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Search Results: 1 - 10 of 139435 matches for " Rodney K. Tweten "
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The Cholesterol-Dependent Cytolysin Signature Motif: A Critical Element in the Allosteric Pathway that Couples Membrane Binding to Pore Assembly
Kelley J. Dowd,Rodney K. Tweten
PLOS Pathogens , 2012, DOI: 10.1371/journal.ppat.1002787
Abstract: The cholesterol-dependent cytolysins (CDCs) constitute a family of pore-forming toxins that contribute to the pathogenesis of a large number of Gram-positive bacterial pathogens.The most highly conserved region in the primary structure of the CDCs is the signature undecapeptide sequence (ECTGLAWEWWR). The CDC pore forming mechanism is highly sensitive to changes in its structure, yet its contribution to the molecular mechanism of the CDCs has remained enigmatic. Using a combination of fluorescence spectroscopic methods we provide evidence that shows the undecapeptide motif of the archetype CDC, perfringolysin O (PFO), is a key structural element in the allosteric coupling of the cholesterol-mediated membrane binding in domain 4 (D4) to distal structural changes in domain 3 (D3) that are required for the formation of the oligomeric pore complex. Loss of the undecapeptide function prevents all measurable D3 structural transitions, the intermolecular interaction of membrane bound monomers and the assembly of the oligomeric pore complex. We further show that this pathway does not exist in intermedilysin (ILY), a CDC that exhibits a divergent undecapeptide and that has evolved to use human CD59 rather than cholesterol as its receptor. These studies show for the first time that the undecapeptide of the cholesterol-binding CDCs forms a critical element of the allosteric pathway that controls the assembly of the pore complex.
Mouse, but Not Human, ApoB-100 Lipoprotein Cholesterol Is a Potent Innate Inhibitor of Streptococcus pneumoniae Pneumolysin
Kristin R. Wade,Eileen M. Hotze,David E. Briles,Rodney K. Tweten
PLOS Pathogens , 2014, DOI: doi/10.1371/journal.ppat.1004353
Abstract: Streptococcus pneumoniae produces the pore-forming toxin pneumolysin (PLY), which is a member of the cholesterol-dependent cytolysin (CDC) family of toxins. The CDCs recognize and bind the 3β-hydroxyl group of cholesterol at the cell surface, which initiates membrane pore formation. The cholesterol transport lipoproteins, which carry cholesterol in their outer monolayer, are potential off-pathway binding targets for the CDCs and are present at significant levels in the serum and the interstitial spaces of cells. Herein we show that cholesterol carried specifically by the ApoB-100-containing lipoprotein particles (CH-ApoB-100) in the mouse, but not that carried by human or guinea pig particles, is a potent inhibitor of the PLY pore-forming mechanism. Cholesterol present in the outer monolayer of mouse ApoB-100 particles is recognized and bound by PLY, which stimulates premature assembly of the PLY oligomeric complex thereby inactivating PLY. These studies further suggest that the vast difference in the inhibitory capacity of mouse CH-ApoB-100 and that of the human and the guinea pig is due to differences in the presentation of cholesterol in the outer monolayer of their ApoB-100 particles. Therefore mouse CH-ApoB-100 represents a significant innate CDC inhibitor that is absent in humans, which may underestimate the contribution of CDCs to human disease when utilizing mouse models of disease.
The Pore-Forming Toxin Listeriolysin O Mediates a Novel Entry Pathway of L. monocytogenes into Human Hepatocytes
Stephen Vadia,Eusondia Arnett,Anne-Cécile Haghighat,Elisabeth M. Wilson-Kubalek,Rodney K. Tweten,Stephanie Seveau
PLOS Pathogens , 2011, DOI: 10.1371/journal.ppat.1002356
Abstract: Intracellular pathogens have evolved diverse strategies to invade and survive within host cells. Among the most studied facultative intracellular pathogens, Listeria monocytogenes is known to express two invasins-InlA and InlB-that induce bacterial internalization into nonphagocytic cells. The pore-forming toxin listeriolysin O (LLO) facilitates bacterial escape from the internalization vesicle into the cytoplasm, where bacteria divide and undergo cell-to-cell spreading via actin-based motility. In the present study we demonstrate that in addition to InlA and InlB, LLO is required for efficient internalization of L. monocytogenes into human hepatocytes (HepG2). Surprisingly, LLO is an invasion factor sufficient to induce the internalization of noninvasive Listeria innocua or polystyrene beads into host cells in a dose-dependent fashion and at the concentrations produced by L. monocytogenes. To elucidate the mechanisms underlying LLO-induced bacterial entry, we constructed novel LLO derivatives locked at different stages of the toxin assembly on host membranes. We found that LLO-induced bacterial or bead entry only occurs upon LLO pore formation. Scanning electron and fluorescence microscopy studies show that LLO-coated beads stimulate the formation of membrane extensions that ingest the beads into an early endosomal compartment. This LLO-induced internalization pathway is dynamin-and F-actin-dependent, and clathrin-independent. Interestingly, further linking pore formation to bacteria/bead uptake, LLO induces F-actin polymerization in a tyrosine kinase-and pore-dependent fashion. In conclusion, we demonstrate for the first time that a bacterial pathogen perforates the host cell plasma membrane as a strategy to activate the endocytic machinery and gain entry into the host cell.
Using the Analytical Hierarchy Process Model in the Prioritization of Information Assurance Defense In-Depth Measures?—A Quantitative Study  [PDF]
Rodney Alexander
Journal of Information Security (JIS) , 2017, DOI: 10.4236/jis.2017.83011
Abstract: Organizational computing devices are increasingly becoming targets of cyber-attacks, and organizations have become dependent on the safety and security of their computer networks and their organizational computing devices. Business and government often use defense in-depth information assurance measures such as firewalls, intrusion detection systems, and password procedures across their enterprises to plan strategically and manage IT security risks. This quantitative study explores whether the analytical hierarchy process (AHP) model can be effectively applied to the prioritization of information assurance defense in-depth measures. In response to these threats, the President, legislators, experts, and others have characterized cyber security as a pressing national security issue. The methods used in this study consisted of emailing study participants a survey requesting that they prioritize five defense in-depth information assurance measures, anti-virus, intrusion detection, password, smart-cards, and encryption, with a range of responses from 1 - 5 using a Likert scale to consider standard cost, effectiveness, and perceived ease of use in terms of protection of organizational computing devices. The measures were then weighted, based on ranking. A pair-wise comparison of each of the five measures is then made using AHP to determine whether the Likert scale and the AHP model could be effectively applied to the prioritization of information assurance measures to protect organizational computing devices. The findings of the research reject the H0 null hypothesis that AHP does not affect the relationship between the information technology analysts’ prioritization of five defense in-depth dependent variables and the independent variables of cost, ease of use, and effectiveness in protecting organizational devices against cyber-attacks.
A Sources-of-Error Model for Acoustic/Infrasonic Yield Estimation for Above-Ground Single-Point Explosions  [PDF]
Stephen J. Arrowsmith, Rodney W. Whitaker, Jonathan K. Maccarthy, Dale N. Anderson
InfraMatics (InfraMatics) , 2012, DOI: 10.4236/inframatics.2012.11001
Abstract: Acoustic/infrasonic measurements contain physical information enabling an estimate of the yield of a single-point explosion that is on or above ground. A variety of semi-empirical and numerical models have been developed for estimating the yield based on the amplitude of a recorded acoustic signal. This paper utilizes existing semi-empirical models-suitable for timely yield estimation—and develops the mathematical framework to properly account for uncertainties in these models, in addition to measurement uncertainties. The inclusion of calibration parameters into our mathematical model allows for the correction of constant path specific effects that are not captured in existing semi-empirical models. The calibrated model provides a yield estimate and associated error bounds that correctly partitions total error into model error and background noise. Yield estimation with the models is demonstrated with single-point, above ground chemical explosions at Los Alamos National Laboratory (LANL) experimental testing facilities.
Is Perioperative Hypothermia a Risk Factor for Post-Cesarean Infection?
Rodney K. Edwards,Kaivou Madani,Patrick Duff
Infectious Diseases in Obstetrics and Gynecology , 2003, DOI: 10.1080/10647440300025502
Abstract: Objective: To determine whether hypothermia during Cesarean delivery is a risk factor for postoperative infection.
Assessment of the Value of Rescreening for Syphilis in the Third Trimester of Pregnancy
Rodney K. Edwards,Margaret Bennett,Carrie Langstraat,Daina Greene
Infectious Diseases in Obstetrics and Gynecology , 2006, DOI: 10.1155/idog/2006/56504
Abstract: Objectives. Our aim is evaluating the need for repeating tests for syphilis on pregnant women in the third trimester. Study design. A single-center retrospective cohort study was performed on all women delivering 7/03–6/04. Results. During the study interval, 2244 women delivered at our hospital. Of those women having available records and attending at least one prenatal visit, 1940 (98.9%) were screened for syphilis at the first prenatal visit. Of the 1627 women beginning prenatal care prior to 27 weeks and delivering after 32 weeks, 1377 (84.6%) were rescreened in the third trimester. No cases of syphilis were identified with either the initial (upper limit of 95% CI 0.24%) or repeat (upper limit of 95% CI 0.34%) screening. Conclusions. In our obstetric population, syphilis is so uncommon that mandated prenatal screening on more than one occasion seems unjustified and laws requiring repeated screening should be reevaluated.
Antimicrobial Susceptibility of Gram-Negative Uropathogens Isolated From Obstetric Patients
Whitney E. Jamie,Rodney K. Edwards,Patrick Duff
Infectious Diseases in Obstetrics and Gynecology , 2002, DOI: 10.1155/s106474490200011x
Abstract: Objective: To evaluate the antimicrobial susceptibility of Gram-negative uropathogens isolated from pregnant women.
Performance Characteristics of Putative Tests for Subclinical Chorioamnionitis
Rodney K. Edwards,Penny Clark,Gregory J. Locksmith,Patrick Duff
Infectious Diseases in Obstetrics and Gynecology , 2001, DOI: 10.1155/s1064744901000345
Abstract: Objective: To evaluate amniotic fluid glucose, matrix metalloproteinase (MMP)-9, interleukin (IL)-6, and IL-12 for diagnosing subclinical chorioamnionitis in women with preterm labor.
Development of peptidomimetic ligands of Pro-Leu-Gly-NH2 as allosteric modulators of the dopamine D2 receptor
Swapna Bhagwanth,Ram K. Mishra,Rodney L. Johnson
Beilstein Journal of Organic Chemistry , 2013, DOI: 10.3762/bjoc.9.24
Abstract: A variety of stable, small-molecule peptidomimetic ligands have been developed to elucidate the mechanism by which the neuropeptide Pro-Leu-Gly-NH2 (PLG) modulates dopaminergic neurotransmission. Photoaffinity labeling ligands based upon PLG peptidomimetics have been used to establish that PLG binds to the D2 dopamine receptor at a site that is different from the orthosteric site, thus making PLG and its peptidomimetics allosteric modulators of the dopamine receptor. Through the design, synthesis and pharmacological evaluation of conformationally constrained peptidomimetics containing lactam, bicyclic, and spiro-bicyclic scaffolds, support was provided for the hypothesis that the bioactive conformation of PLG is a type II β-turn. In addition, studies with peptidomimetics designed to mimic either a type VI β-turn or polyproline II helix conformation yielded molecules that were able to modulate dopamine receptors because of their ability to place the carboxamide NH2 pharmacophore in the same topological space as that seen in the type II β-turn. Extensive studies with the spiro-bicyclic PLG peptidomimetics also established that both positive and negative modes of modulation were possible for the same series of peptidomimetics simply as a result of minor differences in the stereochemistry about the bridgehead carbon within the scaffold. This information was used to transform existing positive modulators into negative modulators, which demonstrated that small structural changes in the spiro-bicyclic dopamine receptor modulators are capable of causing major changes in the modulatory activity of PLG peptidomimetics.
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