@article{pmid23889170,

title = {StressChip as a high-throughput tool for assessing microbial community responses to environmental stresses},

author = {A Zhou and Z He and Y Qin and Z Lu and Y Deng and Q Tu and C L Hemme and J D Van Nostrand and L Wu and T C Hazen and A P Arkin and J Zhou},

year  = {2013},

date = {2013-09-01},

journal = {Environ. Sci. Technol.},

volume = {47},

number = {17},

pages = {9841--9849},

abstract = {Microbial community responses to environmental stresses are critical for microbial growth, survival, and adaptation. To fill major gaps in our ability to discern the influence of environmental changes on microbial communities from engineered and natural environments, a functional gene-based microarray, termed StressChip, has been developed. First, 46 functional genes involved in microbial responses to environmental stresses such as changes to temperature, osmolarity, oxidative status, nutrient limitation, or general stress response were selected and curated. A total of 22,855 probes were designed, covering 79,628 coding sequences from 985 bacterial, 76 archaeal, and 59 eukaryotic species/strains. Probe specificity was computationally verified. Second, the usefulness of functional genes as indicators of stress response was examined by surveying their distribution in metagenome data sets. The abundance of individual stress response genes is consistent with expected distributions based on respective habitats. Third, the StressChip was used to analyze marine microbial communities from the Deepwater Horizon oil spill. That functional stress response genes were detected in higher abundance (p < 0.05) in oil plume compared to nonplume samples indicated shifts in community composition and structure, consistent with previous results. In summary, StressChip provides a new tool for accessing microbial community functional structure and responses to environmental changes.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid23575373,

title = {Characterization of NaCl tolerance in Đesulfovibrio vulgaris Ħildenborough through experimental evolution},

author = {A Zhou and E Baidoo and Z He and A Mukhopadhyay and J K Baumohl and P Benke and M P Joachimiak and M Xie and R Song and A P Arkin and T C Hazen and J D Keasling and J D Wall and D A Stahl and J Zhou},

year  = {2013},

date = {2013-09-01},

journal = {ISME J},

volume = {7},

number = {9},

pages = {1790--1802},

abstract = {Desulfovibrio vulgaris Hildenborough strains with significantly increased tolerance to NaCl were obtained via experimental evolution. A NaCl-evolved strain, ES9-11, isolated from a population cultured for 1200 generations in medium amended with 100 mM NaCl, showed better tolerance to NaCl than a control strain, EC3-10, cultured for 1200 generations in parallel but without NaCl amendment in medium. To understand the NaCl adaptation mechanism in ES9-11, we analyzed the transcriptional, metabolite and phospholipid fatty acid (PLFA) profiles of strain ES9-11 with 0, 100- or 250 mM-added NaCl in medium compared with the ancestral strain and EC3-10 as controls. In all the culture conditions, increased expressions of genes involved in amino-acid synthesis and transport, energy production, cation efflux and decreased expression of flagellar assembly genes were detected in ES9-11. Consistently, increased abundances of organic solutes and decreased cell motility were observed in ES9-11. Glutamate appears to be the most important osmoprotectant in D. vulgaris under NaCl stress, whereas, other organic solutes such as glutamine, glycine and glycine betaine might contribute to NaCl tolerance under low NaCl concentration only. Unsaturation indices of PLFA significantly increased in ES9-11. Branched unsaturated PLFAs i17:1 ω9c, a17:1 ω9c and branched saturated i15:0 might have important roles in maintaining proper membrane fluidity under NaCl stress. Taken together, these data suggest that the accumulation of osmolytes, increased membrane fluidity, decreased cell motility and possibly an increased exclusion of Na(+) contribute to increased NaCl tolerance in NaCl-evolved D. vulgaris.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid23871664,

title = {Effects of genetic variation on the E. coli host-circuit interface},

author = {S Cardinale and M P Joachimiak and A P Arkin},

year  = {2013},

date = {2013-07-01},

journal = {Cell Rep},

volume = {4},

number = {2},

pages = {231--237},

abstract = {Predictable operation of engineered biological circuitry requires the knowledge of host factors that compete or interfere with designed function. Here, we perform a detailed analysis of the interaction between constitutive expression from a test circuit and cell-growth properties in a subset of genetic variants of the bacterium Escherichia coli. Differences in generic cellular parameters such as ribosome availability and growth rate are the main determinants (89%) of strain-specific differences of circuit performance in laboratory-adapted strains but are responsible for only 35% of expression variation across 88 mutants of E. coli BW25113. In the latter strains, we identify specific cell functions, such as nitrogen metabolism, that directly modulate circuit behavior. Finally, we expose aspects of carbon metabolism that act in a strain- and sequence-specific manner. This method of dissecting interactions between host factors and heterologous circuits enables the discovery of mechanisms of interference necessary for the development of design principles for predictable cellular engineering.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid23774757,

title = {Đissecting a complex chemical stress: chemogenomic profiling of plant hydrolysates},

author = {J M Skerker and D Leon and M N Price and J S Mar and D R Tarjan and K M Wetmore and A M Deutschbauer and J K Baumohl and S Bauer and A B Ib??ez and V D Mitchell and C H Wu and P Hu and T Hazen and A P Arkin},

year  = {2013},

date = {2013-06-01},

journal = {Mol. Syst. Biol.},

volume = {9},

pages = {674},

abstract = {The efficient production of biofuels from cellulosic feedstocks will require the efficient fermentation of the sugars in hydrolyzed plant material. Unfortunately, plant hydrolysates also contain many compounds that inhibit microbial growth and fermentation. We used DNA-barcoded mutant libraries to identify genes that are important for hydrolysate tolerance in both Zymomonas mobilis (44 genes) and Saccharomyces cerevisiae (99 genes). Overexpression of a Z. mobilis tolerance gene of unknown function (ZMO1875) improved its specific ethanol productivity 2.4-fold in the presence of miscanthus hydrolysate. However, a mixture of 37 hydrolysate-derived inhibitors was not sufficient to explain the fitness profile of plant hydrolysate. To deconstruct the fitness profile of hydrolysate, we profiled the 37 inhibitors against a library of Z. mobilis mutants and we modeled fitness in hydrolysate as a mixture of fitness in its components. By examining outliers in this model, we identified methylglyoxal as a previously unknown component of hydrolysate. Our work provides a general strategy to dissect how microbes respond to a complex chemical stress and should enable further engineering of hydrolysate tolerance.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid23511967,

title = {Measurement and modeling of intrinsic transcription terminators},

author = {G Cambray and J C Guimaraes and V K Mutalik and C Lam and Q A Mai and T Thimmaiah and J M Carothers and A P Arkin and D Endy},

year  = {2013},

date = {2013-05-01},

journal = {Nucleic Acids Res.},

volume = {41},

number = {9},

pages = {5139--5148},

abstract = {The reliable forward engineering of genetic systems remains limited by the ad hoc reuse of many types of basic genetic elements. Although a few intrinsic prokaryotic transcription terminators are used routinely, termination efficiencies have not been studied systematically. Here, we developed and validated a genetic architecture that enables reliable measurement of termination efficiencies. We then assembled a collection of 61 natural and synthetic terminators that collectively encode termination efficiencies across an ∼800-fold dynamic range within Escherichia coli. We simulated co-transcriptional RNA folding dynamics to identify competing secondary structures that might interfere with terminator folding kinetics or impact termination activity. We found that structures extending beyond the core terminator stem are likely to increase terminator activity. By excluding terminators encoding such context-confounding elements, we were able to develop a linear sequence-function model that can be used to estimate termination efficiencies (r = 0.9},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{price_2013,

title = {Indirect and suboptimal control of gene expression is widespread in bacteria.},

author = {Morgan N Price and Adam M Deutschbauer and Jeffrey M Skerker and Kelly M Wetmore and Troy Ruths and Jordan S Mar and Jennifer V Kuehl and Wenjun Shao and Adam P Arkin},

url = {http://dx.doi.org/10.1038/msb.2013.16},

doi = {10.1038/msb.2013.16},

year  = {2013},

date = {2013-04-16},

urldate = {2021-05-25},

journal = {Molecular Systems Biology},

volume = {9},

pages = {660},

abstract = {Gene regulation in bacteria is usually described as an adaptive response to an environmental change so that genes are expressed when they are required. We instead propose that most genes are under indirect control: their expression responds to signal(s) that are not directly related to the genes' function. Indirect control should perform poorly in artificial conditions, and we show that gene regulation is often maladaptive in the laboratory. In Shewanella oneidensis MR-1, 24% of genes are detrimental to fitness in some conditions, and detrimental genes tend to be highly expressed instead of being repressed when not needed. In diverse bacteria, there is little correlation between when genes are important for optimal growth or fitness and when those genes are upregulated. Two common types of indirect control are constitutive expression and regulation by growth rate; these occur for genes with diverse functions and often seem to be suboptimal. Because genes that have closely related functions can have dissimilar expression patterns, regulation may be suboptimal in the wild as well as in the laboratory.},

keywords = {enigma},

pubstate = {published},

tppubtype = {article}

}

@article{brown_2013,

title = {Draft Genome Sequence for Desulfovibrio africanus Strain PCS.},

author = {Steven D Brown and Sagar M Utturkar and Adam P Arkin and Adam M Deutschbauer and Dwayne A Elias and Terry C Hazen and Romy Chakraborty},

url = {http://dx.doi.org/10.1128/genomeA.00144-13},

doi = {10.1128/genomeA.00144-13},

year  = {2013},

date = {2013-04-11},

urldate = {2021-05-25},

journal = {Genome announcements},

volume = {1},

number = {2},

pages = {e0014413},

abstract = {Desulfovibrio africanus strain PCS is an anaerobic sulfate-reducing bacterium (SRB) isolated from sediment from Paleta Creek, San Diego, CA. Strain PCS is capable of reducing metals such as Fe(III) and Cr(VI), has a cell cycle, and is predicted to produce methylmercury. We present the D. africanus PCS genome sequence.},

keywords = {enigma},

pubstate = {published},

tppubtype = {article}

}

@article{cipriano_2013,

title = {RegTransBase--a database of regulatory sequences and interactions based on literature: a resource for investigating transcriptional regulation in prokaryotes.},

author = {Michael J Cipriano and Pavel N Novichkov and Alexey E Kazakov and Dmitry A Rodionov and Adam P Arkin and Mikhail S Gelfand and Inna Dubchak},

url = {http://dx.doi.org/10.1186/1471-2164-14-213},

doi = {10.1186/1471-2164-14-213},

year  = {2013},

date = {2013-04-02},

urldate = {2021-05-25},

journal = {BMC Genomics},

volume = {14},

pages = {213},

abstract = {BACKGROUND: Due to the constantly growing number of sequenced microbial genomes, comparative genomics has been playing a major role in the investigation of regulatory interactions in bacteria. Regulon inference mostly remains a field of semi-manual examination since absence of a knowledgebase and informatics platform for automated and systematic investigation restricts opportunities for computational prediction. Additionally, confirming computationally inferred regulons by experimental data is critically important. DESCRIPTION: RegTransBase is an open-access platform with a user-friendly web interface publicly available at http://regtransbase.lbl.gov. It consists of two databases - a manually collected hierarchical regulatory interactions database based on more than 7000 scientific papers which can serve as a knowledgebase for verification of predictions, and a large set of curated by experts transcription factor binding sites used in regulon inference by a variety of tools. RegTransBase captures the knowledge from published scientific literature using controlled vocabularies and contains various types of experimental data, such as: the activation or repression of transcription by an identified direct regulator; determination of the transcriptional regulatory function of a protein (or RNA) directly binding to DNA or RNA; mapping of binding sites for a regulatory protein; characterization of regulatory mutations. Analysis of the data collected from literature resulted in the creation of Putative Regulons from Experimental Data that are also available in RegTransBase. CONCLUSIONS: RegTransBase is a powerful user-friendly platform for the investigation of regulation in prokaryotes. It uses a collection of validated regulatory sequences that can be easily extracted and used to infer regulatory interactions by comparative genomics techniques thus assisting researchers in the interpretation of transcriptional regulation data.},

keywords = {enigma},

pubstate = {published},

tppubtype = {article}

}

@article{meyer_2013,

title = {Variation among Desulfovibrio species in electron transfer systems used for syntrophic growth.},

author = {Birte Meyer and Jennifer Kuehl and Adam M Deutschbauer and Morgan N Price and Adam P Arkin and David A Stahl},

url = {http://dx.doi.org/10.1128/JB.01959-12},

doi = {10.1128/JB.01959-12},

year  = {2013},

date = {2013-03-01},

urldate = {2021-05-25},

journal = {Journal of Bacteriology},

volume = {195},

number = {5},

pages = {990-1004},

abstract = {Mineralization of organic matter in anoxic environments relies on the cooperative activities of hydrogen producers and consumers linked by interspecies electron transfer in syntrophic consortia that may include sulfate-reducing species (e.g., Desulfovibrio). Physiological differences and various gene repertoires implicated in syntrophic metabolism among Desulfovibrio species suggest considerable variation in the biochemical basis of syntrophy. In this study, comparative transcriptional and mutant analyses of Desulfovibrio alaskensis strain G20 and Desulfovibrio vulgaris strain Hildenborough growing syntrophically with Methanococcus maripaludis on lactate were used to develop new and revised models for their alternative electron transfer and energy conservation systems. Lactate oxidation by strain G20 generates a reduced thiol-disulfide redox pair(s) and ferredoxin that are energetically coupled to H(+)/CO(2) reduction by periplasmic formate dehydrogenase and hydrogenase via a flavin-based reverse electron bifurcation process (electron confurcation) and a menaquinone (MQ) redox loop-mediated reverse electron flow involving the membrane-bound Qmo and Qrc complexes. In contrast, strain Hildenborough uses a larger number of cytoplasmic and periplasmic proteins linked in three intertwining pathways to couple H(+) reduction to lactate oxidation. The faster growth of strain G20 in coculture is associated with a kinetic advantage conferred by the Qmo-MQ-Qrc loop as an electron transfer system that permits higher lactate oxidation rates under elevated hydrogen levels (thereby enhancing methanogenic growth) and use of formate as the main electron-exchange mediator (textgreater70% electron flux), as opposed to the primarily hydrogen-based exchange by strain Hildenborough. This study further demonstrates the absence of a conserved gene core in Desulfovibrio that would determine the ability for a syntrophic lifestyle.},

keywords = {enigma},

pubstate = {published},

tppubtype = {article}

}

@article{pmid23264581,

title = {Variation among Đesulfovibrio species in electron transfer systems used for syntrophic growth},

author = {B Meyer and J Kuehl and A M Deutschbauer and M N Price and A P Arkin and D A Stahl},

year  = {2013},

date = {2013-03-01},

journal = {J. Bacteriol.},

volume = {195},

number = {5},

pages = {990--1004},

abstract = {Mineralization of organic matter in anoxic environments relies on the cooperative activities of hydrogen producers and consumers linked by interspecies electron transfer in syntrophic consortia that may include sulfate-reducing species (e.g., Desulfovibrio). Physiological differences and various gene repertoires implicated in syntrophic metabolism among Desulfovibrio species suggest considerable variation in the biochemical basis of syntrophy. In this study, comparative transcriptional and mutant analyses of Desulfovibrio alaskensis strain G20 and Desulfovibrio vulgaris strain Hildenborough growing syntrophically with Methanococcus maripaludis on lactate were used to develop new and revised models for their alternative electron transfer and energy conservation systems. Lactate oxidation by strain G20 generates a reduced thiol-disulfide redox pair(s) and ferredoxin that are energetically coupled to H(+)/CO(2) reduction by periplasmic formate dehydrogenase and hydrogenase via a flavin-based reverse electron bifurcation process (electron confurcation) and a menaquinone (MQ) redox loop-mediated reverse electron flow involving the membrane-bound Qmo and Qrc complexes. In contrast, strain Hildenborough uses a larger number of cytoplasmic and periplasmic proteins linked in three intertwining pathways to couple H(+) reduction to lactate oxidation. The faster growth of strain G20 in coculture is associated with a kinetic advantage conferred by the Qmo-MQ-Qrc loop as an electron transfer system that permits higher lactate oxidation rates under elevated hydrogen levels (thereby enhancing methanogenic growth) and use of formate as the main electron-exchange mediator (>70% electron flux), as opposed to the primarily hydrogen-based exchange by strain Hildenborough. This study further demonstrates the absence of a conserved gene core in Desulfovibrio that would determine the ability for a syntrophic lifestyle.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{wang_2013,

title = {Inference of gene regulatory networks from genome-wide knockout fitness data.},

author = {Liming Wang and Xiaodong Wang and Adam P Arkin and Michael S Samoilov},

url = {http://dx.doi.org/10.1093/bioinformatics/bts634},

doi = {10.1093/bioinformatics/bts634},

year  = {2013},

date = {2013-02-01},

urldate = {2021-05-25},

journal = {Bioinformatics},

volume = {29},

number = {3},

pages = {338-346},

abstract = {MOTIVATION: Genome-wide fitness is an emerging type of high-throughput biological data generated for individual organisms by creating libraries of knockouts, subjecting them to broad ranges of environmental conditions, and measuring the resulting clone-specific fitnesses. Since fitness is an organism-scale measure of gene regulatory network behaviour, it may offer certain advantages when insights into such phenotypical and functional features are of primary interest over individual gene expression. Previous works have shown that genome-wide fitness data can be used to uncover novel gene regulatory interactions, when compared with results of more conventional gene expression analysis. Yet, to date, few algorithms have been proposed for systematically using genome-wide mutant fitness data for gene regulatory network inference. RESULTS: In this article, we describe a model and propose an inference algorithm for using fitness data from knockout libraries to identify underlying gene regulatory networks. Unlike most prior methods, the presented approach captures not only structural, but also dynamical and non-linear nature of biomolecular systems involved. A state-space model with non-linear basis is used for dynamically describing gene regulatory networks. Network structure is then elucidated by estimating unknown model parameters. Unscented Kalman filter is used to cope with the non-linearities introduced in the model, which also enables the algorithm to run in on-line mode for practical use. Here, we demonstrate that the algorithm provides satisfying results for both synthetic data as well as empirical measurements of GAL network in yeast Saccharomyces cerevisiae and TyrR-LiuR network in bacteria Shewanella oneidensis. AVAILABILITY: MATLAB code and datasets are available to download at http://www.duke.edu/∼lw174/Fitness.zip and http://genomics.lbl.gov/supplemental/fitness-bioinf/},

keywords = {enigma},

pubstate = {published},

tppubtype = {article}

}

@article{pmid23452860,

title = {Repurposing CRISPR as an RNA-guided platform for sequence-specific control of gene expression},

author = {L S Qi and M H Larson and L A Gilbert and J A Doudna and J S Weissman and A P Arkin and W A Lim},

year  = {2013},

date = {2013-02-01},

journal = {Cell},

volume = {152},

number = {5},

pages = {1173--1183},

abstract = {Targeted gene regulation on a genome-wide scale is a powerful strategy for interrogating, perturbing, and engineering cellular systems. Here, we develop a method for controlling gene expression based on Cas9, an RNA-guided DNA endonuclease from a type II CRISPR system. We show that a catalytically dead Cas9 lacking endonuclease activity, when coexpressed with a guide RNA, generates a DNA recognition complex that can specifically interfere with transcriptional elongation, RNA polymerase binding, or transcription factor binding. This system, which we call CRISPR interference (CRISPRi), can efficiently repress expression of targeted genes in Escherichia coli, with no detectable off-target effects. CRISPRi can be used to repress multiple target genes simultaneously, and its effects are reversible. We also show evidence that the system can be adapted for gene repression in mammalian cells. This RNA-guided DNA recognition platform provides a simple approach for selectively perturbing gene expression on a genome-wide scale.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid23271269,

title = {Inference of gene regulatory networks from genome-wide knockout fitness data},

author = {L Wang and X Wang and A P Arkin and M S Samoilov},

year  = {2013},

date = {2013-02-01},

journal = {Bioinformatics},

volume = {29},

number = {3},

pages = {338--346},

abstract = {Genome-wide fitness is an emerging type of high-throughput biological data generated for individual organisms by creating libraries of knockouts, subjecting them to broad ranges of environmental conditions, and measuring the resulting clone-specific fitnesses. Since fitness is an organism-scale measure of gene regulatory network behaviour, it may offer certain advantages when insights into such phenotypical and functional features are of primary interest over individual gene expression. Previous works have shown that genome-wide fitness data can be used to uncover novel gene regulatory interactions, when compared with results of more conventional gene expression analysis. Yet, to date, few algorithms have been proposed for systematically using genome-wide mutant fitness data for gene regulatory network inference. In this article, we describe a model and propose an inference algorithm for using fitness data from knockout libraries to identify underlying gene regulatory networks. Unlike most prior methods, the presented approach captures not only structural, but also dynamical and non-linear nature of biomolecular systems involved. A state-space model with non-linear basis is used for dynamically describing gene regulatory networks. Network structure is then elucidated by estimating unknown model parameters. Unscented Kalman filter is used to cope with the non-linearities introduced in the model, which also enables the algorithm to run in on-line mode for practical use. Here, we demonstrate that the algorithm provides satisfying results for both synthetic data as well as empirical measurements of GAL network in yeast Saccharomyces cerevisiae and TyrR-LiuR network in bacteria Shewanella oneidensis. MATLAB code and datasets are available to download at http://www.duke.edu/∼lw174/Fitness.zip and http://genomics.lbl.gov/supplemental/fitness-bioinf/},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{baran_2013,

title = {Metabolic footprinting of mutant libraries to map metabolite utilization to genotype.},

author = {Richard Baran and Benjamin P Bowen and Morgan N Price and Adam P Arkin and Adam M Deutschbauer and Trent R Northen},

url = {http://dx.doi.org/10.1021/cb300477w},

doi = {10.1021/cb300477w},

year  = {2013},

date = {2013-01-18},

urldate = {2021-05-25},

journal = {ACS Chemical Biology},

volume = {8},

number = {1},

pages = {189-199},

abstract = {The discrepancy between the pace of sequencing and functional characterization of genomes is a major challenge in understanding complex microbial metabolic processes and metabolic interactions in the environment. Here, we identified and validated genes related to the utilization of specific metabolites in bacteria by profiling metabolite utilization in libraries of mutant strains. Untargeted mass spectrometry based metabolomics was used to identify metabolites utilized by Escherichia coli and Shewanella oneidensis MR-1. Targeted high-throughput metabolite profiling of spent media of 8042 individual mutant strains was performed to link utilization to specific genes. Using this approach we identified genes of known function as well as novel transport proteins and enzymes required for the utilization of tested metabolites. Specific examples include two subunits of a predicted ABC transporter encoded by the genes SO1043 and SO1044 required for the utilization of citrulline and a predicted histidase encoded by the gene SO3057 required for the utilization of ergothioneine by S. oneidensis. In vitro assays with purified proteins showed substrate specificity of SO3057 toward ergothioneine and histidine betaine in contrast to substrate specificity of a paralogous histidase SO0098 toward histidine. This generally applicable, high-throughput workflow has the potential both to discover novel metabolic capabilities of microorganisms and to identify the corresponding genes.},

keywords = {enigma},

pubstate = {published},

tppubtype = {article}

}

@article{pang_2013,

title = {Metallochaperones regulate intracellular copper levels.},

author = {Lee W Pang and Amardeep Kaur and Alexander V Ratushny and Aleksandar Cvetkovic and Sunil Kumar and Min Pan and Adam P Arkin and John D Aitchison and Michael W W Adams and Nitin S Baliga},

url = {http://dx.doi.org/10.1371/journal.pcbi.1002880},

doi = {10.1371/journal.pcbi.1002880},

year  = {2013},

date = {2013-01-17},

urldate = {2021-05-25},

journal = {PLoS Computational Biology},

volume = {9},

number = {1},

pages = {e1002880},

abstract = {Copper (Cu) is an important enzyme co-factor that is also extremely toxic at high intracellular concentrations, making active efflux mechanisms essential for preventing Cu accumulation. Here, we have investigated the mechanistic role of metallochaperones in regulating Cu efflux. We have constructed a computational model of Cu trafficking and efflux based on systems analysis of the Cu stress response of Halobacterium salinarum. We have validated several model predictions via assays of transcriptional dynamics and intracellular Cu levels, discovering a completely novel function for metallochaperones. We demonstrate that in addition to trafficking Cu ions, metallochaperones also function as buffers to modulate the transcriptional responsiveness and efficacy of Cu efflux. This buffering function of metallochaperones ultimately sets the upper limit for intracellular Cu levels and provides a mechanistic explanation for previously observed Cu metallochaperone mutation phenotypes.},

keywords = {enigma},

pubstate = {published},

tppubtype = {article}

}

@article{chivian_2013,

title = {MetaMicrobesOnline: phylogenomic analysis of microbial communities.},

author = {Dylan Chivian and Paramvir S Dehal and Keith Keller and Adam P Arkin},

url = {http://dx.doi.org/10.1093/nar/gks1202},

doi = {10.1093/nar/gks1202},

year  = {2013},

date = {2013-01-01},

urldate = {2021-05-25},

journal = {Nucleic Acids Research},

volume = {41},

number = {Database issue},

pages = {D648-54},

abstract = {The metaMicrobesOnline database (freely available at http://meta.MicrobesOnline.org) offers phylogenetic analysis of genes from microbial genomes and metagenomes. Gene trees are constructed for canonical gene families such as COG and Pfam. Such gene trees allow for rapid homologue analysis and subfamily comparison of genes from multiple metagenomes and comparisons with genes from microbial isolates. Additionally, the genome browser permits genome context comparisons, which may be used to determine the closest sequenced genome or suggest functionally associated genes. Lastly, the domain browser permits rapid comparison of protein domain organization within genes of interest from metagenomes and complete microbial genomes.},

keywords = {enigma},

pubstate = {published},

tppubtype = {article}

}

@article{kazakov_2013a,

title = {Transcription factor family-based reconstruction of singleton regulons and study of the Crp/Fnr, ArsR, and GntR families in Desulfovibrionales genomes.},

author = {Alexey E Kazakov and Dmitry A Rodionov and Morgan N Price and Adam P Arkin and Inna Dubchak and Pavel S Novichkov},

url = {http://dx.doi.org/10.1128/JB.01977-12},

doi = {10.1128/JB.01977-12},

year  = {2013},

date = {2013-01-01},

urldate = {2021-05-25},

journal = {Journal of Bacteriology},

volume = {195},

number = {1},

pages = {29-38},

abstract = {Accurate detection of transcriptional regulatory elements is essential for high-quality genome annotation, metabolic reconstruction, and modeling of regulatory networks. We developed a computational approach for reconstruction of regulons operated by transcription factors (TFs) from large protein families and applied this novel approach to three TF families in 10 Desulfovibrionales genomes. Phylogenetic analyses of 125 regulators from the ArsR, Crp/Fnr, and GntR families revealed that 65% of these regulators (termed reference TFs) are well conserved in Desulfovibrionales, while the remaining 35% of regulators (termed singleton TFs) are species specific and show a mosaic distribution. For regulon reconstruction in the group of singleton TFs, the standard orthology-based approach was inefficient, and thus, we developed a novel approach based on the simultaneous study of all homologous TFs from the same family in a group of genomes. As a result, we identified binding for 21 singleton TFs and for all reference TFs in all three analyzed families. Within each TF family we observed structural similarities between DNA-binding motifs of different reference and singleton TFs. The collection of reconstructed regulons is available at the RegPrecise database (http://regprecise.lbl.gov/RegPrecise/Desulfovibrionales.jsp).},

keywords = {enigma},

pubstate = {published},

tppubtype = {article}

}

@article{pmid24376771,

title = {Ħexavalent chromium reduction under fermentative conditions with lactate stimulated native microbial communities},

author = {A C Somenahally and J J Mosher and T Yuan and M Podar and T J Phelps and S D Brown and Z K Yang and T C Hazen and A P Arkin and A V Palumbo and J D Van Nostrand and J Zhou and D A Elias},

year  = {2013},

date = {2013-01-01},

journal = {PLoS ONE},

volume = {8},

number = {12},

pages = {e83909},

abstract = {Microbial reduction of toxic hexavalent chromium (Cr(VI)) in-situ is a plausible bioremediation strategy in electron-acceptor limited environments. However, higher [Cr(VI)] may impose stress on syntrophic communities and impact community structure and function. The study objectives were to understand the impacts of Cr(VI) concentrations on community structure and on the Cr(VI)-reduction potential of groundwater communities at Hanford, WA. Steady state continuous flow bioreactors were used to grow native communities enriched with lactate (30 mM) and continuously amended with Cr(VI) at 0.0 (No-Cr), 0.1 (Low-Cr) and 3.0 (High-Cr) mg/L. Microbial growth, metabolites, Cr(VI), 16S rRNA gene sequences and GeoChip based functional gene composition were monitored for 15 weeks. Temporal trends and differences in growth, metabolite profiles, and community composition were observed, largely between Low-Cr and High-Cr bioreactors. In both High-Cr and Low-Cr bioreactors, Cr(VI) levels were below detection from week 1 until week 15. With lactate enrichment, native bacterial diversity substantially decreased as Pelosinus spp., and Sporotalea spp., became the dominant groups, but did not significantly differ between Cr concentrations. The Archaea diversity also substantially decreased after lactate enrichment from Methanosaeta (35%), Methanosarcina (17%) and others, to mostly Methanosarcina spp. (95%). Methane production was lower in High-Cr reactors suggesting some inhibition of methanogens. Several key functional genes were distinct in Low-Cr bioreactors compared to High-Cr. Among the Cr resistant microbes, Burkholderia vietnamiensis, Comamonas testosterone and Ralstonia pickettii proliferated in Cr amended bioreactors. In-situ fermentative conditions facilitated Cr(VI) reduction, and as a result 3.0 mg/L Cr(VI) did not impact the overall bacterial community structure.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid24019987,

title = {Metagenomes of tropical soil-derived anaerobic switchgrass-adapted consortia with and without iron},

author = {K M Deangelis and P D'Haeseleer and D Chivian and B Simmons and A P Arkin and K Mavromatis and S Malfatti and S Tringe and T C Hazen},

year  = {2013},

date = {2013-01-01},

journal = {Stand Genomic Sci},

volume = {7},

number = {3},

pages = {382--398},

abstract = {Tropical forest soils decompose litter rapidly with frequent episodes of anoxia, making it likely that bacteria using alternate terminal electron acceptors (TEAs) such as iron play a large role in supporting decomposition under these conditions. The prevalence of many types of metabolism in litter deconstruction makes these soils useful templates for improving biofuel production. To investigate how iron availability affects decomposition, we cultivated feedstock-adapted consortia (FACs) derived from iron-rich tropical forest soils accustomed to experiencing frequent episodes of anaerobic conditions and frequently fluctuating redox. One consortium was propagated under fermenting conditions, with switchgrass as the sole carbon source in minimal media (SG only FACs), and the other consortium was treated the same way but received poorly crystalline iron as an additional terminal electron acceptor (SG + Fe FACs). We sequenced the metagenomes of both consortia to a depth of about 150 Mb each, resulting in a coverage of 26× for the more diverse SG + Fe FACs, and 81× for the relatively less diverse SG only FACs. Both consortia were able to quickly grow on switchgrass, and the iron-amended consortium exhibited significantly higher microbial diversity than the unamended consortium. We found evidence of higher stress in the unamended FACs and increased sugar transport and utilization in the iron-amended FACs. This work provides metagenomic evidence that supplementation of alternative TEAs may improve feedstock deconstruction in biofuel production.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid23874178,

title = {Genetic selection for context-dependent stochastic phenotypes: Sp1 and ŦAŦA mutations increase phenotypic noise in ĦIV-1 gene expression},

author = {K Miller-Jensen and R Skupsky and P S Shah and A P Arkin and D V Schaffer},

year  = {2013},

date = {2013-01-01},

journal = {PLoS Comput. Biol.},

volume = {9},

number = {7},

pages = {e1003135},

abstract = {The sequence of a promoter within a genome does not uniquely determine gene expression levels and their variability; rather, promoter sequence can additionally interact with its location in the genome, or genomic context, to shape eukaryotic gene expression. Retroviruses, such as human immunodeficiency virus-1 (HIV), integrate their genomes into those of their host and thereby provide a biomedically-relevant model system to quantitatively explore the relationship between promoter sequence, genomic context, and noise-driven variability on viral gene expression. Using an in vitro model of the HIV Tat-mediated positive-feedback loop, we previously demonstrated that fluctuations in viral Tat-transactivating protein levels generate integration-site-dependent, stochastically-driven phenotypes, in which infected cells randomly 'switch' between high and low expressing states in a manner that may be related to viral latency. Here we extended this model and designed a forward genetic screen to systematically identify genetic elements in the HIV LTR promoter that modulate the fraction of genomic integrations that specify 'Switching' phenotypes. Our screen identified mutations in core promoter regions, including Sp1 and TATA transcription factor binding sites, which increased the Switching fraction several fold. By integrating single-cell experiments with computational modeling, we further investigated the mechanism of Switching-fraction enhancement for a selected Sp1 mutation. Our experimental observations demonstrated that the Sp1 mutation both impaired Tat-transactivated expression and also altered basal expression in the absence of Tat. Computational analysis demonstrated that the observed change in basal expression could contribute significantly to the observed increase in viral integrations that specify a Switching phenotype, provided that the selected mutation affected Tat-mediated noise amplification differentially across genomic contexts. Our study thus demonstrates a methodology to identify and characterize promoter elements that affect the distribution of stochastic phenotypes over genomic contexts, and advances our understanding of how promoter mutations may control the frequency of latent HIV infection.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}