Iowa stream nitrate and the Gulf of Mexico

<div><p>The main objective of this work was to quantify and update the U.S. Midwest agricultural state of Iowa’s contribution of nitrate-nitrogen to the Mississippi River stream network against the backdrop of the ongoing problem of Gulf of Mexico hypoxia. To achieve this objective, we used stream nitrate and discharge data collected from 1999 until 2016 at 23 Iowa stream sites near watershed outlets, along with publicly-available data for sites downstream of Iowa on the Missouri and Mississippi Rivers. Our analysis shows that Iowa contributes between 11 and 52% of the long-term nitrate load to the Mississippi-Atchafalaya Basin, 20 to 63% to the Upper Mississippi River Basin, and 20 to 89% to the Missouri River Basin, with averages of 29, 45 and 55% respectively. Since 1999, nitrate loads in the Iowa-inclusive basins have increased and these increases do not appear to be driven by changes in discharge and cropping intensity unique to Iowa. The 5-year running annual average of Iowa nitrate loading has been above the 2003 level for ten consecutive years, implying that Gulf hypoxic areal goals, also based on a 5-year running annual average, will be very difficult to achieve if nitrate retention cannot be improved in Iowa. An opportunity exists for land managers, policy makers and conservationists to manifest a positive effect on water quality by targeting and implementing nitrate reducing-practices in areas like Iowa while avoiding areas that are less likely to affect Gulf of Mexico hypoxia.</p></div

Iowa DNR ambient monitoring sites used in this study.

<p>Iowa DNR ambient monitoring sites used in this study.</p

Iowa stream sites and watersheds evaluated in this study.

<p>The red triangle indicates the sample location. Numbers correspond to those listed in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0195930#pone.0195930.t001" target="_blank">Table 1</a>.</p

Flow-weighted average NO3-N concentrations (mg L^-1) in the Mississippi-Atchafalaya River Basin (MARB), Upper Mississippi River Basin (UMRB) and Missouri River Basin (MoRB), the Iowa and non-Iowa portions of each of those basins, and the concentration of the entire basins if the Iowa Nutrient Reduction Strategy goal of 45% load reduction was met.

<p>Flow-weighted average NO3-N concentrations (mg L^-1) in the Mississippi-Atchafalaya River Basin (MARB), Upper Mississippi River Basin (UMRB) and Missouri River Basin (MoRB), the Iowa and non-Iowa portions of each of those basins, and the concentration of the entire basins if the Iowa Nutrient Reduction Strategy goal of 45% load reduction was met.</p

Five-year running annual average of Gulf of Mexico hypoxic area (blue) and Iowa stream NO3-N loads (green).

<p>Five-year running annual average of Gulf of Mexico hypoxic area (blue) and Iowa stream NO3-N loads (green).</p

Areas of Iowa draining to the Missouri River and Mississippi River but not the Missouri River.

<p>Areas of Iowa draining to the Missouri River and Mississippi River but not the Missouri River.</p

Loads of NO3-N (left) and total discharge (right) for the Mississippi-Atchafalaya River Basin (MARB), Upper Mississippi River Basin (UMRB) and Missouri River Basin (MoRB).

<p>The green lines indicate the entire basin; the blue lines indicate the non-Iowa portions.</p

Box plots of water yield (top) and NO3-N yield (bottom) for the period of study.

<p>Streams draining to the Mississippi but not the Missouri are shown in blue while streams draining to the Missouri are shown in brown. The overall Iowa averages are shown in green. The boxes bracket the 25th-75th percentiles; the line in the box indicates the median; the whiskers the 10th and 90th percentiles, and the dots are data points less than (greater than) the 10th (90th) percentiles.</p

Discovery of PF-04449913, a Potent and Orally Bioavailable Inhibitor of Smoothened

Inhibitors of the Hedgehog signaling pathway have generated a great deal of interest in the oncology area due to the mounting evidence of their potential to provide promising therapeutic options for patients. Herein, we describe the discovery strategy to overcome the issues inherent in lead structure <b>1</b> that resulted in the identification of Smoothened inhibitor 1-((2<i>R</i>,4<i>R</i>)-2-(1<i>H</i>-benzo­[<i>d</i>]­imidazol-2-yl)-1-methylpiperidin-4-yl)-3-(4-cyanophenyl)­urea (PF-04449913, <b>26</b>), which has been advanced to human clinical studies

Design and Synthesis of Diazatricyclodecane Agonists of the G‑Protein-Coupled Receptor 119

A series of GPR119 agonists based on a 2,6-diazatricyclo­[3.3.1.1∼3,7∼]­decane ring system is described. Also provided is a detailed account of the development of a multigram scale synthesis of the diazatricyclic ring system, which was achieved using a Hofmann–Löffler–Freytag reaction as the key step. The basis for the use of this complex framework lies in an attempt to constrain one end of the molecule in the “agonist conformation” as was previously described for 3-oxa-7-aza-bicyclo[3.3.1]­nonanes. Optimization of carbamate analogues of the diazatricylic compounds led to the identification of <b>32i</b> as a potent agonist of the GPR119 receptor with low unbound human liver microsomal clearance. The use of an agonist response weighted ligand lipophilic efficiency (LLE) termed AgLLE is discussed along with the issues of applying efficiency measures to agonist programs. Ultimately, solubility limited absorption and poor exposure reduced further interest in these molecules