SPI-2 of Salmonella Typhimurium is not necessary for long term colonization of pigs

Unravelling the role of Salmonella virulence factors in the porcine host could greatly contribute to the development of control measures such as vaccination. The virulence genes located on the Salmonella Pathogenicity Island 2 (SPI-2) are indispensable for the induction of systemic disease and persistence in BALB/c mice. The role of this pathogenicity island in the pathogenesis of Salmonella Typhimurium infections in pigs is not documented. Therefore, in the present study, the interactions of a porcine field strain of Salmonella Typhimurium and a non-polar isogenic SPI-2 (D-ssrA) deletion mutant were compared in both in vitro and in vivo models. The ssrA mutant strain displayed decreased SPI-2 expression levels in vitro and was attenuated in a mouse model after oral inoculation. No difference was seen in the expression of SPI-1 related virulence genes. Through flowcytometric analysis, the ssrA mutant strain was found to be moderately attenuated in intracellular replication in porcine macrophages in vitro. In an infection experiment, 2 groups of 10 piglets were orally inoculated with the wild type or the ssrA mutant strain. The infection of the animals inoculated with the ssrA mutant strain followed a similar course as the animals infected with the wild type strain. At days 5 and 28 post inoculation, the animals of both groups were infected to the same extent in the gut and gut-associated lymphoid tissue, as well as in the mternal organs. These results suggest that SPI-2 of Salmonella Typhimurium may not contribute to the colonization of pigs to the same extent as it contributes to the colonization of BALB/c mice

Intervening with Urinary Tract Infections Using Anti-Adhesives Based on the Crystal Structure of the FimH–Oligomannose-3 Complex

Escherichia coli strains adhere to the normally sterile human uroepithelium using type 1 pili, that are long, hairy surface organelles exposing a mannose-binding FimH adhesin at the tip. A small percentage of adhered bacteria can successfully invade bladder cells, presumably via pathways mediated by the high-mannosylated uroplakin-Ia and alpha3beta1 integrins found throughout the uroepithelium. Invaded bacteria replicate and mature into dense, biofilm-like inclusions in preparation of fluxing and of infection of neighbouring cells, being the major cause of the troublesome recurrent urinary tract infections.We demonstrate that alpha-D-mannose based inhibitors of FimH not only block bacterial adhesion on uroepithelial cells but also antagonize invasion and biofilm formation. Heptyl alpha-D-mannose prevents binding of type 1-piliated E. coli to the human bladder cell line 5637 and reduces both adhesion and invasion of the UTI89 cystitis isolate instilled in mouse bladder via catheterization. Heptyl alpha-D-mannose also specifically inhibited biofilm formation at micromolar concentrations. The structural basis of the great inhibitory potential of alkyl and aryl alpha-D-mannosides was elucidated in the crystal structure of the FimH receptor-binding domain in complex with oligomannose-3. FimH interacts with Man alpha1,3Man beta1,4GlcNAc beta1,4GlcNAc in an extended binding site. The interactions along the alpha1,3 glycosidic bond and the first beta1,4 linkage to the chitobiose unit are conserved with those of FimH with butyl alpha-D-mannose. The strong stacking of the central mannose with the aromatic ring of Tyr48 is congruent with the high affinity found for synthetic inhibitors in which this mannose is substituted for by an aromatic group.The potential of ligand-based design of antagonists of urinary tract infections is ruled by the structural mimicry of natural epitopes and extends into blocking of bacterial invasion, intracellular growth and capacity to fluxing and of recurrence of the infection

Numerical Study of Beam Trapping in Stable Islands for simple 2D model of Betatronic motion

An essential ingredient for the proposed Multi-Turn Extraction (MTE) at the CERN PS is the beam trapping in stable islands. The control of the trapping process is essential for the quality of the final beam in terms of intensity sharing and emittance. In this paper, the splitting process is studied quantitatively by means of numerical simulations performed on 2D model representing the horizontal nonlinear betatronic motion. The results are reviewed and discussed in details

Quantitative Evaluation of Trapping and Overall Efficiency for Simple Models in One-Degree of Freedom

A key ingredient for the Multi-Turn Extraction (MTE) at the CERN Proton Synchrotron is the beam trapping in stable islands of transverse phase space. The control of the trapping process is essential for the quality of the final beam in terms of intensity sharing and emittance. In this paper, a method allowing an analytical estimation of the fraction of beam trapped into resonance islands as a function of the Hamiltonian parameters is presented for a very simple model of the dynamics (pendulum) and is extended to the case of the interpolating Hamiltonian of the H´enon model, the latter being a good 2D model of theMTE dynamics. The analytical results are compared with numerical simulations. Additional numerical simulations are presented for the minimum trapping amplitude and a fitted model is proposed. Results are discussed in detail

Quantitative analysis of trapping probability for quasi-integrable two degree of freedom maps

A key ingredient for the Multi-Turn Extraction (MTE) at the CERN Proton Synchrotron is the beam trapping in stable islands of transverse phase space. In a previous paper a method allowing analytical estimation of the fraction of beam trapped into resonance islands as a function of the Hamiltonian parameters has been presented. Such amethod applies to one-degree of freedom models of betatronic motion. In this paper, the analysis is extended to the more realistic and challenging case of two-degree of freedom systems, in which the interplay between the horizontal and vertical motion is fully included. Numerical simulations are presented and the results are discussed in detail

Numerical Simulations to Evaluate the Performance of CERN PS Dummy Septum to Reduce Irradiation for the Multi-Turn Extraction

The losses created by the proposed Multi-Turn Extraction (MTE) at the CERN PS induce high activation of the magnetic extraction septum due to the de-bunched longitudinal beam structure requested to transfer the beam to the SPS. A mitigation measure is under study aiming at localizing the losses in a well-shielded area by shadowing the magnetic extraction septum thanks to a septum-like passive device. Such a solution is based on a so-called dummy septum, a blade which absorbs particles during the rise time of the extraction kickers for MTE beams. The efficiency of the scheme is presented in this paper. The quantitative estimate is based on detailed simulations that analyze the beam-matter interaction and provide a determination of the shadowing effect of the dummy septum

Modified Extraction Scheme for the CERN PS Multi-Turn Extraction

High-activation of the extraction magnetic septum of the CERN PS machine was observed due to the losses of the continuous beam extracted via the Multi-Turn Extraction (MTE) method. A possible mitigation measure consists of using an existing electrostatic septum, located upstream of the extraction magnetic septum, to deflect the beam. This would highly decrease the beam losses, and hence the induced activation, during the rise time of the MTE kickers due to the reduced thickness of the electrostatic septum with respect to the magnetic one. The layout of this new extraction will be described in detail and the results of beam measurements presented

Automated evaluation of LHC proton losses during high-energy beam dumps for the Post-Mortem System

All high-energy beam dump events at the Large Hadron Collider (LHC) are analysed to verify correct functioning of the Machine Protection System and to allow early identification of potential issues. This includes the evaluation of particle losses before and during the beam dump event.The paper describes a newly developed tool for the automated evaluation of beam losses during high energy proton dumps. It presents the approach to derive individual thresholds for more than 3600 Beam Loss Monitors based on historic data from Run 2 of the LHC (2015–2018) and reviews the performance of the tool