Common Host Responses in Murine Aerosol Models of Infection Caused by Highly Virulent Gram-Negative Bacteria from the Genera Burkholderia, Francisella and Yersinia

This is the final version. Available on open access from MDPI via the DOI in this recordContent includes material subject to © Crown copyright (2019), Dstl. This material is licensed under the terms of the Open Government Licence except where otherwise stated. To view this licence, visit: http://www.nationalarchives.gov.uk/doc/open-government-licence/version/3 or write to the Information Policy Team, The National Archives, Kew, London TW9 4DU, or email: [email protected] virulent bacterial pathogens cause acute infections which are exceptionally difficult to treat with conventional antibiotic therapies alone. Understanding the chain of events that are triggered during an infection of a host has the potential to lead to new therapeutic strategies. For the first time, the transcriptomic responses within the lungs of Balb/C mice have been compared during an acute infection with the intracellular pathogens Burkholderia pseudomallei, Francisella tularensis and Yersinia pestis. Temporal changes were determined using RNAseq and a bioinformatics pipeline; expression of protein was also studied from the same sample. Collectively it was found that early transcriptomic responses within the infected host were associated with the (a) slowing down of critical cellular functions, (b) production of circulatory system components, (c) lung tissue integrity, and (d) intracellular regulatory processes. One common molecule was identified, Errfi1 (ErbB receptor feedback inhibitor 1); upregulated in response to all three pathogens and a potential novel marker of acute infection. Based upon the pro-inflammatory responses observed, we sought to synchronise each infection and report that 24 h p.i. of B. pseudomallei infection closely aligned with 48 h p.i. of infection with F. tularensis and Y. pestis. Post-transcriptional modulation of RANTES expression occurred across all pathogens, suggesting that these infections directly or indirectly modulate cell trafficking through chemokine expression/detection. Collectively, this unbiased NGS approach has provided an in-depth characterisation of the host transcriptome following infection with these highly virulent pathogens ultimately aiding in the development of host-directed therapies as adjuncts or alternatives to antibiotic treatment

A formally verified compiler back-end

This article describes the development and formal verification (proof of semantic preservation) of a compiler back-end from Cminor (a simple imperative intermediate language) to PowerPC assembly code, using the Coq proof assistant both for programming the compiler and for proving its correctness. Such a verified compiler is useful in the context of formal methods applied to the certification of critical software: the verification of the compiler guarantees that the safety properties proved on the source code hold for the executable compiled code as well

Movement of the external ear in human embryo

Introduction: External ears, one of the major face components, show an interesting movement during craniofacial morphogenesis in human embryo. The present study was performed to see if movement of the external ears in a human embryo could be explained by differential growth. Methods: In all, 171 samples between Carnegie stage (CS) 17 and CS 23 were selected from MR image datasets of human embryos obtained from the Kyoto Collection of Human Embryos. The three-dimensional absolute positio

Pointlike probes of superstring-theoretic superfluids

In analogy with an experimental setup used in liquid helium, we use a pointlike probe to study superfluids which have a gravity dual. In the gravity description, the probe is represented by a hanging string. We demonstrate that there is a critical velocity below which the probe particle feels neither drag nor stochastic forces. Above this critical velocity, there is power-law scaling for the drag force, and the stochastic forces are characterized by a finite, velocity-dependent temperature. This temperature participates in two simple and general relations between the drag force and stochastic forces. The formula we derive for the critical velocity indicates that the low-energy excitations are massless, and they demonstrate the power of stringy methods in describing strongly coupled superfluids.Comment: 17 pages, 2 figures, added a figure, a reference, and moved material to an appendi

A broad distribution of the alternative oxidase in microsporidian parasites

Microsporidia are a group of obligate intracellular parasitic eukaryotes that were considered to be amitochondriate until the recent discovery of highly reduced mitochondrial organelles called mitosomes. Analysis of the complete genome of Encephalitozoon cuniculi revealed a highly reduced set of proteins in the organelle, mostly related to the assembly of ironsulphur clusters. Oxidative phosphorylation and the Krebs cycle proteins were absent, in keeping with the notion that the microsporidia and their mitosomes are anaerobic, as is the case for other mitosome bearing eukaryotes, such as Giardia. Here we provide evidence opening the possibility that mitosomes in a number of microsporidian lineages are not completely anaerobic. Specifically, we have identified and characterized a gene encoding the alternative oxidase (AOX), a typically mitochondrial terminal oxidase in eukaryotes, in the genomes of several distantly related microsporidian species, even though this gene is absent from the complete genome of E. cuniculi. In order to confirm that these genes encode functional proteins, AOX genes from both A. locustae and T. hominis were over-expressed in E. coli and AOX activity measured spectrophotometrically using ubiquinol-1 (UQ-1) as substrate. Both A. locustae and T. hominis AOX proteins reduced UQ-1 in a cyanide and antimycin-resistant manner that was sensitive to ascofuranone, a potent inhibitor of the trypanosomal AOX. The physiological role of AOX microsporidia may be to reoxidise reducing equivalents produced by glycolysis, in a manner comparable to that observed in trypanosome

The Frequency Following Response (FFR) May Reflect Pitch-Bearing Information But is Not a Direct Representation of Pitch

The frequency following response (FFR), a scalp-recorded measure of phase-locked brainstem activity, is often assumed to reflect the pitch of sounds as perceived by humans. In two experiments, we investigated the characteristics of the FFR evoked by complex tones. FFR waveforms to alternating-polarity stimuli were averaged for each polarity and added, to enhance envelope, or subtracted, to enhance temporal fine structure information. In experiment 1, frequency-shifted complex tones, with all harmonics shifted by the same amount in Hertz, were presented diotically. Only the autocorrelation functions (ACFs) of the subtraction-FFR waveforms showed a peak at a delay shifted in the direction of the expected pitch shifts. This expected pitch shift was also present in the ACFs of the output of an auditory nerve model. In experiment 2, the components of a harmonic complex with harmonic numbers 2, 3, and 4 were presented either to the same ear (“mono”) or the third harmonic was presented contralaterally to the ear receiving the even harmonics (“dichotic”). In the latter case, a pitch corresponding to the missing fundamental was still perceived. Monaural control conditions presenting only the even harmonics (“2 + 4”) or only the third harmonic (“3”) were also tested. Both the subtraction and the addition waveforms showed that (1) the FFR magnitude spectra for “dichotic” were similar to the sum of the spectra for the two monaural control conditions and lacked peaks at the fundamental frequency and other distortion products visible for “mono” and (2) ACFs for “dichotic” were similar to those for “2 + 4” and dissimilar to those for “mono.” The results indicate that the neural responses reflected in the FFR preserve monaural temporal information that may be important for pitch, but provide no evidence for any additional processing over and above that already present in the auditory periphery, and do not directly represent the pitch of dichotic stimuli

User acceptance of SaaS ERP considering perceived risk, system performance and cost

The use of cloud solution to support ERP system has become the priority of many organizations to stay competitive in the current global world. This research will be focusing on the user acceptance of SaaS ERP (SAP ByDesign) in a global construction tool provider considering perceived risk, cost and system performance. Due to many unique variables, the purpose of this research is to analyze and investigate issues related to acceptance of SaaS in the construction tool provider companies. The results of this research can help both organizations and researchers to build a fundamental level on understanding how these factors that can predict the user acceptance of SaaS ERP in a global construction tool provider company which significantly beneficial. 80 users ranging from executive and higher management level globally were targeted. SAS Enterprise Guide 5.1 was used to analyze respondents' data and SAS dataset was then run by SAS Enterprise Guide 5.1 to produce descriptive analysis, Cronbach alpha, factor analysis and PLS-SEM will be used to analyses the responses and each hypothesis will be tested based on the data consolidated. Lastly, Partial Least Square- SEM will be performed to summarize and give an analysis of the research model propose

Control of sand flies with attractive toxic sugar baits (ATSB) and potential impact on non-target organisms in Morocco

International audienceBackground: The persistence and geographical expansion of leishmaniasis is a major public health problem that requires the development of effective integrated vector management strategies for sand fly control. Moreover, these strategies must be economically and environmentally sustainable approaches that can be modified based on the current knowledge of sand fly vector behavior. The efficacy of using attractive toxic sugar baits (ATSB) for sand fly control and the potential impacts of ATSB on non-target organisms in Morocco was investigated. Methods: Sand fly field experiments were conducted in an agricultural area along the flood plain of the Ourika River. Six study sites (600 m x 600 m); three with ``sugar rich'' (with cactus hedges bearing countless ripe fruits) environments and three with ``sugar poor'' (green vegetation only suitable for plant tissue feeding) environments were selected to evaluate ATSB, containing the toxin, dinotefuran. ATSB applications were made either with bait stations or sprayed on non-flowering vegetation. Control sites were established in both sugar rich and sugar poor environments. Field studies evaluating feeding on vegetation treated with attractive (non-toxic) sugar baits (ASB) by non-target arthropods were conducted at both sites with red stained ASB applied to non-flowering vegetation, flowering vegetation, or on bait stations. Results: At both the sites, a single application of ATSB either applied to vegetation or bait stations significantly reduced densities of both female and male sand flies (Phlebotomus papatasi and P. sergenti) for the five-week trial period. Sand fly populations were reduced by 82.8% and 76.9% at sugar poor sites having ATSB applied to vegetation or presented as a bait station, respectively and by 78.7% and 83.2%, respectively at sugar rich sites. The potential impact of ATSB on non-targets, if applied on green non-flowering vegetation and bait stations, was low for all non-target groups as only 1% and 0.7% were stained with non-toxic bait respectively when monitored after 24 hours. Conclusions: The results of this field study demonstrate ATSB effectively controls both female and male sand flies regardless of competing sugar sources. Furthermore, ATSB applied to foliar vegetation and on bait stations has low non-target impact

Observation of Dirac plasmons in a topological insulator

Plasmons are the quantized collective oscillations of electrons in metals and doped semiconductors. The plasmons of ordinary, massive electrons are since a long time basic ingredients of research in plasmonics and in optical metamaterials. Plasmons of massless Dirac electrons were instead recently observed in a purely two-dimensional electron system (2DEG)like graphene, and their properties are promising for new tunable plasmonic metamaterials in the terahertz and the mid-infrared frequency range. Dirac quasi-particles are known to exist also in the two-dimensional electron gas which forms at the surface of topological insulators due to a strong spin-orbit interaction. Therefore,one may look for their collective excitations by using infrared spectroscopy. Here we first report evidence of plasmonic excitations in a topological insulator (Bi2Se3), that was engineered in thin micro-ribbon arrays of different width W and period 2W to select suitable values of the plasmon wavevector k. Their lineshape was found to be extremely robust vs. temperature between 6 and 300 K, as one may expect for the excitations of topological carriers. Moreover, by changing W and measuring in the terahertz range the plasmonic frequency vP vs. k we could show, without using any fitting parameter, that the dispersion curve is in quantitative agreement with that predicted for Dirac plasmons.Comment: 11 pages, 3 figures, published in Nature Nanotechnology (2013