Quantitative cross-species extrapolation between humans and fish: The case of the anti-depressant fluoxetine

This article has been made available through the Brunel Open Access Publishing Fund.Fish are an important model for the pharmacological and toxicological characterization of human pharmaceuticals in drug discovery, drug safety assessment and environmental toxicology. However, do fish respond to pharmaceuticals as humans do? To address this question, we provide a novel quantitative cross-species extrapolation approach (qCSE) based on the hypothesis that similar plasma concentrations of pharmaceuticals cause comparable target-mediated effects in both humans and fish at similar level of biological organization (Read-Across Hypothesis). To validate this hypothesis, the behavioural effects of the anti-depressant drug fluoxetine on the fish model fathead minnow (Pimephales promelas) were used as test case. Fish were exposed for 28 days to a range of measured water concentrations of fluoxetine (0.1, 1.0, 8.0, 16, 32, 64 μg/L) to produce plasma concentrations below, equal and above the range of Human Therapeutic Plasma Concentrations (HTPCs). Fluoxetine and its metabolite, norfluoxetine, were quantified in the plasma of individual fish and linked to behavioural anxiety-related endpoints. The minimum drug plasma concentrations that elicited anxiolytic responses in fish were above the upper value of the HTPC range, whereas no effects were observed at plasma concentrations below the HTPCs. In vivo metabolism of fluoxetine in humans and fish was similar, and displayed bi-phasic concentration-dependent kinetics driven by the auto-inhibitory dynamics and saturation of the enzymes that convert fluoxetine into norfluoxetine. The sensitivity of fish to fluoxetine was not so dissimilar from that of patients affected by general anxiety disorders. These results represent the first direct evidence of measured internal dose response effect of a pharmaceutical in fish, hence validating the Read-Across hypothesis applied to fluoxetine. Overall, this study demonstrates that the qCSE approach, anchored to internal drug concentrations, is a powerful tool to guide the assessment of the sensitivity of fish to pharmaceuticals, and strengthens the translational power of the cross-species extrapolation

NEMO: A Project for a km3^3 Underwater Detector for Astrophysical Neutrinos in the Mediterranean Sea

The status of the project is described: the activity on long term characterization of water optical and oceanographic parameters at the Capo Passero site candidate for the Mediterranean km$^3$ neutrino telescope; the feasibility study; the physics performances and underwater technology for the km$^3$; the activity on NEMO Phase 1, a technological demonstrator that has been deployed at 2000 m depth 25 km offshore Catania; the realization of an underwater infrastructure at 3500 m depth at the candidate site (NEMO Phase 2).Comment: Proceeding of ISCRA 2006, Erice 20-27 June 200

Moon and Sun shadowing effect in the MACRO detector

Using data collected by the MACRO experiment from 1989 to the end of its operations in 2000, we have studied in the underground muon flux the shadowing effects due to both the Moon and the Sun. We have observed the Moon shadowing effect with a significance of 6.5 sigma and the Sun shadowing effect with a significance of 4.3 sigma. The observed displacement of the Sun shadow, due to the configurations of the solar and interplanetary magnetic fields, has been used to quote the antiproton/proton flux limits for primaries of about 20 TeV energy.Comment: 23 pages, 11 figures, submitted to Astrop.Phy

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

Moon and Sun shadowing effect in the MACRO detector

Using data collected by the MACRO experiment from 1989 to the end of its operations in 2000, we have studied in the underground muon flux the shadowing. effects due to both the Moon and the Sun. We have observed the shadow cast by the Moon at its apparent position with a significance of 6.5sigma. The Moon shadowing effect has been used to verify the pointing capability of the detector and to determine the instrument resolution for the search of muon excesses from any direction of the celestial sphere. The dependence of the effect on the geomagnetic field is clearly shown by splitting the data sample in day and night observations. The Sun shadow, observed with a significance of 4.6sigma is displaced by about 0.6degrees from its apparent position. In this case however the explanation resides in the configuration of the Solar and Interplanetary Magnetic Fields, which affect the propagation of cosmic ray particles between the Sun, and the Earth. The displacement of the Sun shadow with respect to the real Sun position has been used to establish an upper limit on the antimatter flux in cosmic rays of about 48% at 68% c.l. and primary energies of about 20 TeV. (C) 2003 Elsevier B.V. All rights reserved