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The measurements of the production of prompt D0, D+, D∗+, and D+s mesons in proton--proton (pp) collisions at s√=5.02 TeV with the ALICE detector at the Large Hadron Collider (LHC) are reported. D mesons were reconstructed at mid-rapidity (|y|<0.5) via their hadronic decay channels D0→K−π+, D+→K−π+π+, D∗+→D0π+→K−π+π+, D+s→ϕπ+→K+K−π+, and their charge conjugates. The production cross sections were measured in the transverse momentum interval 0<pT<36 GeV/c for D0, 1<pT<36 GeV/c for D+ and D∗+, and in 2<pT<24 GeV/c for D+s mesons. Thanks to the higher integrated luminosity, an analysis in finer pT bins with respect to the previous measurements at s√=7 TeV was performed, allowing for a more detailed description of the cross-section pT shape. The measured pT-differential production cross sections are compared to the results at s√=7 TeV and to four different perturbative QCD calculations. Its rapidity dependence is also tested combining the ALICE and LHCb measurements in pp collisions at s√=5.02 TeV. This measurement will allow for a more accurate determination of the nuclear modification factor in p-Pb and Pb-Pb collisions performed at the same nucleon-nucleon centre-of-mass energy.
Measurements of anisotropic flow coefficients (vn) and their cross-correlations using two- and multi-particle cumulant methods are reported in collisions of pp at s√=13 TeV, p-Pb at sNN−−−√=5.02 TeV, Xe-Xe at sNN−−−√=5.44 TeV, and Pb-Pb at sNN−−−√=5.02 TeV recorded with the ALICE detector. These measurements are performed as a function of multiplicity in the mid-rapidity region |η|<0.8 for the transverse momentum range 0.2<pT<3.0 GeV/c. An ordering of the coefficients v2>v3>v4 is found in pp and p-Pb collisions, similar to that seen in large collision systems, while a weak v2 multiplicity dependence is observed relative to nucleus--nucleus collisions in the same multiplicity range. Using the novel subevent method, v2 measured in pp and p-Pb collisions with four-particle cumulants is found to be compatible with that from six-particle cumulants. The symmetric cumulants SC(m,n) calculated with the subevent method which evaluate the correlation strength between v2n and v2m are also presented. The presented data, which add further support to the existence of long-range multi-particle azimuthal correlations in high multiplicity pp and p-Pb collisions, can neither be described by PYTHIA8 nor by IP-Glasma+MUSIC+UrQMD model calculations, and hence provide new insights into the understanding of collective effects in small collision systems.
Measurements of anisotropic flow coefficients (vn) and their cross-correlations using two- and multi-particle cumulant methods are reported in collisions of pp at s√=13 TeV, p-Pb at sNN−−−√=5.02 TeV, Xe-Xe at sNN−−−√=5.44 TeV, and Pb-Pb at sNN−−−√=5.02 TeV recorded with the ALICE detector. The multiplicity dependence of vn is studied in a very wide range from 20 to 3000 particles produced in the mid-rapidity region |η|<0.8 for the transverse momentum range 0.2<pT<3.0 GeV/c. An ordering of the coefficients v2>v3>v4 is found in pp and p-Pb collisions, similar to that seen in large collision systems, while a weak v2 multiplicity dependence is observed relative to nucleus-nucleus collisions in the same multiplicity range. Using a novel subevent method, v2 measured with four-particle cumulants is found to be compatible with that from six-particle cumulants in pp and p-Pb collisions. The magnitude of the correlation between v2n and v2m, evaluated with the symmetric cumulants SC(m,n) is observed to be positive at all multiplicities for v2 and v4, while for v2 and v3 it is negative and changes sign for multiplicities below 100, which may indicate a different vn fluctuation pattern in this multiplicity range. The observed long-range multi-particle azimuthal correlations in high multiplicity pp and p-Pb collisions can neither be described by PYTHIA 8 nor by IP-Glasma+MUSIC+UrQMD model calculations, and hence provide new insights into the understanding of collective effects in small collision systems.
Measurements of anisotropic flow coefficients (vn) and their cross-correlations using two- and multi-particle cumulant methods are reported in collisions of pp at s√=13 TeV, p-Pb at sNN−−−√=5.02 TeV, Xe-Xe at sNN−−−√=5.44 TeV, and Pb-Pb at sNN−−−√=5.02 TeV recorded with the ALICE detector. These measurements are performed as a function of multiplicity in the mid-rapidity region |η|<0.8 for the transverse momentum range 0.2<pT<3.0 GeV/c. An ordering of the coefficients v2>v3>v4 is found in pp and p-Pb collisions, similar to that seen in large collision systems, while a weak v2 multiplicity dependence is observed relative to nucleus--nucleus collisions in the same multiplicity range. Using the novel subevent method, v2 measured in pp and p-Pb collisions with four-particle cumulants is found to be compatible with that from six-particle cumulants. The symmetric cumulants SC(m,n) calculated with the subevent method which evaluate the correlation strength between v2n and v2m are also presented. The presented data, which add further support to the existence of long-range multi-particle azimuthal correlations in high multiplicity pp and p-Pb collisions, can neither be described by PYTHIA8 nor by IP-Glasma+MUSIC+UrQMD model calculations, and hence provide new insights into the understanding of collective effects in small collision systems.
Size-resolved measurements of atmospheric aerosol and cloud condensation nuclei (CCN) concentrations and hygroscopicity were conducted at the remote Amazon Tall Tower Observatory (ATTO) in the central Amazon Basin over a full seasonal cycle (Mar 2014–Feb 2015). In a companion part 1 paper, we presented an in-depth CCN characterization based on annually as well as seasonally averaged time intervals and discuss different parametrization strategies to represent the Amazonian CCN cycling in modelling studies (M. Pöhlker et al., 2016b). The present part 2 study analyzes the aerosol and CCN variability in original time resolution and, thus, resolves aerosol advection and transformation for the following case studies, which represent the most characteristic states of the Amazonian atmosphere:
1. Near-pristine (NP) conditions, defined as the absence of detectable black carbon (< 0.01 µg m−3), showed their highest occurrence (up to 30 %) in the wet season (i.e., Mar–May). On average, the NP episodes are characterized by a bimodal aerosol size distribution (strong Aitken mode: DAit = 70 nm, NAit = ~ 200 cm−3 vs. weaker accumulation mode: Dacc = 170 nm, Nacc = ~ 60 cm−3), a mostly organic particle composition, and relatively low hygroscopicity levels (κAit = 0.12 vs. κacc = 0.18). The NP CCN efficiency spectrum shows that the CCN population is sensitive to changes in supersaturation (S) over a wide S range.
2. Long-range transport (LRT) conditions frequently mix Saharan dust, African combustion smoke, and sea spray aerosols into the Amazonian wet season atmosphere. The LRT episodes (i.e., Feb–Apr) are characterized by an accumulation mode dominated size distribution (DAit = 80 nm, NAit = 120 cm−3 vs. Dacc = 180 nm, Nacc = 300 cm−3), a clearly increased abundance of dust and salt compounds, and relatively high hygroscopicity levels (κAit = 0.18, κacc = 0.34). The LRT CCN efficiency spectrum shows that the CCN population is highly sensitive to changes in S in the low S regime.
3. Biomass burning (BB) conditions dominate the Amazonian dry season. A selected characteristic BB episode shows a very strong accumulation mode (DAit = 70 nm, NAit = ~ 140 cm−3 vs. Dacc = 170 nm, Nacc = ~ 3400 cm−3), particles with very high organic fractions (> 90 %), and correspondingly low hygroscopicity levels (κAit = 0.14, κacc = 0.17). The BB CCN efficiency spectrum shows that the CCN population is highly sensitive to changes in S in the low S regime.
4. Mixed pollution conditions show the superposition of African (i.e., volcanic) and Amazonian (i.e., biomass burning) aerosol emissions during the dry season. The African aerosols showed a broad monomodal distribution (D = 130 nm, N = ~ 1300 cm−3), with very high sulfate fractions (20 %), and correspondingly high hygroscopicity (κAit = 0.14, κacc = 0.22). This was superimposed by fresh smoke from nearby fires with one strong mode (D = 113 nm, Nacc = ~ 2800 cm−3), an organic-dominated aerosol, and sharply decreased hygroscopicity (κAit = 0.10, κacc = 0.20). These conditions underline the rapidly changing pollution regimes with clear impacts on the aerosol and CCN properties.
Overall, this study provides detailed insights into the CCN cycling in relation to aerosol-cloud interaction in the vulnerable and climate-relevant Amazon region. The detailed analysis of aerosol and CCN key properties and particularly the extracted CCN efficiency spectra with the associated fit parameters provide a basis for an in-depth analysis of aerosol-cloud interaction in the Amazon and beyond.
Size-resolved long-term measurements of atmospheric aerosol and cloud condensation nuclei (CCN) concentrations and hygroscopicity were conducted at the remote Amazon Tall Tower Observatory (ATTO) in the central Amazon Basin over a 1-year period and full seasonal cycle (March 2014–February 2015). The measurements provide a climatology of CCN properties characteristic of a remote central Amazonian rain forest site.
The CCN measurements were continuously cycled through 10 levels of supersaturation (S = 0.11 to 1.10 %) and span the aerosol particle size range from 20 to 245 nm. The mean critical diameters of CCN activation range from 43 nm at S = 1.10 % to 172 nm at S = 0.11 %. The particle hygroscopicity exhibits a pronounced size dependence with lower values for the Aitken mode (κAit = 0.14 ± 0.03), higher values for the accumulation mode (κAcc = 0.22 ± 0.05), and an overall mean value of κmean = 0.17 ± 0.06, consistent with high fractions of organic aerosol.
The hygroscopicity parameter, κ, exhibits remarkably little temporal variability: no pronounced diurnal cycles, only weak seasonal trends, and few short-term variations during long-range transport events. In contrast, the CCN number concentrations exhibit a pronounced seasonal cycle, tracking the pollution-related seasonality in total aerosol concentration. We find that the variability in the CCN concentrations in the central Amazon is mostly driven by aerosol particle number concentration and size distribution, while variations in aerosol hygroscopicity and chemical composition matter only during a few episodes.
For modeling purposes, we compare different approaches of predicting CCN number concentration and present a novel parametrization, which allows accurate CCN predictions based on a small set of input data.
Size-resolved long-term measurements of atmospheric aerosol and cloud condensation nuclei (CCN) concentrations as well as hygroscopicity were conducted at the remote Amazon Tall Tower Observatory (ATTO) in the central Amazon Basin over a one-year period and full seasonal cycle (March 2014 - February 2015). The presented measurements provide a climatology of CCN properties for a characteristic central Amazonian rain forest site.
The CCN measurements were continuously cycled through 10 levels of supersaturation (S = 0.11 to 1.10 %) and span the aerosol particle size range from 20 to 245 nm. The observed mean critical diameters of CCN activation range from 43 nm at S = 1.10 % to 172 nm at S = 0.11 %. The particle hygroscopicity exhibits a pronounced size dependence with lower values for the Aitken mode (κAit = 0.14 ± 0.03), elevated values for the accumulation mode (κAcc = 0.22 ± 0.05), and an overall mean value of κmean = 0.17 ± 0.06, consistent with high fractions of organic aerosol.
The hygroscopicity parameter κ exhibits remarkably little temporal variability: no pronounced diurnal cycles, weak seasonal trends, and few short-term variations during long-range transport events. In contrast, the CCN number concentrations exhibit a pronounced seasonal cycle, tracking the pollution-related seasonality in total aerosol concentration. We find that the variability in the CCN concentrations in the central Amazon is mostly driven by aerosol particle number concentration and size distribution, while variations in aerosol hygroscopicity and chemical composition matter only during a few episodes.
For modelling purposes, we compare different approaches of predicting CCN number concentration and present a novel parameterization, which allows accurate CCN predictions based on a small set of input data.
Background: Alzheimer's disease is a common debilitating dementia with known heritability, for which 20 late onset susceptibility loci have been identified, but more remain to be discovered. This study sought to identify new susceptibility genes, using an alternative gene-wide analytical approach which tests for patterns of association within genes, in the powerful genome-wide association dataset of the International Genomics of Alzheimer's Project Consortium, comprising over 7 m genotypes from 25,580 Alzheimer's cases and 48,466 controls.
Principal findings: In addition to earlier reported genes, we detected genome-wide significant loci on chromosomes 8 (TP53INP1, p = 1.4×10−6) and 14 (IGHV1-67 p = 7.9×10−8) which indexed novel susceptibility loci.
Significance: The additional genes identified in this study, have an array of functions previously implicated in Alzheimer's disease, including aspects of energy metabolism, protein degradation and the immune system and add further weight to these pathways as potential therapeutic targets in Alzheimer's disease.
MKK7 (MEK7) is a key regulator of the JNK stress signaling pathway and targeting MKK7 has been proposed as a chemotherapeutic strategy. Detailed understanding of the MKK7 structure and factors that impact its activity is therefore of critical importance. Here, we present a comprehensive set of MKK7 crystal structures revealing insights into catalytic domain plasticity and the role of the N-terminal regulatory helix, conserved in all MAP2Ks, mediating kinase activation. Crystal structures harboring this regulatory helix revealed typical structural features of active kinase, providing exclusively a first model of the MAP2K active state. A small molecule screening campaign yielded multiple scaffolds, including type-II irreversible inhibitors a binding mode that has not been reported previously. We also observed an unprecedented allosteric pocket located in the N-terminal lobe for the approved drug ibrutinib. Collectively, our structural and functional data expand and provide alternative targeting strategies for this important MAP2K kinase.
DNA methylation profiles of aggressive behavior may capture lifetime cumulative effects of genetic, stochastic, and environmental influences associated with aggression. Here, we report the first large meta-analysis of epigenome-wide association studies (EWAS) of aggressive behavior (N = 15,324 participants). In peripheral blood samples of 14,434 participants from 18 cohorts with mean ages ranging from 7 to 68 years, 13 methylation sites were significantly associated with aggression (alpha = 1.2 × 10−7; Bonferroni correction). In cord blood samples of 2425 children from five cohorts with aggression assessed at mean ages ranging from 4 to 7 years, 83% of these sites showed the same direction of association with childhood aggression (r = 0.74, p = 0.006) but no epigenome-wide significant sites were found. Top-sites (48 at a false discovery rate of 5% in the peripheral blood meta-analysis or in a combined meta-analysis of peripheral blood and cord blood) have been associated with chemical exposures, smoking, cognition, metabolic traits, and genetic variation (mQTLs). Three genes whose expression levels were associated with top-sites were previously linked to schizophrenia and general risk tolerance. At six CpGs, DNA methylation variation in blood mirrors variation in the brain. On average 44% (range = 3–82%) of the aggression–methylation association was explained by current and former smoking and BMI. These findings point at loci that are sensitive to chemical exposures with potential implications for neuronal functions. We hope these results to be a starting point for studies leading to applications as peripheral biomarkers and to reveal causal relationships with aggression and related traits.