DNA Damage and Reactive Nitrogen Species are Barriers to Vibrio cholerae Colonization of the Infant Mouse Intestine

Ingested Vibrio cholerae pass through the stomach and colonize the small intestines of its host. Here, we show that V. cholerae requires at least two types of DNA repair systems to efficiently compete for colonization of the infant mouse intestine. These results show that V. cholerae experiences increased DNA damage in the murine gastrointestinal tract. Agreeing with this, we show that passage through the murine gut increases the mutation frequency of V. cholerae compared to liquid culture passage. Our genetic analysis identifies known and novel defense enzymes required for detoxifying reactive nitrogen species (but not reactive oxygen species) that are also required for V. cholerae to efficiently colonize the infant mouse intestine, pointing to reactive nitrogen species as the potential cause of DNA damage. We demonstrate that potential reactive nitrogen species deleterious for V. cholerae are not generated by host inducible nitric oxide synthase (iNOS) activity and instead may be derived from acidified nitrite in the stomach. Agreeing with this hypothesis, we show that strains deficient in DNA repair or reactive nitrogen species defense that are defective in intestinal colonization have decreased growth or increased mutation frequency in acidified nitrite containing media. Moreover, we demonstrate that neutralizing stomach acid rescues the colonization defect of the DNA repair and reactive nitrogen species defense defective mutants suggesting a common defense pathway for these mutants

Structure-Function Studies of DNA Binding Domain of Response Regulator KdpE Reveals Equal Affinity Interactions at DNA Half-Sites

Expression of KdpFABC, a K+ pump that restores osmotic balance, is controlled by binding of the response regulator KdpE to a specific DNA sequence (kdpFABCBS) via the winged helix-turn-helix type DNA binding domain (KdpEDBD). Exploration of E. coli KdpEDBD and kdpFABCBS interaction resulted in the identification of two conserved, AT-rich 6 bp direct repeats that form half-sites. Despite binding to these half-sites, KdpEDBD was incapable of promoting gene expression in vivo. Structure-function studies guided by our 2.5 Å X-ray structure of KdpEDBD revealed the importance of residues R193 and R200 in the α-8 DNA recognition helix and T215 in the wing region for DNA binding. Mutation of these residues renders KdpE incapable of inducing expression of the kdpFABC operon. Detailed biophysical analysis of interactions using analytical ultracentrifugation revealed a 2∶1 stoichiometry of protein to DNA with dissociation constants of 200±100 and 350±100 nM at half-sites. Inactivation of one half-site does not influence binding at the other, indicating that KdpEDBD binds independently to the half-sites with approximately equal affinity and no discernable cooperativity. To our knowledge, these data are the first to describe in quantitative terms the binding at half-sites under equilibrium conditions for a member of the ubiquitous OmpR/PhoB family of proteins

The Pseudomonas aeruginosa Chemotaxis Methyltransferase CheR1 Impacts on Bacterial Surface Sampling

The characterization of factors contributing to the formation and development of surface-associated bacterial communities known as biofilms has become an area of intense interest since biofilms have a major impact on human health, the environment and industry. Various studies have demonstrated that motility, including swimming, swarming and twitching, seems to play an important role in the surface colonization and establishment of structured biofilms. Thereby, the impact of chemotaxis on biofilm formation has been less intensively studied. Pseudomonas aeruginosa has a very complex chemosensory system with two Che systems implicated in flagella-mediated motility. In this study, we demonstrate that the chemotaxis protein CheR1 is a methyltransferase that binds S-adenosylmethionine and transfers a methyl group from this methyl donor to the chemoreceptor PctA, an activity which can be stimulated by the attractant serine but not by glutamine. We furthermore demonstrate that CheR1 does not only play a role in flagella-mediated chemotaxis but that its activity is essential for the formation and maintenance of bacterial biofilm structures. We propose a model in which motility and chemotaxis impact on initial attachment processes, dispersion and reattachment and increase the efficiency and frequency of surface sampling in P. aeruginosa

Two-component signal transduction in Corynebacterium glutamicum and other corynebacteria: on the way towards stimuli and targets

In bacteria, adaptation to changing environmental conditions is often mediated by two-component signal transduction systems. In the prototypical case, a specific stimulus is sensed by a membrane-bound histidine kinase and triggers autophosphorylation of a histidine residue. Subsequently, the phosphoryl group is transferred to an aspartate residue of the cognate response regulator, which then becomes active and mediates a specific response, usually by activating and/or repressing a set of target genes. In this review, we summarize the current knowledge on two-component signal transduction in Corynebacterium glutamicum. This Gram-positive soil bacterium is used for the large-scale biotechnological production of amino acids and can also be applied for the synthesis of a wide variety of other products, such as organic acids, biofuels, or proteins. Therefore, C. glutamicum has become an important model organism in industrial biotechnology and in systems biology. The type strain ATCC 13032 possesses 13 two-component systems and the role of five has been elucidated in recent years. They are involved in citrate utilization (CitAB), osmoregulation and cell wall homeostasis (MtrAB), adaptation to phosphate starvation (PhoSR), adaptation to copper stress (CopSR), and heme homeostasis (HrrSA). As C. glutamicum does not only face changing conditions in its natural environment, but also during cultivation in industrial bioreactors of up to 500 m3 volume, adaptability can also be crucial for good performance in biotechnological production processes. Detailed knowledge on two-component signal transduction and regulatory networks therefore will contribute to both the application and the systemic understanding of C. glutamicum and related species

The cosmic ray shadow of the Moon observed with the ANTARES neutrino telescope

[EN] One of the main objectives of the ANTARES telescope is the search for point-like neutrino sources. Both the pointing accuracy and the angular resolution of the detector are important in this context and a reliable way to evaluate this performance is needed. In order to measure the pointing accuracy of the detector, one possibility is to study the shadow of the Moon, i.e. the de¿cit of the atmospheric muon ¿ux from the direction of the Moon induced by the absorption of cosmic rays. Analysing the data taken between 2007 and 2016, the Moon shadow is observed with 3.5¿ statistical signi¿cance. The detector angular resolution for downward-going muons is 0.73¿ ±0.14¿. The resulting pointing performance is consistent with the expectations. An independent check of the telescope pointing accuracy is realised with the data collected by a shower array detector onboard of a ship temporarily moving around the ANTARES location.The authors acknowledge the financial support of the funding agencies: Centre National de la Recherche Scientifique (CNRS), Commissariat a l'energie atomique et aux energies alternatives (CEA), Commission Europeenne (FEDER fund and Marie Curie Program), Institut Universitaire de France (IUF), IdEx program and UnivEarthS Labex program at Sorbonne Paris Cite (ANR-10-LABX-0023 and ANR-11-IDEX-0005-02), Labex OCEVU (ANR-11-LABX-0060) and the A*MIDEX project (ANR-11-IDEX-0001-02), Region Ile-de-France (DIM-ACAV), Region Alsace (contrat CPER), Region Provence-Allies-Cote d'Azur, Departement du Var and Ville de La Seyne-sur-Mer, France; Bundesministerium fin Bildung and Forschung (BMBF), Germany; Istituto Naziona-le di Fisica Nucleare (INFN), Italy; Nederlandse organisatie voor Wetenschappelijk Onderzoek (NWO), the Netherlands; Council of the President of the Russian Federation for young scientists and leading scientific schools supporting grants, Russia; National Authority for Scientific Research (ANCS), Romania; Ministerio de Economia y Competitividad (MINE-CO): Plan Estatal de Investigacion (refs. FPA2015-65150-C3-1-P, -2-P and -3-P, (MINECO/FEDER)), Severn Ochoa Centre of Excellence and MultiDark Consolider (MINECO), and Prometeo and Grisolia programs (Generalitat Valencia-na), Spain; Ministry of Higher Education, Scientific Research and Professional Training, Morocco. We also acknowledge the technical support of Ifremer, AIM and Foselev Marine for the sea operation and the CC-IN2P3 for the computing facilities.Albert, A.; Andre, M.; Anghinolfi, M.; Anton, G.; Ardid Ramírez, M.; Aubert, J-.; Aublin, J.... (2018). The cosmic ray shadow of the Moon observed with the ANTARES neutrino telescope. The European Physical Journal C. 78(12):1-9. https://doi.org/10.1140/epjc/s10052-018-6451-3S197812M. G. Aartsen et al. (IceCube Collaboration), Science 342, 1242856 (2013)M. G. Aartsen et al. (IceCube Collaboration), Journal of Instrumentation 12(3), P03012 (2017)M. G. Aartsen et al. (IceCube Collaboration), Phys. Rev. Lett. 113, 101101 (2017)M. Ageron et al. (ANTARES Collaboration), Nucl. Instrum. Meth. A656, 11-38 (2011)M. Ambrosio et al. (MACRO Collaboration), Phys. Rev. D59, 012003 (1999)J. H. Cobb et al. (Soudan 2 Collaboration), Phys. Rev. D61, 092002 (2000)P. Achard et al., Astropart. Phys. 23(4), 411–434 (2005)M. G. Aartsen et al. (IceCube Collaboration), Phys. Rev. D89(10), 102004 (2014)D. E. Alexandreas et al. (CYGNUS Collaboration), Phys. Rev. D43, 1735-1738 (1991)M. Amenomori et al. (Tibet AS gamma Collaboration), Phys. Rev. D47, 2675-2681 (1993)A. Borione et al., Phys. Rev. D 49, 1171–1177 (1994)B. Bartoli et al. (ARGO-YBJ Collaboration), Phys. Rev. D85, 022002 (2012)A. U. Abeysekara et al. (HAWC Collaboration), Phys. Rev. D97(10), 102005 (2018)J. A. Aguilar et al. (ANTARES Collaboration), Astropart. Phys. 34, 539-549 (2011)S. Adrian-Martinez et al. (ANTARES Collaboration), JINST 7, T08002 (2012)J. A. Aguilar et al. (ANTARES Collaboration), Astropart. Phys. 34(9), 652-662 (2011)S. Adrian-Martinez et al. (ANTARES Collaboration), JCAP 1303, 006 (2013)J. A. Aguilar et al. (ANTARES Collaboration), Astropart. Phys. 34(3), 179-184 (2010)J. A. Aguilar et al. (ANTARES Collaboration), Astropart. Phys. 33(2), 86-90 (2010)S. Adrian-Martinez et al. (ANTARES Collaboration), Astropart. Phys. 78(C), 43-51 (2016)C. Distefano (ANTARES Collaboration), Nucl. Instrum. Meth A626-627, S223-S225 (2011)B. Rhodes, in SkyField, Elegant Astronomy for Python, http://rhodesmill.org/skyfield/ . Accessed 31 July 2018K.M. Górski, E. Hivon, A.J. Banday, B.D. Wandelt, F.K. Hansen, M. Reinecke, M. Bartelmann, Astrophys. J. 622, 759–771 (2005)J. H. Meeus, in Astronomical Algorithms., ed. by Willmann-Bell, Incorporated (1991)G. Carminati, A. Margiotta, M. Spurio, Comput. Phys. Commun. 179, 915–923 (2008)A. Albert et al. (ANTARES Collaboration), JHEP 07, 54 (2017)A. Albert et al. (ANTARES Collaboration), Phys. Rev. D96, 082001 (2017)J.A. Aguilar et al. (ANTARES Collaboration), Astropart. Phys. 34, 179-184 (2010)L.A. Fusco, A. Margiotta, EPJ Web Conf. 116, 02002 (2016)H. Yepes-Ramirez (ANTARES Collaboration), Nucl. Instrum. Meth A725, 203-206 (2013)J. Brunner (ANTARES Collaboration), in Proceedings of the VLVnuT Workshop, Amsterdam, Netherlands, October 5-8, 2003, ed. by E. de Wolf (Amsterdam: NIKHEF), http://www.vlvnt.nl/proceedings/A. Margiotta (ANTARES Collaboration), Nucl. Instrum. Meth. A725, 98-101 (2013)S. Baker, R.D. Cousins, Nucl. Instrum. Meth. 221, 437–442 (1984)P. Adamson et al. (MINOS Collaboration), Astropart. Phys. 34(6), 457-466 (2011)G. Cowan, Statistical Data Analysis (Clarendon Press, Oxford, 1998

ARIA digital anamorphosis : Digital transformation of health and care in airway diseases from research to practice

Digital anamorphosis is used to define a distorted image of health and care that may be viewed correctly using digital tools and strategies. MASK digital anamorphosis represents the process used by MASK to develop the digital transformation of health and care in rhinitis. It strengthens the ARIA change management strategy in the prevention and management of airway disease. The MASK strategy is based on validated digital tools. Using the MASK digital tool and the CARAT online enhanced clinical framework, solutions for practical steps of digital enhancement of care are proposed.Peer reviewe

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

Cabbage and fermented vegetables : From death rate heterogeneity in countries to candidates for mitigation strategies of severe COVID-19

Large differences in COVID-19 death rates exist between countries and between regions of the same country. Some very low death rate countries such as Eastern Asia, Central Europe, or the Balkans have a common feature of eating large quantities of fermented foods. Although biases exist when examining ecological studies, fermented vegetables or cabbage have been associated with low death rates in European countries. SARS-CoV-2 binds to its receptor, the angiotensin-converting enzyme 2 (ACE2). As a result of SARS-CoV-2 binding, ACE2 downregulation enhances the angiotensin II receptor type 1 (AT(1)R) axis associated with oxidative stress. This leads to insulin resistance as well as lung and endothelial damage, two severe outcomes of COVID-19. The nuclear factor (erythroid-derived 2)-like 2 (Nrf2) is the most potent antioxidant in humans and can block in particular the AT(1)R axis. Cabbage contains precursors of sulforaphane, the most active natural activator of Nrf2. Fermented vegetables contain many lactobacilli, which are also potent Nrf2 activators. Three examples are: kimchi in Korea, westernized foods, and the slum paradox. It is proposed that fermented cabbage is a proof-of-concept of dietary manipulations that may enhance Nrf2-associated antioxidant effects, helpful in mitigating COVID-19 severity.Peer reviewe