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Search Results: 1 - 10 of 207375 matches for " Richard G. Brennan "
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Promoter Recognition by a Complex of Spx and the C-Terminal Domain of the RNA Polymerase α Subunit
Michiko M. Nakano,Ann Lin,Cole S. Zuber,Kate J. Newberry,Richard G. Brennan,Peter Zuber
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0008664
Abstract: Spx, an ArsC (arsenate reductase) family member, is a global transcriptional regulator of the microbial stress response and is highly conserved amongst Gram-positive bacteria. Bacillus subtilis Spx protein exerts positive and negative control of transcription through its interaction with the C-terminal domain of the RNA polymerase (RNAP) α subunit (αCTD). Spx activates trxA (thioredoxin) and trxB (thioredoxin reductase) in response to thiol stress, and bears an N-terminal C10XXC13 redox disulfide center that is oxidized in active Spx.
A Combination of Independent Transcriptional Regulators Shapes Bacterial Virulence Gene Expression during Infection
Samuel A. Shelburne,Randall J. Olsen,Bryce Suber,Pranoti Sahasrabhojane,Paul Sumby,Richard G. Brennan,James M. Musser
PLOS Pathogens , 2010, DOI: 10.1371/journal.ppat.1000817
Abstract: Transcriptional regulatory networks are fundamental to how microbes alter gene expression in response to environmental stimuli, thereby playing a critical role in bacterial pathogenesis. However, understanding how bacterial transcriptional regulatory networks function during host-pathogen interaction is limited. Recent studies in group A Streptococcus (GAS) suggested that the transcriptional regulator catabolite control protein A (CcpA) influences many of the same genes as the control of virulence (CovRS) two-component gene regulatory system. To provide new information about the CcpA and CovRS networks, we compared the CcpA and CovR transcriptomes in a serotype M1 GAS strain. The transcript levels of several of the same genes encoding virulence factors and proteins involved in basic metabolic processes were affected in both ΔccpA and ΔcovR isogenic mutant strains. Recombinant CcpA and CovR bound with high-affinity to the promoter regions of several co-regulated genes, including those encoding proteins involved in carbohydrate and amino acid metabolism. Compared to the wild-type parental strain, ΔccpA and ΔcovRΔccpA isogenic mutant strains were significantly less virulent in a mouse myositis model. Inactivation of CcpA and CovR alone and in combination led to significant alterations in the transcript levels of several key GAS virulence factor encoding genes during infection. Importantly, the transcript level alterations in the ΔccpA and ΔcovRΔccpA isogenic mutant strains observed during infection were distinct from those occurring during growth in laboratory medium. These data provide new knowledge regarding the molecular mechanisms by which pathogenic bacteria respond to environmental signals to regulate virulence factor production and basic metabolic processes during infection.
Coevolution of Male and Female Genital Morphology in Waterfowl
Patricia L.R. Brennan, Richard O. Prum, Kevin G. McCracken, Michael D. Sorenson, Robert E. Wilson, Tim R. Birkhead
PLOS ONE , 2007, DOI: 10.1371/journal.pone.0000418
Abstract: Most birds have simple genitalia; males lack external genitalia and females have simple vaginas. However, male waterfowl have a phallus whose length (1.5–>40 cm) and morphological elaborations vary among species and are positively correlated with the frequency of forced extra-pair copulations among waterfowl species. Here we report morphological complexity in female genital morphology in waterfowl and describe variation vaginal morphology that is unprecedented in birds. This variation comprises two anatomical novelties: (i) dead end sacs, and (ii) clockwise coils. These vaginal structures appear to function to exclude the intromission of the counter-clockwise spiralling male phallus without female cooperation. A phylogenetically controlled comparative analysis of 16 waterfowl species shows that the degree of vaginal elaboration is positively correlated with phallus length, demonstrating that female morphological complexity has co-evolved with male phallus length. Intersexual selection is most likely responsible for the observed coevolution, although identifying the specific mechanism is difficult. Our results suggest that females have evolved a cryptic anatomical mechanism of choice in response to forced extra-pair copulations.
Regulation of the Escherichia coli HipBA Toxin-Antitoxin System by Proteolysis
Sonja Hansen, Marin Vuli?, Jungki Min, Tien-Jui Yen, Maria A. Schumacher, Richard G. Brennan, Kim Lewis
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0039185
Abstract: Bacterial populations produce antibiotic-tolerant persister cells. A number of recent studies point to the involvement of toxin/antitoxin (TA) modules in persister formation. hipBA is a type II TA module that codes for the HipB antitoxin and the HipA toxin. HipA is an EF-Tu kinase, which causes protein synthesis inhibition and dormancy upon phosphorylation of its substrate. Antitoxins are labile proteins that are degraded by one of the cytosolic ATP-dependent proteases. We followed the rate of HipB degradation in different protease deficient strains and found that HipB was stabilized in a lon- background. These findings were confirmed in an in vitro degradation assay, showing that Lon is the main protease responsible for HipB proteolysis. Moreover, we demonstrated that degradation of HipB is dependent on the presence of an unstructured carboxy-terminal stretch of HipB that encompasses the last 16 amino acid residues. Further, substitution of the conserved carboxy-terminal tryptophan of HipB to alanine or even the complete removal of this 16 residue fragment did not alter the affinity of HipB for hipBA operator DNA or for HipA indicating that the major role of this region of HipB is to control HipB degradation and hence HipA-mediated persistence.
A Single Acidic Residue Can Guide Binding Site Selection but Does Not Govern QacR Cationic-Drug Affinity
Kate M. Peters,Benjamin E. Brooks,Maria A. Schumacher,Ronald A. Skurray,Richard G. Brennan,Melissa H. Brown
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0015974
Abstract: Structures of the multidrug-binding repressor protein QacR with monovalent and bivalent cationic drugs revealed that the carboxylate side-chains of E90 and E120 were proximal to the positively charged nitrogens of the ligands ethidium, malachite green and rhodamine 6G, and therefore may contribute to drug neutralization and binding affinity. Here, we report structural, biochemical and in vivo effects of substituting these glutamate residues. Unexpectedly, substitutions had little impact on ligand affinity or in vivo induction capabilities. Structures of QacR(E90Q) and QacR(E120Q) with ethidium or malachite green took similar global conformations that differed significantly from all previously described QacR-drug complexes but still prohibited binding to cognate DNA. Strikingly, the QacR(E90Q)-rhodamine 6G complex revealed two mutually exclusive rhodamine 6G binding sites. Despite multiple structural changes, all drug binding was essentially isoenergetic. Thus, these data strongly suggest that rather than contributing significantly to ligand binding affinity, the role of acidic residues lining the QacR multidrug-binding pocket is primarily to attract and guide cationic drugs to the “best available” positions within the pocket that elicit QacR induction.
Distinct Single Amino Acid Replacements in the Control of Virulence Regulator Protein Differentially Impact Streptococcal Pathogenesis
Nicola Horstmann,Pranoti Sahasrabhojane,Bryce Suber,Muthiah Kumaraswami,Randall J. Olsen,Anthony Flores,James M. Musser,Richard G. Brennan,Samuel A. Shelburne III
PLOS Pathogens , 2011, DOI: 10.1371/journal.ppat.1002311
Abstract: Sequencing of invasive strains of group A streptococci (GAS) has revealed a diverse array of single nucleotide polymorphisms in the gene encoding the control of virulence regulator (CovR) protein. However, there is limited information regarding the molecular mechanisms by which CovR single amino acid replacements impact GAS pathogenesis. The crystal structure of the CovR C-terminal DNA-binding domain was determined to 1.50 ? resolution and revealed a three-stranded β-sheet followed by a winged helix-turn-helix DNA binding motif. Modeling of the CovR protein-DNA complex indicated that CovR single amino acid replacements observed in clinical GAS isolates could directly alter protein-DNA interaction and impact protein structure. Isoallelic GAS strains that varied by a single amino acid replacement in the CovR DNA binding domain had significantly different transcriptomes compared to wild-type and to each other. Similarly, distinct recombinant CovR variants had differential binding affinity for DNA from the promoter regions of several virulence factor-encoding genes. Finally, mice that were challenged with GAS CovR isoallelic strains had significantly different survival times, which correlated with the transcriptome and protein-DNA binding studies. Taken together, these data provide structural and functional insights into the critical and distinct effects of variation in the CovR protein on GAS pathogenesis.
For the love and respect of the service: Applied aesthetics and palliative care  [PDF]
Marcia Brennan
Journal of Biomedical Science and Engineering (JBiSE) , 2013, DOI: 10.4236/jbise.2013.610A1001
Abstract: In this article, the author discusses her experiences as an artist in residence in the Department of Palliative Care and Rehabilitation Medicine at the University of Texas M. D. Anderson Cancer Center. Emphasis is placed on applied aesthetics in palliative care and their implications for addressing communication, spiritual, and health care issues for military service members. Drawing on six vivid case studies, the author examines the various ways in which end of life narratives can shed valuable light on key issues concerning individuals’ life experiences in the Navy, the Army, and the Air Force. These cherished images strengthened people’s spirits at the end of life, and each of the men told their stories with pride.
Religion, spirituality, and older adults with HIV: critical personal and social resources for an aging epidemic
Vance D, Brennan M, Enah C, Smith G, Kaur J
Clinical Interventions in Aging , 2011, DOI: http://dx.doi.org/10.2147/CIA.S16349
Abstract: ion, spirituality, and older adults with HIV: critical personal and social resources for an aging epidemic Review (4990) Total Article Views Authors: Vance D, Brennan M, Enah C, Smith G, Kaur J Published Date May 2011 Volume 2011:6 Pages 101 - 109 DOI: http://dx.doi.org/10.2147/CIA.S16349 David E Vance1, Mark Brennan2, Comfort Enah1, Glenda L Smith1, Jaspreet Kaur3 1School of Nursing, University of Alabama at Birmingham (UAB), Birmingham, AL, USA; 2New York University College of Nursing, AIDS Community Research Initiative of America, New York, NY, USA; 3Department of Psychology and Edward R. Roybal Center for Translational Research in Aging and Mobility, University of Alabama at Birmingham (UAB), Birmingham, AL, USA Abstract: By 2015, approximately half of adults with HIV in the United States will be 50 and older. The demographic changes in this population due to successful treatment represent a unique challenge, not only in assisting these individuals to cope with their illness, but also in helping them to age successfully with this disease. Religious involvement and spirituality have been observed to promote successful aging in the general population and help those with HIV cope with their disease, yet little is known about how these resources may affect aging with HIV. Also, inherent barriers such as HIV stigma and ageism may prevent people from benefitting from religious and spiritual sources of solace as they age with HIV. In this paper, we present a model of barriers to successful aging with HIV, along with a discussion of how spirituality and religiousness may help people overcome these barriers. From this synthesis, implications for practice and research to improve the quality of life of this aging population are provided.
Tetrakis(1,2-dimethoxyethane-κ2O,O′)ytterbium(II) bis(μ2-phenylselenolato-κ2Se:Se)bis[bis(phenylselenolato-κSe)mercurate(II)]
Michael D. Romanelli,Thomas J. Emge,John G. Brennan
Acta Crystallographica Section E , 2008, DOI: 10.1107/s1600536808019211
Abstract: The title salt, [Yb(C4H10O2)4][Hg2(C6H5Se)6], consists of eight-coordinate homoleptic [Yb(DME)4]2+ dications (DME is 1,2-dimethoxyethane) countered with [Hg2(SePh)6]2 dianions. The cations and anions have twofold rotation and inversion symmetry, respectively. The Yb centre displays a square-antiprismatic coordination geometry and the Hg centre has a distorted tetrahedral coordination environment. One phenylselenolate anion and one methyl group of a DME ligand are disordered over two positions with equal occupancies. This structure is unique in that it represents a less common molecular lanthanide species in which the lanthanide ion is not directly bonded to an anionic ligand. There are no occurrences of the [Hg2(SePh)6]2 dianion in the Cambridge Structural Database (Version of November 2007), but there are similar oligomeric and polymeric Hgx(SePh)y species. The crystal structure is characterized by alternating layers of cations and anions stacked along the c axis.
Impact of VIP and cAMP on the regulation of TNF-α and IL-10 production: implications for rheumatoid arthritis
Andrew D Foey, Sarah Field, Salman Ahmed, Abhilash Jain, Marc Feldmann, Fionula M Brennan, Richard Williams
Arthritis Research & Therapy , 2003, DOI: 10.1186/ar999
Abstract: Rheumatoid arthritis (RA) is a chronic inflammatory disease characterised by the dysregulated expression of many proinflammatory cytokines including tumour necrosis factor α (TNF-α), with increased yet insufficient production of anti-inflammatory cytokines including IL-10 [1]. The validation of TNF-α as a therapeutic target in RA has encouraged the investigation of signalling pathways regulating its production by cells relevant to the pathophysiology of this disease. One pathway known to downregulate proinflammatory TNF-α production and, consequently, upregulate the anti-inflammatory cytokine IL-10 is that elicited by the second messenger cAMP [2,3]. This pathway may therefore represent a good therapeutic target due to its opposing effects on TNF-α and IL-10. Previously, we and others demonstrated that rolipram, a phosphodiesterase (PDE) IV inhibitor, reduced the clinical and histological severity of collagen-induced arthritis (CIA) [4,5]. These studies demonstrated the potential for the cAMP/protein kinase A (PKA) pathway in treatment of autoimmune diseases such as RA.Another stimulator of the cAMP/PKA pathway whose principle immunomodulatory functions are anti-inflammatory is the vasoactive intestinal peptide (VIP). VIP is a 28-aminoacid neuropeptide belonging to the glucagon/secretin family, found in the nervous system and in the immune system, where it is detected in a variety of cell types including mast cells, neutrophils, and mononuclear cells. The effects of VIP are transduced via three known receptors, VPAC1, VPAC2, and PAC1, all of which are coupled to adenylate cyclase via heterotrimeric G proteins. In vivo, VIP has a therapeutic effect in the CIA mouse model [6,7] and protects from lipopolysaccharide (LPS) shock by suppression of TNF-α [8,9] and nuclear factor κB (NF-κB) activation [10]. Furthermore, in vitro studies showed that VIP inhibits the production of proinflammatory factors TNF-α, IL-6, IL-12 [11,12], chemokines [13,14], and nitric oxide (NO) [1
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