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 Gene Profiles


  RV0521C is profiled in 19 experiments

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Unique roles of DosT and DosS in DosR regulon induction and Mycobacterium tuberculosis dormancy.

Honaker RW, et al. (2009) Infect Immun 77(8):3258-63

In Mycobacterium tuberculosis, the sensor kinases DosT and DosS activate the transcriptional regulator DosR, resulting in the induction of the DosR regulon, which is important for anaerobic survival and perhaps latent infection. The individual and collective roles of these sensors have been postulated biochemically, but their roles in vivo have remained unclear. Various DosS and DosT mutant strains were analyzed ... Expand against wild type (reference strain H37Rv, identical conditions as mutant) under various conditions: day 6 in an anaerobic dormancy model, 4 or 24 hours in a GasPak model, or log phase with the addition of a nitric oxide donor. Experiments were repeated in triplicate or quadruplicate. This work demonstrates distinct and additive roles for each sensor during anaerobic dormancy. Both sensors are necessary for wild-type levels of DosR regulon induction, and concomitantly, full induction of the regulon is required for wild-type anaerobic survival. In the anaerobic model, DosT plays an early role, responding to hypoxia. DosT then induces the regulon and with it DosS, which sustains and further induces the regulon. DosT then loses its functionality as oxygen becomes limited, and DosS alone maintains induction of the genes from that point forward. Thus, M. tuberculosis has evolved a system whereby it responds to hypoxic conditions in a stepwise fashion as it enters an anaerobic state. Hide text

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The response of mycobacterium tuberculosis to reactive oxygen and nitrogen species.

Voskuil MI, et al. (2011) Front Microbiol 2():105

The bacteriostatic and bactericidal effects and the corresponding expression profiles of Mycobacterium tuberculosis to representative oxidative and nitrosative stresses were investigated by growth and survival studies and whole genome expression analysis. The response of M. tuberculosis to a range of hydrogen peroxide (H2O2) concentrations tended to fall into three distinct categories: (1) low level exposure ... Expand resulted in induction of few H2O2 sensitive genes, (2) intermediate exposure resulted in massive transcriptional changes without an effect on growth or survival, and (3) high exposure resulted in a muted transcriptional response and eventual death. Nitric oxide (NO) exposure initiated much of the same transcriptional response as H2O2. However, unlike H2O2 exposure, NO exposure affected a dose-dependent bacteriostatic activity without killing and induction of dormancy-related genes. Included in the shared response to H2O2 and NO was the induction of genes encoding oxidative stress detoxification and iron-sulfur cluster repair functions. Expression of several key oxidative stress defense genes was constitutive, or increased moderately from an already elevated level, suggesting bacilli that are continually primed for oxidative stress defense. Deletion of the known oxidative stress responsive regulator, FurA, resulted in the constitutive expression of furA, katG, and Rv1907c; while other genes do not appear to be solely controlled by FurA. In contrast to Escherichia coli, M. tuberculosis appears highly resistant to DNA damage-dependent killing caused by low mill molar levels of H2O2. Furthermore, instead of limiting access to iron to prevent hydroxyl radical formation from H2O2 and thus DNA damage, M. tuberculosis induced iron uptake genes in response to H2O2 and NO. Hide text

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A thiolase of Mycobacterium tuberculosis is required for virulence and production of androstenedione and androstadienedione from cholesterol.

Nesbitt NM, et al. (2010) Infect Immun 78(1):275-82

To determine the genes under control of KstR and the effect of cholesterol in M. tuberculosis, a transposon-disrupted mutant in Rv3574, encoding KstR was generated. This mutant as well as its parent strain, CDC1551 were grown to mid-log phase and RNA was isolated 24 hours later for gene expression analysis by microarray. In one set of experiments no cholesterol was added both to wild type and KstR mutant. In the ... Expand second set both wild type and KstR mutant were exposed to 1mg/ml cholesterol for 24 hrs. Hide text

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DosR-regulon genes induction in Mycobacterium bovis BCG under aerobic conditions.

Flores Valdez MA and Schoolnik GK (2010) Tuberculosis (Edinb) 90(3):197-200

In this report we demonstrated that under aerobic conditions, Mycobacterium bovis BCG expressing an hsp60-driven second copy of the hypoxia-related transcriptional regulator DosR increased 2-fold or greater the expression of 38 out of the 48 genes belonging to the DosR regulon, including the latency antigens Rv1733c, Rv2029, Rv2627, and Rv2628. Expression of DosR under these conditions slightly delayed in vitro ... Expand growth, but did not promote a non-replicating state as opposed to microaerobic and hypoxic adaptation. Our results suggest BCG producing DosR can be cultured under standard in vitro conditions, allowing evaluation of this strain as a latency-specific vaccine candidate. PMID: 20421176 Hide text

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A Mycobacterium tuberculosis sigma factor network responds to cell-envelope damage by the promising anti-mycobacterial thioridazine.

Dutta NK, et al. (2010) PLoS One 5(4):e10069

BACKGROUND: Novel therapeutics are urgently needed to control tuberculosis (TB). Thioridazine (THZ) is a candidate for the therapy of multidrug and extensively drug-resistant TB.

METHODOLOGY/PRINCIPAL FINDINGS: We studied the impact of THZ on Mycobacterium tuberculosis (Mtb) by analyzing gene expression profiles after treatment at the minimal inhibitory (1x MIC) or highly inhibitory (4x MIC) ... Expand
concentrations between 1-6 hours. THZ modulated the expression of genes encoding membrane proteins, efflux pumps, oxido-reductases and enzymes involved in fatty acid metabolism and aerobic respiration. The Rv3160c-Rv3161c operon, a multi-drug transporter and the Rv3614c/3615c/3616c regulon, were highly induced in response to THZ. A significantly high number of Mtb genes co-expressed with sigma(B) (the sigma(B) regulon) was turned on by THZ treatment. sigma(B) has recently been shown to protect Mtb from envelope-damage. We hypothesized that THZ damages the Mtb cell-envelope, turning on the expression of the sigma(B) regulon. Consistent with this hypothesis, we present electron-microscopy data which shows that THZ modulates cell-envelope integrity. Moreover, the Mtb mutants in sigma(H) and sigma(E), two alternate stress response sigma factors that induce the expression of sigma(B), exhibited higher sensitivity to THZ, indicating that the presence and expression of sigma(B) allows Mtb to resist the impact of THZ. Conditional induction of sigma(B) levels increased the survival of Mtb in the presence of THZ.

CONCLUSIONS/SIGNIFICANCE: THZ targets different pathways and can thus be used as a multi-target inhibitor itself as well as provide strategies for multi-target drug development for combination chemotherapy. Our results show that the Mtb sigma factor network comprising of sigma(H), sigma(E) and sigma(B) plays a crucial role in protecting the pathogen against cell-envelope damage. Hide text

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Transcriptional responses of Mycobacterium tuberculosis to lung surfactant.

Schwab U, et al. (2009) Microb Pathog 46(4):185-93

This study uses microarray analyses to examine gene expression profiles for Mycobacterium tuberculosis (Mtb) induced by exposure in vitro to bovine lung surfactant preparations that vary in apoprotein content: (i) whole lung surfactant (WLS) containing the complete mixture of endogenous lipids and surfactant proteins (SP)-A, -B, -C, and -D; (ii) extracted lung surfactant (CLSE) containing lipids plus SP-B and -C; ... Expand (iii) column-purified surfactant lipids (PPL) containing no apoproteins, and (iv) purified human SP-A. Exposure to WLS evoked a multitude of transcriptional responses in Mtb, with 52 genes up-regulated and 23 genes down-regulated at 30min exposure, plus 146 genes up-regulated and 27 genes down-regulated at 2h. Notably, WLS rapidly induced several membrane-associated lipases that presumptively act on surfactant lipids as substrates, and a large number of genes involved in the synthesis of phthiocerol dimycocerosate (PDIM), a cell wall component known to be important in macrophage interactions and Mtb virulence. Exposure of Mtb to CLSE, PPL, or purified SP-A caused a substantially weaker transcriptional response (<=20 genes were induced) suggesting that interactions among multiple lipid-protein components of WLS may contribute to its effects on Mtb transcription. Hide text

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Mycobacterium tuberculosis modulates its cell surface via an oligopeptide permease (Opp) transport system.

Flores-Valdez MA, et al. (2009) FASEB J 23(12):4091-104

M. tuberculosis strain 1254 wild type (WT) and its isogenic delta Rv3662c-Rv3665c KO (opp KO) and complemented opp::opp were cultured in vitro, in liquid 7H9 media supplemented with OADC and 0.05% Tween 80, 0.5% glycerol, in a 150 mL volume, contained in roller bottles, incubated at 37oC. Growth was monitored as OD600 nm and recorded on a daily basis. In all experiments, the starting OD600 nm was 0.04-0.05. ... Expand Aliquots were removed at each OD600 nm to make serial dilutions, plate onto 7H10 OADC agar plates for CFU counts. When cells reached OD600 nm of 0.3, 1.0, and 1.5, a 10-30 mL aliquot was taken, centrifuged 3 min at 3000 g, at room temperature, and the supernatant was discarded, with cell pellets being immediately frozen by inclusion into dry ice. Frozen cell pellets were stored at -80oC for later RNA isolation. In all experiments, RNA from WT was labeled with Cy5, and RNA from the opp KO was labeled with Cy3. In all experiments, the microarray comparsion used RNA from cells of the same growth stage, i.e., WT OD 0.3 vs opp KO OD 0.3, WT OD 1.0 vs opp KO OD 1.0, and WT OD 1.5 vs opp KO OD 1.5. When comparing the Complemented opp::opp vs the mutant opp KO, RNA from the later strain was Cy3-labeled. Hide text

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Functional Genetic Diversity among Mycobacterium tuberculosis Complex Clinical Isolates: Delineation of Conserved Core and Lineage-Specific Transcriptomes during Intracellular Survival.

Homolka S, et al. (2010) PLoS Pathog 6(7):e1000988

This study uses microarray analyses to examine transcriptional responses of Mycobacterium tuberculosis complex clinical isolates to phagosomal cues encountered inside activated (IFN-gamma+LPS) murine bone marrow-derived macrophages 24hr post-infection. Transcript levels of intracellular mycobacteria were compared to extracellular bacteria of the same strain (An aliquot of the inoculum used to infect macrophages was ... Expand incubated in the absence of macrophages for 24hr in an identical flask). Hide text

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Functional Genetic Diversity among Mycobacterium tuberculosis Complex Clinical Isolates: Delineation of Conserved Core and Lineage-Specific Transcriptomes during Intracellular Survival.

Homolka S, et al. (2010) PLoS Pathog 6(7):e1000988

This study uses microarray analyses to examine transcriptional responses of Mycobacterium tuberculosis complex clinical isolates to phagosomal cues encountered inside resting murine bone marrow-derived macrophages 24hr post-infection. Transcript levels of intracellular mycobacteria were compared to extracellular bacteria of the same strain (An aliquot of the inoculum used to infect macrophages was incubated in the ... Expand absence of macrophages for 24hr in an identical flask). Hide text

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Functional Genetic Diversity among Mycobacterium tuberculosis Complex Clinical Isolates: Delineation of Conserved Core and Lineage-Specific Transcriptomes during Intracellular Survival.

Homolka S, et al. (2010) PLoS Pathog 6(7):e1000988

This study uses microarray analyses to examine baseline gene expression profiles for Mycobacterium tuberculosis complex clinical isolates relative to reference strain CDC1551 during log phase growth in vitro in 7H9 broth. For this in vitro analyses, log-phase mycobacteria in starter cultures grown to mid-log from frozen stocks were inoculated into 7H9-OADC medium in 25-cm2 vented flasks at an OD of ~0.05 and grown ... Expand without shaking for ~1 week to an OD of ~0.5-0.6. Hide text

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Bioactive Pyridine-N-oxide Disulfides from Allium stipitatum

O'Donnell G, et al. (2009) J Nat Prod 72(3):360-365

In this study, the researchers isolated a colorless waxy solid from the chloroform extract of Allium stipitatum as Compound 1. They demonstrated compound 1 is a potent bactericidal agent against nonreplicating Mycobacterium tuberculosis. Using microarray technology the authors report gene expression profiles in cells treated with either 2, 5, or 10 ug/ml of compound 1 or an equivalent amount of DMSO as ... Expand control for 6 h. Gene expression studies revealed that transcriptional profiles elicited in response to compound 1 were similar to the profiles generated during treatment of cells with compounds such as menadione and 8-quinolinol that result in oxidative stress. They included the thioredoxin system components encoded by trxB2 and trxC as well as several genes associated with the heat shock response such as clpB, sigH, dnaJ, dnaK, hsp, Rv0331, Rv3463, Rv3054c, and Rv1334-Rv1335. These results suggest that compound 1 possibly generates damaged proteins and other oxidative stress signals as part of its mechanism of action.

The following is the full abstract of this published study.
O'Donnell G, et al. (2009) J Nat Prod 72(3):360-365
From Allium stipitatum, three pyridine-N-oxide alkaloids (1-3) possessing disulfide functional groups were isolated. The structures of these natural products were elucidated by spectroscopic means as 2-(methyldithio)pyridine-N-oxide (1), 2-[(methylthiomethyl)dithio]pyridine-N-oxide (2), and 2,2'-dithio-bis-pyridine-N-oxide (3). The proposed structure of 1 was confirmed by synthetic S-methylthiolation of commercial 2-thiopyridine-N-oxide. Compounds 1 and 2 are new natural products, and 3 is reported for the first time from an Allium species. All compounds were evaluated for activity against fast-growing species of Mycobacterium, methicillin-resistant Staphylococcus aureus, and a multidrug-resistant (MDR) variants of S. aureus. Compounds 1 and 2 exhibited minimum inhibitory concentrations (MICs) of 0.5-8 mug/ml against these strains. A small series of analogues of 1 were synthesized in an attempt to optimize antibacterial activity, although the natural product had the most potent in vitro activity. In a whole-cell assay at 30 mug/ml, 1 was shown to give complete inhibition of the incorporation of (14)C-labeled acetate into soluble fatty acids, indicating that it is potentially an inhibitor of fatty acid biosynthesis. In a human cancer cell line antiproliferative assay, 1 and 2 displayed IC(50) values ranging from 0.3 to 1.8 muM with a selectivity index of 2.3 when compared to a human somatic cell line. Compound 1 was evaluated in a microarray analysis that indicated a similar mode of action to menadione and 8-quinolinol by interfering with the thioredoxin system and up-regulating the production of various heat shock proteins. This compound was also assessed in a mouse model for in vivo toxicity. Hide text

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The Mycobacterium tuberculosis ECF sigma factor sigmaE: role in global gene expression and survival in macrophages.

Manganelli R, et al. (2001) Mol Microbiol 41(2):423-37

In previously published work, we identified three Mycobacterium tuberculosis sigma (s) factor genes responding to heat shock (sigB, sigE and sigH ). Two of them (sigB and sigE ) also responded to SDS exposure. As these responses to stress suggested that the s factors encoded by these genes could be involved in pathogenicity, we are studying their role in physiology and virulence. In this work, we characterize a sigE ... Expand mutant of M. tuberculosis H37Rv. The sigE mutant strain was more sensitive than the wild-type strain to heat shock, SDS and various oxidative stresses. It was also defective in the ability to grow inside both human and murine unactivated macrophages and was more sensitive than the wild-type strain to the killing activity of activated murine macrophages. Using microarray technology and quantitative reverse transcription?polymerase chain reaction (RT?PCR), we started to define the sigmaE regulon of M. tuberculosis and its involvement in the global regulation of the stress induced by SDS. We showed the requirement for a functional sigE gene for full expression of sigB and for its induction after SDS exposure but not after heat shock. We also identified several genes that are no longer induced when sigmaE is absent. These genes encode proteins belonging to different classes including transcriptional regulators, enzymes involved in fatty acid degradation and classical heat shock proteins. Hide text

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Role of the extracytoplasmic-function sigma factor sigma(H) in Mycobacterium tuberculosis global gene expression.

Manganelli R, et al. (2002) Mol Microbiol 45(2):365-74

Like other bacterial species, Mycobacterium tuberculosis has multiple sigma (s) factors encoded in its genome. In previously published work, we and others have shown that mutations in some of these transcriptional activators render M. tuberculosis sensitive to various environmental stresses and, in some cases, cause attenuated virulence phenotypes. In this paper, we characterize a M. tuberculosis mutant lacking the ... Expand ECF s factor sigma-H. This mutant was more sensitive than the wild type to heat shock and to various oxidative stresses, but did not show decreased ability to grow inside macrophages. Using quantitative reverse transcription-PCR and microarray technology, we have started to define the sigma-H regulon and its involvement in the global regulation of the response to heat shock and the thiol-specific oxidizing agent diamide. We identified 48 genes whose expression increased after exposure of M. tuberculosis to diamide; out of these, 39 were not induced in the sigH mutant, showing their direct or indirect dependence on sigma-H. Some of these genes encode proteins whose predicted function is related to thiol metabolism, such as thioredoxin, thioredoxin reductase and enzymes involved in cysteine and molybdopterine biosynthesis. Other genes under sigma-H control encode transcriptional regulators such as sigB, sigE, and sigH itself. Hide text

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Role of the extracytoplasmic-function sigma factor sigma(H) in Mycobacterium tuberculosis global gene expression.

Manganelli R, et al. (2002) Mol Microbiol 45(2):365-74

Like other bacterial species, Mycobacterium tuberculosis has multiple sigma (s) factors encoded in its genome. In previously published work, we and others have shown that mutations in some of these transcriptional activators render M. tuberculosis sensitive to various environmental stresses and, in some cases, cause attenuated virulence phenotypes. In this paper, we characterize a M. tuberculosis mutant lacking the ... Expand ECF s factor sigma-H. This mutant was more sensitive than the wild type to heat shock and to various oxidative stresses, but did not show decreased ability to grow inside macrophages. Using quantitative reverse transcription-PCR and microarray technology, we have started to define the sigma-H regulon and its involvement in the global regulation of the response to heat shock and the thiol-specific oxidizing agent diamide. We identified 48 genes whose expression increased after exposure of M. tuberculosis to diamide; out of these, 39 were not induced in the sigH mutant, showing their direct or indirect dependence on sigma-H. Some of these genes encode proteins whose predicted function is related to thiol metabolism, such as thioredoxin, thioredoxin reductase and enzymes involved in cysteine and molybdopterine biosynthesis. Other genes under sigma-H control encode transcriptional regulators such as sigB, sigE, and sigH itself. Hide text

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The Differential Gene Expression Pattern of Mycobacterium tuberculosis in Response to Capreomycin and PA-824 versus First-Line TB Drugs Reveals Stress- and PE/PPE-Related Drug Targets.

Fu LM and Tai SC (2009) Int J Microbiol 2009():879621

Tuberculosis is a leading infectious disease causing millions of deaths each year. How to eradicate mycobacterial persistence has become a central research focus for developing next-generation TB drugs. Yet, the knowledge in this area is fundamentally limited and only a few drugs, notably capreomycin and PA-824, have been shown to be active against non-replicating persistent TB bacilli. In this study, we performed a ... Expand new bioinformatics analysis on microarray-based gene expression data obtained from the public domain to explore genes that were differentially induced by drugs between the group of capreomycin and PA-824 and the group of mainly the first-line TB drugs. Our study has identified 42 genes specifically induced by capreomycin and PA-824. Many of these genes are related to stress responses. In terms of the distribution of identified genes in a specific category relative to the whole genome, only the categories of PE/PPE and conserved hypotheticals have statistical significance. Six among the 42 genes identified in this study are on the list of the top 100 persistence targets selected by the TB Structural Genomics Consortium. Further biological elucidation of their roles in mycobacterial persistence is warranted. PMID: 20016672 Hide text

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ideR, An essential gene in mycobacterium tuberculosis: role of IdeR in iron-dependent gene expression, iron metabolism, and oxidative stress response.

Rodriguez GM, et al. (2002) Infect Immun 70(7):3371-81

The mycobacterial IdeR protein is a metal-dependent regulator of the DtxR (diphtheria toxin repressor) family. In the presence of iron, it binds to a specific DNA sequence in the promoter regions of the genes that it regulates, thus controlling their transcription. In this study, we provide evidence that ideR is an essential gene in Mycobacterium tuberculosis. ideR cannot normally be disrupted in this mycobacterium ... Expand in the absence of a second functional copy of the gene. However, a rare ideR mutant was obtained in which the lethal effects of ideR inactivation were alleviated by a second-site suppressor mutation and which exhibited restricted iron assimilation capacity. Studies of this strain and a derivative in which IdeR expression was restored allowed us to identify phenotypic effects resulting from ideR inactivation. Using DNA microarrays, the iron-dependent transcriptional profiles of the wild-type, ideR mutant, and ideR complemented mutant strains were analyzed, and the genes regulated by iron and IdeR were identified. These genes encode a variety of proteins, including putative transporters, proteins involved in siderophore synthesis and iron storage, members of the PE/PPE family, a membrane protein involved in virulence, transcriptional regulators, and enzymes involved in lipid metabolism. Hide text

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Altered expression of isoniazid-regulated genes in drug-treated dormant Mycobacterium tuberculosis.

Karakousis PC, et al. (2008) J Antimicrob Chemother 61(2):323-31

These data represent the expression patterns of Mycobacterium tuberculosis in progressive hypoxia, nutrient depletion, and in-vivo hollow fiber models of dormancy. The assumptions are that the set of genes that respond to INH treatment during Log phase growth would not be differentially regulated during INH treatment in the dormancy models, and that the overall number of differentially regulated genes would be ... Expand reduced due to the low metabolic state of the cells. Hide text

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The mechanism of action of PA-824: Novel insights from transcriptional profiling.

Manjunatha U, et al. (2009) Commun Integr Biol 2(3):215-8

The bicyclic nitroimidazole PA-824 is a pro-drug with a very complex mechanism of action active against both replicating and hypoxic, non-replicating Mycobacterium tuberculosis. Microarray analysis of the mode of action of PA-824 showed a puzzling mixed effect both on genes responsive to both cell wall inhibition (like isoniazid) and respiratory poisoning (like cyanide). The aerobic killing mechanism of this drug ... Expand appears to involve inhibition of cell wall mycolic acid biosynthesis through an as yet unknown molecular mechanism. However, the structure-activity relationships governing aerobic activity do not parallel the relationships determining anaerobic activity. Based on the metabolite profiling of PA-824 and various derivatives by Ddn-mediated activation, we have shown that PA-824 acts directly as an NO donor.1 This respiratory poisoning through nitric oxide release seemed to be a crucial element of anaerobic activity by PA-824. The effect of PA-824 on the respiratory complex under hypoxic non-replicating conditions was also manifested in a rapid drop in intracellular ATP levels, again similar to that observed by cyanide treatment. Thus, transcriptional profiling provided valuable clues to elucidating the molecular mechanism of mycobacterial killing. Hide text

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Mycobacterium tuberculosis senses host-derived carbon monoxide during macrophage infection.

Shiloh MU, et al. (2008) Cell Host Microbe 3(5):323-30

Transcriptional profiling of M. tuberculosis growing in log phase treated with various concentrations of carbon monoxide versus untreated controls Keywords: Dose response Two condition experiment, CO treated cells at 2000, 200 and 20 ppm versus untreated controls. Biological replicates: 2 replicates per dose, 1 array per ... Expand replicate Hide text

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