1,226 research outputs found
Trapped lipopolysaccharide and LptD intermediates reveal lipopolysaccharide translocation steps across the Escherichia coli outer membrane
Lipopolysaccharide (LPS) is a main component of the outer membrane of Gram-negative bacteria, which is essential for the vitality of most Gram-negative bacteria and plays a critical role for drug resistance. LptD/E complex forms a N-terminal LPS transport slide, a hydrophobic intramembrane hole and the hydrophilic channel of the barrel, for LPS transport, lipid A insertion and core oligosaccharide and O-antigen polysaccharide translocation, respectively. However, there is no direct evidence to confirm that LptD/E transports LPS from the periplasm to the external leaflet of the outer membrane. By replacing LptD residues with an unnatural amino acid p-benzoyl-L-phenyalanine (pBPA) and UV-photo-cross-linking in E.coli, the translocon and LPS intermediates were obtained at the N-terminal domain, the intramembrane hole, the lumenal gate, the lumen of LptD channel, and the extracellular loop 1 and 4, providing the first direct evidence and βsnapshotsβ to reveal LPS translocation steps across the outer membrane
Risk factors for race-day fatality in flat racing Thoroughbreds in Great Britain (2000 to 2013)
A key focus of the racing industry is to reduce the number of race-day events where horses die suddenly or are euthanased due to catastrophic injury. The objective of this study was therefore to determine risk factors for race-day fatalities in Thoroughbred racehorses, using a cohort of all horses participating in flat racing in Great Britain between 2000 and 2013. Horse-, race- and course-level data were collected and combined with all race-day fatalities, recorded by racecourse veterinarians in a central database. Associations between exposure variables and fatality were assessed using logistic regression analyses for (1) all starts in the dataset and (2) starts made on turf surfaces only. There were 806,764 starts in total, of which 548,571 were on turf surfaces. A total of 610 fatalities were recorded; 377 (61.8%) on turf. In both regression models, increased firmness of the going, increasing racing distance, increasing average horse performance, first year of racing and wearing eye cover for the first time all increased the odds of fatality. Generally, the odds of fatality also increased with increasing horse age whereas increasing number of previous starts reduced fatality odds. In the βall startsβ model, horses racing in an auction race were at 1.46 (95% confidence interval (CI) 1.06β2.01) times the odds of fatality compared with horses not racing in this race type. In the turf starts model, horses racing in Group 1 races were at 3.19 (95% CI 1.71β5.93) times the odds of fatality compared with horses not racing in this race type. Identification of novel risk factors including wearing eye cover and race type will help to inform strategies to further reduce the rate of fatality in flat racing horses, enhancing horse and jockey welfare and safety
Physicists attempt to scale the ivory towers of finance
Physicists have recently begun doing research in finance, and even though
this movement is less than five years old, interesting and useful contributions
have already emerged. This article reviews these developments in four areas,
including empirical statistical properties of prices, random-process models for
price dynamics, agent-based modeling, and practical applications.Comment: 13 pages, 5 figure
Predictive police patrolling to target hotspots and cover response demand
This is an Open Access Article. It is published by Springer under the Creative Commons Attribution 4.0 Unported Licence (CC BY). Full details of this licence are available at: http://creativecommons.org/licenses/by/4.0/Police forces are constantly competing to provide adequate service whilst faced with major funding cuts. The funding cuts result in limited resources hence methods of improving resource efficiency are vital to public safety. One area where improving the efficiency could drastically improve service is the planning of patrol routes for incident response officers. Current methods of patrolling lack direction and do not consider response demand. Police patrols have the potential to deter crime when directed to the right areas. Patrols also have the ability to position officers with access to high demand areas by pre-empting where response demand will arise. The algorithm developed in this work directs patrol routes in real-time by targeting high crime areas whilst maximising demand coverage. Methods used include kernel density estimation for hotspot identification and maximum coverage location problems for positioning. These methods result in more effective daily patrolling which reduces response times and accurately targets problem areas. Though applied in this instance to daily patrol operations, the methodology could help to reduce the need for disaster relief operations whilst also positioning proactively to allow quick response when disaster relief operations are required
Genetic Basis of Hidden Phenotypic Variation Revealed by Increased Translational Readthrough in Yeast
Eukaryotic release factors 1 and 3, encoded by SUP45 and SUP35, respectively, in Saccharomyces cerevisiae, are required for translation termination. Recent studies have shown that, besides these two key factors, several genetic and epigenetic mechanisms modulate the efficiency of translation termination. These mechanisms, through modifying translation termination fidelity, were shown to affect various cellular processes, such as mRNA degradation, and in some cases could confer a beneficial phenotype to the cell. The most studied example of such a mechanism is [PSI+], the prion conformation of Sup35p, which can have pleiotropic effects on growth that vary among different yeast strains. However, genetic loci underlying such readthrough-dependent, background-specific phenotypes have yet to be identified. Here, we used sup35C653R, a partial loss-of-function allele of the SUP35 previously shown to increase readthrough of stop codons and recapitulate some [PSI+]-dependent phenotypes, to study the genetic basis of phenotypes revealed by increased translational readthrough in two divergent yeast strains: BY4724 (a laboratory strain) and RM11_1a (a wine strain). We first identified growth conditions in which increased readthrough of stop codons by sup35C653R resulted in different growth responses between these two strains. We then used a recently developed linkage mapping technique, extreme QTL mapping (X-QTL), to identify readthrough-dependent loci for the observed growth differences. We further showed that variation in SKY1, an SR protein kinase, underlies a readthrough-dependent locus observed for growth on diamide and hydrogen peroxide. We found that the allelic state of SKY1 interacts with readthrough level and the genetic background to determine growth rate in these two conditions
Deep-Sea Nematodes Actively Colonise Sediments, Irrespective of the Presence of a Pulse of Organic Matter: Results from an In-Situ Experiment
A colonisation experiment was performed in situ at 2500 m water depth at the
Arctic deep-sea long-term observatory HAUSGARTEN to determine the response of
deep-sea nematodes to disturbed, newly available patches, enriched with organic
matter. Cylindrical tubes,laterally covered with a 500 Β΅m mesh, were
filled with azoic deep-sea sediment and 13C-labelled food sources
(diatoms and bacteria). After 10 days of incubation the tubes were analysed for
nematode response in terms of colonisation and uptake. Nematodes actively
colonised the tubes,however with densities that only accounted for a maximum of
2.13% (51 ind.10 cmβ2) of the ambient nematode
assemblages. Densities did not differ according to the presence or absence of
organic matter, nor according to the type of organic matter added. The fact that
the organic matter did not function as an attractant to nematodes was confirmed
by the absence of notable 13C assimilation by the colonising
nematodes. Overall, colonisationappears to be a process that yields reproducible
abundance and diversity patterns, with certain taxa showing more efficiency.
Together with the high variability between the colonising nematode assemblages,
this lends experimental support to the existence of a spatio-temporal mosaic
that emerges from highly localised, partially stochastic community dynamics
Jet energy measurement with the ATLAS detector in proton-proton collisions at root s=7 TeV
The jet energy scale and its systematic uncertainty are determined for jets measured with the ATLAS detector at the LHC in proton-proton collision data at a centre-of-mass energy of βs = 7TeV corresponding to an integrated luminosity of 38 pb-1. Jets are reconstructed with the anti-kt algorithm with distance parameters R=0. 4 or R=0. 6. Jet energy and angle corrections are determined from Monte Carlo simulations to calibrate jets with transverse momenta pTβ₯20 GeV and pseudorapidities {pipe}Ξ·{pipe}<4. 5. The jet energy systematic uncertainty is estimated using the single isolated hadron response measured in situ and in test-beams, exploiting the transverse momentum balance between central and forward jets in events with dijet topologies and studying systematic variations in Monte Carlo simulations. The jet energy uncertainty is less than 2. 5 % in the central calorimeter region ({pipe}Ξ·{pipe}<0. 8) for jets with 60β€pT<800 GeV, and is maximally 14 % for pT<30 GeV in the most forward region 3. 2β€{pipe}Ξ·{pipe}<4. 5. The jet energy is validated for jet transverse momenta up to 1 TeV to the level of a few percent using several in situ techniques by comparing a well-known reference such as the recoiling photon pT, the sum of the transverse momenta of tracks associated to the jet, or a system of low-pT jets recoiling against a high-pT jet. More sophisticated jet calibration schemes are presented based on calorimeter cell energy density weighting or hadronic properties of jets, aiming for an improved jet energy resolution and a reduced flavour dependence of the jet response. The systematic uncertainty of the jet energy determined from a combination of in situ techniques is consistent with the one derived from single hadron response measurements over a wide kinematic range. The nominal corrections and uncertainties are derived for isolated jets in an inclusive sample of high-pT jets. Special cases such as event topologies with close-by jets, or selections of samples with an enhanced content of jets originating from light quarks, heavy quarks or gluons are also discussed and the corresponding uncertainties are determined. Β© 2013 CERN for the benefit of the ATLAS collaboration
Bortezomib in combination with celecoxib in patients with advanced solid tumors: a phase I trial
<p>Abstract</p> <p>Background</p> <p>COX-2 inhibitors, such as celecoxib, and ubiquitin-proteasome pathway inhibitors, such as bortezomib, can down-regulate NF-ΞΊB, a transcription factor implicated in tumor growth. The objective of this study was to determine the maximum tolerated dose and dose-limiting toxicities of bortezomib in combination with celecoxib in patients with advanced solid tumors.</p> <p>Methods</p> <p>Patients received escalating doses of bortezomib either on a weekly schedule (days 1, 8, 15, 22, and 29 repeated every 42 days) or on a twice-weekly administration schedule (days 1, 4, 8, and 11 repeated every 21 days), in combination with escalating doses of celecoxib twice daily throughout the study period from 200 mg to 400 mg twice daily.</p> <p>Results</p> <p>No dose-limiting toxicity was observed during the study period. Two patients had stable disease lasting for four and five months each, and sixteen patients developed progressive disease.</p> <p>Conclusion</p> <p>The combination of bortezomib and celecoxib was well tolerated, without dose limiting toxicities observed throughout the dosing ranges tested, and will be studied further at the highest dose levels investigated.</p> <p>Trial registration number</p> <p>NCT00290680.</p
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