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the dynamics of diverse segmental amplifications in populations of saccharomyces cerevisiae adapting to strong selection.population adaptation to strong selection can occur through the sequential or parallel accumulation of competing beneficial mutations. the dynamics, diversity, and rate of fixation of beneficial mutations within and between populations are still poorly understood. to study how the mutational landscape varies across populations during adaptation, we performed experimental evolution on seven parallel populations of saccharomyces cerevisiae continuously cultured in limiting sulfate medium. by combi ...201324368781
the crystal structures of the tri-functional chloroflexus aurantiacus and bi-functional rhodobacter sphaeroides malyl-coa lyases and comparison with cite-like superfamily enzymes and malate synthases.malyl-coa lyase (mcl) is a promiscuous carbon-carbon bond lyase that catalyzes the reversible cleavage of structurally related coenzyme a (coa) thioesters. this enzyme plays a crucial, multifunctional role in the 3-hydroxypropionate bi-cycle for autotrophic co2 fixation in chloroflexus aurantiacus. a second, phylogenetically distinct mcl from rhodobacter sphaeroides is involved in the ethylmalonyl-coa pathway for acetate assimilation. both mcls belong to the large superfamily of cite-like enzyme ...201324206647
plasmids of carotenoid-producing paracoccus spp. (alphaproteobacteria) - structure, diversity and evolution.plasmids are components of many bacterial genomes. they enable the spread of a large pool of genetic information via lateral gene transfer. many bacterial strains contain mega-sized replicons and these are particularly common in alphaproteobacteria. considerably less is known about smaller alphaproteobacterial plasmids. we analyzed the genomes of 14 such plasmids residing in 4 multireplicon carotenoid-producing strains of the genus paracoccus (alphaproteobacteria): p. aestuarii dsm 19484, p. hae ...201324260361
fluorescence-based bacterial bioreporter for specific detection of methyl halide emissions in the environment.methyl halides are volatile one-carbon compounds responsible for substantial depletion of stratospheric ozone. among them, chloromethane (ch3cl) is the most abundant halogenated hydrocarbon in the atmosphere. global budgets of methyl halides in the environment are still poorly understood due to uncertainties in their natural sources, mainly from vegetation, and their sinks, which include chloromethane-degrading bacteria. a bacterial bioreporter for the detection of methyl halides was developed o ...201323956392
metabolic adaptation and trophic strategies of soil bacteria-c1- metabolism and sulfur chemolithotrophy in starkeya novella.the highly diverse and metabolically versatile microbial communities found in soil environments are major contributors to the global carbon, nitrogen, and sulfur cycles. we have used a combination of genome -based pathway analysis with proteomics and gene expression studies to investigate metabolic adaptation in a representative of these bacteria, starkeya novella, which was originally isolated from agricultural soil. this bacterium was the first facultative sulfur chemolithoautotroph that was i ...201324146664
multistep, eight-electron oxidation catalyzed by the cofactorless oxidase, pqqc: identification of chemical intermediates and their dependence on molecular oxygen.the final step of the biosynthesis of prokaryotic cofactor pqq is catalyzed by pqqc, a cofactorless oxidase that brings about a ring closure and overall eight-electron oxidation of its substrate. time-dependent acid quenching and subsequent high-performance liquid chromatography separation and mass spectrometric analyses of reaction mixtures were performed to correlate the structures of intermediates with previously observed uv-visible signatures. the reaction is composed of four stepwise oxidat ...201323718207
draft genome sequence of methylobacterium mesophilicum strain sr1.6/6, isolated from citrus sinensis.methylobacterium mesophilicum strain sr1.6/6 is an endophytic bacterium isolated from a surface-sterilized citrus sinensis branch. ecological and biotechnological aspects of this bacterium, such as the genes involved in its association with the host plant and the primary oxidation of methanol, were annotated in the draft genome.201323788544
identification of opportunistic pathogenic bacteria in drinking water samples of different rural health centers and their clinical impacts on humans.international drinking water quality monitoring programs have been established in order to prevent or to reduce the risk of contracting water-related infections. a survey was performed on groundwater-derived drinking water from 13 different hospitals in the mahabubnagar district. a total of 55 bacterial strains were isolated which belonged to both gram-positive and gram-negative bacteria. all the taxa were identified based on the 16s rrna gene sequence analysis based on which they are phylogenet ...201323862144
autoinhibition and signaling by the switch ii motif in the g-protein chaperone of a radical b12 enzyme.meab is an accessory gtpase protein involved in the assembly, protection, and reactivation of 5'-deoxyadenosyl cobalamin-dependent methylmalonyl-coa mutase (mcm). mutations in the human ortholog of meab result in methylmalonic aciduria, an inborn error of metabolism. g-proteins typically utilize conserved switch i and ii motifs for signaling to effector proteins via conformational changes elicited by nucleotide binding and hydrolysis. our recent discovery that meab utilizes an unusual switch iii ...201323996001
studying the microbiology of the indoor environment.the majority of people in the developed world spend more than 90% of their lives indoors. here, we examine our understanding of the bacteria that co-inhabit our artificial world and how they might influence human health.201323514020
the general stress response factor ecfg regulates expression of the c-2 hopanoid methylase hpnp in rhodopseudomonas palustris tie-1.lipid molecules preserved in sedimentary rocks facilitate the reconstruction of events that have shaped the evolution of the earth's biosphere. a key limitation for the interpretation of many of these molecular fossils is that their biological roles are still poorly understood. here, we use rhodopseudomonas palustris tie-1 to identify factors that induce biosynthesis of 2-methyl hopanoids (2-mebhps), progenitors of 2-methyl hopanes, one of the most abundant biomarkers in the rock record. this is ...201323524612
prerequisites for amplicon pyrosequencing of microbial methanol utilizers in the environment.the commercial availability of next generation sequencing (ngs) technologies facilitated the assessment of functional groups of microorganisms in the environment with high coverage, resolution, and reproducibility. soil methylotrophs were among the first microorganisms in the environment that were assessed with molecular tools, and nowadays, as well with ngs technologies. studies in the past years re-attracted notice to the pivotal role of methylotrophs in global conversions of methanol, which m ...201324046766
an oxidoreductase from 'alphonso' mango catalyzing biosynthesis of furaneol and reduction of reactive carbonyls.two furanones, furaneol (4-hydroxy-2,5-dimethyl-3(2h)-furanone) and mesifuran (2,5-dimethyl-4-methoxy-3(2h)-furanone), are important constituents of flavor of the alphonso cultivar of mango (mangifera indica). to get insights into the biosynthesis of these furanones, we isolated an enone oxidoreductase gene from the alphonso mango. it has high sequence similarity to an alkenal/one oxidoreductase from cucumber (79% identity) and enone oxidoreductases from tomato (73% identity) and strawberry (72% ...201324133645
hydrogen and carbon isotope fractionation during degradation of chloromethane by methylotrophic bacteria.chloromethane (ch3 cl) is a widely studied volatile halocarbon involved in the destruction of ozone in the stratosphere. nevertheless, its global budget still remains debated. stable isotope analysis is a powerful tool to constrain fluxes of chloromethane between various environmental compartments which involve a multiplicity of sources and sinks, and both biotic and abiotic processes. in this study, we measured hydrogen and carbon isotope fractionation of the remaining untransformed chlorometha ...201324019296
the (d)evolution of methanotrophy in the beijerinckiaceae--a comparative genomics analysis.the alphaproteobacterial family beijerinckiaceae contains generalists that grow on a wide range of substrates, and specialists that grow only on methane and methanol. we investigated the evolution of this family by comparing the genomes of the generalist organotroph beijerinckia indica, the facultative methanotroph methylocella silvestris and the obligate methanotroph methylocapsa acidiphila. highly resolved phylogenetic construction based on universally conserved genes demonstrated that the bei ...201323985741
isolation of optically targeted single bacteria by application of fluidic force microscopy to aerobic anoxygenic phototrophs from the phyllosphere.in their natural environment, bacteria often behave differently than they do under laboratory conditions. to gain insight into the physiology of bacteria in situ, dedicated approaches are required to monitor their adaptations and specific behaviors under environmental conditions. optical microscopy is crucial for the observation of fundamental characteristics of bacteria, such as cell shape, size, and marker gene expression. here, fluidic force microscopy (fluidfm) was exploited to isolate optic ...201323770907
mercurial-resistance determinants in pseudomonas strain k-62 plasmid pmr68.we report the complete nucleotide sequence of plasmid pmr68, isolated from pseudomonas strain k-62, two plasmids contribute to broad-spectrum mercury resistance and that the mer operon from one of them (pmr26) has been previously characterized. the plasmid was 71,020 bp in length and contained 75 coding regions. three mer gene clusters were identified. the first comprised merr-orf4-orf5-mert1-merp1-merf-mera-merb1, which confers bacterial resistance to mercuric ions and organomercury. the second ...201323890172
function and x-ray crystal structure of escherichia coli yfde.many food plants accumulate oxalate, which humans absorb but do not metabolize, leading to the formation of urinary stones. the commensal bacterium oxalobacter formigenes consumes oxalate by converting it to oxalyl-coa, which is decarboxylated by oxalyl-coa decarboxylase (oxc). oxc and the class iii coa-transferase formyl-coa:oxalate coa-transferase (fcoct) are widespread among bacteria, including many that have no apparent ability to degrade or to resist external oxalate. the evga acid response ...201323935849
distribution and origin of oxygen-dependent and oxygen-independent forms of mg-protoporphyrin monomethylester cyclase among phototrophic proteobacteria.magnesium-protoporphyrin ix monomethylester cyclase is one of the key enzymes of the bacteriochlorophyll biosynthesis pathway. there exist two fundamentally different forms of this enzyme. the oxygen-dependent form, encoded by the gene acsf, catalyzes the formation of the bacteriochlorophyll fifth ring using oxygen, whereas the oxygen-independent form encoded by the gene bche utilizes an oxygen atom extracted from water. the presence of acsf and bche genes was surveyed in various phototrophic pr ...201323396335
navigating the b(12) road: assimilation, delivery, and disorders of cobalamin.the reactivity of the cobalt-carbon bond in cobalamins is the key to their chemical versatility, supporting both methyl transfer and isomerization reactions. during evolution of higher eukaryotes that utilize vitamin b12, the high reactivity of the cofactor coupled with its low abundance pressured development of an efficient system for uptake, assimilation, and delivery of the cofactor to client b12-dependent enzymes. although most proteins suspected to be involved in b12 trafficking were discov ...201323539619
synchronous waves of failed soft sweeps in the laboratory: remarkably rampant clonal interference of alleles at a single locus.it has increasingly been recognized that adapting populations of microbes contain not one, but many lineages continually arising and competing at once. this process, termed "clonal interference," alters the rate and dynamics of adaptation and biases winning mutations toward those with the largest selective effect. here we uncovered a dramatic example of clonal interference between multiple similar mutations occurring at the same locus within replicate populations of methylobacterium extorquens a ...201323307898
isolation and expression of a cdna encoding methylmalonic aciduria type a protein from euglena gracilis z.in animals, cobalamin (cbl) is a cofactor for methionine synthase and methylmalonyl-coa mutase (mcm), which utilizes methylcobalamin and 5'-deoxyadenosylcobalamin (adocbl), respectively. the cbla complementation class of inborn errors of cbl metabolism in humans is one of three known disorders that affect adocbl synthesis. the gene responsible for cbla has been identified in humans (mmaa) as well as its homolog (meab) in methylobacterium extorquens. recently, it has been reported that human mmaa ...201324957894
fim-1, a new acquired metallo-β-lactamase from a pseudomonas aeruginosa clinical isolate from italy.acquired metallo-β-lactamases (mbls) are resistance determinants of increasing clinical importance in gram-negative bacterial pathogens, which confer a broad-spectrum β-lactam resistance, including carbapenems. several such enzymes have been described since the 1990s. in the present study, a novel acquired mbl, named fim-1, was identified and characterized. the bla(fim-1) gene was cloned from a multidrug-resistant pseudomonas aeruginosa clinical isolate (fi-14/157) cultured from a patient with a ...201323114762
development of an optimized medium, strain and high-throughput culturing methods for methylobacterium extorquens.methylobacterium extorquens strains are the best-studied methylotrophic model system, and their metabolism of single carbon compounds has been studied for over 50 years. here we develop a new system for high-throughput batch culture of m. extorquens in microtiter plates by jointly optimizing the properties of the organism, the growth media and the culturing system. after removing cellulose synthase genes in m. extorquens strains am1 and pa1 to prevent biofilm formation, we found that currently a ...201323646164
global molecular analyses of methane metabolism in methanotrophic alphaproteobacterium, methylosinus trichosporium ob3b. part ii. metabolomics and 13c-labeling study.in this work we use metabolomics and (13)c-labeling data to refine central metabolic pathways for methane utilization in methylosinus trichosporium ob3b, a model alphaproteobacterial methanotrophic bacterium. we demonstrate here that similar to non-methane utilizing methylotrophic alphaproteobacteria the core metabolism of the microbe is represented by several tightly connected metabolic cycles, such as the serine pathway, the ethylmalonyl-coa (emc) pathway, and the citric acid (tca) cycle. both ...201323565113
global molecular analyses of methane metabolism in methanotrophic alphaproteobacterium, methylosinus trichosporium ob3b. part i: transcriptomic study.methane utilizing bacteria (methanotrophs) are important in both environmental and biotechnological applications, due to their ability to convert methane to multicarbon compounds. however, systems-level studies of methane metabolism have not been carried out in methanotrophs. in this work we have integrated genomic and transcriptomic information to provide an overview of central metabolic pathways for methane utilization in methylosinus trichosporium ob3b, a model alphaproteobacterial methanotro ...201323565111
a switch iii motif relays signaling between a b12 enzyme and its g-protein chaperone.fidelity during cofactor assembly is essential for the proper functioning of metalloenzymes and is ensured by specific chaperones. meab, a g-protein chaperone for the coenzyme b12-dependent radical enzyme methylmalonyl-coa mutase (mcm), uses the energy of gtp binding, hydrolysis or both to regulate cofactor loading into mcm, protect mcm from inactivation and rescue mcm that is inactivated during turnover. typically, g proteins signal to client proteins using the conformationally mobile switch i ...201323873214
blue light regulated two-component systems: enzymatic and functional analyses of light-oxygen-voltage (lov)-histidine kinases and downstream response regulators.light is an essential environmental cue for diverse organisms. many prokaryotic blue light photoreceptors use light, oxygen, voltage (lov) sensory domains to control the activities of diverse output domains, including histidine kinases (hk). upon activation, these proteins autophosphorylate a histidine residue before subsequently transferring the phosphate to an aspartate residue in the receiver domain of a cognate response regulator (rr). such phosphorylation activates the output domain of the ...201323806044
crystallization and preliminary x-ray crystallographic analysis of mxaj, a component of the methanol-oxidizing system operon from the marine bacterium methylophaga aminisulfidivorans mpt.the methanol-oxidizing system (mox) is essential for methylotrophic bacteria to extract energy during the oxidoreduction reaction and consists of a series of electron-transfer proteins encoded by the mox operon. one of the key enzymes is the α₂β₂ methanol dehydrogenase complex (type i mdh), which converts methanol to formaldehyde during the 2e⁻ transfer through the prosthetic group pyrroloquinoline quinone. mxaj, a product of mxaj of the mox operon, is a component of the mdh complex and enhances ...201323908039
the methanol dehydrogenase gene, mxaf, as a functional and phylogenetic marker for proteobacterial methanotrophs in natural environments.the mxaf gene, coding for the large (α) subunit of methanol dehydrogenase, is highly conserved among distantly related methylotrophic species in the alpha-, beta- and gammaproteobacteria. it is ubiquitous in methanotrophs, in contrast to other methanotroph-specific genes such as the pmoa and mmox genes, which are absent in some methanotrophic proteobacterial genera. this study examined the potential for using the mxaf gene as a functional and phylogenetic marker for methanotrophs. mxaf and 16s r ...201323451130
intrigues and intricacies of the biosynthetic pathways for the enzymatic quinocofactors: pqq, ttq, ctq, tpq, and ltq. 201324350630
intrigues and intricacies of the biosynthetic pathways for the enzymatic quinocofactors: pqq, ttq, ctq, tpq, and ltq. 201324350630
cumate-inducible gene expression system for sphingomonads and other alphaproteobacteria.tunable promoters represent a pivotal genetic tool for a wide range of applications. here we present such a system for sphingomonads, a phylogenetically diverse group of bacteria that have gained much interest for their potential in bioremediation and their use in industry and for which no dedicated inducible gene expression system has been described so far. a strong, constitutive synthetic promoter was first identified through a genetic screen and subsequently combined with the repressor and th ...201323995928
bacterial endosymbiosis in a chordate host: long-term co-evolution and conservation of secondary metabolism.intracellular symbiosis is known to be widespread in insects, but there are few described examples in other types of host. these symbionts carry out useful activities such as synthesizing nutrients and conferring resistance against adverse events such as parasitism. such symbionts persist through host speciation events, being passed down through vertical transmission. due to various evolutionary forces, symbionts go through a process of genome reduction, eventually resulting in tiny genomes wher ...201324324632
whole-proteome analysis of twelve species of alphaproteobacteria links four pathogens.thousands of whole-genome and whole-proteome sequences have been made available through advances in sequencing technology, and sequences of millions more organisms will become available in the coming years. this wealth of genetic information will provide numerous opportunities to enhance our understanding of these organisms including a greater understanding of relationships among species. researchers have used 16s rrna and other gene sequences to study the evolutionary origins of bacteria, but t ...201325437336
c1 metabolism in corynebacterium glutamicum: an endogenous pathway for oxidation of methanol to carbon dioxide.methanol is considered an interesting carbon source in "bio-based" microbial production processes. since corynebacterium glutamicum is an important host in industrial biotechnology, in particular for amino acid production, we performed studies of the response of this organism to methanol. the c. glutamicum wild type was able to convert (13)c-labeled methanol to (13)co2. analysis of global gene expression in the presence of methanol revealed several genes of ethanol catabolism to be upregulated, ...201324014532
type i pyridoxal 5'-phosphate dependent enzymatic domains embedded within multimodular nonribosomal peptide synthetase and polyketide synthase assembly lines.pyridoxal 5'-phosphate (plp)-dependent enzymes of fold type i, the most studied structural class of the plp-dependent enzyme superfamily, are known to exist as stand-alone homodimers or homotetramers. these enzymes have been found also embedded in multimodular and multidomain assembly lines involved in the biosynthesis of polyketides (pks) and nonribosomal peptides (nrps). the aim of this work is to provide a proteome-wide view of the distribution and characteristics of type i domains covalently ...201324148833
beating the acetyl coenzyme a-pathway to the origin of life.attempts to draft plausible scenarios for the origin of life have in the past mainly built upon palaeogeochemical boundary conditions while, as detailed in a companion article in this issue, frequently neglecting to comply with fundamental thermodynamic laws. even if demands from both palaeogeochemistry and thermodynamics are respected, then a plethora of strongly differing models are still conceivable. although we have no guarantee that life at its origin necessarily resembled biology in extant ...201323754811
molecular adaptation mechanisms employed by ethanologenic bacteria in response to lignocellulose-derived inhibitory compounds.current international interest in finding alternative sources of energy to the diminishing supplies of fossil fuels has encouraged research efforts in improving biofuel production technologies. in countries which lack sufficient food, the use of sustainable lignocellulosic feedstocks, for the production of bioethanol, is an attractive option. in the pre-treatment of lignocellulosic feedstocks for ethanol production, various chemicals and/or enzymatic processes are employed. these methods general ...201323847442
diverse capacity for 2-methylhopanoid production correlates with a specific ecological niche.molecular fossils of 2-methylhopanoids are prominent biomarkers in modern and ancient sediments that have been used as proxies for cyanobacteria and their main metabolism, oxygenic photosynthesis. however, substantial culture and genomic-based evidence now indicates that organisms other than cyanobacteria can make 2-methylhopanoids. because few data directly address which organisms produce 2-methylhopanoids in the environment, we used metagenomic and clone library methods to determine the enviro ...201324152713
diverse capacity for 2-methylhopanoid production correlates with a specific ecological niche.molecular fossils of 2-methylhopanoids are prominent biomarkers in modern and ancient sediments that have been used as proxies for cyanobacteria and their main metabolism, oxygenic photosynthesis. however, substantial culture and genomic-based evidence now indicates that organisms other than cyanobacteria can make 2-methylhopanoids. because few data directly address which organisms produce 2-methylhopanoids in the environment, we used metagenomic and clone library methods to determine the enviro ...201324152713
elucidation of the role of the methylene-tetrahydromethanopterin dehydrogenase mtda in the tetrahydromethanopterin-dependent oxidation pathway in methylobacterium extorquens am1.the methylotroph methylobacterium extorquens am1 oxidizes methanol and methylamine to formaldehyde and subsequently to formate, an intermediate that serves as the branch point between assimilation (formation of biomass) and dissimilation (oxidation to co₂). the oxidation of formaldehyde to formate is dephosphotetrahydromethanopterin (dh₄mpt) dependent, while the assimilation of carbon into biomass is tetrahydrofolate (h₄f) dependent. this bacterium contains two different enzymes, mtda and mtdb, ...201323504017
lateral transfer and gc content of bacterial resistant genes. 201323487592
the 380 kb pcmu01 plasmid encodes chloromethane utilization genes and redundant genes for vitamin b12- and tetrahydrofolate-dependent chloromethane metabolism in methylobacterium extorquens cm4: a proteomic and bioinformatics study.chloromethane (ch3cl) is the most abundant volatile halocarbon in the atmosphere and contributes to the destruction of stratospheric ozone. the only known pathway for bacterial chloromethane utilization (cmu) was characterized in methylobacterium extorquens cm4, a methylotrophic bacterium able to utilize compounds without carbon-carbon bonds such as methanol and chloromethane as the sole carbon source for growth. previous work demonstrated that tetrahydrofolate and vitamin b12 are essential cofa ...201323593113
plant-bacterium interactions analyzed by proteomics.the evolution of the plant immune response has resulted in a highly effective defense system that is able to resist potential attack by microbial pathogens. the primary immune response is referred to as pathogen associated molecular pattern (pamp) triggered immunity and has evolved to recognize common features of microbial pathogens. in response to the delivery of pathogen effector proteins, plants acquired r proteins to fight against pathogen attack. r-dependent defense response is important in ...201323424014
insights into denitrification in methylotenera mobilis from denitrification pathway and methanol metabolism mutants.we investigated phenotypes of mutants of methylotenera mobilis jlw8 with lesions in genes predicted to encode functions of the denitrification pathway, as well as mutants with mutations in methanol dehydrogenase-like structural genes xoxf1 and xoxf2, in order to obtain insights into denitrification and methanol metabolism by this bacterium. by monitoring the accumulation of nitrous oxide, we demonstrate that a periplasmic nitrate reductase, nad(p)-linked and copper-containing nitrite reductases, ...201323475964
evolution after introduction of a novel metabolic pathway consistently leads to restoration of wild-type physiology.organisms cope with physiological stressors through acclimatizing mechanisms in the short-term and adaptive mechanisms over evolutionary timescales. during adaptation to an environmental or genetic perturbation, beneficial mutations can generate numerous physiological changes: some will be novel with respect to prior physiological states, while others might either restore acclimatizing responses to a wild-type state, reinforce them further, or leave them unchanged. we examined the interplay of a ...201323593025
the bartonella quintana extracytoplasmic function sigma factor rpoe has a role in bacterial adaptation to the arthropod vector environment.bartonella quintana is a vector-borne bacterial pathogen that causes fatal disease in humans. during the infectious cycle, b. quintana transitions from the hemin-restricted human bloodstream to the hemin-rich body louse vector. because extracytoplasmic function (ecf) sigma factors often regulate adaptation to environmental changes, we hypothesized that a previously unstudied b. quintana ecf sigma factor, rpoe, is involved in the transition from the human host to the body louse vector. the genomi ...201323564167
a novel pair of inducible expression vectors for use in methylobacterium extorquens.due to the ever increasing use of diverse microbial taxa in basic research and industrial settings, there is a growing need for genetic tools to alter the physiology of these organisms. in particular, there is a dearth of inducible expression systems available for bacteria outside commonly used γ-proteobacteria, such as escherichia coli or pseudomonas species. to this end, we have sought to develop a pair of inducible expression vectors for use in the α-proteobacterium methylobacterium extorquen ...201323648175
rhizosphere microbiome assemblage is affected by plant development.there is a concerted understanding of the ability of root exudates to influence the structure of rhizosphere microbial communities. however, our knowledge of the connection between plant development, root exudation and microbiome assemblage is limited. here, we analyzed the structure of the rhizospheric bacterial community associated with arabidopsis at four time points corresponding to distinct stages of plant development: seedling, vegetative, bolting and flowering. overall, there were no sign ...201324196324
rhizosphere microbiome assemblage is affected by plant development.there is a concerted understanding of the ability of root exudates to influence the structure of rhizosphere microbial communities. however, our knowledge of the connection between plant development, root exudation and microbiome assemblage is limited. here, we analyzed the structure of the rhizospheric bacterial community associated with arabidopsis at four time points corresponding to distinct stages of plant development: seedling, vegetative, bolting and flowering. overall, there were no sign ...201324196324
detection of organic compounds with whole-cell bioluminescent bioassays.natural and manmade organic chemicals are widely deposited across a diverse range of ecosystems including air, surface water, groundwater, wastewater, soil, sediment, and marine environments. some organic compounds, despite their industrial values, are toxic to living organisms and pose significant health risks to humans and wildlife. detection and monitoring of these organic pollutants in environmental matrices therefore is of great interest and need for remediation and health risk assessment. ...201425084996
heterologous expression and characterization of the manganese-oxidizing protein from erythrobacter sp. strain sd21.the manganese (mn)-oxidizing protein (mopa) from erythrobacter sp. strain sd21 is part of a unique enzymatic family that is capable of oxidizing soluble mn(ii). this enzyme contains two domains, an animal heme peroxidase domain, which contains the catalytic site, followed by a c-terminal calcium binding domain. different from the bacterial mn-oxidizing multicopper oxidase enzymes, little is known about mopa. to gain a better understanding of mopa and its role in mn(ii) oxidation, the 238-kda ful ...201425172859
the bacterial rhizobiome of hyperaccumulators: future perspectives based on omics analysis and advanced microscopy.hyperaccumulators are plants that can extract heavy metal ions from the soil and translocate those ions to the shoots, where they are sequestered and detoxified. hyperaccumulation depends not only on the availability of mobilized metal ions in the soil, but also on the enhanced activity of metal transporters and metal chelators which may be provided by the plant or its associated microbes. the rhizobiome is captured by plant root exudates from the complex microbial community in the soil, and may ...201425709609
the bacterial rhizobiome of hyperaccumulators: future perspectives based on omics analysis and advanced microscopy.hyperaccumulators are plants that can extract heavy metal ions from the soil and translocate those ions to the shoots, where they are sequestered and detoxified. hyperaccumulation depends not only on the availability of mobilized metal ions in the soil, but also on the enhanced activity of metal transporters and metal chelators which may be provided by the plant or its associated microbes. the rhizobiome is captured by plant root exudates from the complex microbial community in the soil, and may ...201425709609
kdo hydroxylase is an inner core assembly enzyme in the ko-containing lipopolysaccharide biosynthesis.the lipopolysaccharide (lps) isolated from certain important gram-negative pathogens including a human pathogen yersinia pestis and opportunistic pathogens burkholderia mallei and burkholderia pseudomallei contains d-glycero-d-talo-oct-2-ulosonic acid (ko), an isosteric analog of 3-deoxy-d-manno-oct-2-ulosonic acid (kdo). kdo 3-hydroxylase (kdoo), a fe(2+)/α-kg/o2 dependent dioxygenase from burkholderia ambifaria and yersinia pestis is responsible for ko formation with kdo2-lipid a as a substrat ...201425204504
a closer look on the polyhydroxybutyrate- (phb-) negative phenotype of ralstonia eutropha phb-4.the undefined poly(3-hydroxybutyrate)- (phb-) negative mutant r. eutropha phb-4 was generated in 1970 by 1-nitroso-3-nitro-1-methylguanidine (nmg) treatment. although being scientific relevant, its genotype remained unknown since its isolation except a recent first investigation. in this study, the mutation causing the pha-negative phenotype of r. eutropha phb-4 was confirmed independently: sequence analysis of the phacab operon identified a g320a mutation in phac yielding a stop codon, leading ...201424787649
bacterial metabolism of methylated amines and identification of novel methylotrophs in movile cave.movile cave, romania, is an unusual underground ecosystem that has been sealed off from the outside world for several million years and is sustained by non-phototrophic carbon fixation. methane and sulfur-oxidising bacteria are the main primary producers, supporting a complex food web that includes bacteria, fungi and cave-adapted invertebrates. a range of methylotrophic bacteria in movile cave grow on one-carbon compounds including methylated amines, which are produced via decomposition of orga ...201425050523
bacterial metabolism of methylated amines and identification of novel methylotrophs in movile cave.movile cave, romania, is an unusual underground ecosystem that has been sealed off from the outside world for several million years and is sustained by non-phototrophic carbon fixation. methane and sulfur-oxidising bacteria are the main primary producers, supporting a complex food web that includes bacteria, fungi and cave-adapted invertebrates. a range of methylotrophic bacteria in movile cave grow on one-carbon compounds including methylated amines, which are produced via decomposition of orga ...201425050523
cecafdb: a curated database for the documentation, visualization and comparative analysis of central carbon metabolic flux distributions explored by 13c-fluxomics.the central carbon metabolic flux database (cecafdb, available at http://www.cecafdb.org) is a manually curated, multipurpose and open-access database for the documentation, visualization and comparative analysis of the quantitative flux results of central carbon metabolism among microbes and animal cells. it encompasses records for more than 500 flux distributions among 36 organisms and includes information regarding the genotype, culture medium, growth conditions and other specific information ...201425392417
cecafdb: a curated database for the documentation, visualization and comparative analysis of central carbon metabolic flux distributions explored by 13c-fluxomics.the central carbon metabolic flux database (cecafdb, available at http://www.cecafdb.org) is a manually curated, multipurpose and open-access database for the documentation, visualization and comparative analysis of the quantitative flux results of central carbon metabolism among microbes and animal cells. it encompasses records for more than 500 flux distributions among 36 organisms and includes information regarding the genotype, culture medium, growth conditions and other specific information ...201425392417
a putative bifunctional histidine kinase/phosphatase of the hwe family exerts positive and negative control on the sinorhizobium meliloti general stress response.the ecfg-type sigma factor rpoe2 is the regulator of the general stress response in sinorhizobium meliloti. rpoe2 activity is negatively regulated by two nepr-type anti-sigma factors (rsia1/a2), themselves under the control of two anti-anti-sigma factors (rsib1/b2) belonging to the phyr family of response regulators. the current model of rpoe2 activation suggests that in response to stress, rsib1/b2 are activated by phosphorylation of an aspartate residue in their receiver domain. once activated ...201424794560
spectroscopic characterization of a green copper site in a single-domain cupredoxin.cupredoxins are widespread copper-binding proteins, mainly involved in electron transfer pathways. they display a typical rigid greek key motif consisting of an eight stranded β-sandwich. a fascinating feature of cupredoxins is the natural diversity of their copper center geometry. these geometry variations give rise to drastic changes in their color, such as blue, green, red or purple. based on several spectroscopic and structural analyses, a connection between the geometry of their copper-bind ...201424932914
complex two-component signaling regulates the general stress response in alphaproteobacteria.the general stress response (gsr) in alphaproteobacteria was recently shown to be controlled by a partner-switching mechanism that is triggered by phosphorylation of the response regulator phyr. activation of phyr ultimately results in release of the alternative extracytoplasmic function sigma factor σ(ecfg), which redirects transcription toward the gsr. little is known about the signal transduction pathway(s) controlling phyr phosphorylation. here, we identified the single-domain response regul ...201425404331
novel characteristics of succinate coenzyme a (succinate-coa) ligases: conversion of malate to malyl-coa and coa-thioester formation of succinate analogues in vitro.three succinate coenzyme a (succinate-coa) ligases (succd) from escherichia coli, advenella mimigardefordensis dpn7(t), and alcanivorax borkumensis sk2 were characterized regarding their substrate specificity concerning succinate analogues. previous studies had suggested that succd enzymes might be promiscuous toward succinate analogues, such as itaconate and 3-sulfinopropionate (3sp). the latter is an intermediate of the degradation pathway of 3,3'-dithiodipropionate (dtdp), a precursor for the ...201424141127
metalloproteins containing cytochrome, iron-sulfur, or copper redox centers. 201424758379
community acquired roseomonas infection in a pre-existing tubercular lung lesion.roseomonas are nonfermenting opportunistic gram-negative bacilli belonging to the newly established genus of roseomonas. the clinical experience with the species is limited and is difficult to diagnose because of limited expertise and lack of commercially available identification kits with any of the automated systems. this is a first ever reported case of secondary bacterial infection due to roseomonas genomospecies 6 in a patient of pulmonary tuberculosis from the indian subcontinent.201425125823
evolution of mitochondria reconstructed from the energy metabolism of living bacteria.the ancestors of mitochondria, or proto-mitochondria, played a crucial role in the evolution of eukaryotic cells and derived from symbiotic α-proteobacteria which merged with other microorganisms - the basis of the widely accepted endosymbiotic theory. however, the identity and relatives of proto-mitochondria remain elusive. here we show that methylotrophic α-proteobacteria could be the closest living models for mitochondrial ancestors. we reached this conclusion after reconstructing the possibl ...201424804722
metabolic engineering of methylobacterium extorquens am1 for 1-butanol production.butanol is a promising next generation fuel and a bulk chemical precursor. although clostridia are the primary industrial microbes for the fermentative production of 1-butanol, alternative engineered hosts have the potential to generate 1-butanol from alternative carbon feedstocks via synthetic metabolic pathways. methylobacterium extorquens am1, a facultative methylotrophic α-proteobacterium, is a model system for assessing the possibility of generating products such as 1-butanol from one-carbo ...201425349627
molecular characterization of a novel temperate sinorhizobium bacteriophage, фlm21, encoding dna methyltransferase with ccrm-like specificity.φlm21 is a temperate phage isolated from sinorhizobium sp. strain lm21 (alphaproteobacteria). genomic analysis and electron microscopy suggested that φlm21 is a member of the family siphoviridae. the phage has an isometric head and a long noncontractile tail. the genome of φlm21 has 50,827 bp of linear double-stranded dna encoding 72 putative proteins, including proteins responsible for the assembly of the phage particles, dna packaging, transcription, replication, and lysis. virion proteins wer ...201425187538
riboregulation in plant-associated α-proteobacteria.the symbiotic α-rhizobia sinorhizobium meliloti, bradyrhizobium japonicum, rhizobium etli and the related plant pathogen agrobacterium tumefaciens are important model organisms for studying plant-microbe interactions. these metabolically versatile soil bacteria are characterized by complex lifestyles and large genomes. here we summarize the recent knowledge on their small non-coding rnas (srnas) including conservation, function, and interaction of the srnas with the rna chaperone hfq. in each of ...201425003187
the moxr atpase rava and its cofactor viaa interact with the nadh:ubiquinone oxidoreductase i in escherichia coli.moxr atpases are widespread throughout bacteria and archaea. the experimental evidence to date suggests that these proteins have chaperone-like roles in facilitating the maturation of dedicated protein complexes that are functionally diverse. in escherichia coli, the moxr atpase rava and its putative cofactor viaa are found to exist in early stationary-phase cells at 37 °c at low levels of about 350 and 90 molecules per cell, respectively. both proteins are predominantly localized to the cytopla ...201424454883
molecular, physiological and phenotypic characterization of paracoccus denitrificans atcc 19367 mutant strain p-87 producing improved coenzyme q10.coenzyme q10 (coq10) is a blockbuster nutraceutical molecule which is often used as an oral supplement in the supportive therapy for cardiovascular diseases, cancer and neurodegenerative diseases. it is commercially produced by fermentation process, hence constructing the high yielding coq10 producing strains is a pre-requisite for cost effective production. paracoccus denitrificans atcc 19367, a biochemically versatile organism was selected to carry out the studies on coq10 yield improvement. t ...201425805905
molecular, physiological and phenotypic characterization of paracoccus denitrificans atcc 19367 mutant strain p-87 producing improved coenzyme q10.coenzyme q10 (coq10) is a blockbuster nutraceutical molecule which is often used as an oral supplement in the supportive therapy for cardiovascular diseases, cancer and neurodegenerative diseases. it is commercially produced by fermentation process, hence constructing the high yielding coq10 producing strains is a pre-requisite for cost effective production. paracoccus denitrificans atcc 19367, a biochemically versatile organism was selected to carry out the studies on coq10 yield improvement. t ...201425805905
biotechnological strategies to improve production of microbial poly-(3-hydroxybutyrate): a review of recent research work.poly-(3-hydroxybutyrate) [p(3hb)] is a polyester synthesized as a carbon and energy reserve material by a wide number of bacteria. this polymer is characterized by its thermo-plastic properties similar to plastics derived from petrochemical industry, such as polyethylene and polypropylene. furthermore, p(3hb) is an inert, biocompatible and biodegradable material which has been proposed for several uses in medical and biomedical areas. currently, only few bacterial species such as cupriavidus nec ...201424898500
ethylmalonyl coenzyme a mutase operates as a metabolic control point in methylobacterium extorquens am1.the metabolism of one- and two-carbon compounds by the methylotrophic bacterium methylobacterium extorquens am1 involves high carbon flux through the ethylmalonyl coenzyme a (ethylmalonyl-coa) pathway (emc pathway). during growth on ethylamine, the emc pathway operates as a linear pathway carrying the full assimilatory flux to produce glyoxylate, malate, and succinate. assimilatory carbon enters the ethylmalonyl-coa pathway directly as acetyl-coa, bypassing pathways for formaldehyde oxidation/as ...201425448820
methylamine utilization via the n-methylglutamate pathway in methylobacterium extorquens pa1 involves a novel flow of carbon through c1 assimilation and dissimilation pathways.methylotrophs grow on reduced single-carbon compounds like methylamine as the sole source of carbon and energy. in methylobacterium extorquens am1, the best-studied aerobic methylotroph, a periplasmic methylamine dehydrogenase that catalyzes the primary oxidation of methylamine to formaldehyde has been examined in great detail. however, recent metagenomic data from natural ecosystems are revealing the abundance and importance of lesser-known routes, such as the n-methylglutamate pathway, for met ...201425225269
ethylmalonyl coenzyme a mutase operates as a metabolic control point in methylobacterium extorquens am1.the metabolism of one- and two-carbon compounds by the methylotrophic bacterium methylobacterium extorquens am1 involves high carbon flux through the ethylmalonyl coenzyme a (ethylmalonyl-coa) pathway (emc pathway). during growth on ethylamine, the emc pathway operates as a linear pathway carrying the full assimilatory flux to produce glyoxylate, malate, and succinate. assimilatory carbon enters the ethylmalonyl-coa pathway directly as acetyl-coa, bypassing pathways for formaldehyde oxidation/as ...201425448820
emergent biosynthetic capacity in simple microbial communities.microbes have an astonishing capacity to transform their environments. yet, the metabolic capacity of a single species is limited and the vast majority of microorganisms form complex communities and join forces to exhibit capabilities far exceeding those achieved by any single species. such enhanced metabolic capacities represent a promising route to many medical, environmental, and industrial applications and call for the development of a predictive, systems-level understanding of synergistic m ...201424992662
phylogeny poorly predicts the utility of a challenging horizontally transferred gene in methylobacterium strains.horizontal gene transfer plays a crucial role in microbial evolution. while much is known about the mechanisms that determine whether physical dna can be transferred into a new host, the factors determining the utility of the transferred genes are less clear. we have explored this issue using dichloromethane consumption in methylobacterium strains. methylobacterium extorquens dm4 expresses a dichloromethane dehalogenase (dcma) that has been acquired through horizontal gene transfer and allows th ...201424682326
stable isotope-labeling studies in metabolomics: new insights into structure and dynamics of metabolic networks.the rapid emergence of metabolomics has enabled system-wide measurements of metabolites in various organisms. however, advances in the mechanistic understanding of metabolic networks remain limited, as most metabolomics studies cannot routinely provide accurate metabolite identification, absolute quantification and flux measurement. stable isotope labeling offers opportunities to overcome these limitations. here we describe some current approaches to stable isotope-labeled metabolomics and provi ...201424568354
laboratory divergence of methylobacterium extorquens am1 through unintended domestication and past selection for antibiotic resistance.a common assumption of microorganisms is that laboratory stocks will remain genetically and phenotypically constant over time, and across laboratories. it is becoming increasingly clear, however, that mutations can ruin strain integrity and drive the divergence or "domestication" of stocks. since its discovery in 1960, a stock of methylobacterium extorquens am1 ("am1") has remained in the lab, propagated across numerous growth and storage conditions, researchers, and facilities. to explore the e ...201424384040
variation in the fitness effects of mutations with population density and size in escherichia coli.the fitness effects of mutations are context specific and depend on both external (e.g., environment) and internal (e.g., cellular stress, genetic background) factors. the influence of population size and density on fitness effects are unknown, despite the central role population size plays in the supply and fixation of mutations. we addressed this issue by comparing the fitness of 92 keio strains (escherichia coli k12 single gene knockouts) at comparatively high (1.2×10(7) cfus/ml) and low (2.5 ...201425121498
tunable control of polyproline helix (ppii) structure via aromatic electronic effects: an electronic switch of polyproline helix.aromatic rings exhibit defined interactions via the unique aromatic π face. aromatic amino acids interact favorably with proline residues via both the hydrophobic effect and aromatic-proline interactions, c-h/π interactions between the aromatic π face and proline ring c-h bonds. the canonical aromatic amino acids trp, tyr, and phe strongly disfavor a polyproline helix (ppii) when they are present in proline-rich sequences because of the large populations of cis amide bonds induced by favorable a ...201425075447
genetic and phenotypic comparison of facultative methylotrophy between methylobacterium extorquens strains pa1 and am1.methylobacterium extorquens am1, a strain serendipitously isolated half a century ago, has become the best-characterized model system for the study of aerobic methylotrophy (the ability to grow on reduced single-carbon compounds). however, with 5 replicons and 174 insertion sequence (is) elements in the genome as well as a long history of domestication in the laboratory, genetic and genomic analysis of m. extorquens am1 face several challenges. on the contrary, a recently isolated strain - m. ex ...201425232997
genome information of methylobacterium oryzae, a plant-probiotic methylotroph in the phyllosphere.pink-pigmented facultative methylotrophs in the rhizobiales are widespread in the environment, and many methylobacterium species associated with plants produce plant growth-promoting substances. to gain insights into the life style at the phyllosphere and the genetic bases of plant growth promotion, we determined and analyzed the complete genome sequence of methylobacterium oryzae cbmb20t, a strain isolated from rice stem. the genome consists of a 6.29-mb chromosome and four plasmids, designated ...201425211235
evolution of escherichia coli to 42 °c and subsequent genetic engineering reveals adaptive mechanisms and novel mutations.adaptive laboratory evolution (ale) has emerged as a valuable method by which to investigate microbial adaptation to a desired environment. here, we performed ale to 42 °c of ten parallel populations of escherichia coli k-12 mg1655 grown in glucose minimal media. tightly controlled experimental conditions allowed selection based on exponential-phase growth rate, yielding strains that uniformly converged toward a similar phenotype along distinct genetic paths. adapted strains possessed as few as ...201425015645
draft genome sequence of methylobacterium sp. strain l2-4, a leaf-associated endophytic n-fixing bacterium isolated from jatropha curcas l.methylobacterium sp. strain l2-4 is an efficient nitrogen-fixing leaf colonizer of biofuel crop jatropha curcas. this strain is able to greatly improve the growth and seed yield of jatropha curcas and is the second reported genome sequence of plant growth-promoting bacteria isolated from jatropha curcas.201425502683
probing the diversity of chloromethane-degrading bacteria by comparative genomics and isotopic fractionation.chloromethane (ch3cl) is produced on earth by a variety of abiotic and biological processes. it is the most important halogenated trace gas in the atmosphere, where it contributes to ozone destruction. current estimates of the global ch3cl budget are uncertain and suggest that microorganisms might play a more important role in degrading atmospheric ch3cl than previously thought. its degradation by bacteria has been demonstrated in marine, terrestrial, and phyllospheric environments. improving ou ...201425360131
contribution of silent mutations to thermal adaptation of rna bacteriophage qβ.changes in protein function and other biological properties, such as rna structure, are crucial for adaptation of organisms to novel or inhibitory environments. to investigate how mutations that do not alter amino acid sequence may be positively selected, we performed a thermal adaptation experiment using the single-stranded rna bacteriophage qβ in which the culture temperature was increased from 37.2°c to 41.2°c and finally to an inhibitory temperature of 43.6°c in a stepwise manner in three in ...201425056887
effective use of a horizontally-transferred pathway for dichloromethane catabolism requires post-transfer refinement.when microbes acquire new abilities through horizontal gene transfer, the genes and pathways must function under conditions with which they did not coevolve. if newly-acquired genes burden the host, their utility will depend on further evolutionary refinement of the recombinant strain. we used laboratory evolution to recapitulate this process of transfer and refinement, demonstrating that effective use of an introduced dichloromethane degradation pathway required one of several mutations to the ...201425418043
structure of the methanofuran/methanopterin-biosynthetic enzyme mj1099 from methanocaldococcus jannaschii.prior studies have indicated that mj1099 from methanocaldococcus jannaschii has roles in the biosynthesis of tetrahydromethanopterin and methanofuran, two key cofactors of one-carbon (c1) metabolism in diverse organisms including the methanogenic archaea. here, the structure of mj1099 has been solved to 1.7 å resolution using anomalous scattering methods. the results indicate that mj1099 is a member of the tim-barrel superfamily and that it is a homohexamer. bioinformatic analyses identified a p ...201425372812
trade-offs drive resource specialization and the gradual establishment of ecotypes.speciation is driven by many different factors. among those are trade-offs between different ways an organism utilizes resources, and these trade-offs can constrain the manner in which selection can optimize traits. limited migration among allopatric populations and species interactions can also drive speciation, but here we ask if trade-offs alone are sufficient to drive speciation in the absence of other factors.201424885598
metabolomic strategies for the identification of new enzyme functions and metabolic pathways.recent technological advances in accurate mass spectrometry and data analysis have revolutionized metabolomics experimentation. activity-based and global metabolomic profiling methods allow simultaneous and rapid screening of hundreds of metabolites from a variety of chemical classes, making them useful tools for the discovery of novel enzymatic activities and metabolic pathways. by using the metabolome of the relevant organism or close species, these methods capitalize on biological relevance, ...201424829223
metabolic resource allocation in individual microbes determines ecosystem interactions and spatial dynamics.the interspecies exchange of metabolites plays a key role in the spatiotemporal dynamics of microbial communities. this raises the question of whether ecosystem-level behavior of structured communities can be predicted using genome-scale metabolic models for multiple organisms. we developed a modeling framework that integrates dynamic flux balance analysis with diffusion on a lattice and applied it to engineered communities. first, we predicted and experimentally confirmed the species ratio to w ...201424794435
genomic and transcriptomic analyses of the facultative methanotroph methylocystis sp. strain sb2 grown on methane or ethanol.a minority of methanotrophs are able to utilize multicarbon compounds as growth substrates in addition to methane. the pathways utilized by these microorganisms for assimilation of multicarbon compounds, however, have not been explicitly examined. here, we report the draft genome of the facultative methanotroph methylocystis sp. strain sb2 and perform a detailed transcriptomic analysis of cultures grown with either methane or ethanol. evidence for use of the canonical methane oxidation pathway a ...201424610846
methylobacterium and its role in health care-associated infection.methylobacterium species are a cause of health care-associated infection, including infections in immunocompromised hosts. the ability of methylobacterium species to form biofilms and to develop resistance to high temperatures, drying, and disinfecting agents may explain the colonization of methylobacterium in the hospital environment in, e.g., endoscopes. due to its slow growth, it can be easily missed during microbiological surveillance of endoscope reprocessing. the purpose of this minireview ...201424430456
new vectors for chromosomal integration enable high-level constitutive or inducible magnetosome expression of fusion proteins in magnetospirillum gryphiswaldense.the alphaproteobacterium magnetospirillum gryphiswaldense biomineralizes magnetosomes, which consist of monocrystalline magnetite cores enveloped by a phospholipid bilayer containing specific proteins. magnetosomes represent magnetic nanoparticles with unprecedented magnetic and physicochemical characteristics. these make them potentially useful in a number of biotechnological and biomedical applications. further functionalization can be achieved by expression of foreign proteins via genetic fus ...201424532068
application of stable isotope-assisted metabolomics for cell metabolism studies.the applications of stable isotopes in metabolomics have facilitated the study of cell metabolisms. stable isotope-assisted metabolomics requires: (1) properly designed tracer experiments; (2) stringent sampling and quenching protocols to minimize isotopic alternations; (3) efficient metabolite separations; (4) high resolution mass spectrometry to resolve overlapping peaks and background noises; and (5) data analysis methods and databases to decipher isotopic clusters over a broad m/z range (mas ...201424957020
mapping the fitness landscape of gene expression uncovers the cause of antagonism and sign epistasis between adaptive mutations.how do adapting populations navigate the tensions between the costs of gene expression and the benefits of gene products to optimize the levels of many genes at once? here we combined independently-arising beneficial mutations that altered enzyme levels in the central metabolism of methylobacterium extorquens to uncover the fitness landscape defined by gene expression levels. we found strong antagonism and sign epistasis between these beneficial mutations. mutations with the largest individual b ...201424586190
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