The Arabian Peninsula is characterized by high and
increasing levels of photochemical air pollution. Strong solar irradiation,
high temperatures and large anthropogenic emissions of reactive trace ...gases
result in intense photochemical activity, especially during the summer
months. However, air chemistry measurements in the region are scarce. In
order to assess regional pollution sources and oxidation rates, the first
ship-based direct measurements of total OH reactivity were performed in
summer 2017 from a vessel traveling around the peninsula during the AQABA
(Air Quality and Climate Change in the Arabian Basin) campaign. Total OH
reactivity is the total loss frequency of OH radicals due to all reactive
compounds present in air and defines the local lifetime of OH, the most
important oxidant in the troposphere. During the AQABA campaign, the total
OH reactivity ranged from below the detection limit (5.4 s−1) over the
northwestern Indian Ocean (Arabian Sea) to a maximum of 32.8±9.6 s−1 over the Arabian Gulf (also known as Persian Gulf) when air
originated from large petroleum extraction/processing facilities in Iraq and
Kuwait. In the polluted marine regions, OH reactivity was broadly comparable
to highly populated urban centers in intensity and composition. The
permanent influence of heavy maritime traffic over the seaways of the Red
Sea, Gulf of Aden and Gulf of Oman resulted in median OH sinks of
7.9–8.5 s−1. Due to the rapid oxidation of direct volatile organic
compound (VOC) emissions, oxygenated volatile organic compounds (OVOCs) were
observed to be the main contributor to OH reactivity around the Arabian
Peninsula (9 %–35 % by region). Over the Arabian Gulf, alkanes and
alkenes from the petroleum extraction and processing industry were an
important OH sink with ∼9 % of total OH reactivity each,
whereas NOx and aromatic hydrocarbons (∼10 % each)
played a larger role in the Suez Canal, which is influenced more by ship
traffic and urban emissions. We investigated the number and identity of
chemical species necessary to explain the total OH sink. Taking into account
∼100 individually measured chemical species, the observed
total OH reactivity can typically be accounted for within the measurement
uncertainty (50 %), with 10 dominant trace gases accounting for
20 %–39 % of regional total OH reactivity. The chemical regimes causing
the intense ozone pollution around the Arabian Peninsula were investigated
using total OH reactivity measurements. Ozone vs. OH reactivity
relationships were found to be a useful tool for differentiating between
ozone titration in fresh emissions and photochemically aged air masses. Our
results show that the ratio of NOx- and VOC-attributed OH reactivity
was favorable for ozone formation almost all around the Arabian Peninsula,
which is due to NOx and VOCs from ship exhausts and, often, oil/gas
production. Therewith, total OH reactivity measurements help to elucidate
the chemical processes underlying the extreme tropospheric ozone
concentrations observed in summer over the Arabian Basin.
Liquid chromatography (LC) combined with atmospheric pressure chemical ionization mass spectrometry was used to identify phase I and II metabolites of the drug BW 1370U87 in dog and human urine. ...Additional analysis of individual high-performance liquid chromatograph fractions collected from dog urine by combined gas chromatography/mass spectrometry identified one metabolite which was not detected by LC/MS methods. Using negative-ion LC/MS, the majority of BW 1370U87 metabolites in human urine were identified as glucuronic acid conjugates of phase I oxidative metabolites. The negative-ion fragmentation produced by low-energy collisionally activated decomposition (CAD), studied by tandem mass spectrometry experiments, confirmed that these compounds were drug-related and allowed metabolite structures to be assigned. Product-ion spectra of the metabolites were dominated by the loss of neutral molecules from even-electron deprotonated M-H- ions.
Optimal decision-making balances exploration for new information against exploitation of known rewards, a process mediated by the locus coeruleus and its norepinephrine projections. We predicted that ...an exploitation-bias that emerges in older adulthood would be associated with lower microstructural integrity of the locus coeruleus. Leveraging in vivo histological methods from quantitative MRI-magnetic transfer saturation-we provide evidence that older age is associated with lower locus coeruleus integrity. Critically, we demonstrate that an exploitation bias in older adulthood, assessed with a foraging task, is sensitive and specific to lower locus coeruleus integrity. Because the locus coeruleus is uniquely vulnerable to Alzheimer's disease pathology, our findings suggest that aging, and a presymptomatic trajectory of Alzheimer's related decline, may fundamentally alter decision-making abilities in later life.
Lapatinib N-{3-chloro-4-(3-fluorobenzyl)oxyphenyl}-6-5-({2-(methylsulfonyl)ethylamino}methyl)-2-furyl-4-quinazolinamine, GW572016, Tykerb is a tyrosine kinase inhibitor approved for use in ...combination with capecitabine to treat advanced or metastatic breast cancers overexpressing HER2 (ErbB2). In this work we investigated the role of efflux and uptake transporters in lapatinib disposition and drug interactions. In vitro studies evaluated whether lapatinib is a substrate for efflux transporters or an inhibitor of efflux/uptake transporters. In vivo studies included whole-body autoradiography and an evaluation of the role of efflux transporters on the intestinal absorption and brain penetration of lapatinib using chemical or genetic knockout animals. Lapatinib is a substrate for the efflux transporters P-glycoprotein (Pgp) and breast cancer resistance protein (BCRP). Furthermore, lapatinib is an inhibitor (IC(50) values 0.025-5 muM) of Pgp, BCRP, and organic anion transporting polypeptide 1B1 (a hepatic uptake transporter). In contrast, lapatinib yielded little inhibition on renal transporters (organic anion transporters, organic cation transporters, and uric acid transporter). In vivo studies demonstrated that brain concentrations of lapatinib were low and influenced by efflux transporters at the blood-brain barrier. In contrast, systemic exposure of lapatinib after oral dosing was unchanged when efflux by Pgp and BCRP was absent from the gastrointestinal tract. These in vitro and in vivo preclinical investigations provide a mechanistic basis for elucidating clinical drug interactions.
The laboratory mouse is the most widely used animal model for biomedical research, due in part to its well-annotated genome, wealth of genetic resources, and the ability to precisely manipulate its ...genome. Despite the importance of genetics for mouse research, genetic quality control (QC) is not standardized, in part due to the lack of cost-effective, informative, and robust platforms. Genotyping arrays are standard tools for mouse research and remain an attractive alternative even in the era of high-throughput whole-genome sequencing. Here, we describe the content and performance of a new iteration of the Mouse Universal Genotyping Array (MUGA), MiniMUGA, an array-based genetic QC platform with over 11,000 probes. In addition to robust discrimination between most classical and wild-derived laboratory strains, MiniMUGA was designed to contain features not available in other platforms: (1) chromosomal sex determination, (2) discrimination between substrains from multiple commercial vendors, (3) diagnostic SNPs for popular laboratory strains, (4) detection of constructs used in genetically engineered mice, and (5) an easy-to-interpret report summarizing these results. In-depth annotation of all probes should facilitate custom analyses by individual researchers. To determine the performance of MiniMUGA, we genotyped 6899 samples from a wide variety of genetic backgrounds. The performance of MiniMUGA compares favorably with three previous iterations of the MUGA family of arrays, both in discrimination capabilities and robustness. We have generated publicly available consensus genotypes for 241 inbred strains including classical, wild-derived, and recombinant inbred lines. Here, we also report the detection of a substantial number of XO and XXY individuals across a variety of sample types, new markers that expand the utility of reduced complexity crosses to genetic backgrounds other than C57BL/6, and the robust detection of 17 genetic constructs. We provide preliminary evidence that the array can be used to identify both partial sex chromosome duplication and mosaicism, and that diagnostic SNPs can be used to determine how long inbred mice have been bred independently from the relevant main stock. We conclude that MiniMUGA is a valuable platform for genetic QC, and an important new tool to increase the rigor and reproducibility of mouse research.
Heritability of bone mineral density (BMD) varies across skeletal sites, reflecting different relative contributions of genetic and environmental influences. To quantify the degree to which common ...genetic variants tag and environmental factors influence BMD, at different sites, we estimated the genetic (rg) and residual (re) correlations between BMD measured at the upper limbs (UL-BMD), lower limbs (LL-BMD) and skull (SK-BMD), using total-body DXA scans of ~4,890 participants recruited by the Avon Longitudinal Study of Parents and their Children (ALSPAC). Point estimates of rg indicated that appendicular sites have a greater proportion of shared genetic architecture (LL-/UL-BMD rg = 0.78) between them, than with the skull (UL-/SK-BMD rg = 0.58 and LL-/SK-BMD rg = 0.43). Likewise, the residual correlation between BMD at appendicular sites (re = 0.55) was higher than the residual correlation between SK-BMD and BMD at appendicular sites (re = 0.20-0.24). To explore the basis for the observed differences in rg and re, genome-wide association meta-analyses were performed (n~9,395), combining data from ALSPAC and the Generation R Study identifying 15 independent signals from 13 loci associated at genome-wide significant level across different skeletal regions. Results suggested that previously identified BMD-associated variants may exert site-specific effects (i.e. differ in the strength of their association and magnitude of effect across different skeletal sites). In particular, variants at CPED1 exerted a larger influence on SK-BMD and UL-BMD when compared to LL-BMD (P = 2.01×10-37), whilst variants at WNT16 influenced UL-BMD to a greater degree when compared to SK- and LL-BMD (P = 2.31×10-14). In addition, we report a novel association between RIN3 (previously associated with Paget's disease) and LL-BMD (rs754388: β = 0.13, SE = 0.02, P = 1.4×10-10). Our results suggest that BMD at different skeletal sites is under a mixture of shared and specific genetic and environmental influences. Allowing for these differences by performing genome-wide association at different skeletal sites may help uncover new genetic influences on BMD.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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