Submicron particles were collected on board the NOAA R/V Ronald H. Brown during the VAMOS Ocean‐Cloud‐Atmosphere‐Land Study Regional Experiment (VOCALS‐REx) in the southeast Pacific marine boundary ...layer in October and November 2008. The aerosol in this region was characterized by low numbers of particles (150–700 cm−3) that were dominated by sulfate ions at concentrations of 0.9 ± 0.7 μg m−3 and organic mass at 0.6 ± 0.4 μg m−3, with no measurable nitrate and low ammonium ion concentrations. Measurements of submicron organic aerosol functional groups and trace elements show that continental outflow of anthropogenic emissions is the dominant source of organic mass (OM) to the southeast Pacific with an additional, smaller contribution of organic mass from primary marine sources. This continental source is supported by a correlation between OM and radon. Saturated aliphatic C‐CH (alkane) composed 41 ± 27% of OM. Carboxylic acid COOH (32 ± 23% of OM) was observed in single particles internally mixed with ketonic carbonyl, carbonate, and potassium. Organosulfate COSO3 (4 ± 8% of OM) was observed only during the periods of highest organic and sulfate concentrations and lowest ammonium concentrations, consistent with a sulfuric acid epoxide hydrolysis for proposed surrogate compounds (e.g., isoprene oxidation products) or reactive glyoxal uptake mechanisms from laboratory studies. This correlation suggests that in high‐sulfate, low‐ammonium conditions, the formation of organosulfate compounds in the atmosphere contributes a significant fraction of aerosol OM (up to 13% in continental air masses). Organic hydroxyl C‐OH composed 20 ± 12% of OM and up to 50% of remote marine OM and was inversely correlated with radon indicating a marine source. A two‐factor solution of positive matrix factorization (PMF) analysis resulted in one factor dominated by organic hydroxyl (>70% by mass) and one factor dominated by saturated aliphatic C‐CH (alkane) and carboxylic acid (together, 90% by mass), identified as the marine and combustion factors, respectively. Measurements of particle concentrations in the study region compared with concentrations estimated from MODIS aerosol optical depth indicate that continental outflow results in MBL particle concentrations elevated up to 2 times the background level (less than 300 cm−3) away from shore and up to 10 times the background level at the coast. The presence of both coastal fossil fuel combustion and marine sources of oxygenated organic aerosol results in little change in the oxygenated fraction and oxygen to carbon ratio (O/C) along the outflow of the region's dominant organic particle source.
Opioids represent a highly-abused and highly potent class of drugs that have become a significant threat to public safety. Often there are little to no pharmacological and toxicological data ...available for new, illicitly used and abused opioids, and this has resulted in a growing number of serious adverse events, including death. The large influx of new synthetic opioids permeating the street-drug market, including fentanyl and fentanyl analogs, has generated the need for a fast and effective method to evaluate the risk a substance poses to public safety. In response, the US FDA's Center for Drug Evaluation and Research (CDER) has developed a rapidly-deployable, multi-pronged computational approach to assess a drug's risk to public health. A key component of this approach is a molecular docking model to predict the binding affinity of biologically uncharacterized fentanyl analogs to the mu opioid receptor. The model was validated by correlating the docking scores of structurally diverse opioids with experimentally determined binding affinities. Fentanyl derivatives with sub-nanomolar binding affinity at the mu receptor (e.g. carfentanil and lofentanil) have significantly lower binding scores, while less potent fentanyl derivatives have increased binding scores. The strong correlation between the binding scores and the experimental binding affinities suggests that this approach can be used to accurately predict the binding strength of newly identified fentanyl analogs at the mu receptor in the absence of in vitro data and may assist in the temporary scheduling of those substances that pose a risk to public safety.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
We evaluate a regional-scale simulation with the WRF-Chem model for the VAMOS (Variability of the American Monsoon Systems) Ocean-Cloud-Atmosphere-Land Study Regional Experiment (VOCALS-REx), which ...sampled the Southeast Pacific's persistent stratocumulus deck. Evaluation of VOCALS-REx ship-based and three aircraft observations focuses on analyzing how aerosol loading affects marine boundary layer (MBL) dynamics and cloud microphysics. We compare local time series and campaign-averaged longitudinal gradients, and highlight differences in model simulations with (W) and without (NW) wet deposition processes. The higher aerosol loadings in the NW case produce considerable changes in MBL dynamics and cloud microphysics, in accordance with the established conceptual model of aerosol indirect effects. These include increase in cloud albedo, increase in MBL and cloud heights, drizzle suppression, increase in liquid water content, and increase in cloud lifetime. Moreover, better statistical representation of aerosol mass and number concentration improves model fidelity in reproducing observed spatial and temporal variability in cloud properties, including top and base height, droplet concentration, water content, rain rate, optical depth (COD) and liquid water path (LWP). Together, these help to quantify confidence in WRF-Chem's modeled aerosol-cloud interactions, especially in the activation parameterization, while identifying structural and parametric uncertainties including: irreversibility in rain wet removal; overestimation of marine DMS and sea salt emissions, and accelerated aqueous sulfate conversion. Our findings suggest that WRF-Chem simulates marine cloud-aerosol interactions at a level sufficient for applications in forecasting weather and air quality and studying aerosol climate forcing, and may do so with the reliability required for policy analysis.
Primary marine aerosol (PMA)‐cloud interactions off the coast of California were investigated using observations of marine aerosol, cloud condensation nuclei (CCN), and stratocumulus clouds during ...the Eastern Pacific Emitted Aerosol Cloud Experiment (E‐PEACE) and the Stratocumulus Observations of Los‐Angeles Emissions Derived Aerosol‐Droplets (SOLEDAD) studies. Based on recently reported measurements of PMA size distributions, a constrained lognormal‐mode‐fitting procedure was devised to isolate PMA number size distributions from total aerosol size distributions and applied to E‐PEACE measurements. During the 12 day E‐PEACE cruise on the R/V Point Sur, PMA typically contributed less than 15% of total particle concentrations. PMA number concentrations averaged 12 cm−3 during a relatively calmer period (average wind speed 12 m/s1) lasting 8 days, and 71 cm−3 during a period of higher wind speeds (average 16 m/s1) lasting 5 days. On average, PMA contributed less than 10% of total CCN at supersaturations up to 0.9% during the calmer period; however, during the higher wind speed period, PMA comprised 5–63% of CCN (average 16–28%) at supersaturations less than 0.3%. Sea salt was measured directly in the dried residuals of cloud droplets during the SOLEDAD study. The mass fractions of sea salt in the residuals averaged 12 to 24% during three cloud events. Comparing the marine stratocumulus clouds sampled in the two campaigns, measured peak supersaturations were 0.2 ± 0.04% during E‐PEACE and 0.05–0.1% during SOLEDAD. The available measurements show that cloud droplet number concentrations increased with >100 nm particles in E‐PEACE but decreased in the three SOLEDAD cloud events.
Key Points
New method of analyzing primary marine aerosol (PMA) number size distributions
PMA <15% of aerosol number concentrations, <58% of CCN in E–PEACE
CDNC increased with increasing >100 nm particles in E-PEACE but not SOLEDAD
Retinoblastoma is an eye tumour of childhood that occurs in heritable and non-heritable forms. In the heritable form, there is a predisposition to the development of non-ocular subsequent primary ...tumours (SPTs).
This study included 1927 retinoblastoma patients diagnosed in Britain from 1951 to 2004. Ascertainment was through the (UK) National Registry of Childhood Tumours; cases were followed-up for the occurrence of SPTs. Standardised incidence ratios (SIRs) were calculated.
We identified 169 SPTs in 152 patients. The SIR analysis included 145 SPTs with cancer registrations from the years 1971 to 2009. These tumours occurred in 132 patients: 112 of the 781 heritable and 20 of the 1075 (presumed) non-heritable cases under surveillance at the start of this period developed at least one registered SPT. The SIRs for all tumours combined were 13.7 (95% confidence interval 11.3-16.5) in heritable cases and 1.5 (0.9-2.3) in non-heritable cases. The main types of SPT in the heritable cases were leiomyosarcoma, (31 cases; SIR 1018.7 (692.2-1446.0)), osteosarcoma (26 cases; SIR 444.6 (290.4-651.4)), and skin melanoma (12 cases; SIR 18.6 (9.6-32.4)).
The risk of SPTs in heritable retinoblastoma is extremely high. This has important implications for the clinical follow-up and counselling of survivors and their families.
Submicron particles collected on Teflon filters aboard the R/V Ronald Brown during the Texas Air Quality Study and Gulf of Mexico Atmospheric Composition and Climate Study (TexAQS/GoMACCS) 2006 in ...and around the port of Houston, Texas, were measured by Fourier transform infrared (FTIR) and X‐ray fluorescence for organic functional groups and elemental composition. Organic mass (OM) concentrations (1–25 μg m−3) for ambient particle samples measured by FTIR showed good agreement with measurements made with an aerosol mass spectrometer. The fractions of organic mass identified as alkane and carboxylic acid groups were 47% and 32%, respectively. Three different types of air masses were identified on the basis of the air mass origin and the radon concentration, with significantly higher carboxylic acid group mass fractions in air masses from the north (35%) than the south (29%) or Gulf of Mexico (26%). Positive matrix factorization analysis attributed carboxylic acid fractions of 30–35% to factors with mild or strong correlations (r > 0.5) to elemental signatures of oil combustion and 9–24% to wood smoke, indicating that part of the carboxylic acid fraction of OM was formed by the same sources that controlled the metal emissions, namely the oil and wood combustion activities. The implication is that a substantial part of the measured carboxylic acid contribution was formed independently of traditionally “secondary” processes, which would be affected by atmospheric (both photochemical and meteorological) conditions and other emission sources. The carboxylic acid group fractions in the Gulf of Mexico and south air masses (GAM and SAM, respectively) were largely oil combustion emissions from ships as well as background marine sources, with only limited recent land influences (based on radon concentrations). Alcohol groups accounted for 14% of OM (mostly associated with oil combustion emissions and background sources), and amine groups accounted for 4% of OM in all air masses. Organosulfate groups were found in GAM and SAM, accounting for 1% and 3% of OM, respectively. Two thirds of the OM and oxygen‐to‐carbon (O/C) measured could be attributed to oil and wood combustion sources on the basis of mild or strong correlations to coemitted, nonvolatile trace metals, with the remaining one third being associated with atmospherically processed organic aerosol. The cloud condensation nuclei (CCN) fraction (normalized by total condensation nuclei) had weak correlations to the alcohol and amine group fractions and mild correlation with O/C, also varying inversely with alkane group fraction. The chemical components that influenced f(RH) were sulfate, organic, and nitrate fraction, but this contrast is consistent with the size‐distribution dependence of CCN counters and nephelometers.
MR imaging-based modeling of tumor cell density can substantially improve targeted treatment of glioblastoma. Unfortunately, interpatient variability limits the predictive ability of many modeling ...approaches. We present a transfer learning method that generates individualized patient models, grounded in the wealth of population data, while also detecting and adjusting for interpatient variabilities based on each patient's own histologic data.
We recruited patients with primary glioblastoma undergoing image-guided biopsies and preoperative imaging, including contrast-enhanced MR imaging, dynamic susceptibility contrast MR imaging, and diffusion tensor imaging. We calculated relative cerebral blood volume from DSC-MR imaging and mean diffusivity and fractional anisotropy from DTI. Following image coregistration, we assessed tumor cell density for each biopsy and identified corresponding localized MR imaging measurements. We then explored a range of univariate and multivariate predictive models of tumor cell density based on MR imaging measurements in a generalized one-model-fits-all approach. We then implemented both univariate and multivariate individualized transfer learning predictive models, which harness the available population-level data but allow individual variability in their predictions. Finally, we compared Pearson correlation coefficients and mean absolute error between the individualized transfer learning and generalized one-model-fits-all models.
Tumor cell density significantly correlated with relative CBV (
= 0.33,
< .001), and T1-weighted postcontrast (
= 0.36,
< .001) on univariate analysis after correcting for multiple comparisons. With single-variable modeling (using relative CBV), transfer learning increased predictive performance (
= 0.53, mean absolute error = 15.19%) compared with one-model-fits-all (
= 0.27, mean absolute error = 17.79%). With multivariate modeling, transfer learning further improved performance (
= 0.88, mean absolute error = 5.66%) compared with one-model-fits-all (
= 0.39, mean absolute error = 16.55%).
Transfer learning significantly improves predictive modeling performance for quantifying tumor cell density in glioblastoma.
The heme enzyme indoleamine 2,3-dioxygenase-1 (IDO1) catalyzes the first reaction of l-tryptophan oxidation along the kynurenine pathway. IDO1 is a central immunoregulatory enzyme with important ...implications for inflammation, infectious disease, autoimmune disorders, and cancer. Here we demonstrate that IDO1 is a mammalian nitrite reductase capable of chemically reducing nitrite to nitric oxide (NO) under hypoxia. Ultraviolet–visible absorption and resonance Raman spectroscopy showed that incubation of dithionite-reduced, ferrous–IDO1 protein (FeII–IDO1) with nitrite under anaerobic conditions resulted in the time-dependent formation of an FeII–nitrosyl IDO1 species, which was inhibited by substrate l-tryptophan, dependent on the concentration of nitrite or IDO1, and independent of the concentration of the reductant, dithionite. The bimolecular rate constant for IDO1 nitrite reductase activity was determined as 5.4 M–1 s–1 (pH 7.4, 23 °C), which was comparable to that measured for myoglobin (3.6 M–1 s–1; pH 7.4, 23 °C), an efficient and biologically important mammalian heme-based nitrite reductase. IDO1 nitrite reductase activity was pH-dependent but differed with myoglobin in that it showed a reduced proton dependency at pH >7. Electron paramagnetic resonance studies measuring NO production showed that the conventional IDO1 dioxygenase reducing cofactors, ascorbate and methylene blue, enhanced IDO1’s nitrite reductase activity and the time- and IDO1 concentration-dependent release of NO in a manner inhibited by l-tryptophan or the IDO inhibitor 1-methyl-l-tryptophan. These data identify IDO1 as an efficient mammalian nitrite reductase that is capable of generating NO under anaerobic conditions. IDO1’s nitrite reductase activity may have important implications for the enzyme’s biological actions when expressed within hypoxic tissues.
Simulating aqueous brown carbon (aqBrC) formation from small molecule amines and aldehydes in cloud water mimics provides insight into potential humic-like substance (HULIS) contributors and their ...effect on local and global aerosol radiative forcing. Previous work has shown that these (Maillard type) reactions generate products that are chemically, physically, and optically similar to atmospheric HULIS in many significant ways, including in their complexity. Despite numerous characterization studies, attribution of the intense brown color of many aqBrC systems to specific compounds remains incomplete. In this work, we present evidence of novel pyrazine-based chromophores (PBCs) in the product mixture of aqueous solutions containing methylglyoxal and ammonium sulfate. PBCs observed here include 2,5-dimethyl pyrazine (DMP) and products of methylglyoxal addition to the pyrazine ring. This finding is significant as the literature of Maillard reactions in food chemistry tightly links the formation of pyrazine (and related compounds) to browning in foods. We investigated the roles of both cloud processing (by bulk evaporation) and pH in absorptivity and product distribution in microliter samples to understand the contribution of these PBCs to aqBrC properties. In agreement with previous work, we observed elevated absorptivity across the entire UV–visible spectrum following simulated cloud processing as well as higher absorptivity in more basic samples. Absorptivity of the pH 2 sample, following evaporation over a period of days, exceeded that of the unevaporated pH 9 sample. In addition, mixtures of ammonium sulfate and methylglyoxal at pH 5 that were dried in under 1 h and analyzed 24 h later were as absorptive as pH 9 samples allowed to react for 7 days, indicating that evaporation occurring during cloud processing may provide a reaction pathway favorable for carbonyl–ammonia chemistry even under acidic conditions of aerosol and cloud water. The fraction of pyrazine compounds in the product mixture increased by up to a factor of 4 in response to drying with a maximum observed contribution of 16 % at pH 5. Therefore, cloud processing under acidic conditions may produce PBCs at the expense of imine- and imidazole-derived compounds. This finding has implications for further BrC reactivity and degradation pathways.
Alpha-dicarbonyl compounds are believed to form brown
carbon in the atmosphere via reactions with ammonium sulfate (AS) in cloud
droplets and aqueous aerosol particles. In this work, brown carbon ...formation
in AS and other aerosol particles was quantified as a function of relative
humidity (RH) during exposure to gas-phase glyoxal (GX) in chamber
experiments. Under dry conditions (RH < 5 %), solid AS,
AS–glycine, and methylammonium sulfate (MeAS) aerosol particles brown within
minutes upon exposure to GX, while sodium sulfate particles do not. When GX
concentrations decline, browning goes away, demonstrating that this dry
browning process is reversible. Declines in aerosol albedo are found to be a
function of GX2 and are consistent between AS and AS–glycine
aerosol. Dry methylammonium sulfate aerosol browns 4 times more than dry
AS aerosol, but deliquesced AS aerosol browns much less than dry AS aerosol.
Optical measurements at 405, 450, and 530 nm provide an estimated
Ångstrom absorbance coefficient of -16±4. This coefficient and
the empirical relationship between GX and albedo are used to estimate an
upper limit to global radiative forcing by brown carbon formed by 70 ppt GX
reacting with AS (+7.6×10-5 W m−2). This quantity is
< 1 % of the total radiative forcing by secondary brown carbon
but occurs almost entirely in the ultraviolet range.
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