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  • 1
    Publication Date: 2012-07-17
    Description: Alterations in intestinal microbiota composition are associated with several chronic conditions, including obesity and inflammatory diseases. The microbiota of older people displays greater inter-individual variation than that of younger adults. Here we show that the faecal microbiota composition from 178 elderly subjects formed groups, correlating with residence location in the community, day-hospital, rehabilitation or in long-term residential care. However, clustering of subjects by diet separated them by the same residence location and microbiota groupings. The separation of microbiota composition significantly correlated with measures of frailty, co-morbidity, nutritional status, markers of inflammation and with metabolites in faecal water. The individual microbiota of people in long-stay care was significantly less diverse than that of community dwellers. Loss of community-associated microbiota correlated with increased frailty. Collectively, the data support a relationship between diet, microbiota and health status, and indicate a role for diet-driven microbiota alterations in varying rates of health decline upon ageing.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Claesson, Marcus J -- Jeffery, Ian B -- Conde, Susana -- Power, Susan E -- O'Connor, Eibhlis M -- Cusack, Siobhan -- Harris, Hugh M B -- Coakley, Mairead -- Lakshminarayanan, Bhuvaneswari -- O'Sullivan, Orla -- Fitzgerald, Gerald F -- Deane, Jennifer -- O'Connor, Michael -- Harnedy, Norma -- O'Connor, Kieran -- O'Mahony, Denis -- van Sinderen, Douwe -- Wallace, Martina -- Brennan, Lorraine -- Stanton, Catherine -- Marchesi, Julian R -- Fitzgerald, Anthony P -- Shanahan, Fergus -- Hill, Colin -- Ross, R Paul -- O'Toole, Paul W -- England -- Nature. 2012 Aug 9;488(7410):178-84. doi: 10.1038/nature11319.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Microbiology, University College Cork, Ireland.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22797518" target="_blank"〉PubMed〈/a〉
    Keywords: Aged ; Aged, 80 and over ; Aging/*physiology ; Cohort Studies ; Diet/*statistics & numerical data ; Diet Surveys ; Feces/*microbiology ; Fruit ; Geriatric Assessment ; Health ; *Health Status ; Health Surveys ; Homes for the Aged ; Hospitals, Community ; Humans ; Intestines/*microbiology ; Meat ; Metagenome/*physiology ; Rehabilitation Centers ; Surveys and Questionnaires ; Vegetables
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 2
    Publication Date: 2012-08-11
    Description: Biological dinitrogen fixation provides the largest input of nitrogen to the oceans, therefore exerting important control on the ocean's nitrogen inventory and primary productivity. Nitrogen-isotope data from ocean sediments suggest that the marine-nitrogen inventory has been balanced for the past 3,000 years (ref. 4). Producing a balanced marine-nitrogen budget based on direct measurements has proved difficult, however, with nitrogen loss exceeding the gain from dinitrogen fixation by approximately 200 Tg N yr-1 (refs 5, 6). Here we present data from the Atlantic Ocean and show that the most widely used method of measuring oceanic N2-fixation rates underestimates the contribution of N2-fixing microorganisms (diazotrophs) relative to a newly developed method. Using molecular techniques to quantify the abundance of specific clades of diazotrophs in parallel with rates of 15N2 incorporation into particulate organic matter, we suggest that the difference between N2-fixation rates measured with the established method and those measured with the new method can be related to the composition of the diazotrophic community. Our data show that in areas dominated by Trichodesmium, the established method underestimates N2-fixation rates by an average of 62%. We also find that the newly developed method yields N2-fixation rates more than six times higher than those from the established method when unicellular, symbiotic cyanobacteria and gamma-proteobacteria dominate the diazotrophic community. On the basis of average areal rates measured over the Atlantic Ocean, we calculated basin-wide N2-fixation rates of 14 +/- 1 Tg N yr-1 and 24 +/-1 Tg N yr-1 for the established and new methods, respectively. If our findings can be extrapolated to other ocean basins, this suggests that the global marine N2-fixation rate derived from direct measurements may increase from 103 +/- 8 Tg N yr-1 to 177 +/- 8 Tg N yr-1, and that the contribution of N2 fixers other than Trichodesmium is much more significant than was previously thought.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Grosskopf, Tobias -- Mohr, Wiebke -- Baustian, Tina -- Schunck, Harald -- Gill, Diana -- Kuypers, Marcel M M -- Lavik, Gaute -- Schmitz, Ruth A -- Wallace, Douglas W R -- LaRoche, Julie -- England -- Nature. 2012 Aug 16;488(7411):361-4. doi: 10.1038/nature11338.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Helmholtz Centre for Ocean Research Kiel, Kiel, Germany. tgrosskopf@geomar.de〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22878720" target="_blank"〉PubMed〈/a〉
    Keywords: Aquatic Organisms/*metabolism ; Atlantic Ocean ; Cyanobacteria/genetics/metabolism ; Diatoms/metabolism ; Kinetics ; Nitrogen/*metabolism ; Nitrogen Fixation/*physiology ; Oxidoreductases/genetics ; Proteobacteria/genetics/metabolism ; Seawater/chemistry ; Taq Polymerase/metabolism ; Temperature ; Tropical Climate
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 3
    Publication Date: 2013-05-28
    Description: Fusing left and right eye images into a single view is dependent on precise ocular alignment, which relies on coordinated eye movements. During movements of the head this alignment is maintained by numerous reflexes. Although rodents share with other mammals the key components of eye movement control, the coordination of eye movements in freely moving rodents is unknown. Here we show that movements of the two eyes in freely moving rats differ fundamentally from the precisely controlled eye movements used by other mammals to maintain continuous binocular fusion. The observed eye movements serve to keep the visual fields of the two eyes continuously overlapping above the animal during free movement, but not continuously aligned. Overhead visual stimuli presented to rats freely exploring an open arena evoke an immediate shelter-seeking behaviour, but are ineffective when presented beside the arena. We suggest that continuously overlapping visual fields overhead would be of evolutionary benefit for predator detection by minimizing blind spots.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Wallace, Damian J -- Greenberg, David S -- Sawinski, Juergen -- Rulla, Stefanie -- Notaro, Giuseppe -- Kerr, Jason N D -- England -- Nature. 2013 Jun 6;498(7452):65-9. doi: 10.1038/nature12153. Epub 2013 May 26.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Network Imaging Group, Max Planck Institute for Biological Cybernetics, Spemannstrasse 41, 72076 Tubingen, Germany.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23708965" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Escape Reaction/physiology ; Exploratory Behavior/physiology ; Eye Movements/physiology ; Head/physiology ; Models, Biological ; Movement/physiology ; Optic Disk/physiology ; Predatory Behavior ; Rats ; Retina/physiology ; Vision, Binocular/*physiology ; Visual Fields/*physiology
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 4
    Publication Date: 2014-05-09
    Description: Rapid Arctic warming and sea-ice reduction in the Arctic Ocean are widely attributed to anthropogenic climate change. The Arctic warming exceeds the global average warming because of feedbacks that include sea-ice reduction and other dynamical and radiative feedbacks. We find that the most prominent annual mean surface and tropospheric warming in the Arctic since 1979 has occurred in northeastern Canada and Greenland. In this region, much of the year-to-year temperature variability is associated with the leading mode of large-scale circulation variability in the North Atlantic, namely, the North Atlantic Oscillation. Here we show that the recent warming in this region is strongly associated with a negative trend in the North Atlantic Oscillation, which is a response to anomalous Rossby wave-train activity originating in the tropical Pacific. Atmospheric model experiments forced by prescribed tropical sea surface temperatures simulate the observed circulation changes and associated tropospheric and surface warming over northeastern Canada and Greenland. Experiments from the Coupled Model Intercomparison Project Phase 5 (ref. 16) models with prescribed anthropogenic forcing show no similar circulation changes related to the North Atlantic Oscillation or associated tropospheric warming. This suggests that a substantial portion of recent warming in the northeastern Canada and Greenland sector of the Arctic arises from unforced natural variability.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Ding, Qinghua -- Wallace, John M -- Battisti, David S -- Steig, Eric J -- Gallant, Ailie J E -- Kim, Hyung-Jin -- Geng, Lei -- England -- Nature. 2014 May 8;509(7499):209-12. doi: 10.1038/nature13260.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Earth and Space Sciences and Quaternary Research Center, University of Washington, Seattle, Washington 98195, USA. ; Department of Atmospheric Sciences, University of Washington, Seattle, Washington 98195, USA. ; School of Geography and Environmental Science, Monash University, Victoria 3800, Australia. ; Climate Research Department, APEC Climate Center, 12 Centum 7-ro, Haeundae-gu, Busan 612-020, South Korea.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24805345" target="_blank"〉PubMed〈/a〉
    Keywords: Air ; Arctic Regions ; Canada ; *Feedback ; Global Warming/*statistics & numerical data ; Greenland ; Hot Temperature ; Human Activities ; Ice Cover ; Models, Theoretical ; Pacific Ocean ; Seawater ; *Tropical Climate
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 5
    Publication Date: 2016-03-05
    Description: It is often thought that the ability to control reaction rates with an applied electrical potential gradient is unique to redox systems. However, recent theoretical studies suggest that oriented electric fields could affect the outcomes of a range of chemical reactions, regardless of whether a redox system is involved. This possibility arises because many formally covalent species can be stabilized via minor charge-separated resonance contributors. When an applied electric field is aligned in such a way as to electrostatically stabilize one of these minor forms, the degree of resonance increases, resulting in the overall stabilization of the molecule or transition state. This means that it should be possible to manipulate the kinetics and thermodynamics of non-redox processes using an external electric field, as long as the orientation of the approaching reactants with respect to the field stimulus can be controlled. Here, we provide experimental evidence that the formation of carbon-carbon bonds is accelerated by an electric field. We have designed a surface model system to probe the Diels-Alder reaction, and coupled it with a scanning tunnelling microscopy break-junction approach. This technique, performed at the single-molecule level, is perfectly suited to deliver an electric-field stimulus across approaching reactants. We find a fivefold increase in the frequency of formation of single-molecule junctions, resulting from the reaction that occurs when the electric field is present and aligned so as to favour electron flow from the dienophile to the diene. Our results are qualitatively consistent with those predicted by quantum-chemical calculations in a theoretical model of this system, and herald a new approach to chemical catalysis.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Aragones, Albert C -- Haworth, Naomi L -- Darwish, Nadim -- Ciampi, Simone -- Bloomfield, Nathaniel J -- Wallace, Gordon G -- Diez-Perez, Ismael -- Coote, Michelle L -- England -- Nature. 2016 Mar 3;531(7592):88-91. doi: 10.1038/nature16989.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Departament de Quimica-Fisica, Universitat de Barcelona, Diagonal 645, Barcelona 08028, Catalonia, Spain. ; Institut de Bioenginyeria de Catalunya (IBEC), Baldiri Reixac 15-21, Barcelona 08028, Catalonia, Spain. ; Centro Investigacion Biomedica en Red (CIBER-BBN), Campus Rio Ebro-Edificio I+D, Poeta Mariano Esquillor s/n, Zaragoza 50018, Spain. ; ARC Centre of Excellence for Electromaterials Science, Research School of Chemistry, Australian National University, Canberra, Australian Capital Territory 2601, Australia. ; ARC Centre of Excellence for Electromaterials Science, Intelligent Polymer Research Institute, University of Wollongong, Wollongong, New South Wales 2500, Australia.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26935697" target="_blank"〉PubMed〈/a〉
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 6
    Publication Date: 2018-04-27
    Description: Ceftazidime-avibactam is a "second-generation" β-lactam–β-lactamase inhibitor combination that is effective against Enterobacteriaceae expressing class A extended-spectrum β-lactamases, class A carbapenemases, and/or class C cephalosporinases. Knowledge of the interactions of avibactam, a diazabicyclooctane with different β-lactamases, is required to anticipate future resistance threats. FOX family β-lactamases possess unique hydrolytic properties with a broadened substrate profile to include cephamycins, partly as a result of an isoleucine at position 346, instead of the conserved asparagine found in most AmpCs. Interestingly, a single amino acid substitution at N346 in the Citrobacter AmpC is implicated in resistance to the aztreonam-avibactam combination. In order to understand how diverse active-site topologies affect avibactam inhibition, we tested a panel of clinical Enterobacteriaceae isolates producing bla FOX using ceftazidime-avibactam, determined the biochemical parameters for inhibition using the FOX-4 variant, and probed the atomic structure of avibactam with FOX-4. Avibactam restored susceptibility to ceftazidime for most isolates producing bla FOX ; two isolates, one expressing bla FOX-4 and the other producing bla FOX-5 , displayed an MIC of 16 μg/ml for the combination. FOX-4 possessed a k 2 / K value of 1,800 ± 100 M –1 · s –1 and an off rate ( k off ) of 0.0013 ± 0.0003 s –1 . Mass spectrometry showed that the FOX-4–avibactam complex did not undergo chemical modification for 24 h. Analysis of the crystal structure of FOX-4 with avibactam at a 1.5-Å resolution revealed a unique characteristic of this AmpC β-lactamase. Unlike in the Pseudomonas -derived cephalosporinase 1 (PDC-1)–avibactam crystal structure, interactions (e.g., hydrogen bonding) between avibactam and position I346 in FOX-4 are not evident. Furthermore, another residue is not observed to be close enough to compensate for the loss of these critical hydrogen-bonding interactions. This observation supports findings from the inhibition analysis of FOX-4; FOX-4 possessed the highest K d (dissociation constant) value (1,600 nM) for avibactam compared to other AmpCs (7 to 660 nM). Medicinal chemists must consider the properties of extended-spectrum AmpCs, such as the FOX β-lactamases, for the design of future diazabicyclooctanes.
    Print ISSN: 0066-4804
    Electronic ISSN: 1098-6596
    Topics: Biology , Medicine
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  • 7
    Publication Date: 2018-04-27
    Description: Pseudomonas aeruginosa is a prevalent and life-threatening Gram-negative pathogen. Pseudomonas -derived cephlosporinase (PDC) is the major inducible cephalosporinase in P. aeruginosa . In this investigation, we show that relebactam, a diazabicyclooctane β-lactamase inhibitor, potently inactivates PDC-3, with a k 2 / K of 41,400 M –1 s –1 and a k off of 0.00095 s –1 . Relebactam restored susceptibility to imipenem in 62% of multidrug-resistant P. aeruginosa clinical isolates, while only 21% of isolates were susceptible to imipenem-cilastatin alone. Relebactam promises to increase the efficacy of imipenem-cilastatin against P. aeruginosa .
    Print ISSN: 0066-4804
    Electronic ISSN: 1098-6596
    Topics: Biology , Medicine
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  • 8
    Publication Date: 2018-05-15
    Description: Apoptotic cell–induced AhR activity is required for immunological tolerance and suppression of systemic lupus erythematosus in mice and humans Apoptotic cell–induced AhR activity is required for immunological tolerance and suppression of systemic lupus erythematosus in mice and humans, Published online: 14 May 2018; doi:10.1038/s41590-018-0107-1 McGaha and colleagues show that phagocytosis of apoptotic cells leads to activation of the transcription factor AhR and production of the cytokine IL-10 in phagocytes, in a manner dependent on the recognition of DNA.
    Print ISSN: 1529-2908
    Electronic ISSN: 1529-2916
    Topics: Biology , Medicine
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  • 9
    Publication Date: 2018-05-26
    Description: The imipenem-relebactam combination is in development as a potential treatment regimen for infections caused by Enterobacteriaceae possessing complex β-lactamase backgrounds. Relebactam is a β-lactamase inhibitor that possesses the diazabicyclooctane core, as in avibactam; however, the R1 side chain of relebactam also includes a piperidine ring, whereas that of avibactam is a carboxyamide. Here, we investigated the inactivation of the Klebsiella pneumoniae carbapenemase KPC-2, the most widespread class A carbapenemase, by relebactam and performed susceptibility testing with imipenem-relebactam using KPC-producing clinical isolates of Enterobacteriaceae . MIC measurements using agar dilution methods revealed that all 101 clinical isolates of KPC-producing Enterobacteriaceae ( K. pneumoniae , Klebsiella oxytoca , Enterobacter cloacae , Enterobacter aerogenes , Citrobacter freundii , Citrobacter koseri , and Escherichia coli ) were highly susceptible to imipenem-relebactam (MICs ≤ 2 mg/liter). Relebactam inhibited KPC-2 with a second-order onset of acylation rate constant ( k 2 / K ) value of 24,750 M –1 s –1 and demonstrated a slow off-rate constant ( k off ) of 0.0002 s –1 . Biochemical analysis using time-based mass spectrometry to map intermediates revealed that the KPC-2–relebactam acyl-enzyme complex was stable for up to 24 h. Importantly, desulfation of relebactam was not observed using mass spectrometry. Desulfation and subsequent deacylation have been observed during the reaction of KPC-2 with avibactam. Upon molecular dynamics simulations of relebactam in the KPC-2 active site, we found that the positioning of active-site water molecules is less favorable for desulfation in the KPC-2 active site than it is in the KPC-2–avibactam complex. In the acyl complexes, the water molecules are within 2.5 to 3 Å of the avibactam sulfate; however, they are more than 5 to 6 Å from the relebactam sulfate. As a result, we propose that the KPC-2–relebactam acyl complex is more stable than the KPC-2–avibactam complex. The clinical implications of this difference are not currently known.
    Print ISSN: 0066-4804
    Electronic ISSN: 1098-6596
    Topics: Biology , Medicine
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  • 10
    Publication Date: 2018-06-22
    Description: The interactions between Klebsiella pneumoniae and the host environment at the site of infection are largely unknown. Pulmonary surfactant serves as an initial point of contact for inhaled bacteria entering the lung and is thought to contain molecular cues that aid colonization and pathogenesis. To gain insight into this ecological transition, we characterized the transcriptional response of K. pneumoniae MGH 78578 to purified pulmonary surfactant. This work revealed changes within the K. pneumoniae transcriptome that likely contribute to host colonization, adaptation, and virulence in vivo . Notable transcripts expressed under these conditions include genes involved in capsule synthesis, lipopolysaccharide modification, antibiotic resistance, biofilm formation, and metabolism. In addition, we tested the contributions of other surfactant-induced transcripts to K. pneumoniae survival using engineered isogenic KPPR1 deletion strains in a murine model of acute pneumonia. In these infection studies, we identified the MdtJI polyamine efflux pump and the ProU glycine betaine ABC transporter to be significant mediators of K. pneumoniae survival within the lung and confirmed previous evidence for the importance of de novo leucine synthesis to bacterial survival during infection. Finally, we determined that pulmonary surfactant promoted type 3 fimbria-mediated biofilm formation in K. pneumoniae and identified two surfactant constituents, phosphatidylcholine and cholesterol, that drive this response. This study provides novel insight into the interactions occurring between K. pneumoniae and the host at an important infection site and demonstrates the utility of purified lung surfactant preparations for dissecting host-lung pathogen interactions in vitro .
    Print ISSN: 0019-9567
    Electronic ISSN: 1098-5522
    Topics: Medicine
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