411 research outputs found

    Descriptive epidemiology of Escherichia coli bacteraemia in England, April 2012 to March 2014

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    We determined the incidence, risk factors and antimicrobial susceptibility associated with Escherichia coli bacteraemia in England over a 24 month period. Case data were obtained from the national mandatory surveillance database, with susceptibility data linked from LabBase2, a voluntary national microbiology database. Between April 2012 and March 2014, 66,512 E. coli bacteraemia cases were reported. Disease incidence increased by 6% from 60.4 per 100,000 population in 2012-13 to 63.5 per 100,000 population in 2013-14 (p < 0.0001). Rates of E. coli bacteraemia varied with patient age and sex, with 70.5% (46,883/66,512) of cases seen in patients aged ≥ 65 years and 52.4% (33,969/64,846) of cases in females. The most common underlying cause of bacteraemia was infection of the genital/urinary tract (41.1%; 27,328/66,512), of which 98.4% (26,891/27,328) were urinary tract infections (UTIs). The majority of cases (76.1%; 50,617/66,512) had positive blood cultures before or within two days of admission and were classified as community onset cases, however 15.7% (10,468/66,512) occurred in patients who had been hospitalised for over a week. Non-susceptibility to ciprofloxacin, third-generation cephalosporins, piperacillin-tazobactam, gentamicin and carbapenems were 18.4% (8,439/45,829), 10.4% (4,256/40,734), 10.2% (4,694/46,186), 9.7% (4,770/49,114) and 0.2% (91/42,986), respectively. Antibiotic non-susceptibility was higher in hospital-onset cases than for those presenting from the community (e.g. ciprofloxacin non-susceptibility was 22.1% (2,234/10,105) for hospital-onset vs 17.4% (5,920/34,069) for community-onset cases). Interventions to reduce the incidence of E. coli bacteraemia will have to target the community setting and UTIs if substantial reductions are to be realised

    Bacterial ribosome requires multiple L12 dimers for efficient initiation and elongation of protein synthesis involving IF2 and EF-G

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    The ribosomal stalk in bacteria is composed of four or six copies of L12 proteins arranged in dimers that bind to the adjacent sites on protein L10, spanning 10 amino acids each from the L10 C-terminus. To study why multiple L12 dimers are required on the ribosome, we created a chromosomally engineered Escherichia coli strain, JE105, in which the peripheral L12 dimer binding site was deleted. Thus JE105 harbors ribosomes with only a single L12 dimer. Compared to MG1655, the parental strain with two L12 dimers, JE105 showed significant growth defect suggesting suboptimal function of the ribosomes with one L12 dimer. When tested in a cell-free reconstituted transcription–translation assay the synthesis of a full-length protein, firefly luciferase, was notably slower with JE105 70S ribosomes and 50S subunits. Further, in vitro analysis by fast kinetics revealed that single L12 dimer ribosomes from JE105 are defective in two major steps of translation, namely initiation and elongation involving translational GTPases IF2 and EF-G. Varying number of L12 dimers on the ribosome can be a mechanism in bacteria for modulating the rate of translation in response to growth condition

    Validation of thermal-mechanical modeling of stainless steel forgings

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    A constitutive model for recrystallization has been developed within the framework of an existing dislocation-based rate and temperature-dependent plasticity model. The theory has been implemented and tested in a finite element code. Material parameters were fit to data from monotonic compression tests on 304L steel for a wide range of temperatures and strain rates. The model is then validated by using the same parameter set in predictive thermal-mechanical simulations of experiments in which wedge forgings were produced at elevated temperatures. Model predictions of the final yield strengths compare well to the experimental results

    A disease-linked ULBP6 polymorphism inhibits NKG2D-mediated target cell killing by enhancing the stability of NKG2D-ligand binding

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    This is an accepted manuscript of an article published by AAAS in Science Signaling on 30/05/2017, available online: https://stke.sciencemag.org/content/10/481/eaai8904 The accepted version of the publication may differ from the final published version.NKG2D (natural killer group 2, member D) is an activating receptor found on the surface of immune cells, including natural killer (NK) cells, which regulates innate and adaptive immunity through recognition of the stress-induced ligands ULBP1 (UL16 binding protein 1) to ULBP6 and MICA/B. Similar to class I human leukocyte antigen (HLA), these NKG2D ligands have a major histocompatibility complex–like fold and exhibit pronounced polymorphism, which influences human disease susceptibility. However, whereas class I HLA polymorphisms occur predominantly in the α1α2 groove and affect antigen binding, the effects of most NKG2D ligand polymorphisms are unclear. We studied the molecular and functional consequences of the two major alleles of ULBP6, the most polymorphic ULBP gene, which are associated with autoimmunity and relapse after stem cell transplantation. Surface plasmon resonance and crystallography studies revealed that the arginine-to-leucine polymorphism within ULBP0602 affected the NKG2D-ULBP6 interaction by generating an energetic hotspot. This resulted in an NKG2D-ULBP0602 affinity of 15.5 nM, which is 10- to 1000-fold greater than the affinities of other ULBP-NKG2D interactions and limited NKG2D-mediated activation. In addition, soluble ULBP0602 exhibited high-affinity competitive binding for NKG2D and partially suppressed NKG2D-mediated activation of NK cells by other NKG2D ligands. These effects resulted in a decrease in a range of NKG2D-mediated effector functions. Our results reveal that ULBP polymorphisms affect the strength of human lymphocyte responses to cellular stress signals and may offer opportunities for therapeutic intervention.Leukaemia and Lymphoma Researc

    Pushouts in software architecture design

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    A classical approach to program derivation is to progressively extend a simple specification and then incrementally refine it to an implementation. We claim this approach is hard or impractical when reverse engineering legacy software architectures. We present a case study that shows optimizations and pushouts--in addition to refinements and extensions--are essential for practical stepwise development of complex software architectures.NSF CCF 0724979NSF CNS 0509338NSF CCF 0917167NSF DGE-1110007FCT SFRH/BD/47800/2008FCT UTAustin/CA/0056/200

    Important performance characteristics in elite clay and grass court tennis match-play.

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    The performance characteristics of elite tennis match-play differ depending on court surface. However, the performance characteristics (e.g. aces, first serve points won, forced errors) most associated with success on different surfaces are currently unknown. With three weeks typically separating Roland Garros and Wimbledon, the transition from clay to grass courts, whereby players must adapt their game style between surfaces, is crucial to understand. Using the recently validated PWOL method, we analysed 984 singles matches across the 2016 and 2017 Roland Garros and Wimbledon tournaments, to identify the most important performance characteristics in clay and grass court tennis. Results revealed that points won of 0-4 shot rally length, first serve points won and baseline points won were most strongly associated with success for both sexes; serve-related performance characteristics (aces, double faults and average first serve speed) were among the least associated with success. Furthermore, winning short points (points of 0-4 shots) was more closely associated with success than winning medium-length (5-8 shots) and long points (9+ shots). To be representative of match-play, findings suggest that players should afford sufficient practise time to short rallies and point-ending strategies during the clay and grass court seasons, rather than over-emphasising long rallies

    Ribosome formation from subunits studied by stopped-flow and Rayleigh light scattering

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    Light scattering and standard stopped-flow techniques were used to monitor rapid association of ribosomal subunits during initiation of eubacterial protein synthesis. The effects of the initiation factors IF1, IF2, IF3 and buffer conditions on subunit association were studied along with the role of GTP in this process. The part of light scattering theory that is essential for kinetic measurements is high-lighted in the main text and a more general treatment of Rayleigh scattering from macromolecules is given in an appendix
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