Impact of Influenza A Virus Infection on Growth and Metabolism of Suspension MDCK Cells Using a Dynamic Model

Cell cultured-based influenza virus production is a viable option for vaccine manufacturing. In order to achieve a high concentration of viable cells, is requirement to have not only optimal process conditions, but also an active metabolism capable of intracellular synthesis of viral components. Experimental metabolic data collected in such processes are complex and difficult to interpret, for which mathematical models are an appropriate way to simulate and analyze the complex and dynamic interaction between the virus and its host cell. A dynamic model with 35 states was developed in this study to describe growth, metabolism, and influenza A virus production in shake flask cultivations of suspension Madin-Darby Canine Kidney (MDCK) cells. It considers cell growth (concentration of viable cells, mean cell diameters, volume of viable cells), concentrations of key metabolites both at the intracellular and extracellular level and virus titers. Using one set of parameters, the model accurately simulates the dynamics of mock-infected cells and correctly predicts the overall dynamics of virus-infected cells for up to 60 h post infection (hpi). The model clearly suggests that most changes observed after infection are related to cessation of cell growth and the subsequent transition to apoptosis and cell death. However, predictions do not cover late phases of infection, particularly for the extracellular concentrations of glutamate and ammonium after about 12 hpi. Results obtained from additional in silico studies performed indicated that amino acid degradation by extracellular enzymes resulting from cell lysis during late infection stages may contribute to this observed discrepancy

ABC Transporter Pdr10 Regulates the Membrane Microenvironment of Pdr12 in Saccharomyces cerevisiae

The eukaryotic plasma membrane exhibits both asymmetric distribution of lipids between the inner and the outer leaflet and lateral segregation of membrane components within the plane of the bilayer. In budding yeast (Saccharomyces cerevisiae), maintenance of leaflet asymmetry requires P-type ATPases, which are proposed to act as inward-directed lipid translocases (Dnf1, Dnf2, and the associated protein Lem3), and ATP-binding cassette (ABC) transporters, which are proposed to act as outward-directed lipid translocases (Pdr5 and Yor1). The S. cerevisiae genome encodes two other Pdr5-related ABC transporters: Pdr10 (67% identity) and Pdr15 (75% identity). We report the first analysis of Pdr10 localization and function. A Pdr10-GFP chimera was located in discrete puncta in the plasma membrane and was found in the detergent-resistant membrane fraction. Compared to control cells, a pdr10∆ mutant was resistant to sorbate but hypersensitive to the chitin-binding agent Calcofluor White. Calcofluor sensitivity was attributable to a partial defect in endocytosis of the chitin synthase Chs3, while sorbate resistance was attributable to accumulation of a higher than normal level of the sorbate exporter Pdr12. Epistasis analysis indicated that Pdr10 function requires Pdr5, Pdr12, Lem3, and mature sphingolipids. Strikingly, Pdr12 was shifted to the detergent-resistant membrane fraction in pdr10∆ cells. Pdr10 therefore acts as a negative regulator for incorporation of Pdr12 into detergent-resistant membranes, a novel role for members of the ABC transporter superfamily

ANTARES search for point-sources of neutrinos using astrophysical catalogs: a likelihood stacking analysis

A search for astrophysical point-like neutrino sources using the data collected by the ANTARES detector between January 29, 2007 and December 31, 2017 is presented. A likelihood stacking method is used to assess the significance of an excess of muon neutrinos inducing track-like events in correlation with the location of a list of possible sources. Different sets of objects are tested in the analysis: a) a sub-sample of the \textit{Fermi} 3LAC catalog of blazars, b) a jet-obscured AGN population, c) a sample of soft gamma-ray selected radio galaxies, d) a star-forming galaxy catalog , and e) a public sample of 56 very-high-energy track events from the IceCube experiment. None of the tested sources shows a significant association with the sample of neutrinos detected by ANTARES. The smallest p-value is obtained for the radio galaxies catalog with an equal weights hypothesis, with a pre-trial p-value equivalent to a $2.8 \, \sigma$ excess, equivalent to $1.6 \, \sigma$ post-trial. In addition, the results of a dedicated analysis for the blazar MG3 J225517+2409 are also reported: this source is found to be the most significant within the \textit{Fermi} 3LAC sample, with 5 ANTARES events located at less than one degree from the source. This blazar showed evidence of flaring activity in \textit{Fermi} data, in space-time coincidence with a high-energy track detected by IceCube. An \emph{a posteriori} significance of $2.0\, \sigma$ for the combination of ANTARES and IceCube data is reported

Observation of the cosmic ray shadow of the Sun with the ANTARES neutrino telescope

[EN] The ANTARES detector is an undersea neutrino telescope in the Mediterranean Sea. The search for pointlike neutrino sources is one of the main goals of the ANTARES telescope, requiring a reliable method to evaluate the detector angular resolution and pointing accuracy. This work describes the study of the Sun ¿shadow¿ effect with the ANTARES detector. The shadow is the deficit in the atmospheric muon flux in the direction of the Sun caused by the absorption of the primary cosmic rays. This analysis is based on the data collected between 2008 and 2017 by the ANTARES telescope. The observed statistical significance of the Sun shadow detection is 3.7¿, with an estimated angular resolution of 0.59° +- 0.10°for downward-going muons. The pointing accuracy is found to be consistent with the expectations and no evidence of systematic pointing shifts is observed.The authors acknowledge the financial support of the funding agencies: Centre National de la Recherche Scientifique, Commissariat `a l'' energie atomique et aux energies alternatives, Commission Europeenne (FEDER fund and Marie Curie Program), Institut Universitaire de France, LabEx UnivEarthS (ANR-10-LABX-0023 and ANR-18-IDEX-0001), R ' egion Ile-de-France (DIM-ACAV), Region Alsace (contract CPER), Region Provence-Alpes-Cote d'Azur, Departement du Var and Ville de La Seyne-sur-Mer, France; Bundesministerium fur Bildung und Forschung, Germany; Istituto Nazionale di Fisica Nucleare, Italy; Nederlandse organisatie voor Wetenschappelijk Onderzoek, the Netherlands; Council of the President of the Russian Federation for Young Scientists and Leading Scientific Schools supporting grants, Russia; Executive Unit for Financing Higher Education, Research, Development and Innovation (UEFISCDI), Romania; Ministerio de Ciencia, Innovacion, Investigacion y Universidades (MCIU): Programa Estatal de Generacion de Conocimiento (refs. PGC2018-096663-B-C41, -A-C42, -B-C43, -B-C44) (MCIU/FEDER), Severo Ochoa Centre of Excellence and MultiDark Consolider (MCIU), Junta de Andalucia (refs. SOMM17/6104/UGR and A-FQM-053-UGR18), Generalitat Valenciana: Grisolia (ref. GRISOLIA/2018/119), 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.... (2020). Observation of the cosmic ray shadow of the Sun with the ANTARES neutrino telescope. Physical Review D: covering particles, fields, gravitation, and cosmology. 102(12):1-7. https://doi.org/10.1103/PhysRevD.102.122007S1710212Ageron, M., Aguilar, J. A., Al Samarai, I., Albert, A., Ameli, F., André, M., … Ardid, M. (2011). ANTARES: The first undersea neutrino telescope. Nuclear Instruments and Methods in Physics Research Section A: Accelerators, Spectrometers, Detectors and Associated Equipment, 656(1), 11-38. doi:10.1016/j.nima.2011.06.103Alexandreas, D. E., Allen, R. C., Berley, D., Biller, S. D., Burman, R. L., Cady, D. R., … Zhang, W. (1991). Observation of shadowing of ultrahigh-energy cosmic rays by the Moon and the Sun. Physical Review D, 43(5), 1735-1738. doi:10.1103/physrevd.43.1735Andreyev, Y. M., Zakidyshev, V. N., Karpov, S. N., & Khodov, V. N. (2002). Cosmic Research, 40(6), 559-564. doi:10.1023/a:1021553713199Borione, A., Catanese, M., Covault, C. E., Cronin, J. W., Fick, B. E., Gibbs, K. G., … van der Velde, J. C. (1994). Observation of the shadows of the Moon and Sun using 100 TeV cosmic rays. Physical Review D, 49(3), 1171-1177. doi:10.1103/physrevd.49.1171Cobb, J. H., Marshak, M. L., Allison, W. W. M., Alner, G. J., Ayres, D. S., Barrett, W. L., … Wall, D. (2000). Observation of a shadow of the Moon in the underground muon flux in the Soudan 2 detector. Physical Review D, 61(9). doi:10.1103/physrevd.61.092002Bartoli, B., Bernardini, P., Bi, X. J., Bleve, C., Bolognino, I., Branchini, P., … Cao, Z. (2012). Measurement of the cosmic ray antiproton/proton flux ratio at TeV energies with the ARGO-YBJ detector. Physical Review D, 85(2). doi:10.1103/physrevd.85.022002Abeysekara, A. U., Albert, A., Alfaro, R., Alvarez, C., Álvarez, J. D., Arceo, R., … Belmont-Moreno, E. (2018). Constraining the p¯/p ratio in TeV cosmic rays with observations of the Moon shadow by HAWC. Physical Review D, 97(10). doi:10.1103/physrevd.97.102005Adamson, P., Andreopoulos, C., Ayres, D. S., Backhouse, C., Barr, G., Barrett, W. L., … Bock, G. J. (2011). Observation in the MINOS far detector of the shadowing of cosmic rays by the sun and moon. Astroparticle Physics, 34(6), 457-466. doi:10.1016/j.astropartphys.2010.10.010Aartsen, M. G., Ackermann, M., Adams, J., Aguilar, J. A., Ahlers, M., Ahrens, M., … Ansseau, I. (2019). Detection of the Temporal Variation of the Sun’s Cosmic Ray Shadow with the IceCube Detector. The Astrophysical Journal, 872(2), 133. doi:10.3847/1538-4357/aaffd1Albert, A., André, M., Anghinolfi, M., Anton, G., Ardid, M., Aubert, J.-J., … Barrios-Martít, J. (2018). The cosmic ray shadow of the Moon observed with the ANTARES neutrino telescope. The European Physical Journal C, 78(12). doi:10.1140/epjc/s10052-018-6451-3First search for neutrinos in correlation with gamma-ray bursts with the ANTARES neutrino telescope. (2013). Journal of Cosmology and Astroparticle Physics, 2013(03), 006-006. doi:10.1088/1475-7516/2013/03/006Aguilar, J. A., Al Samarai, I., Albert, A., André, M., Anghinolfi, M., Anton, G., … Astraatmadja, T. (2011). A fast algorithm for muon track reconstruction and its application to the ANTARES neutrino telescope. Astroparticle Physics, 34(9), 652-662. doi:10.1016/j.astropartphys.2011.01.003BECHERINI, Y., MARGIOTTA, A., SIOLI, M., & SPURIO, M. (2006). A parameterisation of single and multiple muons in the deep water or ice. Astroparticle Physics, 25(1), 1-13. doi:10.1016/j.astropartphys.2005.10.005Carminati, G., Bazzotti, M., Margiotta, A., & Spurio, M. (2008). Atmospheric MUons from PArametric formulas: a fast GEnerator for neutrino telescopes (MUPAGE). Computer Physics Communications, 179(12), 915-923. doi:10.1016/j.cpc.2008.07.014Yepes-Ramírez, H. (2013). Characterization of optical properties of the site of the ANTARES neutrino telescope. Nuclear Instruments and Methods in Physics Research Section A: Accelerators, Spectrometers, Detectors and Associated Equipment, 725, 203-206. doi:10.1016/j.nima.2012.11.143Fusco, L. A., & Margiotta, A. (2016). The Run-by-Run Monte Carlo simulation for the ANTARES experiment. EPJ Web of Conferences, 116, 02002. doi:10.1051/epjconf/201611602002Albert, A., André, M., Anghinolfi, M., Anton, G., Ardid, M., Aubert, J.-J., … Basa, S. (2017). First all-flavor neutrino pointlike source search with the ANTARES neutrino telescope. Physical Review D, 96(8). doi:10.1103/physrevd.96.082001Albert, A., André, M., Anghinolfi, M., Anton, G., Ardid, M., Aubert, J.-J., … Belhorma, B. (2020). ANTARES and IceCube Combined Search for Neutrino Point-like and Extended Sources in the Southern Sky. The Astrophysical Journal, 892(2), 92. doi:10.3847/1538-4357/ab7afbAdrián-Martínez, S., Albert, A., André, M., Anghinolfi, M., Anton, G., Ardid, M., … Basa, S. (2014). SEARCHES FOR POINT-LIKE AND EXTENDED NEUTRINO SOURCES CLOSE TO THE GALACTIC CENTER USING THE ANTARES NEUTRINO TELESCOPE. The Astrophysical Journal, 786(1), L5. doi:10.1088/2041-8205/786/1/l

Limits on the nuclearite flux using the ANTARES neutrino telescope

In this work, a search for nuclearites of strange quark matter by using nine years of ANTARES data taken in the period 2009-2017 is presented. The passage through matter of these particles is simulated %according to the model of de R\'{u}jula and Glashow taking into account a detailed description of the detector response to nuclearites and of the data acquisition conditions. A down-going flux of cosmic nuclearites with Galactic velocities ($\beta = 10^{-3}$) was considered for this study. The mass threshold for detecting these particles at the detector level is \mbox{ $4 \times 10^{13}$ GeV/c$^{2}$}. Upper limits on the nuclearite flux for masses up to $10^{17}$ GeV/c$^{2}$ at the level of $\sim 5 \times 10^{-17}$ cm$^{-2}$ s$^{-1}$ sr$^{-1}$ are obtained. These are the first upper limits on nuclearites established with a neutrino telescope and the most stringent ever set for Galactic velocities.Comment: 17 pages, 7 figure

Search for magnetic monopoles with ten years of the ANTARES neutrino telescope

This work presents a new search for magnetic monopoles using data taken with the ANTARES neutrino telescope over a period of 10 years (January 2008 to December 2017). Compared to previous ANTARES searches, this analysis uses a run-by-run simulation strategy, with a larger exposure as well as a new simulation of magnetic monopoles taking into account the Kasama, Yang and Goldhaber model for their interaction cross-section with matter. No signal compatible with the passage of relativistic magnetic monopoles is observed, and upper limits on the flux of magnetic monopoles with β=v/c≥0.55, are presented. For ultra-relativistic magnetic monopoles the flux limit is ∼7×10−18 cm−2s−1sr−1