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Functional genetic screen of human diversity reveals that a methionine salvage enzyme regulates inflammatory cell death.
Ko DC, Gamazon ER, Shukla KP, Pfuetzner RA, Whittington D, Holden TD, Brittnacher MJ, Fong C, Radey M, Ogohara C, Stark AL, Akey JM, Dolan ME, Wurfel MM, Miller SI
(2012) Proc Natl Acad Sci U S A 109: E2343-52
MeSH Terms: Adult, Aged, Aged, 80 and over, Animals, Apoptosis, Apoptosis Regulatory Proteins, Bone Marrow Cells, Caspase 1, Caspase 9, Deoxyadenosines, Genetic Predisposition to Disease, Genetic Variation, HEK293 Cells, HapMap Project, Humans, Methionine, Mice, Mice, Inbred C57BL, Middle Aged, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Salmonella Infections, Salmonella typhimurium, Thionucleosides, Young Adult
Show Abstract · Added April 13, 2017
Genome-wide association studies can identify common differences that contribute to human phenotypic diversity and disease. When genome-wide association studies are combined with approaches that test how variants alter physiology, biological insights can emerge. Here, we used such an approach to reveal regulation of cell death by the methionine salvage pathway. A common SNP associated with reduced expression of a putative methionine salvage pathway dehydratase, apoptotic protease activating factor 1 (APAF1)-interacting protein (APIP), was associated with increased caspase-1-mediated cell death in response to Salmonella. The role of APIP in methionine salvage was confirmed by growth assays with methionine-deficient media and quantitation of the methionine salvage substrate, 5'-methylthioadenosine. Reducing expression of APIP or exogenous addition of 5'-methylthioadenosine increased Salmonellae-induced cell death. Consistent with APIP originally being identified as an inhibitor of caspase-9-dependent apoptosis, the same allele was also associated with increased sensitivity to the chemotherapeutic agent carboplatin. Our results show that common human variation affecting expression of a single gene can alter susceptibility to two distinct cell death programs. Furthermore, the same allele that promotes cell death is associated with improved survival of individuals with systemic inflammatory response syndrome, suggesting a possible evolutionary pressure that may explain the geographic pattern observed for the frequency of this SNP. Our study shows that in vitro association screens of disease-related traits can not only reveal human genetic differences that contribute to disease but also provide unexpected insights into cell biology.
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25 MeSH Terms
Zinc sequestration by the neutrophil protein calprotectin enhances Salmonella growth in the inflamed gut.
Liu JZ, Jellbauer S, Poe AJ, Ton V, Pesciaroli M, Kehl-Fie TE, Restrepo NA, Hosking MP, Edwards RA, Battistoni A, Pasquali P, Lane TE, Chazin WJ, Vogl T, Roth J, Skaar EP, Raffatellu M
(2012) Cell Host Microbe 11: 227-39
MeSH Terms: ATP-Binding Cassette Transporters, Animals, Bacterial Proteins, Cecum, Diarrhea, Feces, Host-Pathogen Interactions, Immunity, Innate, Inflammation, Leukocyte L1 Antigen Complex, Mice, Mice, Inbred C57BL, Mice, Knockout, Neutrophils, Protein Binding, Salmonella Infections, Animal, Salmonella typhimurium, Transcription, Genetic, Zinc
Show Abstract · Added March 12, 2014
Neutrophils are innate immune cells that counter pathogens by many mechanisms, including release of antimicrobial proteins such as calprotectin to inhibit bacterial growth. Calprotectin sequesters essential micronutrient metals such as zinc, thereby limiting their availability to microbes, a process termed nutritional immunity. We find that while calprotectin is induced by neutrophils during infection with the gut pathogen Salmonella Typhimurium, calprotectin-mediated metal sequestration does not inhibit S. Typhimurium proliferation. Remarkably, S. Typhimurium overcomes calprotectin-mediated zinc chelation by expressing a high affinity zinc transporter (ZnuABC). A S. Typhimurium znuA mutant impaired for growth in the inflamed gut was rescued in the absence of calprotectin. ZnuABC was also required to promote the growth of S. Typhimurium over that of competing commensal bacteria. Thus, our findings indicate that Salmonella thrives in the inflamed gut by overcoming the zinc sequestration of calprotectin and highlight the importance of zinc acquisition in bacterial intestinal colonization.
Copyright © 2012 Elsevier Inc. All rights reserved.
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19 MeSH Terms
Conjugation of butadiene diepoxide with glutathione yields DNA adducts in vitro and in vivo.
Cho SH, Guengerich FP
(2012) Chem Res Toxicol 25: 706-12
MeSH Terms: Animals, Cross-Linking Reagents, DNA Adducts, Epoxy Compounds, Glutathione, Liver, Mice, Mutagenicity Tests, Mutagens, Rats, Rats, Sprague-Dawley, Salmonella typhi
Show Abstract · Added March 7, 2014
1,2,3,4-Diepoxybutane (DEB) is reported to be the most potent mutagenic metabolite of 1,3-butadiene, an important industrial chemical and environmental pollutant. DEB is capable of inducing the formation of monoalkylated DNA adducts and DNA-DNA and DNA-protein cross-links. We previously reported that DEB forms a conjugate with glutathione (GSH) and that the conjugate is considerably more mutagenic than several other butadiene-derived epoxides, including DEB, in the base pair tester strain Salmonella typhimurium TA1535 [Cho et al. (2010) Chem. Res. Toxicol. 23, 1544-1546]. In the present study, we determined steady-state kinetic parameters of the conjugation of the three DEB stereoisomers-R,R, S,S, and meso (all formed by butadiene oxidation)-with GSH by six GSH transferases. Only small differences (<3-fold) were found in the catalytic efficiency of conjugate formation (k(cat)/K(m)) with all three DEB stereoisomers and the six GSH transferases. The three stereochemical DEB-GSH conjugates had similar mutagenicity. Six DNA adducts (N(3)-adenyl, N(6)-adenyl, N(7)-guanyl, N(1)-guanyl, N(4)-cytidyl, and N(3)-thymidyl) were identified in the reactions of DEB-GSH conjugate with nucleosides and calf thymus DNA using LC-MS and UV and NMR spectroscopy. N(6)-Adenyl and N(7)-guanyl GSH adducts were identified and quantitated in vivo in the livers of mice and rats treated with DEB ip. These results indicate that such DNA adducts are formed from the DEB-GSH conjugate, are mutagenic regardless of sterochemistry, and are therefore expected to contribute to the carcinogenicity of DEB.
© 2011 American Chemical Society
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12 MeSH Terms
Mutagenicity of a glutathione conjugate of butadiene diepoxide.
Cho SH, Loecken EM, Guengerich FP
(2010) Chem Res Toxicol 23: 1544-6
MeSH Terms: Animals, Butadienes, DNA, Epoxy Compounds, Glutathione, Glutathione Transferase, Mutagenicity Tests, Rats, Salmonella typhimurium
Show Abstract · Added March 7, 2014
The mutagenicity and carcinogenicity of the important commodity chemical 1,3-butadiene are attributed to the epoxide products. We confirmed our previous work showing that expression of rat glutathione (GSH) transferase 5-5 enhances the mutagenicity of butadiene diepoxide in Salmonella typhimurium TA1535. A GSH-butadiene diepoxide conjugate was isolated and fully characterized by mass spectrometry and nuclear magnetic resonance as S-(2-hydroxy-3,4-epoxybutyl)GSH. The conjugate had a t(½) of 2.6 h (pH 7.4, 37 °C) and was considerably more mutagenic than butadiene diepoxide or monoepoxide in S. typhimurium. We propose that the GSH conjugate may be a major species involved in butadiene genotoxicity, not a detoxication product.
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9 MeSH Terms
SLAM is a microbial sensor that regulates bacterial phagosome functions in macrophages.
Berger SB, Romero X, Ma C, Wang G, Faubion WA, Liao G, Compeer E, Keszei M, Rameh L, Wang N, Boes M, Regueiro JR, Reinecker HC, Terhorst C
(2010) Nat Immunol 11: 920-7
MeSH Terms: Animals, Antigens, CD, Apoptosis Regulatory Proteins, Bacterial Proteins, Beclin-1, Cells, Cultured, Endosomal Sorting Complexes Required for Transport, Escherichia coli, Escherichia coli Infections, Macrophages, Male, Membrane Glycoproteins, Mice, Mice, Inbred BALB C, Mice, Knockout, Molecular Chaperones, NADPH Oxidase 2, NADPH Oxidases, Phagocytosis, Phagosomes, Phosphatidylinositol 3-Kinases, Porins, Protein-Serine-Threonine Kinases, Receptors, Cell Surface, Salmonella Infections, Salmonella typhimurium, Signaling Lymphocytic Activation Molecule Family Member 1, Vacuolar Sorting Protein VPS15
Show Abstract · Added December 10, 2018
Phagocytosis is a pivotal process by which macrophages eliminate microorganisms after recognition by pathogen sensors. Here we unexpectedly found that the self ligand and cell surface receptor SLAM functioned not only as a costimulatory molecule but also as a microbial sensor that controlled the killing of gram-negative bacteria by macrophages. SLAM regulated activity of the NADPH oxidase NOX2 complex and phagolysosomal maturation after entering the phagosome, following interaction with the bacterial outer membrane proteins OmpC and OmpF. SLAM recruited a complex containing the intracellular class III phosphatidylinositol kinase Vps34, its regulatory protein kinase Vps15 and the autophagy-associated molecule beclin-1 to the phagosome, which was responsible for inducing the accumulation of phosphatidylinositol-3-phosphate, a regulator of both NOX2 function and phagosomal or endosomal fusion. Thus, SLAM connects the gram-negative bacterial phagosome to ubiquitous cellular machinery responsible for the control of bacterial killing.
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MeSH Terms
Subversion of antimicrobial calprotectin (S100A8/S100A9 complex) in the cytoplasm of TR146 epithelial cells after invasion by Listeria monocytogenes.
Zaia AA, Sappington KJ, Nisapakultorn K, Chazin WJ, Dietrich EA, Ross KF, Herzberg MC
(2009) Mucosal Immunol 2: 43-53
MeSH Terms: Anti-Infective Agents, Calcium, Cell Line, Cytoplasm, Epithelial Cells, Humans, Leukocyte L1 Antigen Complex, Listeria monocytogenes, Protein Binding, Salmonella typhimurium, Tubulin
Show Abstract · Added May 19, 2014
Expressed by squamous mucosal keratinocytes, calprotectin is a complex of two EF-hand calcium-binding proteins of the S100 subfamily (S100A8 and S100A9) with significant antimicrobial activity. Calprotectin-expressing cells resist invasion by Porphyromonas gingivalis, Listeria monocytogenes, and Salmonella enterica serovar Typhimurium (S. typhimurium). To understand the interactions between calprotectin and invasive bacteria, we studied the distribution of calprotectin in the cytoplasm of TR146 epithelial cells. In response to L. monocytogenes, calprotectin mobilized from a diffuse cytoplasmic distribution to a filamentous pattern and colocalized with the microtubule network. Listeria more frequently invaded cells with mobilized calprotectin. Calprotectin mobilization was listeriolysin O-dependent and required calcium (extracellular and intracellular) and an intact microtubule network. In the presence of preformed microtubules in vitro, the anti-Listeria activity of calprotectin was abrogated. To facilitate intraepithelial survival, therefore, Listeria mobilizes calprotectin to colocalize with cytoplasmic microtubules, subverting anti-Listeria activity and autonomous cellular immunity.
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11 MeSH Terms
3'-Intercalation of a N2-dG 1R-trans-anti-benzo[c]phenanthrene DNA adduct in an iterated (CG)3 repeat.
Wang Y, Schnetz-Boutaud NC, Kroth H, Yagi H, Sayer JM, Kumar S, Jerina DM, Stone MP
(2008) Chem Res Toxicol 21: 1348-58
MeSH Terms: CpG Islands, DNA, DNA Adducts, Genes, Bacterial, Intercalating Agents, Magnetic Resonance Spectroscopy, Models, Molecular, Mutagens, Nucleic Acid Conformation, Oligodeoxyribonucleotides, Phenanthrenes, Salmonella typhimurium, Sequence Deletion
Show Abstract · Added May 29, 2014
The conformation of the 1 R,2 S,3 R,4 S-benzo[ c]phenanthrene- N (2)-dG adduct, arising from trans opening of the (+)-1 S,2 R,3 R,4 S- anti-benzo[ c]phenanthrene diol epoxide, was examined in 5'- d(ATCGC XCGGCATG)-3'.5'-d(CATGCCG CGCGAT)-3', where X = 1 R,2 S,3 R,4 S-B[ c]P- N (2)-dG. This duplex, derived from the hisD3052 frameshift tester strain of Salmonella typhimurium, contains a (CG) 3 iterated repeat, a hotspot for frameshift mutagenesis. NMR experiments showed a disconnection in sequential NOE connectivity between X (4) and C (5), and in the complementary strand, they showed another disconnection between G (18) and C (19). In the imino region of the (1)H NMR spectrum, a resonance was observed at the adducted base pair X (4) x C (19). The X (4) N1H and G (18) N1H resonances shifted upfield as compared to the other guanine imino proton resonances. NOEs were observed between X (4) N1H and C (19) N (4)H and between C (5) N (4)H and G (18) N1H, indicating that base pairs X (4) x C (19) and C (5) x G (18) maintained Watson-Crick hydrogen bonding. No NOE connectivity was observed between X (4) and G (18) in the imino region of the spectrum. Chemical shift perturbations of greater than 0.1 ppm were localized at nucleotides X (4) and C (5) in the modified strand and G (18) and C (19) in the complementary strand. A total of 13 NOEs between the protons of the 1 R-B[ c]Ph moiety and the DNA were observed between B[ c]Ph and major groove aromatic or amine protons at base pairs X (4) x C (19) and 3'-neighbor C (5) x G (18). Structural refinement was achieved using molecular dynamics calculations restrained by interproton distances and torsion angle restraints obtained from NMR data. The B[ c]Ph moiety intercalated on the 3'-face of the X (4) x C (19) base pair such that the terminal ring of 1 R-B[ c]Ph threaded the duplex and faced into the major groove. The torsion angle alpha' [X (4)]-N3-C2-N2-B[ c]Ph]-C1 was calculated to be -177 degrees, maintaining an orientation in which the X (4) exocyclic amine remained in plane with the purine. The torsion angle beta' [X (4)]-C2-N2-[B[ c]Ph]-C1-C2 was calculated to be 75 degrees. This value governed the 3'-orientation of the B[ c]Ph moiety with respect to X (4). The helical rise between base pairs X (4) x C (19) and C (5) x G (18) increased and resulted in unwinding of the right-handed helix. The aromatic rings of the B[ c]Ph moiety were below the Watson-Crick hydrogen-bonding face of the modified base pair X (4) x C (19). The B[c]Ph moiety was stacked above nucleotide G (18), in the complementary strand.
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13 MeSH Terms
Bulge migration of the malondialdehyde OPdG DNA adduct when placed opposite a two-base deletion in the (CpG)3 frameshift hotspot of the Salmonella typhimurium hisD3052 gene.
Wang Y, Schnetz-Boutaud NC, Saleh S, Marnett LJ, Stone MP
(2007) Chem Res Toxicol 20: 1200-10
MeSH Terms: Base Pairing, CpG Islands, DNA Adducts, DNA-Binding Proteins, Deoxyguanosine, Frameshift Mutation, Genes, Bacterial, Histidine, Magnetic Resonance Spectroscopy, Malondialdehyde, Salmonella typhimurium, Time Factors
Show Abstract · Added March 5, 2014
The OPdG adduct N (2)-(3-oxo-1-propenyl)dG, formed in DNA exposed to malondialdehyde, was introduced into 5'-d(ATCGC XCGGCATG)-3'.5'-d(CATGCCGCGAT)-3' at pH 7 (X = OPdG). The OPdG adduct is the base-catalyzed rearrangement product of the M 1dG adduct, 3-(beta- d-ribofuranosyl)pyrimido[1,2- a]purin-10(3 H)-one. This duplex, named the OPdG-2BD oligodeoxynucleotide, was derived from a frameshift hotspot of the Salmonella typhimuium hisD3052 gene and contained a two-base deletion in the complementary strand. NMR spectroscopy revealed that the OPdG-2BD oligodeoxynucleotide underwent rapid bulge migration. This hindered its conversion to the M 1dG-2BD duplex, in which the bulge was localized and consisted of the M 1dG adduct and the 3'-neighbor dC [ Schnetz-Boutaud, N. C. , Saleh, S. , Marnett, L. J. , and Stone, M. P. ( 2001) Biochemistry 40, 15638- 15649 ]. The spectroscopic data suggested that bulge migration transiently positioned OPdG opposite dC in the complementary strand, hindering formation of the M 1dG-2BD duplex, or alternatively, reverting rapidly formed intermediates in the OPdG to M 1dG reaction pathway when dC was placed opposite from OPdG. The approach of initially formed M 1dG-2BD or OPdG-2BD duplexes to an equilibrium mixture of the M 1dG-2BD and OPdG-2BD duplexes was monitored as a function of time, using NMR spectroscopy. Both samples attained equilibrium in approximately 140 days at pH 7 and 25 degrees C.
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12 MeSH Terms
Enhanced immunity to Plasmodium falciparum circumsporozoite protein (PfCSP) by using Salmonella enterica serovar Typhi expressing PfCSP and a PfCSP-encoding DNA vaccine in a heterologous prime-boost strategy.
Chinchilla M, Pasetti MF, Medina-Moreno S, Wang JY, Gomez-Duarte OG, Stout R, Levine MM, Galen JE
(2007) Infect Immun 75: 3769-79
MeSH Terms: Amino Acid Sequence, Animals, Antibodies, Protozoan, Bacterial Proteins, Cells, Cultured, Epitopes, Female, Genetic Vectors, Hemolysin Proteins, Immunity, Mucosal, Immunization, Secondary, Interferon-gamma, Leukocytes, Mononuclear, Malaria Vaccines, Mice, Mice, Inbred BALB C, Models, Animal, Molecular Sequence Data, Plasmodium falciparum, Protozoan Proteins, Recombinant Fusion Proteins, Salmonella typhi, Vaccines, DNA
Show Abstract · Added May 27, 2014
Two Salmonella enterica serovar Typhi strains that express and export a truncated version of Plasmodium falciparum circumsporozoite surface protein (tCSP) fused to Salmonella serovar Typhi cytolysin A (ClyA) were constructed as a first step in the development of a preerythrocytic malaria vaccine. Synthetic codon-optimized genes (t-csp1 and t-csp2), containing immunodominant B- and T-cell epitopes present in native P. falciparum circumsporozoite surface protein (PfCSP), were fused in frame to the carboxyl terminus of the ClyA gene (clyA::t-csp) in genetically stabilized expression plasmids. Expression and export of ClyA-tCSP1 and ClyA-tCSP2 by Salmonella serovar Typhi vaccine strain CVD 908-htrA were demonstrated by immunoblotting of whole-cell lysates and culture supernatants. The immunogenicity of these constructs was evaluated using a "heterologous prime-boost" approach consisting of mucosal priming with Salmonella serovar Typhi expressing ClyA-tCSP1 and ClyA-tCSP2, followed by parenteral boosting with PfCSP DNA vaccines pVR2510 and pVR2571. Mice primed intranasally on days 0 and 28 with CVD 908-htrA(pSEC10tcsp2) and boosted intradermally on day 56 with PfCSP DNA vaccine pVR2571 induced high titers of serum NANP immunoglobulin G (IgG) (predominantly IgG2a); no serological responses to DNA vaccination were observed in the absence of Salmonella serovar Typhi-PfCSP priming. Mice primed with Salmonella serovar Typhi expressing tCSP2 and boosted with PfCSP DNA also developed high frequencies of gamma interferon-secreting cells, which surpassed those produced by PfCSP DNA in the absence of priming. A prime-boost regimen consisting of mucosal delivery of PfCSP exported from a Salmonella-based live-vector vaccine followed by a parenteral PfCSP DNA boosting is a promising strategy for the development of a live-vector-based malaria vaccine.
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23 MeSH Terms
DNA damage recognition and repair by 3-methyladenine DNA glycosylase I (TAG).
Metz AH, Hollis T, Eichman BF
(2007) EMBO J 26: 2411-20
MeSH Terms: Adenine, Amino Acid Sequence, Bacterial Proteins, Binding Sites, DNA Damage, DNA Glycosylases, DNA Repair, DNA, Bacterial, Models, Molecular, Molecular Sequence Data, Mutation, Nucleic Acid Conformation, Protein Structure, Tertiary, Recombinant Fusion Proteins, Salmonella typhi
Show Abstract · Added March 11, 2014
DNA glycosylases help maintain the genome by excising chemically modified bases from DNA. Escherichia coli 3-methyladenine DNA glycosylase I (TAG) specifically catalyzes the removal of the cytotoxic lesion 3-methyladenine (3mA). The molecular basis for the enzymatic recognition and removal of 3mA from DNA is currently a matter of speculation, in part owing to the lack of a structure of a 3mA-specific glycosylase bound to damaged DNA. Here, high-resolution crystal structures of Salmonella typhi TAG in the unliganded form and in a ternary product complex with abasic DNA and 3mA nucleobase are presented. Despite its structural similarity to the helix-hairpin-helix superfamily of DNA glycosylases, TAG has evolved a modified strategy for engaging damaged DNA. In contrast to other glycosylase-DNA structures, the abasic ribose is not flipped into the TAG active site. This is the first structural demonstration that conformational relaxation must occur in the DNA upon base hydrolysis. Together with mutational studies of TAG enzymatic activity, these data provide a model for the specific recognition and hydrolysis of 3mA from DNA.
1 Communities
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15 MeSH Terms