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Search Results: 1 - 10 of 165519 matches for " Robert K. Ernst "
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Activation of Toll-like receptors by Burkholderia pseudomallei
T Eoin West, Robert K Ernst, Malinka J Jansson-Hutson, Shawn J Skerrett
BMC Immunology , 2008, DOI: 10.1186/1471-2172-9-46
Abstract: In HEK293 cells transfected with murine or human TLRs, CD14, and MD-2, heat-killed B. pseudomallei activated TLR2 (in combination with TLR1 or TLR6) and TLR4. B. pseudomallei LPS and lipid A activated TLR4 and this TLR4-mediated signaling required MD-2. In TLR2-/- macrophages, stimulation with heat-killed B. pseudomallei augmented TNF-α and MIP-2 production whereas in TLR4-/- cells, TNF-α, MIP-2, and IL-10 production was reduced. Cytokine production by macrophages stimulated with B. pseudomallei LPS or lipid A was entirely dependent on TLR4 but was increased in the absence of TLR2. TLR adaptor molecule MyD88 strongly regulated TNF-α production in response to heat-killed B. pseudomallei.B. pseudomallei activates TLR2 and TLR4. In the presence of MD-2, B. pseudomallei LPS and lipid A are TLR4 ligands. Although the macrophage cytokine response to B. pseudomallei LPS or lipid A is completely dependent on TLR4, in TLR2-/- macrophages stimulated with B. pseudomallei, B. pseudomallei LPS or lipid A, cytokine production is augmented. Other MyD88-dependent signaling pathways may also be important in the host response to B. pseudomallei infection. These findings provide new insights into critical mechanisms of host defense in melioidosis.Melioidosis is an endemic and poorly understood infectious disease in much of the tropical world; it is particularly prevalent in east Asia and northern Australia. The disease accounts for 20% of community-acquired sepsis in parts of northeast Thailand. Despite antibiotic treatment, mortality rates approach 40% [1]. The causative organism, Burkholderia pseudomallei (Bp), is a Gram-negative environmental saprophyte. Aerosol or transcutaneous infection results in an extensive range of disease – from chronic, relapsing illness with abscess formation to fulminant pneumonia and septicemia [2]. The lung is the most commonly affected organ. Concern about the use of Bp as a bioweapon has led to its classification as a CDC Category B pathogen. While t
Influence of Lipid A Acylation Pattern on Membrane Permeability and Innate Immune Stimulation
Yanyan Li,Zhou Wang,Jiuzhou Chen,Robert K. Ernst,Xiaoyuan Wang
Marine Drugs , 2013, DOI: 10.3390/md11093197
Abstract: Lipid A, the hydrophobic anchor of lipopolysaccharide (LPS), is an essential component in the outer membrane of Gram-negative bacteria. It can stimulate the innate immune system via Toll-like receptor 4/myeloid differentiation factor 2 (TLR4/MD2), leading to the release of inflammatory cytokines. In this study, six Escherichia coli strains which can produce lipid A with different acylation patterns were constructed; the influence of lipid A acylation pattern on the membrane permeability and innate immune stimulation has been systematically investigated. The lipid A species were isolated and identified by matrix assisted laser ionization desorption-time of flight/tandem mass spectrometry. N-Phenyl naphthylamine uptake assay and antibiotic susceptibility test showed that membrane permeability of these strains were different. The lower the number of acyl chains in lipid A, the stronger the membrane permeability. LPS purified from these strains were used to stimulate human or mouse macrophage cells, and different levels of cytokines were induced. Compared with wild type hexa-acylated LPS, penta-acylated, tetra-acylated and tri-acylated LPS induced lower levels of cytokines. These results suggest that the lipid A acylation pattern influences both the bacterial membrane permeability and innate immune stimulation. The results would be useful for redesigning the bacterial membrane structure and for developing lipid A vaccine adjuvant.
Ernst Jean-Robert Michel
Revista Eletr?nica Espa?o Teológico , 2009,
Abstract: Este artigo quer ressalvar como a postura ética é fundamental num contexto de pluralismo religioso – na perspectiva de diálogo interreligioso. Focalizando o encontro entre o cristianismo e as religi es de matrizes africanas no Brasil, a teologia negra desenvolvida no Brasil fala em jun o. O problema caracterizado quer trazer alguma marca das experiências de incultura o (experiência do sagrado). Este tema da incultura o na América Latina revela que é importante analisar no vai-e-vem da miss o junto aos Negros, a articula o dos aspectos seguintes: identidades, poderes e diálogos. Por isso, abordo a quest o ética a partir da defini o identitária, e o processo de incultura o no encontro do cristianismo com as religi es de matrizes africanas, para indicar possíveis rumos do diálogo neste contexto.
Evaluation of the Ability of LL-37 to Neutralise LPS In Vitro and Ex Vivo
Aaron Scott, Sinéad Weldon, Paul J. Buchanan, Bettina Schock, Robert K. Ernst, Danny F. McAuley, Michael M. Tunney, Chris R. Irwin, J. Stuart Elborn, Clifford C. Taggart
PLOS ONE , 2011, DOI: 10.1371/journal.pone.0026525
Abstract: Background Human cathelicidin LL-37 is a cationic antimicrobial peptide (AMP) which possesses a variety of activities including the ability to neutralise endotoxin. In this study, we investigated the role of LPS neutralisation in mediating LL-37's ability to inhibit Pseudomonas aeruginosa LPS signalling in human monocytic cells. Methodology/Principal Findings Pre-treatment of monocytes with LL-37 significantly inhibited LPS-induced IL-8 production and the signalling pathway of associated transcription factors such as NF-κB. However, upon removal of LL-37 from the media prior to LPS stimulation, these inhibitory effects were abolished. These findings suggest that the ability of LL-37 to inhibit LPS signalling is largely dependent on extracellular LPS neutralisation. In addition, LL-37 potently inhibited cytokine production induced by LPS extracted from P. aeruginosa isolated from the lungs of cystic fibrosis (CF) patients. In the CF lung, polyanionic molecules such as glycosaminoglycans (GAGs) and DNA bind LL-37 and impact negatively on its antibacterial activity. In order to determine whether such interactions interfere with the LPS neutralising ability of LL-37, the status of LL-37 and its ability to bind LPS in CF sputum were investigated. Overall our findings suggest that in the CF lung, the ability of LL-37 to bind LPS and inhibit LPS-induced IL-8 production is attenuated as a result of binding to DNA and GAGs. However, LL-37 levels and its concomitant LPS-binding activity can be increased with a combination of DNase and GAG lyase (heparinase II) treatment. Conclusions/Significance Overall, these findings suggest that a deficiency in available LL-37 in the CF lung may contribute to greater LPS-induced inflammation during CF lung disease.
Mutations of Francisella novicida that Alter the Mechanism of Its Phagocytosis by Murine Macrophages
Xin-He Lai,Renee L. Shirley,Lidia Crosa,Duangjit Kanistanon,Rebecca Tempel,Robert K. Ernst,Larry A. Gallagher,Colin Manoil,Fred Heffron
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0011857
Abstract: Infection with the bacterial pathogen Francisella tularensis tularensis (F. tularensis) causes tularemia, a serious and debilitating disease. Francisella tularensis novicida strain U112 (abbreviated F. novicida), which is closely related to F. tularensis, is pathogenic for mice but not for man, making it an ideal model system for tularemia. Intracellular pathogens like Francisella inhibit the innate immune response, thereby avoiding immune recognition and death of the infected cell. Because activation of inflammatory pathways may lead to cell death, we reasoned that we could identify bacterial genes involved in inhibiting inflammation by isolating mutants that killed infected cells faster than the wild-type parent. We screened a comprehensive transposon library of F. novicida for mutant strains that increased the rate of cell death following infection in J774 macrophage-like cells, as compared to wild-type F. novicida. Mutations in 28 genes were identified as being hypercytotoxic to both J774 and primary macrophages of which 12 were less virulent in a mouse infection model. Surprisingly, we found that F. novicida with mutations in four genes (lpcC, manB, manC and kdtA) were taken up by and killed macrophages at a much higher rate than the parent strain, even upon treatment with cytochalasin D (cytD), a classic inhibitor of macrophage phagocytosis. At least 10-fold more mutant bacteria were internalized by macrophages as compared to the parent strain if the bacteria were first fixed with formaldehyde, suggesting a surface structure is required for the high phagocytosis rate. However, bacteria were required to be viable for macrophage toxicity. The four mutant strains do not make a complete LPS but instead have an exposed lipid A. Interestingly, other mutations that result in an exposed LPS core were not taken up at increased frequency nor did they kill host cells more than the parent. These results suggest an alternative, more efficient macrophage uptake mechanism for Francisella that requires exposure of a specific bacterial surface structure(s) but results in increased cell death following internalization of live bacteria.
Francisella Tularensis Blue–Gray Phase Variation Involves Structural Modifications of Lipopolysaccharide O-Antigen, Core and Lipid A and Affects Intramacrophage Survival and Vaccine Efficacy
Shilpa Soni,Robert K. Ernst,Artur Muszyński,Nrusingh P. Mohapatra,Malcolm B. Perry,Evgeny Vinogradov,Russell W. Carlson,John S. Gunn
Frontiers in Microbiology , 2010, DOI: 10.3389/fmicb.2010.00129
Abstract: Francisella tularensis is a CDC Category A biological agent and a potential bioterrorist threat. There is no licensed vaccine against tularemia in the United States. A long-standing issue with potential Francisella vaccines is strain phase variation to a gray form that lacks protective capability in animal models. Comparisons of the parental strain (LVS) and a gray variant (LVSG) have identified lipopolysaccharide (LPS) alterations as a primary change. The LPS of the F. tularensis variant strain gains reactivity to F. novicida anti-LPS antibodies, suggesting structural alterations to the O-antigen. However, biochemical and structural analysis of the F. tularensis LVSG and LVS LPS demonstrated that LVSG has less O-antigen but no major O-antigen structural alterations. Additionally, LVSG possesses structural differences in both the core and lipid A regions, the latter being decreased galactosamine modification. Recent work has identified two genes important in adding galactosamine (flmF2 and flmK) to the lipid A. Quantitative real-time PCR showed reduced transcripts of both of these genes in the gray variant when compared to LVS. Loss of flmF2 or flmK caused less frequent phase conversion but did not alter intramacrophage survival or colony morphology. The LVSG strain demonstrated an intramacrophage survival defect in human and rat but not mouse macrophages. Consistent with this result, the LVSG variant demonstrated little change in LD50 in the mouse model of infection. Furthermore, the LVSG strain lacks the protective capacity of F. tularensis LVS against virulent Type A challenge. These data suggest that the LPS of the F. tularensis LVSG phase variant is dramatically altered. Understanding the mechanism of blue to gray phase variation may lead to a way to inhibit this variation, thus making future F. tularensis vaccines more stable and efficacious.
Increased Long Chain acyl-Coa Synthetase Activity and Fatty Acid Import Is Linked to Membrane Synthesis for Development of Picornavirus Replication Organelles
Jules A. Nchoutmboube equal contributor,Ekaterina G. Viktorova equal contributor,Alison J. Scott,Lauren A. Ford,Zhengtong Pei,Paul A. Watkins,Robert K. Ernst,George A. Belov
PLOS Pathogens , 2013, DOI: 10.1371/journal.ppat.1003401
Abstract: All positive strand (+RNA) viruses of eukaryotes replicate their genomes in association with membranes. The mechanisms of membrane remodeling in infected cells represent attractive targets for designing future therapeutics, but our understanding of this process is very limited. Elements of autophagy and/or the secretory pathway were proposed to be hijacked for building of picornavirus replication organelles. However, even closely related viruses differ significantly in their requirements for components of these pathways. We demonstrate here that infection with diverse picornaviruses rapidly activates import of long chain fatty acids. While in non-infected cells the imported fatty acids are channeled to lipid droplets, in infected cells the synthesis of neutral lipids is shut down and the fatty acids are utilized in highly up-regulated phosphatidylcholine synthesis. Thus the replication organelles are likely built from de novo synthesized membrane material, rather than from the remodeled pre-existing membranes. We show that activation of fatty acid import is linked to the up-regulation of cellular long chain acyl-CoA synthetase activity and identify the long chain acyl-CoA syntheatse3 (Acsl3) as a novel host factor required for polio replication. Poliovirus protein 2A is required to trigger the activation of import of fatty acids independent of its protease activity. Shift in fatty acid import preferences by infected cells results in synthesis of phosphatidylcholines different from those in uninfected cells, arguing that the viral replication organelles possess unique properties compared to the pre-existing membranes. Our data show how poliovirus can change the overall cellular membrane homeostasis by targeting one critical process. They explain earlier observations of increased phospholipid synthesis in infected cells and suggest a simple model of the structural development of the membranous scaffold of replication complexes of picorna-like viruses, that may be relevant for other (+)RNA viruses as well.
Ukrain – a new cancer cure? A systematic review of randomised clinical trials
E Ernst, K Schmidt
BMC Cancer , 2005, DOI: 10.1186/1471-2407-5-69
Abstract: Seven electronic databases were searched for all relevant randomised clinical trials. Data were extracted and validated by both authors, tabulated and summarised narratively. The methodological quality was assessed with the Jadad score.Seven trials met our inclusion criteria. Without exception, their findings suggest that Ukrain has curative effects on a range of cancers. However, the methodological quality of most studies was poor. In addition, the interpretation of several trials was impeded by other problems.The data from randomised clinical trials suggest Ukrain to have potential as an anticancer drug. However, numerous caveats prevent a positive conclusion, and independent rigorous studies are urgently needed.Ukrain (NSC-631570) is a semi-synthetic compound derived from the common weed, greater celandine (Chelidonium majus L.). This plant contains a range of alkaloids, most notably chelidonine, also known as benzophenanthridine alkaloid. A leaflet distributed to patients at the Bristol Cancer Help Centre, United Kingdom, describes Ukrain as " the only known product, which at present does not also destroy healthy cells, and which reduces tumors and boosts the immune system..." [1]. Ukrain is most commonly administered intravenously and consists of one molecule thiophosphoric acid conjugated to three molecules of chelidonine. It has drug licenses in several states of the former Soviet Union.Research on Ukrain started about 20 years ago. Meanwhile, numerous in-vitro studies [2-37] animal experiments [38-83], case reports [84-97], and case series [98-108] have emerged. Collectively, these data suggest that Ukrain has anticancer activity in a wide range of cell lines, which could be of clinical value. Whether or not this translates into clinical effectiveness and whether or not Ukrain does indeed cure some type of cancer or improves their prognosis can best be decided on the basis of randomised clinical trials (RCTs). This systematic review is aimed at summarising a
Impact of a physician-supervised exercise-nutrition program with testosterone substitution in partial androgen-deficient middle-aged obese men
Ernst R Schwarz,Robert D Willix Jr
老年心脏病学杂志(英文版) , 2011,
Abstract: Background Partial androgen deficiency syndrome in the aging male is associated with signs of aging such as a development of abdominal obesity, sexual dysfunction, increase body fat, weight gain and the development of cardiac disease. Objective We assessed the outcome of a commercially available physician supervised nutrition and exercise program with concomitant testosterone replacement therapy in middle age obese men with partial androgen deficiency in order to reduce cardiac risks factors. Methods Fifty-six self referred men without diabetes mellitus, hypertension, or cardiovascular disease (ages 52.3 ± 7.8 years) were randomly selected from a large cohort. Baseline weight, body fat composition, fasting glucose, hemoglobin A1c and fasting lipid levels, as well as free and total testosterone levels were assessed. All patients were assessed and followed 6–18 months after initiation of the program. The program consisted of a low glycemic load balanced nutrition diet, a recommended structured daily exercise program of 30–60 minutes, as well as once to twice weekly intramuscular testosterone injections (113.0 ± 27.8 mg). Results At follow up, weight was reduced from 233.9 ± 30.0 pounds (lbs) to 221.3 ± 25.1 lbs (P < 0.001), BMI was reduced from 33.2 ± 3.3 kg/m2 to 31.3 ± 2.8 kg/m2 (P < 0.0001). Total body fat was 27.1% ± 5.2% vs. 34.3% ± 5.7% at baseline (P < 0.0001). Fasting glucose was reduced from 95.3 ± 14.4 mg/dL to 87.5 ± 12.6 mg/dL (P < 0.0001). Total cholesterol was reduced from 195.4 ± 33.0 mg/dL to 172.7 ± 35.0 mg/dL (P < 0.005). No clinically significant adverse events were recorded. Conclusions Testosterone replacement therapy in middle aged obese men with partial androgen deficiency appeared safe and might have promoted the effects of a weight reduction diet and daily exercise program as long as an adequate physician supervision and follow up was granted. The combination therapy significantly reduced coronary risk factors such as glucose intolerance and hyperlipidemia.
Protein structure determination via an efficient geometric build-up algorithm
Davis Robert T,Ernst Claus,Wu Di
BMC Structural Biology , 2010, DOI: 10.1186/1472-6807-10-s1-s7
Abstract: Background A protein structure can be determined by solving a so-called distance geometry problem whenever a set of inter-atomic distances is available and sufficient. However, the problem is intractable in general and has proved to be a NP hard problem. An updated geometric build-up algorithm (UGB) has been developed recently that controls numerical errors and is efficient in protein structure determination for cases where only sparse exact distance data is available. In this paper, the UGB method has been improved and revised with aims at solving distance geometry problems more efficiently and effectively. Methods An efficient algorithm (called the revised updated geometric build-up algorithm (RUGB)) to build up a protein structure from atomic distance data is presented and provides an effective way of determining a protein structure with sparse exact distance data. In the algorithm, the condition to determine an unpositioned atom iteratively is relaxed (when compared with the UGB algorithm) and data structure techniques are used to make the algorithm more efficient and effective. The algorithm is tested on a set of proteins selected randomly from the Protein Structure Database-PDB. Results We test a set of proteins selected randomly from the Protein Structure Database-PDB. We show that the numerical errors produced by the new RUGB algorithm are smaller when compared with the errors of the UGB algorithm and that the novel RUGB algorithm has a significantly smaller runtime than the UGB algorithm. Conclusions The RUGB algorithm relaxes the condition for updating and incorporates the data structure for accessing neighbours of an atom. The revisions result in an improvement over the UGB algorithm in two important areas: a reduction on the overall runtime and decrease of the numeric error.
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