The Influence of Escherichia coli Metabolism on Antibiotic Resistance

Antibiotics are important tools to fight bacteria in complement to vaccines and public hygiene regulation. Antibiotics are molecules that interfere with key bacterial processes, ranging from translation and transcription to cell wall synthesis. This results in arrest of bacterial proliferation. Because of the selective pressure antibiotics impose on microbes, they are challenged by the formidable capacities of evolution. Indeed, bacteria have been shown to counteract antibiotics through multiple strategies, either at population or clonal levels. This is notably the case for ESKAPE pathogens (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter braumannii, Pseudomonas aeruginosa and species of the genus Enterobacter). These bacterial species quickly evolve escape mechanisms to currently used antibiotics as well as new-to-market antibiotics. Two main routes of antibiotic escape are resistance and tolerance. Antibiotic tolerance permits to withstand antibiotic treatment for a longer period of time while antibiotic resistance allows to grow in the presence of the antibiotic at normally non-permissive concentrations. Resistant or tolerant pathogens often require the use of last-resort antibiotics or longer and heavier treatments to be eradicated. However, these alternatives are also met with evolutionary escape while the development of new antibiotics takes a substantial time. This leads to a sharp decrease of new antibiotic development and ever-increasing pressure on health authorities. Therefore, it is pressing to understand evolutionary strategies employed by bacterial pathogens to escape antibiotic treatment in order to anticipate and counter them. One key evolutionary weapon is the acquisition of genomic mutations that confer antibiotic resistance or tolerance. Some of these mutations have relatively trivial effects. Mutations in the direct target of an antibiotic alter binding interactions and nullify antibiotic effects. Efflux pumps regulators can also be mutated to affect antibiotic import or export towards their targets. More recently, mutations in core metabolic genes have been shown to affect antibiotic treatments. However, how these mutations affect metabolism and lead to antibiotic treatment failure remains poorly understood. It is generally assumed that antibiotic treatments could be globally affected by a general “metabolic state”, or metabolic-dependent phenomenon such as growth rate. However, these observations were made while studying antibiotic tolerance and not antibiotic resistance. Whether a general “metabolic state” could confer resistance to multiple antibiotics remains unknown. Here is presented a body of work that investigates the link between metabolism and antibiotic treatment in the ESKAPE pathogen Escherichia coli with a focus on antibiotic resistance. The following question is formulated for this thesis: Do mutations in metabolic genes of E. coli have a general impact on antibiotic resistance? This thesis will first present a general introduction of its scientific framework. Chapter 1 discusses the elaboration of the main tool used in the thesis: a library of E. coli strains each with a genomic mutation in an essential gene. Chapter 2 covers the main body of work done in this thesis and present its most important findings. Chapter 3 further discusses findings made in Chapter 2 and provides additional experiments and hypothesis

Laser produced electromagnetic pulses : Generation, detection and mitigation

This paper provides an up-to-date review of the problems related to the generation, detection and mitigation of strong electromagnetic pulses created in the interaction of high-power, high-energy laser pulses with different types of solid targets. It includes new experimental data obtained independently at several international laboratories. The mechanisms of electromagnetic field generation are analyzed and considered as a function of the intensity and the spectral range of emissions they produce. The major emphasis is put on the gHz frequency domain, which is the most damaging for electronics and may have important applications. The physics of electromagnetic emissions in other spectral domains, in particular THz and MHz, is also discussed. The theoretical models and numerical simulations are compared with the results of experimental measurements, with special attention to the methodology of measurements and complementary diagnostics. Understanding the underlying physical processes is the basis for developing techniques to mitigate the electromagnetic threat and to harness electromagnetic emissions, which may have promising applications

The Mental Health of Children and Young People

Children and young people were not a priority in the early stages of the pandemic. Whilst children and young people were considered to be at ‘low health risk’ but this did not account for the seriousness of mental health issues. Evidence of the psychological impact of Covid-19 on children and young people is fast emerging. A concerning number of studies and systemic reviews suggest the overwhelming negative impact on child and adolescent mental health. The Buttle UK survey (June 22 – 15 July 2021) revealed that the Covid-19 pandemic had exacerbated an ‘under the radar’ mental health crisis leaving a generation of children traumatised and unable to benefit from the Government’s educational recovery programmes. ‘We must listen to frontline professionals and prioritise mental health support’: https://buttleuk.org/news/news-list/state-of-child-poverty-202

The Third Fermi Large Area Telescope Catalog of Gamma-ray Pulsars

We present 294 pulsars found in GeV data from the Large Area Telescope (LAT) on the Fermi Gamma-ray Space Telescope. Another 33 millisecond pulsars (MSPs) discovered in deep radio searches of LAT sources will likely reveal pulsations once phase-connected rotation ephemerides are achieved. A further dozen optical and/or X-ray binary systems co-located with LAT sources also likely harbor gamma-ray MSPs. This catalog thus reports roughly 340 gamma-ray pulsars and candidates, 10% of all known pulsars, compared to $\leq 11$ known before Fermi. Half of the gamma-ray pulsars are young. Of these, the half that are undetected in radio have a broader Galactic latitude distribution than the young radio-loud pulsars. The others are MSPs, with 6 undetected in radio. Overall, >235 are bright enough above 50 MeV to fit the pulse profile, the energy spectrum, or both. For the common two-peaked profiles, the gamma-ray peak closest to the magnetic pole crossing generally has a softer spectrum. The spectral energy distributions tend to narrow as the spindown power $\dot E$ decreases to its observed minimum near $10^{33}$ erg s$^{-1}$, approaching the shape for synchrotron radiation from monoenergetic electrons. We calculate gamma-ray luminosities when distances are available. Our all-sky gamma-ray sensitivity map is useful for population syntheses. The electronic catalog version provides gamma-ray pulsar ephemerides, properties and fit results to guide and be compared with modeling results.Comment: 142 pages. Accepted by the Astrophysical Journal Supplemen

A Population of Gamma-Ray Millisecond Pulsars Seen with the Fermi Large Area Telescope

Gamma-Ray Pulsar Bonanza Most of the pulsars we know about were detected through their radio emission; a few are known to pulse gamma rays but were first detected at other wavelengths (see the Perspective by Halpern ). Using the Fermi Gamma-Ray Space Telescope, Abdo et al. (p. 840 , published online 2 July; see the cover) report the detection of 16 previously unknown pulsars based on their gamma-ray emission alone. Thirteen of these coincide with previously unidentified gamma-ray sources, solving the 30-year-old mystery of their identities. Pulsars are fast-rotating neutron stars. With time they slow down and cease to radiate; however, if they are in a binary system, they can have their spin rates increased by mass transfer from their companion stars, starting a new life as millisecond pulsars. In another study, Abdo et al. (p. 845 ) report the detection of gamma-ray emission from the globular cluster 47 Tucanae, which is coming from an ensemble of millisecond pulsars in the cluster's core. The data imply that there are up to 60 millisecond pulsars in 47 Tucanae, twice as many as predicted by radio observations. In a further companion study, Abdo et al. (p. 848 , published online 2 July) searched Fermi Large Area Telescope data for pulsations from all known millisecond pulsars outside of stellar clusters, finding gamma-ray pulsations for eight of them. Their properties resemble those of other gamma-ray pulsars, suggesting that they share the same basic emission mechanism. Indeed, both sets of pulsars favor emission models in which the gamma rays are produced in the outer magnetosphere of the neutron star

Multi-messenger observations of a binary neutron star merger

On 2017 August 17 a binary neutron star coalescence candidate (later designated GW170817) with merger time 12:41:04 UTC was observed through gravitational waves by the Advanced LIGO and Advanced Virgo detectors. The Fermi Gamma-ray Burst Monitor independently detected a gamma-ray burst (GRB 170817A) with a time delay of ~1.7 s with respect to the merger time. From the gravitational-wave signal, the source was initially localized to a sky region of 31 deg2 at a luminosity distance of 40+8-8 Mpc and with component masses consistent with neutron stars. The component masses were later measured to be in the range 0.86 to 2.26 Mo. An extensive observing campaign was launched across the electromagnetic spectrum leading to the discovery of a bright optical transient (SSS17a, now with the IAU identification of AT 2017gfo) in NGC 4993 (at ~40 Mpc) less than 11 hours after the merger by the One- Meter, Two Hemisphere (1M2H) team using the 1 m Swope Telescope. The optical transient was independently detected by multiple teams within an hour. Subsequent observations targeted the object and its environment. Early ultraviolet observations revealed a blue transient that faded within 48 hours. Optical and infrared observations showed a redward evolution over ~10 days. Following early non-detections, X-ray and radio emission were discovered at the transient’s position ~9 and ~16 days, respectively, after the merger. Both the X-ray and radio emission likely arise from a physical process that is distinct from the one that generates the UV/optical/near-infrared emission. No ultra-high-energy gamma-rays and no neutrino candidates consistent with the source were found in follow-up searches. These observations support the hypothesis that GW170817 was produced by the merger of two neutron stars in NGC4993 followed by a short gamma-ray burst (GRB 170817A) and a kilonova/macronova powered by the radioactive decay of r-process nuclei synthesized in the ejecta

Measurement of the very rare K+→π+ννˉK^+ \to \pi^+ \nu \bar\nu decay

The decay K+→π+νν¯ , with a very precisely predicted branching ratio of less than 10−10 , is among the best processes to reveal indirect effects of new physics. The NA62 experiment at CERN SPS is designed to study the K+→π+νν¯ decay and to measure its branching ratio using a decay-in-flight technique. NA62 took data in 2016, 2017 and 2018, reaching the sensitivity of the Standard Model for the K+→π+νν¯ decay by the analysis of the 2016 and 2017 data, and providing the most precise measurement of the branching ratio to date by the analysis of the 2018 data. This measurement is also used to set limits on BR(K+→π+X ), where X is a scalar or pseudo-scalar particle. The final result of the BR(K+→π+νν¯ ) measurement and its interpretation in terms of the K+→π+X decay from the analysis of the full 2016-2018 data set is presented, and future plans and prospects are reviewed

Processing of 2007 VSP campaign in Soultz-sous-Forêts for the characterization of the fracturation within the geothermal reservoir

Les données de VSP multi-source/multi-offset acquises en 2007 sur le site géothermique de Soultz-sous-Forêts sont traitées et analysées. Des géophones placés dans les puits GPK3 et GPK4 entre 3 et 5 km de profondeur ont enregistré les ondes sismiques émises par deux vibrateurs placés en 24 positions de tir réparties dans un rayon de 5 km autour des puits. Après corrélation des enregistrements avec la source associée à chaque vibrateur, les différentes composantes du champ d'onde sont séparées par filtrage en vitesse apparente. La comparaison des résultats obtenus par filtrage médian ou dans le domaine FK montre des signaux similaires. Un modèle de vitesse est établi pour pouvoir calculer les temps d'arrivée. Il comporte deux couches sédimentaires sur le socle granitique et des interfaces planes pentées. Le champ d'onde descendant de forte vitesse apparente est interprété comme des réflexions sur des structures subverticales autour des puits. Leur pendage, azimut et extension latérale sont déterminés en ajustant les temps de trajet observés et calculés par tracé de rayons 3D. Les structures à pendage vers l'ouest connues par les observations en forage et la microsismicité sont retrouvées. Une structure antithétique nouvelle est déterminée. Nos résultats permettent de compléter le modèle structural de la fracturation dans le réservoir géothermique.The vertical seismic profiles (VSP) acquired in 2007 with multi-component geophones placed at depths between 3 and 5 km in two wells at the Soultz-sous-Forêts geothermal site are processed and analyzed. The multi-offset, multi-azimuth VSP were acquired with two simultaneously vibrating sources located in 24 distinct shot positions. After correlation of the raw records with the proper sweep sequence, the different components of the wavefield are separated according to their apparent velocities. The results obtained by median or FK filtering are similar. A velocity model is created in order to compute traveltimes. Two layers in the sediments above the granitic basement are separated by plane dipping interfaces. The downgoing waves having a fast apparent velocity are interpreted as reflections on steeply dipping reflectors. The dip, the azimuth and the lateral extent of these structures away from the well are determined by fitting the observed traveltimes with those computed by 3D ray tracing. The west dipping structures already known from borehole logging and the trends of microseismicity are constrained. A new antithetic structure is determined. Our results improve the structural model of fracturation in the geothermal reservoir

Traitement des données de sismique de puits acquises en 2007 sur le site de Soultz-sous-Forêts pour la caractérisation de la fracturation du réservoir géothermique

The vertical seismic profiles (VSP) acquired in 2007 with multi-component geophones placed at depths between 3 and 5 km in two wells at the Soultz-sous-Forêts geothermal site are processed and analyzed. The multi-offset, multi-azimuth VSP were acquired with two simultaneously vibrating sources located in 24 distinct shot positions. After correlation of the raw records with the proper sweep sequence, the different components of the wavefield are separated according to their apparent velocities. The results obtained by median or FK filtering are similar. A velocity model is created in order to compute traveltimes. Two layers in the sediments above the granitic basement are separated by plane dipping interfaces. The downgoing waves having a fast apparent velocity are interpreted as reflections on steeply dipping reflectors. The dip, the azimuth and the lateral extent of these structures away from the well are determined by fitting the observed traveltimes with those computed by 3D ray tracing. The west dipping structures already known from borehole logging and the trends of microseismicity are constrained. A new antithetic structure is determined. Our results improve the structural model of fracturation in the geothermal reservoir.Les données de VSP multi-source/multi-offset acquises en 2007 sur le site géothermique de Soultz-sous-Forêts sont traitées et analysées. Des géophones placés dans les puits GPK3 et GPK4 entre 3 et 5 km de profondeur ont enregistré les ondes sismiques émises par deux vibrateurs placés en 24 positions de tir réparties dans un rayon de 5 km autour des puits. Après corrélation des enregistrements avec la source associée à chaque vibrateur, les différentes composantes du champ d'onde sont séparées par filtrage en vitesse apparente. La comparaison des résultats obtenus par filtrage médian ou dans le domaine FK montre des signaux similaires. Un modèle de vitesse est établi pour pouvoir calculer les temps d'arrivée. Il comporte deux couches sédimentaires sur le socle granitique et des interfaces planes pentées. Le champ d'onde descendant de forte vitesse apparente est interprété comme des réflexions sur des structures subverticales autour des puits. Leur pendage, azimut et extension latérale sont déterminés en ajustant les temps de trajet observés et calculés par tracé de rayons 3D. Les structures à pendage vers l'ouest connues par les observations en forage et la microsismicité sont retrouvées. Une structure antithétique nouvelle est déterminée. Nos résultats permettent de compléter le modèle structural de la fracturation dans le réservoir géothermique