The pattern of structural brain alterations associated with major depressive disorder (MDD) remains unresolved. This is in part due to small sample sizes of neuroimaging studies resulting in limited ...statistical power, disease heterogeneity and the complex interactions between clinical characteristics and brain morphology. To address this, we meta-analyzed three-dimensional brain magnetic resonance imaging data from 1728 MDD patients and 7199 controls from 15 research samples worldwide, to identify subcortical brain volumes that robustly discriminate MDD patients from healthy controls. Relative to controls, patients had significantly lower hippocampal volumes (Cohen's d=-0.14, % difference=-1.24). This effect was driven by patients with recurrent MDD (Cohen's d=-0.17, % difference=-1.44), and we detected no differences between first episode patients and controls. Age of onset ⩽21 was associated with a smaller hippocampus (Cohen's d=-0.20, % difference=-1.85) and a trend toward smaller amygdala (Cohen's d=-0.11, % difference=-1.23) and larger lateral ventricles (Cohen's d=0.12, % difference=5.11). Symptom severity at study inclusion was not associated with any regional brain volumes. Sample characteristics such as mean age, proportion of antidepressant users and proportion of remitted patients, and methodological characteristics did not significantly moderate alterations in brain volumes in MDD. Samples with a higher proportion of antipsychotic medication users showed larger caudate volumes in MDD patients compared with controls. This currently largest worldwide effort to identify subcortical brain alterations showed robust smaller hippocampal volumes in MDD patients, moderated by age of onset and first episode versus recurrent episode status.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
We present few-femtosecond shadowgraphic snapshots taken during the nonlinear evolution of the plasma wave in a laser wakefield accelerator with transverse synchronized few-cycle probe pulses. These ...snapshots can be directly associated with the electron density distribution within the plasma wave and give quantitative information about its size and shape. Our results show that self-injection of electrons into the first plasma-wave period is induced by a lengthening of the first plasma period. Three-dimensional particle-in-cell simulations support our observations.
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CMK, CTK, FMFMET, IJS, NUK, PNG, UM
Recent increases in oil and natural gas (NG) production throughout the western US have come with scientific and public interest in emission rates, air quality and climate impacts related to this ...industry. This study uses a regional-scale air quality model (WRF-Chem) to simulate high ozone (O3) episodes during the winter of 2013 over the Uinta Basin (UB) in northeastern Utah, which is densely populated by thousands of oil and NG wells. The high-resolution meteorological simulations are able qualitatively to reproduce the wintertime cold pool conditions that occurred in 2013, allowing the model to reproduce the observed multi-day buildup of atmospheric pollutants and the accompanying rapid photochemical ozone formation in the UB. Two different emission scenarios for the oil and NG sector were employed in this study. The first emission scenario (bottom-up) was based on the US Environmental Protection Agency (EPA) National Emission Inventory (NEI) (2011, version 1) for the oil and NG sector for the UB. The second emission scenario (top-down) was based on estimates of methane (CH4) emissions derived from in situ aircraft measurements and a regression analysis for multiple species relative to CH4 concentration measurements in the UB. Evaluation of the model results shows greater underestimates of CH4 and other volatile organic compounds (VOCs) in the simulation with the NEI-2011 inventory than in the case when the top-down emission scenario was used. Unlike VOCs, the NEI-2011 inventory significantly overestimates the emissions of nitrogen oxides (NOx), while the top-down emission scenario results in a moderate negative bias. The model simulation using the top-down emission case captures the buildup and afternoon peaks observed during high O3 episodes. In contrast, the simulation using the bottom-up inventory is not able to reproduce any of the observed high O3 concentrations in the UB. Simple emission reduction scenarios show that O3 production is VOC sensitive and NOx insensitive within the UB. The model results show a disproportionate contribution of aromatic VOCs to O3 formation relative to all other VOC emissions. The model analysis reveals that the major factors driving high wintertime O3 in the UB are shallow boundary layers with light winds, high emissions of VOCs from oil and NG operations compared to NOx emissions, enhancement of photolysis fluxes and reduction of O3 loss from deposition due to snow cover.
From the ensemble of stations that monitor surface air quality over the United States and Europe, we identify extreme ozone pollution events and find that they occur predominantly in clustered, ...multiday episodes with spatial extents of more than 1000 km. Such scales are amenable to forecasting with current global atmospheric chemistry models. We develop an objective mapping algorithm that uses the heterogeneous observations of the individual surface sites to calculate surface ozone averaged over 1° by 1° grid cells, matching the resolution of a global model. Air quality extreme (AQX) events are identified locally as statistical extremes of the ozone climatology and not as air quality exceedances. With the University of California, Irvine chemistry-transport model (UCI CTM) we find there is skill in hindcasting these extreme episodes, and thus identify a new diagnostic using global chemistry-climate models (CCMs) to identify changes in the characteristics of extreme pollution episodes in a warming climate.
We test the current generation of global chemistry-climate models in their ability to simulate observed, present-day surface ozone. Models are evaluated against hourly surface ozone from 4217 ...stations in North America and Europe that are averaged over 1 degree 1 degree grid cells, allowing commensurate model-measurement comparison. Models are generally biased high during all hours of the day and in all regions. Most models simulate the shape of regional summertime diurnal and annual cycles well, correctly matching the timing of hourly (~ 15:00 local time (LT)) and monthly (mid-June) peak surface ozone abundance. The amplitude of these cycles is less successfully matched. The observed summertime diurnal range (~ 25 ppb) is underestimated in all regions by about 7 ppb, and the observed seasonal range (~ 21 ppb) is underestimated by about 5 ppb except in the most polluted regions, where it is overestimated by about 5 ppb. The models generally match the pattern of the observed summertime ozone enhancement, but they overestimate its magnitude in most regions. Most models capture the observed distribution of extreme episode sizes, correctly showing that about 80 % of individual extreme events occur in large-scale, multi-day episodes of more than 100 grid cells. The models also match the observed linear relationship between episode size and a measure of episode intensity, which shows increases in ozone abundance by up to 6 ppb for larger-sized episodes. We conclude that the skill of the models evaluated here provides confidence in their projections of future surface ozone.
The modelling of thermodynamic properties of liquids from local density fluctuations is relevant to many chemical and biological processes. The Kirkwood-Buff (KB) theory connects the microscopic ...structure of isotropic liquids with macroscopic properties such as partial derivatives of activity coefficients, partial molar volumes and compressibilities. Originally, KB integrals were formulated for open and infinite systems which are difficult to access with standard Molecular Dynamics (MD) simulations. Recently, KB integrals for finite and open systems were formulated (J Phys Chem Lett. 2013;4:235). From the scaling of KB integrals for finite subvolumes, embedded in larger reservoirs, with the inverse of the size of these subvolumes, estimates for KB integrals in the thermodynamic limit are obtained. Two system size effects are observed in MD simulations: (1) effects due to the size of the simulation box and the size of the finite subvolume embedded in the simulation box, and (2) effects due to computing radial distribution functions (RDF) from a closed and finite system. In this study, we investigate the two effects in detail by computing KB integrals using the following methods: (1) Monte Carlo simulations of finite subvolumes of a liquid with an analytic RDF and (2) MD simulations of a WCA mixture for various simulation box sizes, but at the same thermodynamic state. We investigate the effect of the size of the simulation box and quantify the differences compared to KB integrals computed in the thermodynamic limit. We demonstrate that calculations of KB integrals should not be extended beyond half the size of the simulation box. For finite-size effects related to the RDF, we find that the Van der Vegt correction (J Chem Theory Comput. 2013;9:1347) yields the most accurate results.
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BFBNIB, GIS, IJS, KISLJ, NUK, PNG, UL, UM, UPUK
In the adult intestine, an organized array of finger-like projections, called villi, provide an enormous epithelial surface area for absorptive function. Villi first emerge at embryonic day (E) 14.5 ...from a previously flat luminal surface. Here, we analyze the cell biology of villus formation and examine the role of paracrine epithelial Hedgehog (Hh) signals in this process. We find that, before villus emergence, tight clusters of Hh-responsive mesenchymal cells form just beneath the epithelium. Cluster formation is dynamic; clusters first form dorsally and anteriorly and spread circumferentially and posteriorly. Statistical analysis of cluster distribution reveals a patterned array; with time, new clusters form in spaces between existing clusters, promoting approximately four rounds of villus emergence by E18.5. Cells within mesenchymal clusters express Patched1 and Gli1, as well as Pdgfrα, a receptor previously shown to participate in villus development. BrdU-labeling experiments show that clusters form by migration and aggregation of Hh-responsive cells. Inhibition of Hh signaling prevents cluster formation and villus development, but does not prevent emergence of villi in areas where clusters have already formed. Conversely, increasing Hh signaling increases the size of villus clusters and results in exceptionally wide villi. We conclude that Hh signals dictate the initial aspects of the formation of each villus by controlling mesenchymal cluster aggregation and regulating cluster size.
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BFBNIB, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
Purpose: Comparison of the antiangiogenic/vascular properties of the oral mammalian target of rapamycin (mTOR) inhibitor RAD001 (everolimus)
and the vascular endothelial growth factor receptor ...(VEGFR) inhibitor vatalanib (PTK/ZK).
Experimental Design: Antiproliferative activity against various tumor histotypes and downstream effects on the mTOR pathway were measured in vitro. In vivo , antitumor activity, plasma, and tumor RAD001 levels were measured. Activity in several different angiogenic/vascular assays
in vitro and in vivo was assessed and compared with PTK/ZK.
Results: RAD001 inhibited proliferation in vitro (IC 50 values <1 nmol/L to >1 μmol/L), and in sensitive and insensitive tumor cells, pS6 kinase and 4E-BP1 were inhibited. Activity
in vitro did not correlate with activity in vivo and significant responses were seen in tumors with IC 50 values >10-fold higher than tumor RAD001 concentrations. In vitro , RAD001 inhibited the proliferation of VEGF-stimulated and fibroblast growth factor-stimulated human endothelial cells but
not dermal fibroblasts and impaired VEGF release from both sensitive and insensitive tumor cells but did not inhibit migration
of human endothelial cells. In vivo , in tumor models derived from either sensitive or insensitive cells, RAD001 reduced Tie-2 levels, the amount of mature and
immature vessels, total plasma, and tumor VEGF. RAD001 did not affect blood vessel leakiness in normal vasculature acutely
exposed to VEGF nor did it affect tumor vascular permeability ( K trans ) as measured by dynamic contrast-enhanced magnetic resonance imaging. However, the pan-VEGFR inhibitor PTK/ZK inhibited endothelial
cell migration and vascular permeability but had less effect on mature vessels compared with RAD001.
Conclusions: VEGFR and mTOR inhibitors show similar but also distinct effects on tumor vascular biology, which has implications for their
clinical activity alone or in combination.
Aerosols that serve as ice nucleating particles (INPs) have the potential to
modulate cloud microphysical properties and can therefore impact cloud
radiative forcing (CRF) and precipitation formation ...processes. In remote
regions such as the Arctic, aerosol–cloud interactions are severely
understudied yet may have significant implications for the surface energy
budget and its impact on sea ice and snow surfaces. Further, uncertainties in
model representations of heterogeneous ice nucleation are a significant
hindrance to simulating Arctic mixed-phase cloud processes. We present
results from a campaign called INPOP (Ice Nucleating Particles at Oliktok
Point), which took place at a US Department of Energy Atmospheric Radiation
Measurement (DOE ARM) facility in the northern Alaskan Arctic. Three time-
and size-resolved aerosol impactors were deployed from 1 March to 31 May 2017
for offline ice nucleation and chemical analyses and were co-located with
routine measurements of aerosol number and size. The largest particles (i.e.,
≥ 3 µm or “coarse mode”) were the most efficient INPs by
inducing freezing at the warmest temperatures. During periods with snow- and
ice-covered surfaces, coarse mode INP concentrations were very low (maximum
of 6 × 10−4 L−1 at −15 ∘C), but higher
concentrations of warm-temperature INPs were observed during late May
(maximum of 2 × 10−2 L−1 at −15 ∘C). These
higher concentrations were attributed to air masses originating from over
open Arctic Ocean water and tundra surfaces. To our knowledge, these results
represent the first INP characterization measurements in an Arctic oilfield
location and demonstrate strong influences from mineral and marine sources
despite the relatively high springtime pollution levels. Ultimately, these
results can be used to evaluate the anthropogenic and natural influences on
aerosol composition and Arctic cloud properties.
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