260 research outputs found
The GRO remote terminal system
In March 1992, NASA HQ challenged GSFC/Code 531 to propose a fast, low-cost approach to close the Tracking Data Relay Satellite System (TDRSS) Zone-of-Exclusion (ZOE) over the Indian Ocean in order to provide global communications coverage for the Compton Gamma Ray Observatory (GRO) spacecraft. GRO had lost its tape recording capability which limited its valuable science data return to real-time contacts with the TDRS-E and TDRS-W synchronous data relay satellites, yielding only approximately 62 percent of the possible data obtainable. To achieve global coverage, a TDRS spacecraft would have to be moved over the Indian Ocean out of line-of-sight control of White Sands Ground Terminal (WSGT). To minimize operations life cycle costs, Headquarters also set a goal for remote control, from the WSGT, of the overseas ground station which was required for direct communications with TDRS-1. On August 27, 1992, Code 531 was given the go ahead to implement the proposed GRO Relay Terminal System (GRTS). This paper describes the Remote Ground Relay Terminal (RGRT) which went operational at the Canberra Deep Space Communications Complex (CDSCC) in Canberra, Australia in December 1993 and is currently augmenting the TDRSS constellation in returning between 80-100 percent of GRO science data under the control of a single operator at WSGT
Tissue drives lesion: computational evidence of interspecies variability in cardiac radiofrequency ablation
Radiofrequency catheter ablation (RFCA) is widely used for the treatment of various types of cardiac arrhythmias. Typically, the efficacy and the safety of the ablation protocols used in the clinics are derived from tests carried out on animal specimens, including swines. However, these experimental findings cannot be immediately translated to clinical practice on human patients, due to the difference in the physical properties of the types of tissue. Computational models can assist in the quantification of this variability and can provide insights in the results of the RFCA for different species. In this work, we consider a standard ablation protocol of 10g force, 30W power for 30s. We simulate its application on a porcine cardiac tissue, a human ventricle and a human atrium. Using a recently developed computational model that accounts for the mechanical properties of the tissue, we explore the onset and the growth of the lesion along time by tracking its depth and width, and we compare the lesion size and dimensions at the end of the ablation
Antibiotic capture by bacterial lipocalins uncovers an extracellular mechanism of intrinsic antibiotic resistance
15 p.-6 fig.The potential for microbes to overcome antibiotics of different classes before they reach bacterial cells is largely unexplored. Here we show that a soluble bacterial lipocalin produced by Burkholderia cenocepacia upon exposure to sublethal antibiotic concentrations increases resistance to diverse antibiotics in vitro and in vivo. These phenotypes were recapitulated by heterologous expression in B. cenocepacia of lipocalin genes from Pseudomonas aeruginosa, Mycobacterium tuberculosis,and methicillin-resistant Staphylococcus aureus. Purified lipocalin bound different classes of bactericidal antibiotics and contributed to bacterial survival in vivo. Experimental and X-ray crystal structure-guided computational studies revealed that lipocalins counteract antibiotic action by capturing antibiotics in the extracellular space. We also demonstrated that fat-soluble vitamins prevent antibiotic capture by binding bacterial lipocalin with higher affinity than antibiotics. Therefore, bacterial lipocalins contribute to antimicrobial resistance by capturing diverse antibiotics in the extracellular space at the site of infection, which can be counteracted by known vitamins.This work was funded by grants from Cystic Fibrosis Canada, the European Commission,a Marie Curie Career Integration grant (projects 618095, NONANTIRES), and the Infection and Immunity Translational Research Group, Northern Ireland HSC to M.A.V.;the Spanish Ministry for Economy and Competitiveness (MINECO CTQ2011-22724 and CTQ2014-57141-R), European Commission Marie Curie grants GLYCOPHARM FP7-PITNGA-2012-317297 and TOLLerant H2020-MSC-ETN-642157 to S.M.S.; and Canadian Institutes of Health research grant MOP-49597 and a grant from Cystic Fibrosis Canada to M.E.P.M.Peer reviewe
Transcriptional responses of Burkholderia cenocepacia to polymyxin B in isogenic strains with diverse polymyxin B resistance phenotypes
<p>Abstract</p> <p>Background</p> <p><it>Burkholderia cenocepacia </it>is a Gram-negative opportunistic pathogen displaying high resistance to antimicrobial peptides and polymyxins. We identified mechanisms of resistance by analyzing transcriptional changes to polymyxin B treatment in three isogenic <it>B. cenocepacia </it>strains with diverse polymyxin B resistance phenotypes: the polymyxin B-resistant parental strain K56-2, a polymyxin B-sensitive K56-2 mutant strain with heptoseless lipopolysaccharide (LPS) (RSF34), and a derivative of RSF34 (RSF34 4000B) isolated through multiple rounds of selection in polymyxin B that despite having a heptoseless LPS is highly polymyxin B-resistant.</p> <p>Results</p> <p>A heptoseless LPS mutant of <it>B. cenocepacia </it>was passaged through multiple rounds of selection to regain high levels of polymyxin B-resistance. This process resulted in various phenotypic changes in the isolate that could contribute to polymyxin B resistance and are consistent with LPS-independent changes in the outer membrane. The transcriptional response of three <it>B. cenocepacia </it>strains to subinhibitory concentrations of polymyxin B was analyzed using microarray analysis and validated by quantitative Real Time-PCR. There were numerous baseline changes in expression between the three strains in the absence of polymyxin B. In both K56-2 and RSF34, similar transcriptional changes upon treatment with polymyxin B were found and included upregulation of various genes that may be involved in polymyxin B resistance and downregulation of genes required for the synthesis and operation of flagella. This last result was validated phenotypically as both swimming and swarming motility were impaired in the presence of polymyxin B. RSF34 4000B had altered the expression in a larger number of genes upon treatment with polymyxin B than either K56-2 or RSF34, but the relative fold-changes in expression were lower.</p> <p>Conclusions</p> <p>It is possible to generate polymyxin B-resistant isolates from polymyxin B-sensitive mutant strains of <it>B. cenocepacia</it>, likely due to the multifactorial nature of polymyxin B resistance of this bacterium. Microarray analysis showed that <it>B. cenocepacia </it>mounts multiple transcriptional responses following exposure to polymyxin B. Polymyxin B-regulated genes identified in this study may be required for polymyxin B resistance, which must be tested experimentally. Exposure to polymyxin B also decreases expression of flagellar genes resulting in reduced swimming and swarming motility.</p
What Do Firms Know? What Do They Produce? A New Look at the Relationship between Patenting Profiles and Patterns of Product Diversification
The structure of sedoheptulose-7-phosphate isomerase from Burkholderia pseudomallei reveals a zinc binding site at the heart of the active site
Copyright © 2010 Elsevier. NOTICE: this is the author’s version of a work that was accepted for publication in Journal of Molecular Biology. Changes resulting from the publishing process, such as peer review, editing, corrections, structural formatting, and other quality control mechanisms may not be reflected in this document. Changes may have been made to this work since it was submitted for publication. A definitive version was subsequently published in Journal of Molecular Biology, 2010, Vol. 400, Issue 3, pp. 379 – 392 DOI: http://dx.doi.org/10.1016/j.jmb.2010.04.058Heptoses are found in the surface polysaccharides of most bacteria, contributing to structures that are essential for virulence and antibiotic resistance. Consequently, the biosynthetic enzymes for these sugars are attractive targets for novel antibiotics. The best characterized biosynthetic enzyme is GmhA, which catalyzes the conversion of sedoheptulose-7-phosphate into D-glycero-D-manno-heptopyranose-7-phosphate, the first step in the biosynthesis of heptose. Here, the structure of GmhA from Burkholderia pseudomallei is reported. This enzyme contains a zinc ion at the heart of its active site: this ion stabilizes the active, closed form of the enzyme and presents coordinating side chains as a potential acid and base to drive catalysis. A complex with the product demonstrates that the enzyme retains activity in the crystal and thus suggests that the closed conformation is catalytically relevant and is an excellent target for the development of therapeutics. A revised mechanism for the action of GmhA is postulated on the basis of this structure and the activity of B. pseudomallei GmhA mutants
A half-site multimeric enzyme achieves its cooperativity without conformational changes
Cooperativity is a feature many multimeric proteins use to control activity. Here we show that the bacterial heptose isomerase GmhA displays homotropic positive and negative cooperativity among its four protomers. Most similar proteins achieve this through conformational changes: GmhA instead employs a delicate network of hydrogen bonds, and couples pairs of active sites controlled by a unique water channel. This network apparently raises the Lewis acidity of the catalytic zinc, thus increasing the activity at one active site at the cost of preventing substrate from adopting a reactive conformation at the paired negatively cooperative site – a “half-site” behavior. Our study establishes the principle that multimeric enzymes can exploit this cooperativity without conformational changes to maximize their catalytic power and control. More broadly, this subtlety by which enzymes regulate functions could be used to explore new inhibitor design strategies
Mesoglycan connects Syndecan-4 and VEGFR2 through Annexin A1 and formyl peptide receptors to promote angiogenesis in vitro.
Mesoglycan is a mixture of glycosaminoglycans (GAG) with fibrinolytic effects and the potential to enhance skin wound repair. Here, we have used endothelial cells isolated from Wild Type (WT) and Syndecan-4 null (Sdc4-/-) C57BL/6 mice to demonstrate that mesoglycan promotes cell motility and in vitro angiogenesis acting on the co-receptor Syndecan-4 (SDC4). This latter is known to participate in the formation and release of extracellular vesicles (EVs). We characterized EVs released by HUVECs and assessed their effect on angiogenesis. Particularly, we focused on Annexin A1 (ANXA1) containing EVs, since they may contribute to tube formation via interactions with Formyl peptide receptors (FPRs). In our model, the bond ANXA1-FPRs stimulates the release of vascular endothelial growth factor (VEGF-A) that interacts with vascular endothelial receptor-2 (VEGFR2) and activates the pathway enhancing cell motility in an autocrine manner, as shown by Wound-Healing/invasion assays, and the induction of Endothelial to Mesenchymal Transition (EndMT). Thus, we have shown for the first time that mesoglycan exerts its pro-angiogenic effects in the healing process triggering the activation of the three interconnected molecular axis: mesoglycan-SDC4, EVs-ANXA1-FPRs and VEGF-A-VEGFR2
The ArcAB two-component regulatory system promotes resistance to reactive oxygen species and systemic infection by Salmonella Typhimurium
Indexación: Scopus.Funding:Thisworkwassupportedby"Fondo NacionaldeCienciayTecnologia"FONDECYT Grants#1120384and#1160315(toCPS),Grant PFB-16(toRP)from"Comisio ´nNacionalde Investigacio ´ n Cientı ´ fica y Tecnolo ´ gica de Chile" (CONICYT)andUniversidadAndresBelloNucleo GrantDI-3-17/N(toCPS),andDoctoralSalmonella enterica Serovar Typhimurium (S. Typhimurium) is an intracellular bacterium that overcomes host immune system barriers for successful infection. The bacterium colonizes the proximal small intestine, penetrates the epithelial layer, and is engulfed by macrophages and neutrophils. Intracellularly, S. Typhimurium encounters highly toxic reactive oxygen species including hydrogen peroxide and hypochlorous acid. The molecular mechanisms of Salmonella resistance to intracellular oxidative stress is not completely understood. The ArcAB two-component system is a global regulatory system that responds to oxygen. In this work, we show that the ArcA response regulator participates in Salmonella adaptation to changing oxygen levels and is also involved in promoting intracellular survival in macrophages and neutrophils, enabling S. Typhimurium to successfully establish a systemic infection. © 2018 Pardo-Esté et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.https://journals.plos.org/plosone/article?id=10.1371/journal.pone.020349
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