gov/llda.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
In haploinsufficiency profiling data, pleiotropic genes are often misclassified by clustering algorithms that impose the constraint that a gene or experiment belong to only one cluster. We have developed a general probabilistic model that clusters genes and experiments without requiring that a given gene or drug only appear in one cluster. The model also incorporates the functional annotation of known genes to guide the clustering procedure. We applied our model to the clustering of 79 chemogenomic experiments in yeast. Known pleiotropic genes PDR5 and MAL11 are more accurately represented by the model than by a clustering procedure that requires genes to belong to a single cluster. Drugs such as miconazole and fenpropimorph that have different targets but similar off-target genes are clustered more accurately by the model-based framework. We show that this model is useful for summarizing the relationship among treatments and genes affected by those treatments in a compendium of microarray profiles. Supplementary information and computer code at http://genomics.lbl.gov/llda.
23.
McAdams, H H; Srinivasan, B; Arkin, A P
Ŧhe evolution of genetic regulatory systems in bacteria Journal Article
In: Nat. Rev. Genet., vol. 5, no. 3, pp. 169–178, 2004.
BibTeX | Tags:
@article{pmid14970819,
title = {Ŧhe evolution of genetic regulatory systems in bacteria},
author = {H H McAdams and B Srinivasan and A P Arkin},
year = {2004},
date = {2004-03-01},
journal = {Nat. Rev. Genet.},
volume = {5},
number = {3},
pages = {169--178},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
22.
Rao, C V; Kirby, J R; Arkin, A P
Đesign and diversity in bacterial chemotaxis: a comparative study in Escherichia coli and Bacillus subtilis Journal Article
In: PLoS Biol., vol. 2, no. 2, pp. E49, 2004.
@article{pmid14966542,
title = {Đesign and diversity in bacterial chemotaxis: a comparative study in Escherichia coli and Bacillus subtilis},
author = {C V Rao and J R Kirby and A P Arkin},
year = {2004},
date = {2004-02-01},
journal = {PLoS Biol.},
volume = {2},
number = {2},
pages = {E49},
abstract = {Comparable processes in different species often involve homologous genes. One question is whether the network structure, in particular the feedback control structure, is also conserved. The bacterial chemotaxis pathways in E. coli and B. subtilis both regulate the same task, namely, excitation and adaptation to environmental signals. Both pathways employ many orthologous genes. Yet how these orthologs contribute to network function in each organism is different. To investigate this problem, we propose what is to our knowledge the first computational model for B. subtilis chemotaxis and compare it to previously published models for chemotaxis in E. coli. The models reveal that the core control strategy for signal processing is the same in both organisms, though in B. subtilis there are two additional feedback loops that provide an additional layer of regulation and robustness. Furthermore, the network structures are different despite the similarity of the proteins in each organism. These results demonstrate the limitations of pathway inferences based solely on homology and suggest that the control strategy is an evolutionarily conserved property.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Comparable processes in different species often involve homologous genes. One question is whether the network structure, in particular the feedback control structure, is also conserved. The bacterial chemotaxis pathways in E. coli and B. subtilis both regulate the same task, namely, excitation and adaptation to environmental signals. Both pathways employ many orthologous genes. Yet how these orthologs contribute to network function in each organism is different. To investigate this problem, we propose what is to our knowledge the first computational model for B. subtilis chemotaxis and compare it to previously published models for chemotaxis in E. coli. The models reveal that the core control strategy for signal processing is the same in both organisms, though in B. subtilis there are two additional feedback loops that provide an additional layer of regulation and robustness. Furthermore, the network structures are different despite the similarity of the proteins in each organism. These results demonstrate the limitations of pathway inferences based solely on homology and suggest that the control strategy is an evolutionarily conserved property.
21.
Giaever, G; Flaherty, P; Kumm, J; Proctor, M; Nislow, C; Jaramillo, D F; Chu, A M; Jordan, M I; Arkin, A P; Davis, R W
Chemogenomic profiling: identifying the functional interactions of small molecules in yeast Journal Article
In: Proc. Natl. Acad. Sci. U.S.A., vol. 101, no. 3, pp. 793–798, 2004.
@article{pmid14718668,
title = {Chemogenomic profiling: identifying the functional interactions of small molecules in yeast},
author = {G Giaever and P Flaherty and J Kumm and M Proctor and C Nislow and D F Jaramillo and A M Chu and M I Jordan and A P Arkin and R W Davis},
year = {2004},
date = {2004-01-01},
journal = {Proc. Natl. Acad. Sci. U.S.A.},
volume = {101},
number = {3},
pages = {793--798},
abstract = {We demonstrate the efficacy of a genome-wide protocol in yeast that allows the identification of those gene products that functionally interact with small molecules and result in the inhibition of cellular proliferation. Here we present results from screening 10 diverse compounds in 80 genome-wide experiments against the complete collection of heterozygous yeast deletion strains. These compounds include anticancer and antifungal agents, statins, alverine citrate, and dyclonine. In several cases, we identified previously known interactions; furthermore, in each case, our analysis revealed novel cellular interactions, even when the relationship between a compound and its cellular target had been well established. In addition, we identified a chemical core structure shared among three therapeutically distinct compounds that inhibit the ERG24 heterozygous deletion strain, demonstrating that cells may respond similarly to compounds of related structure. The ability to identify on-and-off target effects in vivo is fundamental to understanding the cellular response to small-molecule perturbants.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
We demonstrate the efficacy of a genome-wide protocol in yeast that allows the identification of those gene products that functionally interact with small molecules and result in the inhibition of cellular proliferation. Here we present results from screening 10 diverse compounds in 80 genome-wide experiments against the complete collection of heterozygous yeast deletion strains. These compounds include anticancer and antifungal agents, statins, alverine citrate, and dyclonine. In several cases, we identified previously known interactions; furthermore, in each case, our analysis revealed novel cellular interactions, even when the relationship between a compound and its cellular target had been well established. In addition, we identified a chemical core structure shared among three therapeutically distinct compounds that inhibit the ERG24 heterozygous deletion strain, demonstrating that cells may respond similarly to compounds of related structure. The ability to identify on-and-off target effects in vivo is fundamental to understanding the cellular response to small-molecule perturbants.
20.
Rao, C V; Frenklach, M; Arkin, A P
An allosteric model for transmembrane signaling in bacterial chemotaxis Journal Article
In: J. Mol. Biol., vol. 343, no. 2, pp. 291–303, 2004.
@article{pmid15451661,
title = {An allosteric model for transmembrane signaling in bacterial chemotaxis},
author = {C V Rao and M Frenklach and A P Arkin},
year = {2004},
date = {2004-00-01},
journal = {J. Mol. Biol.},
volume = {343},
number = {2},
pages = {291--303},
abstract = {Bacteria are able to sense chemical gradients over a wide range of concentrations. However, calculations based on the known number of receptors do not predict such a range unless receptors interact with one another in a cooperative manner. A number of recent experiments support the notion that this remarkable sensitivity in chemotaxis is mediated by localized interactions or crosstalk between neighboring receptors. A number of simple, elegant models have proposed mechanisms for signal integration within receptor clusters. What is a lacking is a model, based on known molecular mechanisms and our accumulated knowledge of chemotaxis, that integrates data from multiple, heterogeneous sources. To address this question, we propose an allosteric mechanism for transmembrane signaling in bacterial chemotaxis based on the "trimer of dimers" model, where three receptor dimers form a stable complex with CheW and CheA. The mechanism is used to integrate a diverse set of experimental data in a consistent framework. The main predictions are: (1) trimers of receptor dimers form the building blocks for the signaling complexes; (2) receptor methylation increases the stability of the active state and retards the inhibition arising from ligand-bound receptors within the signaling complex; (3) trimer of dimer receptor complexes aggregate into clusters through their mutual interactions with CheA and CheW; (4) cooperativity arises from neighboring interaction within these clusters; and (5) cluster size is determined by the concentration of receptors, CheA, and CheW. The model is able to explain a number of seemingly contradictory experiments in a consistent manner and, in the process, explain how bacteria are able to sense chemical gradients over a wide range of concentrations by demonstrating how signals are integrated within the signaling complex.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Bacteria are able to sense chemical gradients over a wide range of concentrations. However, calculations based on the known number of receptors do not predict such a range unless receptors interact with one another in a cooperative manner. A number of recent experiments support the notion that this remarkable sensitivity in chemotaxis is mediated by localized interactions or crosstalk between neighboring receptors. A number of simple, elegant models have proposed mechanisms for signal integration within receptor clusters. What is a lacking is a model, based on known molecular mechanisms and our accumulated knowledge of chemotaxis, that integrates data from multiple, heterogeneous sources. To address this question, we propose an allosteric mechanism for transmembrane signaling in bacterial chemotaxis based on the "trimer of dimers" model, where three receptor dimers form a stable complex with CheW and CheA. The mechanism is used to integrate a diverse set of experimental data in a consistent framework. The main predictions are: (1) trimers of receptor dimers form the building blocks for the signaling complexes; (2) receptor methylation increases the stability of the active state and retards the inhibition arising from ligand-bound receptors within the signaling complex; (3) trimer of dimer receptor complexes aggregate into clusters through their mutual interactions with CheA and CheW; (4) cooperativity arises from neighboring interaction within these clusters; and (5) cluster size is determined by the concentration of receptors, CheA, and CheW. The model is able to explain a number of seemingly contradictory experiments in a consistent manner and, in the process, explain how bacteria are able to sense chemical gradients over a wide range of concentrations by demonstrating how signals are integrated within the signaling complex.
19.
Weinberger, L S; Schaffer, D V; Arkin, A P
Ŧheoretical design of a gene therapy to prevent AIĐS but not human immunodeficiency virus type 1 infection Journal Article
In: J. Virol., vol. 77, no. 18, pp. 10028–10036, 2003.
@article{pmid12941913,
title = {Ŧheoretical design of a gene therapy to prevent AIĐS but not human immunodeficiency virus type 1 infection},
author = {L S Weinberger and D V Schaffer and A P Arkin},
year = {2003},
date = {2003-09-01},
journal = {J. Virol.},
volume = {77},
number = {18},
pages = {10028--10036},
abstract = {Recent reports confirm that, due to the presence of long-lived, latently infected cell populations, eradication of human immunodeficiency virus type 1 (HIV-1) from infected patients by using antiretroviral drugs will be exceedingly difficult. An alternative to virus eradication may be to use gene therapy to induce a pseudo-latent state in virus-producing cells, thus transforming HIV-1 into a lifelong, but manageable, virus. Conditionally replicating HIV-1 (crHIV-1) gene therapy vectors provide an avenue for subduing HIV-1 expression in infected cells (by creating a parasite, crHIV-1, of the parasite HIV-1), potentially reducing the HIV-1 set point and delaying AIDS onset. Development of crHIV-1 vectors has proceeded in vitro, but the requirements for a crHIV-1 vector to proliferate and persist in vivo have not been explored. We expand a widely accepted mathematical model of HIV-1 in vivo dynamics to include a crHIV-1 gene therapy virus and derive a simple criterion for designing crHIV-1 viruses that will persist in vivo. The model introduces only two new parameters-HIV-1 inhibition and crHIV-1 production-and both can be experimentally engineered and controlled. Analysis demonstrates that crHIV-1 gene therapy can indefinitely reduce HIV-1 set point to levels comparable to those achieved with highly active antiretroviral therapy, provided crHIV-1 production is more efficient than HIV-1. Paradoxically, highly efficient therapeutic inhibition of HIV-1 was found to be disadvantageous. Thus, the field may benefit by shifting the search for more potent antiviral genes toward engineering optimized therapy viruses that package ultra-efficiently while downregulating viral production moderately.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Recent reports confirm that, due to the presence of long-lived, latently infected cell populations, eradication of human immunodeficiency virus type 1 (HIV-1) from infected patients by using antiretroviral drugs will be exceedingly difficult. An alternative to virus eradication may be to use gene therapy to induce a pseudo-latent state in virus-producing cells, thus transforming HIV-1 into a lifelong, but manageable, virus. Conditionally replicating HIV-1 (crHIV-1) gene therapy vectors provide an avenue for subduing HIV-1 expression in infected cells (by creating a parasite, crHIV-1, of the parasite HIV-1), potentially reducing the HIV-1 set point and delaying AIDS onset. Development of crHIV-1 vectors has proceeded in vitro, but the requirements for a crHIV-1 vector to proliferate and persist in vivo have not been explored. We expand a widely accepted mathematical model of HIV-1 in vivo dynamics to include a crHIV-1 gene therapy virus and derive a simple criterion for designing crHIV-1 viruses that will persist in vivo. The model introduces only two new parameters-HIV-1 inhibition and crHIV-1 production-and both can be experimentally engineered and controlled. Analysis demonstrates that crHIV-1 gene therapy can indefinitely reduce HIV-1 set point to levels comparable to those achieved with highly active antiretroviral therapy, provided crHIV-1 production is more efficient than HIV-1. Paradoxically, highly efficient therapeutic inhibition of HIV-1 was found to be disadvantageous. Thus, the field may benefit by shifting the search for more potent antiviral genes toward engineering optimized therapy viruses that package ultra-efficiently while downregulating viral production moderately.
18.
Hucka, M; Finney, A; Sauro, H M; Bolouri, H; Doyle, J C; Kitano, H; Arkin, A P; Bornstein, B J; Bray, D; Cornish-Bowden, A; Cuellar, A A; Dronov, S; Gilles, E D; Ginkel, M; Gor, V; Goryanin, I I; Hedley, W J; Hodgman, T C; Hofmeyr, J H; Hunter, P J; Juty, N S; Kasberger, J L; Kremling, A; Kummer, U; Nov?re, N Le; Loew, L M; Lucio, D; Mendes, P; Minch, E; Mjolsness, E D; Nakayama, Y; Nelson, M R; Nielsen, P F; Sakurada, T; Schaff, J C; Shapiro, B E; Shimizu, T S; Spence, H D; Stelling, J; Takahashi, K; Tomita, M; Wagner, J; Wang, J
Ŧhe systems biology markup language (SBML): a medium for representation and exchange of biochemical network models Journal Article
In: Bioinformatics, vol. 19, no. 4, pp. 524–531, 2003.
@article{pmid12611808,
title = {Ŧhe systems biology markup language (SBML): a medium for representation and exchange of biochemical network models},
author = {M Hucka and A Finney and H M Sauro and H Bolouri and J C Doyle and H Kitano and A P Arkin and B J Bornstein and D Bray and A Cornish-Bowden and A A Cuellar and S Dronov and E D Gilles and M Ginkel and V Gor and I I Goryanin and W J Hedley and T C Hodgman and J H Hofmeyr and P J Hunter and N S Juty and J L Kasberger and A Kremling and U Kummer and N Le Nov?re and L M Loew and D Lucio and P Mendes and E Minch and E D Mjolsness and Y Nakayama and M R Nelson and P F Nielsen and T Sakurada and J C Schaff and B E Shapiro and T S Shimizu and H D Spence and J Stelling and K Takahashi and M Tomita and J Wagner and J Wang},
year = {2003},
date = {2003-03-01},
journal = {Bioinformatics},
volume = {19},
number = {4},
pages = {524--531},
abstract = {Molecular biotechnology now makes it possible to build elaborate systems models, but the systems biology community needs information standards if models are to be shared, evaluated and developed cooperatively. We summarize the Systems Biology Markup Language (SBML) Level 1, a free, open, XML-based format for representing biochemical reaction networks. SBML is a software-independent language for describing models common to research in many areas of computational biology, including cell signaling pathways, metabolic pathways, gene regulation, and others. The specification of SBML Level 1 is freely available from http://www.sbml.org/},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Molecular biotechnology now makes it possible to build elaborate systems models, but the systems biology community needs information standards if models are to be shared, evaluated and developed cooperatively. We summarize the Systems Biology Markup Language (SBML) Level 1, a free, open, XML-based format for representing biochemical reaction networks. SBML is a software-independent language for describing models common to research in many areas of computational biology, including cell signaling pathways, metabolic pathways, gene regulation, and others. The specification of SBML Level 1 is freely available from http://www.sbml.org/
17.
Biological networks Journal Article
In: Curr. Opin. Struct. Biol., vol. 13, no. 2, pp. 193–202, 2003.
@article{pmid12727512,
title = {Biological networks},
year = {2003},
date = {2003-00-01},
journal = {Curr. Opin. Struct. Biol.},
volume = {13},
number = {2},
pages = {193--202},
abstract = {Recent advances in high-throughput methods have provided us with a first glimpse of the overall structure of molecular interaction networks in biological systems. Ultimately, we expect that such information will change how we think about biological systems in a fundamental way. Instead of viewing the genetic parts list of an organism as a loose collection of biochemical activities, in the best case, we anticipate discrete networks of function to bridge the gap between genotype and phenotype, and to do so in a more profound way than the current qualitative classification of linked reactions into familiar pathways, such as glycolysis and the MAPK signal transduction cascades. At the present time, however, we are still far from a complete answer to the most basic question: what can we learn about biology by studying networks? Promising steps in this direction have come from such diverse approaches as mathematical analysis of global network structure, partitioning networks into functionally related modules and motifs, and even de novo design of networks. A complete picture will probably require integrating the data obtained from all of these approaches with modeling efforts at many different levels of detail.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Recent advances in high-throughput methods have provided us with a first glimpse of the overall structure of molecular interaction networks in biological systems. Ultimately, we expect that such information will change how we think about biological systems in a fundamental way. Instead of viewing the genetic parts list of an organism as a loose collection of biochemical activities, in the best case, we anticipate discrete networks of function to bridge the gap between genotype and phenotype, and to do so in a more profound way than the current qualitative classification of linked reactions into familiar pathways, such as glycolysis and the MAPK signal transduction cascades. At the present time, however, we are still far from a complete answer to the most basic question: what can we learn about biology by studying networks? Promising steps in this direction have come from such diverse approaches as mathematical analysis of global network structure, partitioning networks into functionally related modules and motifs, and even de novo design of networks. A complete picture will probably require integrating the data obtained from all of these approaches with modeling efforts at many different levels of detail.
16.
Wolf, D M; Arkin, A P
Motifs, modules and games in bacteria Journal Article
In: Curr. Opin. Microbiol., vol. 6, no. 2, pp. 125–134, 2003.
@article{pmid12732301,
title = {Motifs, modules and games in bacteria},
author = {D M Wolf and A P Arkin},
year = {2003},
date = {2003-00-01},
journal = {Curr. Opin. Microbiol.},
volume = {6},
number = {2},
pages = {125--134},
abstract = {Global explorations of regulatory network dynamics, organization and evolution have become tractable thanks to high-throughput sequencing and molecular measurement of bacterial physiology. From these, a nascent conceptual framework is developing, that views the principles of regulation in term of motifs, modules and games. Motifs are small, repeated, and conserved biological units ranging from molecular domains to small reaction networks. They are arranged into functional modules, genetically dissectible cellular functions such as the cell cycle, or different stress responses. The dynamical functioning of modules defines the organism's strategy to survive in a game, pitting cell against cell, and cell against environment. Placing pathway structure and dynamics into an evolutionary context begins to allow discrimination between those physical and molecular features that particularize a species to its surroundings, and those that provide core physiological function. This approach promises to generate a higher level understanding of cellular design, pathway evolution and cellular bioengineering.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Global explorations of regulatory network dynamics, organization and evolution have become tractable thanks to high-throughput sequencing and molecular measurement of bacterial physiology. From these, a nascent conceptual framework is developing, that views the principles of regulation in term of motifs, modules and games. Motifs are small, repeated, and conserved biological units ranging from molecular domains to small reaction networks. They are arranged into functional modules, genetically dissectible cellular functions such as the cell cycle, or different stress responses. The dynamical functioning of modules defines the organism's strategy to survive in a game, pitting cell against cell, and cell against environment. Placing pathway structure and dynamics into an evolutionary context begins to allow discrimination between those physical and molecular features that particularize a species to its surroundings, and those that provide core physiological function. This approach promises to generate a higher level understanding of cellular design, pathway evolution and cellular bioengineering.
15.
Gilman, A G; Simon, M I; Bourne, H R; Harris, B A; Long, R; Ross, E M; Stull, J T; Taussig, R; Bourne, H R; Arkin, A P; Cobb, M H; Cyster, J G; Devreotes, P N; Ferrell, J E; Fruman, D; Gold, M; Weiss, A; Stull, J T; Berridge, M J; Cantley, L C; Catterall, W A; Coughlin, S R; Olson, E N; Smith, T F; Brugge, J S; Botstein, D; Dixon, J E; Hunter, T; Lefkowitz, R J; Pawson, A J; Sternberg, P W; Varmus, H; Subramaniam, S; Sinkovits, R S; Li, J; Mock, D; Ning, Y; Saunders, B; Sternweis, P C; Hilgemann, D; Scheuermann, R H; DeCamp, D; Hsueh, R; Lin, K M; Ni, Y; Seaman, W E; Simpson, P C; O'Connell, T D; Roach, T; Simon, M I; Choi, S; Eversole-Cire, P; Fraser, I; Mumby, M C; Zhao, Y; Brekken, D; Shu, H; Meyer, T; Chandy, G; Heo, W D; Liou, J; O'Rourke, N; Verghese, M; Mumby, S M; Han, H; Brown, H A; Forrester, J S; Ivanova, P; Milne, S B; Casey, P J; Harden, T K; Arkin, A P; Doyle, J; Gray, M L; Meyer, T; Michnick, S; Schmidt, M A; Toner, M; Tsien, R Y; Natarajan, M; Ranganathan, R; Sambrano, G R
Overview of the Alliance for Cellular Signaling Journal Article
In: Nature, vol. 420, no. 6916, pp. 703–706, 2002.
@article{pmid12478301,
title = {Overview of the Alliance for Cellular Signaling},
author = {A G Gilman and M I Simon and H R Bourne and B A Harris and R Long and E M Ross and J T Stull and R Taussig and H R Bourne and A P Arkin and M H Cobb and J G Cyster and P N Devreotes and J E Ferrell and D Fruman and M Gold and A Weiss and J T Stull and M J Berridge and L C Cantley and W A Catterall and S R Coughlin and E N Olson and T F Smith and J S Brugge and D Botstein and J E Dixon and T Hunter and R J Lefkowitz and A J Pawson and P W Sternberg and H Varmus and S Subramaniam and R S Sinkovits and J Li and D Mock and Y Ning and B Saunders and P C Sternweis and D Hilgemann and R H Scheuermann and D DeCamp and R Hsueh and K M Lin and Y Ni and W E Seaman and P C Simpson and T D O'Connell and T Roach and M I Simon and S Choi and P Eversole-Cire and I Fraser and M C Mumby and Y Zhao and D Brekken and H Shu and T Meyer and G Chandy and W D Heo and J Liou and N O'Rourke and M Verghese and S M Mumby and H Han and H A Brown and J S Forrester and P Ivanova and S B Milne and P J Casey and T K Harden and A P Arkin and J Doyle and M L Gray and T Meyer and S Michnick and M A Schmidt and M Toner and R Y Tsien and M Natarajan and R Ranganathan and G R Sambrano},
year = {2002},
date = {2002-12-01},
journal = {Nature},
volume = {420},
number = {6916},
pages = {703--706},
abstract = {The Alliance for Cellular Signaling is a large-scale collaboration designed to answer global questions about signalling networks. Pathways will be studied intensively in two cells--B lymphocytes (the cells of the immune system) and cardiac myocytes--to facilitate quantitative modelling. One goal is to catalyse complementary research in individual laboratories; to facilitate this, all alliance data are freely available for use by the entire research community.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
The Alliance for Cellular Signaling is a large-scale collaboration designed to answer global questions about signalling networks. Pathways will be studied intensively in two cells--B lymphocytes (the cells of the immune system) and cardiac myocytes--to facilitate quantitative modelling. One goal is to catalyse complementary research in individual laboratories; to facilitate this, all alliance data are freely available for use by the entire research community.
14.
Rao, C V; Wolf, D M; Arkin, A P
Control, exploitation and tolerance of intracellular noise Journal Article
In: Nature, vol. 420, no. 6912, pp. 231–237, 2002.
@article{pmid12432408,
title = {Control, exploitation and tolerance of intracellular noise},
author = {C V Rao and D M Wolf and A P Arkin},
year = {2002},
date = {2002-11-01},
journal = {Nature},
volume = {420},
number = {6912},
pages = {231--237},
abstract = {Noise has many roles in biological function, including generation of errors in DNA replication leading to mutation and evolution, noise-driven divergence of cell fates, noise-induced amplification of signals, and maintenance of the quantitative individuality of cells. Yet there is order to the behaviour and development of cells. They operate within strict parameters and in many cases this behaviour seems robust, implying that noise is largely filtered by the system. How can we explain the use, rejection and sensitivity to noise that is found in biological systems? An exploration of the sources and consequences of noise calls for the use of stochastic models.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Noise has many roles in biological function, including generation of errors in DNA replication leading to mutation and evolution, noise-driven divergence of cell fates, noise-induced amplification of signals, and maintenance of the quantitative individuality of cells. Yet there is order to the behaviour and development of cells. They operate within strict parameters and in many cases this behaviour seems robust, implying that noise is largely filtered by the system. How can we explain the use, rejection and sensitivity to noise that is found in biological systems? An exploration of the sources and consequences of noise calls for the use of stochastic models.
13.
Giaever, G; Chu, A M; Ni, L; Connelly, C; Riles, L; Ronneau, S V; Dow, S; Lucau-Danila, A; Anderson, K; Andre, B; Arkin, A P; Astromoff, A; El-Bakkoury, M; Bangham, R; Benito, R; Brachat, S; Campanaro, S; Curtiss, M; Davis, K; Deutschbauer, A; Entian, K D; Flaherty, P; Foury, F; Garfinkel, D J; Gerstein, M; Gotte, D; G?ldener, U; Hegemann, J H; Hempel, S; Herman, Z; Jaramillo, D F; Kelly, D E; Kelly, S L; K?tter, P; LaBonte, D; Lamb, D C; Lan, N; Liang, H; Liao, H; Liu, L; Luo, C; Lussier, M; Mao, R; Menard, P; Ooi, S L; Revuelta, J L; Roberts, C J; Rose, M; Ross-Macdonald, P; Scherens, B; Schimmack, G; Shafer, B; Shoemaker, D D; Sookhai-Mahadeo, S; Storms, R K; Strathern, J N; Valle, G; Voet, M; Volckaert, G; Wang, C Y; Ward, T R; Wilhelmy, J; Winzeler, E A; Yang, Y; Yen, G; Youngman, E; Yu, K; Bussey, H; Boeke, J D; Snyder, M; Philippsen, P; Davis, R W; Johnston, M
Functional profiling of the Saccharomyces cerevisiae genome Journal Article
In: Nature, vol. 418, no. 6896, pp. 387–391, 2002.
@article{pmid12140549,
title = {Functional profiling of the Saccharomyces cerevisiae genome},
author = {G Giaever and A M Chu and L Ni and C Connelly and L Riles and S V Ronneau and S Dow and A Lucau-Danila and K Anderson and B Andre and A P Arkin and A Astromoff and M El-Bakkoury and R Bangham and R Benito and S Brachat and S Campanaro and M Curtiss and K Davis and A Deutschbauer and K D Entian and P Flaherty and F Foury and D J Garfinkel and M Gerstein and D Gotte and U G?ldener and J H Hegemann and S Hempel and Z Herman and D F Jaramillo and D E Kelly and S L Kelly and P K?tter and D LaBonte and D C Lamb and N Lan and H Liang and H Liao and L Liu and C Luo and M Lussier and R Mao and P Menard and S L Ooi and J L Revuelta and C J Roberts and M Rose and P Ross-Macdonald and B Scherens and G Schimmack and B Shafer and D D Shoemaker and S Sookhai-Mahadeo and R K Storms and J N Strathern and G Valle and M Voet and G Volckaert and C Y Wang and T R Ward and J Wilhelmy and E A Winzeler and Y Yang and G Yen and E Youngman and K Yu and H Bussey and J D Boeke and M Snyder and P Philippsen and R W Davis and M Johnston},
year = {2002},
date = {2002-07-01},
journal = {Nature},
volume = {418},
number = {6896},
pages = {387--391},
abstract = {Determining the effect of gene deletion is a fundamental approach to understanding gene function. Conventional genetic screens exhibit biases, and genes contributing to a phenotype are often missed. We systematically constructed a nearly complete collection of gene-deletion mutants (96% of annotated open reading frames, or ORFs) of the yeast Saccharomyces cerevisiae. DNA sequences dubbed 'molecular bar codes' uniquely identify each strain, enabling their growth to be analysed in parallel and the fitness contribution of each gene to be quantitatively assessed by hybridization to high-density oligonucleotide arrays. We show that previously known and new genes are necessary for optimal growth under six well-studied conditions: high salt, sorbitol, galactose, pH 8, minimal medium and nystatin treatment. Less than 7% of genes that exhibit a significant increase in messenger RNA expression are also required for optimal growth in four of the tested conditions. Our results validate the yeast gene-deletion collection as a valuable resource for functional genomics.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Determining the effect of gene deletion is a fundamental approach to understanding gene function. Conventional genetic screens exhibit biases, and genes contributing to a phenotype are often missed. We systematically constructed a nearly complete collection of gene-deletion mutants (96% of annotated open reading frames, or ORFs) of the yeast Saccharomyces cerevisiae. DNA sequences dubbed 'molecular bar codes' uniquely identify each strain, enabling their growth to be analysed in parallel and the fitness contribution of each gene to be quantitatively assessed by hybridization to high-density oligonucleotide arrays. We show that previously known and new genes are necessary for optimal growth under six well-studied conditions: high salt, sorbitol, galactose, pH 8, minimal medium and nystatin treatment. Less than 7% of genes that exhibit a significant increase in messenger RNA expression are also required for optimal growth in four of the tested conditions. Our results validate the yeast gene-deletion collection as a valuable resource for functional genomics.
12.
Gilman, A; Arkin, A P
Genetic "code": representations and dynamical models of genetic components and networks Journal Article
In: vol. 3, pp. 341–369, 2002.
@article{pmid12142360,
title = {Genetic "code": representations and dynamical models of genetic components and networks},
author = {A Gilman and A P Arkin},
year = {2002},
date = {2002-01-01},
volume = {3},
pages = {341--369},
abstract = {Dynamical modeling of biological systems is becoming increasingly widespread as people attempt to grasp biological phenomena in their full complexity and make sense of an accelerating stream of experimental data. We review a number of recent modeling studies that focus on systems specifically involving gene expression and regulation. These systems include bacterial metabolic operons and phase-variable piliation, bacteriophages T7 and lambda, and interacting networks of eukaryotic developmental genes. A wide range of conceptual and mathematical representations of genetic components and phenomena appears in these works. We discuss these representations in depth and give an overview of the tools currently available for creating and exploring dynamical models. We argue that for modeling to realize its full potential as a mainstream biological research technique the tools must become more general and flexible, and formal, standardized representations of biological knowledge and data must be developed.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Dynamical modeling of biological systems is becoming increasingly widespread as people attempt to grasp biological phenomena in their full complexity and make sense of an accelerating stream of experimental data. We review a number of recent modeling studies that focus on systems specifically involving gene expression and regulation. These systems include bacterial metabolic operons and phase-variable piliation, bacteriophages T7 and lambda, and interacting networks of eukaryotic developmental genes. A wide range of conceptual and mathematical representations of genetic components and phenomena appears in these works. We discuss these representations in depth and give an overview of the tools currently available for creating and exploring dynamical models. We argue that for modeling to realize its full potential as a mainstream biological research technique the tools must become more general and flexible, and formal, standardized representations of biological knowledge and data must be developed.
11.
Wolf, D M; Arkin, A P
Fifteen minutes of fim: control of type 1 pili expression in E. coli Journal Article
In: vol. 6, no. 1, pp. 91–114, 2002.
@article{pmid11881836,
title = {Fifteen minutes of fim: control of type 1 pili expression in E. coli},
author = {D M Wolf and A P Arkin},
year = {2002},
date = {2002-01-01},
volume = {6},
number = {1},
pages = {91--114},
abstract = {Pili are used by Escherichia coli to attach to and invade mammalian tissues during host infection and colonization. Expression of type 1 pili, believed to act as virulence factors in urinary tract infections, is under control of the 'firm' genetic network. This network is able to sense the environment and actuate phase variation control. It is a prime exemplar of an integrative regulatory system because of its role in mediating a complex infection process, and because it instantiates a number of regulatory motifs, including DNA inversion and stochastic variation. With the help of a mathematical model, we explore the mechanisms and architecture of the fim network. We explain (1) basic network operation, including the roles of the recombinase and global regulatory protein concentrations, their DNA binding affinities, and their switching rates in observed phase variation behavior; (2) why there are two recombinases when one would seem to suffice; (3) the source of on-to-off switching specificity of FimE; (4) the role of fimE orientational control in switch dynamics; and (5) how temperature tuning of piliation is achieved. In the process, we identify a general regulatory motif that tunes phenotype to an environmental variable, and explain a number of apparent experimental inconsistencies.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Pili are used by Escherichia coli to attach to and invade mammalian tissues during host infection and colonization. Expression of type 1 pili, believed to act as virulence factors in urinary tract infections, is under control of the 'firm' genetic network. This network is able to sense the environment and actuate phase variation control. It is a prime exemplar of an integrative regulatory system because of its role in mediating a complex infection process, and because it instantiates a number of regulatory motifs, including DNA inversion and stochastic variation. With the help of a mathematical model, we explore the mechanisms and architecture of the fim network. We explain (1) basic network operation, including the roles of the recombinase and global regulatory protein concentrations, their DNA binding affinities, and their switching rates in observed phase variation behavior; (2) why there are two recombinases when one would seem to suffice; (3) the source of on-to-off switching specificity of FimE; (4) the role of fimE orientational control in switch dynamics; and (5) how temperature tuning of piliation is achieved. In the process, we identify a general regulatory motif that tunes phenotype to an environmental variable, and explain a number of apparent experimental inconsistencies.
10.
Arkin, A P
Synthetic cell biology Journal Article
In: Curr. Opin. Biotechnol., vol. 12, no. 6, pp. 638–644, 2001.
@article{pmid11849948,
title = {Synthetic cell biology},
author = {A P Arkin},
year = {2001},
date = {2001-12-01},
journal = {Curr. Opin. Biotechnol.},
volume = {12},
number = {6},
pages = {638--644},
abstract = {Synthesis of data into formal models of cellular function is rapidly becoming a necessary industry. The complexity of the interactions among cellular constituents and the quantity of data about these interactions hinders the ability to predict how cells will respond to perturbation and how they can be engineered for industrial or medical purposes. Models provide a systematic framework to describe and analyze these complex systems. In the past few years, models have begun to have an impact on mainstream biology by creating deeper insight into the design rules of cellular signal processing, providing a basis for rational engineering of cells, and for resolving debates about the root causes of certain cellular behaviors. This review covers some of the recent work and challenges in developing these "synthetic cell" models and their growing practical applications.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Synthesis of data into formal models of cellular function is rapidly becoming a necessary industry. The complexity of the interactions among cellular constituents and the quantity of data about these interactions hinders the ability to predict how cells will respond to perturbation and how they can be engineered for industrial or medical purposes. Models provide a systematic framework to describe and analyze these complex systems. In the past few years, models have begun to have an impact on mainstream biology by creating deeper insight into the design rules of cellular signal processing, providing a basis for rational engineering of cells, and for resolving debates about the root causes of certain cellular behaviors. This review covers some of the recent work and challenges in developing these "synthetic cell" models and their growing practical applications.
9.
Rao, C V; Arkin, A P
Control motifs for intracellular regulatory networks Journal Article
In: vol. 3, pp. 391–419, 2001.
@article{pmid11447069,
title = {Control motifs for intracellular regulatory networks},
author = {C V Rao and A P Arkin},
year = {2001},
date = {2001-01-01},
volume = {3},
pages = {391--419},
abstract = {A number of technological innovations are yielding unprecedented data on the networks of biochemical, genetic, and biophysical reactions that underlie cellular behavior and failure. These networks are composed of hundreds to thousands of chemical species and structures, interacting via nonlinear and possibly stochastic physical processes. A central goal of modern biology is to optimally use the data on these networks to understand how their design leads to the observed cellular behaviors and failures. Ultimately, this knowledge should enable cellular engineers to redesign cellular processes to meet industrial needs (such as optimal natural product synthesis), aid in choosing the most effective targets for pharmaceuticals, and tailor treatment for individual genotypes. The size and complexity of these networks and the inevitable lack of complete data, however, makes reaching these goals extremely difficult. If it proves possible to modularize these networks into functional subnetworks, then these smaller networks may be amenable to direct analysis and might serve as regulatory motifs. These motifs, recurring elements of control, may help to deduce the structure and function of partially known networks and form the basis for fulfilling the goals described above. A number of approaches to identifying and analyzing control motifs in intracellular networks are reviewed.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
A number of technological innovations are yielding unprecedented data on the networks of biochemical, genetic, and biophysical reactions that underlie cellular behavior and failure. These networks are composed of hundreds to thousands of chemical species and structures, interacting via nonlinear and possibly stochastic physical processes. A central goal of modern biology is to optimally use the data on these networks to understand how their design leads to the observed cellular behaviors and failures. Ultimately, this knowledge should enable cellular engineers to redesign cellular processes to meet industrial needs (such as optimal natural product synthesis), aid in choosing the most effective targets for pharmaceuticals, and tailor treatment for individual genotypes. The size and complexity of these networks and the inevitable lack of complete data, however, makes reaching these goals extremely difficult. If it proves possible to modularize these networks into functional subnetworks, then these smaller networks may be amenable to direct analysis and might serve as regulatory motifs. These motifs, recurring elements of control, may help to deduce the structure and function of partially known networks and form the basis for fulfilling the goals described above. A number of approaches to identifying and analyzing control motifs in intracellular networks are reviewed.
8.
Swanson, C A; Arkin, A P; Ross, J
An endogenous calcium oscillator may control early embryonic division Journal Article
In: Proc. Natl. Acad. Sci. U.S.A., vol. 94, no. 4, pp. 1194–1199, 1997.
@article{pmid9037029,
title = {An endogenous calcium oscillator may control early embryonic division},
author = {C A Swanson and A P Arkin and J Ross},
year = {1997},
date = {1997-02-01},
journal = {Proc. Natl. Acad. Sci. U.S.A.},
volume = {94},
number = {4},
pages = {1194--1199},
abstract = {Transient elevations in the concentration of free cytosolic calcium ion ([Ca2+]i) promote cell phase transitions in early embryonic division and persist even if these transitions are blocked. These observations suggest that a [Ca2+]i oscillator is an essential timing element of the early embryonic "master clock." We explore this possibility by coupling a [Ca2+]i oscillator model to an early embryonic cell cycle model based on the protein interactions that govern the activity of the M-phase-promoting factor (MPF). We hypothesize three dynamical states of the MPF system and choose parameter sets to represent each. We then investigate how [Ca2+]i dynamics may control early embryonic division in both sea urchin and Xenopus embryos. To investigate both systems, distinct [Ca2+]i profiles matching those observed in sea urchin embryos (in which [Ca2+]i exhibits sharp transients) and Xenopus embryos (in which [Ca2+]i is elevated and oscillates sinusoidally) are imposed on each of the hypothesized dynamical states of MPF. In the first hypothesis, [Ca2+]i oscillations entrain the autonomous MPF oscillator. In the second and third hypotheses, where the MPF system rests in excitatory and bistable states, respectively, [Ca2+]i oscillations drive MPF activation cycles. Simulation results show that hypotheses two and three, in which a [Ca2+]i oscillator is a fundamental timing element of the master clock, best account for key experimental observations and the questions that they raise. Finally, we propose experiments to elucidate further [Ca2+]i regulation and the fundamental components of the early embryonic master clock.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Transient elevations in the concentration of free cytosolic calcium ion ([Ca2+]i) promote cell phase transitions in early embryonic division and persist even if these transitions are blocked. These observations suggest that a [Ca2+]i oscillator is an essential timing element of the early embryonic "master clock." We explore this possibility by coupling a [Ca2+]i oscillator model to an early embryonic cell cycle model based on the protein interactions that govern the activity of the M-phase-promoting factor (MPF). We hypothesize three dynamical states of the MPF system and choose parameter sets to represent each. We then investigate how [Ca2+]i dynamics may control early embryonic division in both sea urchin and Xenopus embryos. To investigate both systems, distinct [Ca2+]i profiles matching those observed in sea urchin embryos (in which [Ca2+]i exhibits sharp transients) and Xenopus embryos (in which [Ca2+]i is elevated and oscillates sinusoidally) are imposed on each of the hypothesized dynamical states of MPF. In the first hypothesis, [Ca2+]i oscillations entrain the autonomous MPF oscillator. In the second and third hypotheses, where the MPF system rests in excitatory and bistable states, respectively, [Ca2+]i oscillations drive MPF activation cycles. Simulation results show that hypotheses two and three, in which a [Ca2+]i oscillator is a fundamental timing element of the master clock, best account for key experimental observations and the questions that they raise. Finally, we propose experiments to elucidate further [Ca2+]i regulation and the fundamental components of the early embryonic master clock.
7.
Ärkin, A P; Youvan, D C "
Optimizing nucleotide mixtures to encode specific subsets of amino acids for semi-random mutagenesis Journal Article
In: Biotechnology (N.Y.), vol. 10, no. 3, pp. 297–300, 1992.
@article{pmid1368102,
title = {Optimizing nucleotide mixtures to encode specific subsets of amino acids for semi-random mutagenesis},
author = {A P Ärkin and D C " Youvan},
year = {1992},
date = {1992-03-01},
journal = {Biotechnology (N.Y.)},
volume = {10},
number = {3},
pages = {297--300},
abstract = {In random mutagenesis, synthesis of an NNN triplet (i.e. equiprobable A, C, G, and T at each of the three positions in the codon) could be considered an optimal nucleotide mixture because all 20 amino acids are encoded. NN(G,C) might be considered a slightly more intelligent "dope" because the entire set of amino acids is still encoded using only half as many codons. Using a general algorithm described herein, it is possible to formulate more complex doping schemes which encode specific subsets of the twenty amino acids, excluding others from the mix. Maximizing the equiprobability of amino acid residues contributing to such a subset is suggested as an optimal basis for performing semi-random mutagenesis. This is important for reducing the nucleotide complexity of combinatorial cassettes so that "sequence space" can be searched more efficiently. Computer programs have been developed to provide tables of optimized dopes compatible with automated DNA synthesizers.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
In random mutagenesis, synthesis of an NNN triplet (i.e. equiprobable A, C, G, and T at each of the three positions in the codon) could be considered an optimal nucleotide mixture because all 20 amino acids are encoded. NN(G,C) might be considered a slightly more intelligent "dope" because the entire set of amino acids is still encoded using only half as many codons. Using a general algorithm described herein, it is possible to formulate more complex doping schemes which encode specific subsets of the twenty amino acids, excluding others from the mix. Maximizing the equiprobability of amino acid residues contributing to such a subset is suggested as an optimal basis for performing semi-random mutagenesis. This is important for reducing the nucleotide complexity of combinatorial cassettes so that "sequence space" can be searched more efficiently. Computer programs have been developed to provide tables of optimized dopes compatible with automated DNA synthesizers.
6.
An algorithm for protein engineering: simulations of recursive ensemble mutagenesis Journal Article
In: Proc. Natl. Acad. Sci. U.S.A., vol. 89, no. 16, pp. 7811–7815, 1992.
@article{pmid1502200,
title = {An algorithm for protein engineering: simulations of recursive ensemble mutagenesis},
year = {1992},
date = {1992-00-01},
journal = {Proc. Natl. Acad. Sci. U.S.A.},
volume = {89},
number = {16},
pages = {7811--7815},
abstract = {An algorithm for protein engineering, termed recursive ensemble mutagenesis, has been developed to produce diverse populations of phenotypically related mutants whose members differ in amino acid sequence. This method uses a feedback mechanism to control successive rounds of combinatorial cassette mutagenesis. Starting from partially randomized "wild-type" DNA sequences, a highly parallel search of sequence space for peptides fitting an experimenter's criteria is performed. Each iteration uses information gained from the previous rounds to search the space more efficiently. Simulations of the technique indicate that, under a variety of conditions, the algorithm can rapidly produce a diverse population of proteins fitting specific criteria. In the experimental analog, genetic selection or screening applied during recursive ensemble mutagenesis should force the evolution of an ensemble of mutants to a targeted cluster of related phenotypes.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
An algorithm for protein engineering, termed recursive ensemble mutagenesis, has been developed to produce diverse populations of phenotypically related mutants whose members differ in amino acid sequence. This method uses a feedback mechanism to control successive rounds of combinatorial cassette mutagenesis. Starting from partially randomized "wild-type" DNA sequences, a highly parallel search of sequence space for peptides fitting an experimenter's criteria is performed. Each iteration uses information gained from the previous rounds to search the space more efficiently. Simulations of the technique indicate that, under a variety of conditions, the algorithm can rapidly produce a diverse population of proteins fitting specific criteria. In the experimental analog, genetic selection or screening applied during recursive ensemble mutagenesis should force the evolution of an ensemble of mutants to a targeted cluster of related phenotypes.
5.
Applications of imaging spectroscopy in molecular biology. II. Colony screening based on absorption spectra Journal Article
In: Biotechnology (N.Y.), vol. 8, no. 8, pp. 746–749, 1990.
@article{pmid1366901,
title = {Applications of imaging spectroscopy in molecular biology. II. Colony screening based on absorption spectra},
year = {1990},
date = {1990-00-01},
journal = {Biotechnology (N.Y.)},
volume = {8},
number = {8},
pages = {746--749},
abstract = {Digital imaging spectroscopy has been used to obtain the grayscale spectrum of colored bacterial colonies directly from petri dishes. Up to 500 individual colony spectra can be simultaneously recorded and processed from a single plate. Spectra can be obtained in the visible to near infrared region (400nm-900nm) with 10nm resolution. Instrument response is normalized through run-time radiometric calibration such that each grayscale spectrum can be converted to the ground-state absorption spectrum of the colony. In this study, mutants of the photosynthetic bacterium Rhodobacter capsulatus have been differentiated by the absorption spectra of their pigment-protein complexes. This imaging technique is applicable to chromogenic systems in which colony and/or media color (e.g. indicator plates) provides a quantitative indicator of gene expression.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Digital imaging spectroscopy has been used to obtain the grayscale spectrum of colored bacterial colonies directly from petri dishes. Up to 500 individual colony spectra can be simultaneously recorded and processed from a single plate. Spectra can be obtained in the visible to near infrared region (400nm-900nm) with 10nm resolution. Instrument response is normalized through run-time radiometric calibration such that each grayscale spectrum can be converted to the ground-state absorption spectrum of the colony. In this study, mutants of the photosynthetic bacterium Rhodobacter capsulatus have been differentiated by the absorption spectra of their pigment-protein complexes. This imaging technique is applicable to chromogenic systems in which colony and/or media color (e.g. indicator plates) provides a quantitative indicator of gene expression.
