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

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

Far-from-equilibrium monopole dynamics in spin ice

Condensed matter in the low-temperature limit reveals exotic physics associated with unusual orders and excitations, with examples ranging from helium superfluidity1 to magnetic monopoles in spin ice2, 3. The far-from-equilibrium physics of such low-temperature states may be even more exotic, yet to access it in the laboratory remains a challenge. Here we demonstrate a simple and robust technique—the ‘magnetothermal avalanche quench’—and its use in the controlled creation of non-equilibrium populations of magnetic monopoles in spin ice at millikelvin temperatures. These populations are found to exhibit spontaneous dynamical effects that typify far-from-equilibrium systems and yet are captured by simple models. Our method thus opens new directions in the study of far-from-equilibrium states in spin ice and other exotic magnets

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

Vegetation Leachate During Arctic Thaw Enhances Soil Microbial Phosphorus

Leachate from litter and vegetation penetrates permafrost surface soils during thaw before being exported to aquatic systems. We know this leachate is critical to ecosystem function downstream and hypothesized that thaw leachate inputs would also drive terrestrial microbial activity and nutrient uptake. However, we recognized two potential endpoint scenarios: vegetation leachate is an important source of C for microbes in thawing soil; or vegetation leachate is irrelevant next to the large background C, N, and P pools in thaw soil solution. We assessed these potential outcomes by making vegetation leachate from frozen vegetation and litter in four Arctic ecosystems that have a variety of litter quality and soil C, N, and P contents; one of these ecosystems included a disturbance recovery chronosequence that allowed us to test our second hypothesis that thaw leachate response would be enhanced in disturbed ecosystems. We added water or vegetation leachate to intact, frozen, winter soil cores and incubated the cores through thaw. We measured soil respiration throughout, and soil solution and microbial biomass C, N, and P pools and gross N mineralization immediately after a thaw incubation (−10 to 2°C) lasting 6 days. Vegetation leachate varied strongly by ecosystem in C, N, and P quantity and stoichiometry. Regardless, all vegetated ecosystems responded to leachate additions at thaw with an increase in the microbial biomass phosphate flush and an increase in soil solution carbon and nitrogen, implying a selective microbial uptake of phosphate from plant and litter leachate at thaw. This response to leachate additions was absent in recently disturbed, exposed mineral soil but otherwise did not differ between disturbed and undisturbed ecosystems. The selective uptake of P by microbes implies either thaw microbial P limitation or thaw microbial P uptake opportunism, and that spring thaw is an important time for P retention in several Arctic ecosystems

Galaxy And Mass Assembly (GAMA): Data Release 4 and the z < 0.1 total and z < 0.08 morphological galaxy stellar mass functions

In Galaxy And Mass Assembly Data Release 4 (GAMA DR4), we make available our full spectroscopic redshift sample. This includes 248 682 galaxy spectra, and, in combination with earlier surveys, results in 330 542 redshifts across five sky regions covering similar to 250 deg(2). The redshift density, is the highest available over such a sustained area, has exceptionally high completeness (95 per cent to r(KiDS) = 19.65 mag), and is well-suited for the study of galaxy mergers, galaxy groups, and the low redshift (z < 0.25) galaxy population. DR4 includes 32 value-added tables or Data Management Units (DMUs) that provide a number of measured and derived data products including GALEX, ESO KiDS, ESO VIKING, WISE, and HerschelSpace Observatory imaging. Within this release, we provide visual morphologies for 15 330 galaxies to z < 0.08, photometric redshift estimates for all 18 million objects to r(KiDS) similar to 25 mag, and stellar velocity dispersions for 111 830 galaxies. We conclude by deriving the total galaxy stellar mass function (GSMF) and its sub-division by morphological class (elliptical, compact-bulge and disc, diffuse-bulge and disc, and disc only). This extends our previous measurement of the total GSMF down to 10(6.75) M-circle dot h(70)(-2) and we find a total stellar mass density of rho(*) = (2.97 +/- 0.04) x 10(8) M-circle dot h(70) Mpc(-3) or Omega(*)=(2.17 +/- 0.03) x 10(-3) h(70)(-1). We conclude that at z < 0.1, the Universe has converted 4.9 +/- 0.1 per cent of the baryonic mass implied by big bang Nucleosynthesis into stars that are gravitationally bound within the galaxy population