Information-Derived Mechanistic Hypotheses for Structural Cardiotoxicity

Adverse events resulting from drug therapy can be a cause of drug withdrawal, reduced and or restricted clinical use, as well as a major economic burden for society. To increase the safety of new drugs, there is a need to better understand the mechanisms causing the adverse events. One way to derive new mechanistic hypotheses is by linking data on drug adverse events with the drugs’ biological targets. In this study, we have used data mining techniques and mutual information statistical approaches to find associations between reported adverse events collected from the FDA Adverse Event Reporting System and assay outcomes from ToxCast, with the aim to generate mechanistic hypotheses related to structural cardiotoxicity (morphological damage to cardiomyocytes and/or loss of viability). Our workflow identified 22 adverse event-assay outcome associations. From these associations, 10 implicated targets could be substantiated with evidence from previous studies reported in the literature. For two of the identified targets, we also describe a more detailed mechanism, forming putative adverse outcome pathways associated with structural cardiotoxicity. Our study also highlights the difficulties deriving these type of associations from the very limited amount of data available

Cosmological phase transitions in warped space: gravitational waves and collider signatures

We study the electroweak phase transition within a 5D warped model including a scalar potential with an exponential behavior, and strong back-reaction over the metric, in the infrared. By means of a novel treatment of the superpotential formalism, we explore parameter regions that were previously inaccessible. We nd that for large enough values of the t'Hooft parameter (e.g. N = 25) the holographic phase transition occurs, and it can force the Higgs to undergo a rst order electroweak phase transition, suitable for electroweak baryogenesis. The model exhibits gravitational waves and colliders signatures. It typically predicts a stochastic gravitational wave background observable both at the Laser Interferometer Space Antenna and at the Einstein Telescope. Moreover the radion tends to be heavy enough such that it evades current constraints, but may show up in future LHC runs.The work of EM is supported by the Spanish MINEICO under Grant FPA2015-64041-C2-1-P and FIS2017-85053-C2-1-P, by the Junta de Andaluc a under Grant FQM-225, by the Basque Government under Grant IT979-16, and by the Spanish Consolider Ingenio 2010 Programme CPAN (CSD2007-00042). The research of EM is also supported by the Ram on y Cajal Program of the Spanish MINEICO, and by the Universidad del Pa s Vasco UPV/EHU, Bilbao, Spain, as a Visiting Professor. GN is supported by the Swiss National Science Foundation (SNF) under grant 200020-168988. The work of MQ is partly supported by Spanish MINEICO under Grant CICYT-FEDER-FPA2014- 55613-P and FPA2017-88915-P, by the Severo Ochoa Excellence Program of MINEICO under Grant SEV-2016-0588, and by CNPq PVE fellowship project 405559/2013-5

Climate and species affect fine root production with long-term fertilization in acidic tussock tundra near Toolik Lake, Alaska

Author Posting. © The Author(s), 2007. This is the author's version of the work. It is posted here by permission of Springer for personal use, not for redistribution. The definitive version was published in Oecologia 153 (2007): 643-652, doi:10.1007/s00442-007-0753-8.Long-term fertilization of acidic tussock tundra has led to changes in plant species composition, increases in aboveground production and biomass and substantial losses of soil organic carbon (SOC). Root litter is an important input to SOC pools, though little is known about fine root demography in tussock tundra. In this study, we examined the response of fine root production and live standing fine root biomass to short- and long-term fertilization, as changes in fine root demography may contribute to observed declines in SOC. Live standing fine root biomass increased with long-term fertilization, while fine root production declined, reflecting replacement of the annual fine root system of Eriophorum vaginatum, with the long-lived fine roots of Betula nana. Fine root production increased in fertilized plots during an unusually warm growing season, but remained unchanged in control plots, consistent with observations that B. nana shows a positive response to climate warming. Calculations based on a few simple assumptions suggest changes in fine root demography with long-term fertilization and species replacement could account for between 20 and 39% of observed declines in SOC stocks.This project was supported by National Science Foundation research grants 9810222, 9911681, 0221606 and 0528748

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

Scalar gravitational radiation from binaries: Vainshtein mechanism in time-dependent systems

We develop a full four-dimensional numerical code to study scalar gravitational radiation emitted from binary systems and probe the Vainshtein mechanism in situations that break the static and spherical symmetry, relevant for binary pulsars as well as black holes and neutron stars binaries. The present study focuses on the cubic Galileon which arises as the decoupling limit of massive theories of gravity. Limitations associated with the numerical methods prevent us from reaching a physically realistic hierarchy of scales; nevertheless, within this context we observe the same power law scaling of the radiated power as previous analytic estimates, and confirm a strong suppression of the power emitted in the monopole and dipole as compared with quadrupole radiation. Following the trend to more physically realistic parameters, we confirm the suppression of the power emitted in scalar gravitational radiation and the recovery of general relativity with good accuracy. This paves the way for future numerical work, probing more generic, physically relevant situations and sets of interactions that may exhibit the Vainshtein mechanism

Constraining axion inflation with gravitational waves across 29 decades in frequency

We demonstrate that gravitational waves generated by efficient gauge preheating after axion inflation generically contribute significantly to the effective number of relativistic degrees of freedom N eff . We show that, with existing Planck limits, gravitational waves from preheating already place the strongest constraints on the inflaton’s possible axial coupling to Abelian gauge fields. We demonstrate that gauge preheating can completely reheat the Universe regardless of the inflationary potential. Further, we quantify the variation of the efficiency of gravitational wave production from model to model and show that it is correlated with the tensor-to-scalar ratio. In particular, when combined with constraints on models whose tensor-to-scalar ratios would be detected by next-generation cosmic microwave background experiments, r ≳ 10 − 3 , constraints from N eff will probe or rule out the entire coupling regime for which gauge preheating is efficient