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Measurement of electrons from semileptonic heavy-flavor hadron decays in pp collisions at √s = 7 TeV
(2012)
The differential production cross section of electrons from semileptonic heavy-flavour hadron decays has been measured at mid-rapidity (|y|<0.5) in proton-proton collisions at s√=7 TeV with ALICE at the LHC. Electrons were measured in the transverse momentum range 0.5 <pT< 8 GeV/c. Predictions from a fixed order perturbative QCD calculation with next-to-leading-log resummation agree with the data within the theoretical and experimental uncertainties.
Measurement of charm production at central rapidity in proton-proton collisions at √s = 2.76 TeV
(2012)
The pT-differential production cross sections of the prompt (B feed-down subtracted) charmed mesons D0, D+, and D∗+ in the rapidity range |y|<0.5, and for transverse momentum 1<pT<12 GeV/c, were measured in proton-proton collisions at s√=2.76 TeV with the ALICE detector at the Large Hadron Collider. The analysis exploited the hadronic decays D0→Kπ, D+→Kππ, D∗+→D0π, and their charge conjugates, and was performed on a Lint=1.1 nb−1 event sample collected in 2011 with a minimum-bias trigger. The total charm production cross section at s√=2.76 TeV and at 7 TeV was evaluated by extrapolating to the full phase space the pT-differential production cross sections at s√=2.76 TeV and our previous measurements at s√=7 TeV. The results were compared to existing measurements and to perturbative-QCD calculations. The fraction of cdbar D mesons produced in a vector state was also determined.
Major mood disorders, which primarily include bipolar disorder and major depressive disorder, are the leading cause of disability worldwide and pose a major challenge in identifying robust risk genes. Here, we present data from independent large-scale clinical data sets (including 29 557 cases and 32 056 controls) revealing brain expressed protocadherin 17 (PCDH17) as a susceptibility gene for major mood disorders. Single-nucleotide polymorphisms (SNPs) spanning the PCDH17 region are significantly associated with major mood disorders; subjects carrying the risk allele showed impaired cognitive abilities, increased vulnerable personality features, decreased amygdala volume and altered amygdala function as compared with non-carriers. The risk allele predicted higher transcriptional levels of PCDH17 mRNA in postmortem brain samples, which is consistent with increased gene expression in patients with bipolar disorder compared with healthy subjects. Further, overexpression of PCDH17 in primary cortical neurons revealed significantly decreased spine density and abnormal dendritic morphology compared with control groups, which again is consistent with the clinical observations of reduced numbers of dendritic spines in the brains of patients with major mood disorders. Given that synaptic spines are dynamic structures which regulate neuronal plasticity and have crucial roles in myriad brain functions, this study reveals a potential underlying biological mechanism of a novel risk gene for major mood disorders involved in synaptic function and related intermediate phenotypes.
Mutations of the isocitrate dehydrogenase-1 (IDH1) and IDH2 genes are among the most frequent alterations in acute myeloid leukemia (AML) and can be found in ∼20% of patients at diagnosis. Among 4930 patients (median age, 56 years; interquartile range, 45-66) with newly diagnosed, intensively treated AML, we identified IDH1 mutations in 423 (8.6%) and IDH2 mutations in 575 (11.7%). Overall, there were no differences in response rates or survival for patients with mutations in IDH1 or IDH2 compared with patients without mutated IDH1/2. However, distinct clinical and comutational phenotypes of the most common subtypes of IDH1/2 mutations could be associated with differences in outcome. IDH1-R132C was associated with increased age, lower white blood cell (WBC) count, less frequent comutation of NPM1 and FLT3 internal tandem mutation (ITD) as well as with lower rate of complete remission and a trend toward reduced overall survival (OS) compared with other IDH1 mutation variants and wild-type (WT) IDH1/2. In our analysis, IDH2-R172K was associated with significantly lower WBC count, more karyotype abnormalities, and less frequent comutations of NPM1 and/or FLT3-ITD. Among patients within the European LeukemiaNet 2017 intermediate- and adverse-risk groups, relapse-free survival and OS were significantly better for those with IDH2-R172K compared with WT IDH, providing evidence that AML with IDH2-R172K could be a distinct entity with a specific comutation pattern and favorable outcome. In summary, the presented data from a large cohort of patients with IDH1/2 mutated AML indicate novel and clinically relevant findings for the most common IDH mutation subtypes.
The Coulomb Dissociation (CD) cross sections of the stable isotopes 92,94,100Mo and of the unstable isotope 93Mo were measured at the LAND/R3B setup at GSI Helmholtzzentrum für Schwerionenforschung in Darmstadt, Germany. Experimental data on these isotopes may help to explain the problem of the underproduction of 92,94Mo and 96,98Ru in the models of p-process nucleosynthesis. The CD cross sections obtained for the stable Mo isotopes are in good agreement with experiments performed with real photons, thus validating the method of Coulomb Dissociation. The result for the reaction 93Mo(γ,n) is especially important since the corresponding cross section has not been measured before. A preliminary integral Coulomb Dissociation cross section of the 94Mo(γ,n) reaction is presented. Further analysis will complete the experimental database for the (γ,n) production chain of the p-isotopes of molybdenum.
Simple Summary: Acute myeloid leukemia (AML) is a genetically heterogeneous disease. Clinical phenotypes of frequent mutations and their impact on patient outcome are well established. However, the role of rare mutations often remains elusive. We retrospectively analyzed 1529 newly diagnosed and intensively treated AML patients for mutations of BCOR and BCORL1. We report a distinct co-mutational pattern that suggests a role in disease progression rather than initiation, especially affecting mechanisms of DNA-methylation. Further, we found loss-of-function mutations of BCOR to be independent markers of poor outcomes in multivariable analysis. Therefore, loss-of-function mutations of BCOR need to be considered for AML management, as they may influence risk stratification and subsequent treatment allocation.
Abstract: Acute myeloid leukemia (AML) is characterized by recurrent genetic events. The BCL6 corepressor (BCOR) and its homolog, the BCL6 corepressor-like 1 (BCORL1), have been reported to be rare but recurrent mutations in AML. Previously, smaller studies have reported conflicting results regarding impacts on outcomes. Here, we retrospectively analyzed a large cohort of 1529 patients with newly diagnosed and intensively treated AML. BCOR and BCORL1 mutations were found in 71 (4.6%) and 53 patients (3.5%), respectively. Frequently co-mutated genes were DNTM3A, TET2 and RUNX1. Mutated BCORL1 and loss-of-function mutations of BCOR were significantly more common in the ELN2017 intermediate-risk group. Patients harboring loss-of-function mutations of BCOR had a significantly reduced median event-free survival (HR = 1.464 (95%-Confidence Interval (CI): 1.005–2.134), p = 0.047), relapse-free survival (HR = 1.904 (95%-CI: 1.163–3.117), p = 0.01), and trend for reduced overall survival (HR = 1.495 (95%-CI: 0.990–2.258), p = 0.056) in multivariable analysis. Our study establishes a novel role for loss-of-function mutations of BCOR regarding risk stratification in AML, which may influence treatment allocation.
Bipolar disorder (BD) is a highly heritable neuropsychiatric disease characterized by recurrent episodes of mania and depression. BD shows substantial clinical and genetic overlap with other psychiatric disorders, in particular schizophrenia (SCZ). The genes underlying this etiological overlap remain largely unknown. A recent SCZ genome wide association study (GWAS) by the Psychiatric Genomics Consortium identified 128 independent genome-wide significant single nucleotide polymorphisms (SNPs). The present study investigated whether these SCZ-associated SNPs also contribute to BD development through the performance of association testing in a large BD GWAS dataset (9747 patients, 14278 controls). After re-imputation and correction for sample overlap, 22 of 107 investigated SCZ SNPs showed nominal association with BD. The number of shared SCZ-BD SNPs was significantly higher than expected (p = 1.46x10-8). This provides further evidence that SCZ-associated loci contribute to the development of BD. Two SNPs remained significant after Bonferroni correction. The most strongly associated SNP was located near TRANK1, which is a reported genome-wide significant risk gene for BD. Pathway analyses for all shared SCZ-BD SNPs revealed 25 nominally enriched gene-sets, which showed partial overlap in terms of the underlying genes. The enriched gene-sets included calcium- and glutamate signaling, neuropathic pain signaling in dorsal horn neurons, and calmodulin binding. The present data provide further insights into shared risk loci and disease-associated pathways for BD and SCZ. This may suggest new research directions for the treatment and prevention of these two major psychiatric disorders.
The current pandemic situation caused by the Betacoronavirus SARS-CoV-2 (SCoV2) highlights the need for coordinated research to combat COVID-19. A particularly important aspect is the development of medication. In addition to viral proteins, structured RNA elements represent a potent alternative as drug targets. The search for drugs that target RNA requires their high-resolution structural characterization. Using nuclear magnetic resonance (NMR) spectroscopy, a worldwide consortium of NMR researchers aims to characterize potential RNA drug targets of SCoV2. Here, we report the characterization of 15 conserved RNA elements located at the 5′ end, the ribosomal frameshift segment and the 3′-untranslated region (3′-UTR) of the SCoV2 genome, their large-scale production and NMR-based secondary structure determination. The NMR data are corroborated with secondary structure probing by DMS footprinting experiments. The close agreement of NMR secondary structure determination of isolated RNA elements with DMS footprinting and NMR performed on larger RNA regions shows that the secondary structure elements fold independently. The NMR data reported here provide the basis for NMR investigations of RNA function, RNA interactions with viral and host proteins and screening campaigns to identify potential RNA binders for pharmaceutical intervention.
HLA-DRB1 and HLA-DQB1 genetic diversity modulates response to lithium in bipolar affective disorders
(2021)
Bipolar affective disorder (BD) is a severe psychiatric illness, for which lithium (Li) is the gold standard for acute and maintenance therapies. The therapeutic response to Li in BD is heterogeneous and reliable biomarkers allowing patients stratification are still needed. A GWAS performed by the International Consortium on Lithium Genetics (ConLiGen) has recently identified genetic markers associated with treatment responses to Li in the human leukocyte antigens (HLA) region. To better understand the molecular mechanisms underlying this association, we have genetically imputed the classical alleles of the HLA region in the European patients of the ConLiGen cohort. We found our best signal for amino-acid variants belonging to the HLA-DRB1*11:01 classical allele, associated with a better response to Li (p < 1 × 10−3; FDR < 0.09 in the recessive model). Alanine or Leucine at position 74 of the HLA-DRB1 heavy chain was associated with a good response while Arginine or Glutamic acid with a poor response. As these variants have been implicated in common inflammatory/autoimmune processes, our findings strongly suggest that HLA-mediated low inflammatory background may contribute to the efficient response to Li in BD patients, while an inflammatory status overriding Li anti-inflammatory properties would favor a weak response.
1H, 13C and 15N chemical shift assignment of the stem-loops 5b + c from the 5′-UTR of SARS-CoV-2
(2022)
The ongoing pandemic of the respiratory disease COVID-19 is caused by the SARS-CoV-2 (SCoV2) virus. SCoV2 is a member of the Betacoronavirus genus. The 30 kb positive sense, single stranded RNA genome of SCoV2 features 5′- and 3′-genomic ends that are highly conserved among Betacoronaviruses. These genomic ends contain structured cis-acting RNA elements, which are involved in the regulation of viral replication and translation. Structural information about these potential antiviral drug targets supports the development of novel classes of therapeutics against COVID-19. The highly conserved branched stem-loop 5 (SL5) found within the 5′-untranslated region (5′-UTR) consists of a basal stem and three stem-loops, namely SL5a, SL5b and SL5c. Both, SL5a and SL5b feature a 5′-UUUCGU-3′ hexaloop that is also found among Alphacoronaviruses. Here, we report the extensive 1H, 13C and 15N resonance assignment of the 37 nucleotides (nts) long sequence spanning SL5b and SL5c (SL5b + c), as basis for further in-depth structural studies by solution NMR spectroscopy.
Significant reductions in stratospheric ozone occur inside the polar vortices each spring when chlorine radicals produced by heterogeneous reactions on cold particle surfaces in winter destroy ozone mainly in two catalytic cycles, the ClO dimer cycle and the ClO/BrO cycle. Chlorofluorocarbons (CFCs), which are responsible for most of the chlorine currently present in the stratosphere, have been banned by the Montreal Protocol and its amendments, and the ozone layer is predicted to recover to 1980 levels within the next few decades. During the same period, however, climate change is expected to alter the temperature, circulation patterns and chemical composition in the stratosphere, and possible geo-engineering ventures to mitigate climate change may lead to additional changes. To realistically predict the response of the ozone layer to such influences requires the correct representation of all relevant processes. The European project RECONCILE has comprehensively addressed remaining questions in the context of polar ozone depletion, with the objective to quantify the rates of some of the most relevant, yet still uncertain physical and chemical processes. To this end RECONCILE used a broad approach of laboratory experiments, two field missions in the Arctic winter 2009/10 employing the high altitude research aircraft M55-Geophysica and an extensive match ozone sonde campaign, as well as microphysical and chemical transport modelling and data assimilation. Some of the main outcomes of RECONCILE are as follows: (1) vortex meteorology: the 2009/10 Arctic winter was unusually cold at stratospheric levels during the six-week period from mid-December 2009 until the end of January 2010, with reduced transport and mixing across the polar vortex edge; polar vortex stability and how it is influenced by dynamic processes in the troposphere has led to unprecedented, synoptic-scale stratospheric regions with temperatures below the frost point; in these regions stratospheric ice clouds have been observed, extending over >106km2 during more than 3 weeks. (2) Particle microphysics: heterogeneous nucleation of nitric acid trihydrate (NAT) particles in the absence of ice has been unambiguously demonstrated; conversely, the synoptic scale ice clouds also appear to nucleate heterogeneously; a variety of possible heterogeneous nuclei has been characterised by chemical analysis of the non-volatile fraction of the background aerosol; substantial formation of solid particles and denitrification via their sedimentation has been observed and model parameterizations have been improved. (3) Chemistry: strong evidence has been found for significant chlorine activation not only on polar stratospheric clouds (PSCs) but also on cold binary aerosol; laboratory experiments and field data on the ClOOCl photolysis rate and other kinetic parameters have been shown to be consistent with an adequate degree of certainty; no evidence has been found that would support the existence of yet unknown chemical mechanisms making a significant contribution to polar ozone loss. (4) Global modelling: results from process studies have been implemented in a prognostic chemistry climate model (CCM); simulations with improved parameterisations of processes relevant for polar ozone depletion are evaluated against satellite data and other long term records using data assimilation and detrended fluctuation analysis. Finally, measurements and process studies within RECONCILE were also applied to the winter 2010/11, when special meteorological conditions led to the highest chemical ozone loss ever observed in the Arctic. In addition to quantifying the 2010/11 ozone loss and to understand its causes including possible connections to climate change, its impacts were addressed, such as changes in surface ultraviolet (UV) radiation in the densely populated northern mid-latitudes.
The international research project RECONCILE has addressed central questions regarding polar ozone depletion, with the objective to quantify some of the most relevant yet still uncertain physical and chemical processes and thereby improve prognostic modelling capabilities to realistically predict the response of the ozone layer to climate change. This overview paper outlines the scope and the general approach of RECONCILE, and it provides a summary of observations and modelling in 2010 and 2011 that have generated an in many respects unprecedented dataset to study processes in the Arctic winter stratosphere. Principally, it summarises important outcomes of RECONCILE including (i) better constraints and enhanced consistency on the set of parameters governing catalytic ozone destruction cycles, (ii) a better understanding of the role of cold binary aerosols in heterogeneous chlorine activation, (iii) an improved scheme of polar stratospheric cloud (PSC) processes that includes heterogeneous nucleation of nitric acid trihydrate (NAT) and ice on non-volatile background aerosol leading to better model parameterisations with respect to denitrification, and (iv) long transient simulations with a chemistry-climate model (CCM) updated based on the results of RECONCILE that better reproduce past ozone trends in Antarctica and are deemed to produce more reliable predictions of future ozone trends. The process studies and the global simulations conducted in RECONCILE show that in the Arctic, ozone depletion uncertainties in the chemical and microphysical processes are now clearly smaller than the sensitivity to dynamic variability.
Bipolar disorder (BD) is a heritable mental illness with complex etiology. While the largest published genome-wide association study identified 64 BD risk loci, the causal SNPs and genes within these loci remain unknown. We applied a suite of statistical and functional fine-mapping methods to these loci, and prioritized 22 likely causal SNPs for BD. We mapped these SNPs to genes, and investigated their likely functional consequences by integrating variant annotations, brain cell-type epigenomic annotations, brain quantitative trait loci, and results from rare variant exome sequencing in BD. Convergent lines of evidence supported the roles of SCN2A, TRANK1, DCLK3, INSYN2B, SYNE1, THSD7A, CACNA1B, TUBBP5, PLCB3, PRDX5, KCNK4, AP001453.3, TRPT1, FKBP2, DNAJC4, RASGRP1, FURIN, FES, YWHAE, DPH1, GSDMB, MED24, THRA, EEF1A2, and KCNQ2 in BD. These represent promising candidates for functional experiments to understand biological mechanisms and therapeutic potential. Additionally, we demonstrated that fine-mapping effect sizes can improve performance and transferability of BD polygenic risk scores across ancestrally diverse populations, and present a high-throughput fine-mapping pipeline (https://github.com/mkoromina/SAFFARI).
Bipolar disorder (BD) is a genetically complex mental illness characterized by severe oscillations of mood and behavior. Genome-wide association studies (GWAS) have identified several risk loci that together account for a small portion of the heritability. To identify additional risk loci, we performed a two-stage meta-analysis of >9 million genetic variants in 9,784 bipolar disorder patients and 30,471 controls, the largest GWAS of BD to date. In this study, to increase power we used ~2,000 lithium-treated cases with a long-term diagnosis of BD from the Consortium on Lithium Genetics, excess controls, and analytic methods optimized for markers on the Xchromosome. In addition to four known loci, results revealed genome-wide significant associations at two novel loci: an intergenic region on 9p21.3 (rs12553324, p = 5.87×10-9; odds ratio = 1.12) and markers within ERBB2 (rs2517959, p = 4.53×10-9; odds ratio = 1.13). No significant X-chromosome associations were detected and X-linked markers explained very little BD heritability. The results add to a growing list of common autosomal variants involved in BD and illustrate the power of comparing well-characterized cases to an excess of controls in GWAS.
The ALICE experiment has measured low-mass dimuon production in pp collisions at √s=7 TeV in the dimuon rapidity region 2.5<y<4. The observed dimuon mass spectrum is described as a superposition of resonance decays (η,ρ,ω,η′,ϕ) into muons and semi-leptonic decays of charmed mesons. The measured production cross sections for ω and ϕ are σω(1<pt<5 GeV/c,2.5<y<4)=5.28±0.54(stat)±0.49(syst) mb and σϕ(1<pt<5 GeV/c,2.5<y<4)=0.940±0.084(stat)±0.076(syst) mb. The differential cross sections d2σ/dydpt are extracted as a function of pt for ω and ϕ. The ratio between the ρ and ω cross section is obtained. Results for the ϕ are compared with other measurements at the same energy and with predictions by models.
The ALICE Collaboration reports the measurement of the relative J/ψ yield as a function of charged particle pseudorapidity density dNch/dη in pp collisions at √s=7 TeV at the LHC. J/ψ particles are detected for pt>0, in the rapidity interval |y|<0.9 via decay into e+e−, and in the interval 2.5<y<4.0 via decay into μ+μ− pairs. An approximately linear increase of the J/ψ yields normalized to their event average (dNJ/ψ/dy)/〈dNJ/ψ/dy〉 with (dNch/dη)/〈dNch/dη〉 is observed in both rapidity ranges, where dNch/dη is measured within |η|<1 and pt>0. In the highest multiplicity interval with 〈dNch/dη(bin)〉=24.1, corresponding to four times the minimum bias multiplicity density, an enhancement relative to the minimum bias J/ψ yield by a factor of about 5 at 2.5<y<4 (8 at |y|<0.9) is observed.
he first measurements of the invariant differential cross sections of inclusive π0 and η meson production at mid-rapidity in proton–proton collisions at s=0.9 TeV and s=7 TeV are reported. The π0 measurement covers the ranges 0.4<pT<7 GeV/c and 0.3<pT<25 GeV/c for these two energies, respectively. The production of η mesons was measured at s=√7 TeV in the range 0.4<pT<15 GeV/c. Next-to-Leading Order perturbative QCD calculations, which are consistent with the π0 spectrum at s=0.9 TeV, overestimate those of π0 and η mesons at s=√7 TeV, but agree with the measured η/π0 ratio at s=√7 TeV.
The first measurement of two-pion Bose–Einstein correlations in central Pb–Pb collisions at √sNN=2.76 TeV at the Large Hadron Collider is presented. We observe a growing trend with energy now not only for the longitudinal and the outward but also for the sideward pion source radius. The pion homogeneity volume and the decoupling time are significantly larger than those measured at RHIC.
Harmonic decomposition of two particle angular correlations in Pb–Pb collisions at √sNN=2.76 TeV
(2012)
Angular correlations between unidentified charged trigger (t) and associated (a) particles are measured by the ALICE experiment in Pb–Pb collisions at √sNN=2.76 TeV for transverse momenta 0.25<pTt,a<15 GeV/c, where pTt>pTa. The shapes of the pair correlation distributions are studied in a variety of collision centrality classes between 0 and 50% of the total hadronic cross section for particles in the pseudorapidity interval |η|<1.0. Distributions in relative azimuth Δϕ≡ϕt−ϕa are analyzed for |Δη|≡|ηt−ηa|>0.8, and are referred to as “long-range correlations”. Fourier components VnΔ≡〈cos(nΔϕ)〉 are extracted from the long-range azimuthal correlation functions. If particle pairs are correlated to one another through their individual correlation to a common symmetry plane, then the pair anisotropy VnΔ(pTt,pTa) is fully described in terms of single-particle anisotropies vn(pT) as VnΔ(pTt,pTa)=vn(pTt)vn(pTa). This expectation is tested for 1⩽n⩽5 by applying a global fit of all VnΔ(pTt,pTa) to obtain the best values vn{GF}(pT). It is found that for 2⩽n⩽5, the fit agrees well with data up to pTa∼3–4 GeV/c, with a trend of increasing deviation as pTt and pTa are increased or as collisions become more peripheral. This suggests that no pair correlation harmonic can be described over the full 0.25<pT<15 GeV/c range using a single vn(pT) curve; such a description is however approximately possible for 2⩽n⩽5 when pTa<4 GeV/c. For the n=1 harmonic, however, a single v1(pT) curve is not obtained even within the reduced range pTa<4 GeV/c.
The ALICE Collaboration has measured inclusive J/ψ production in pp collisions at a center-of-mass energy √s=2.76 TeV at the LHC. The results presented in this Letter refer to the rapidity ranges |y|<0.9 and 2.5<y<4 and have been obtained by measuring the electron and muon pair decay channels, respectively. The integrated luminosities for the two channels are Linte=1.1 nb−1 and Lintμ=19.9 nb−1, and the corresponding signal statistics are NJ/ψe+e−=59±14 and NJ/ψμ+μ−=1364±53. We present dσJ/ψ/dy for the two rapidity regions under study and, for the forward-y range, d2σJ/ψ/dydpt in the transverse momentum domain 0<pt<8 GeV/c. The results are compared with previously published results at s=7 TeV and with theoretical calculations.
Rapidity and transverse momentum dependence of inclusive J/ψ production in pp collisions at √s=7 TeV
(2011)
The ALICE experiment at the LHC has studied inclusive J/ψ production at central and forward rapidities in pp collisions at √s=7 TeV. In this Letter, we report on the first results obtained detecting the J/ψ through the dilepton decay into e+e− and μ+μ− pairs in the rapidity ranges |y|<0.9 and 2.5<y<4, respectively, and with acceptance down to zero pT. In the dielectron channel the analysis was carried out on a data sample corresponding to an integrated luminosity Lint=5.6 nb−1 and the number of signal events is NJ/ψ=352±32(stat.)±28(syst.); the corresponding figures in the dimuon channel are Lint=15.6 nb−1 and NJ/ψ=1924±77(stat.)±144(syst.). The measured production cross sections are σJ/ψ(|y|<0.9)=10.7±1.0(stat.)±1.6(syst.)−2.3+1.6(syst.pol.)μb and σJ/ψ(2.5<y<4)=6.31±0.25(stat.)±0.76(syst.)−1.96+0.95(syst.pol.)μb. The differential cross sections, in transverse momentum and rapidity, of the J/ψ were also measured.
A measurement of the multi-strange Ξ− and Ω− baryons and their antiparticles by the ALICE experiment at the CERN Large Hadron Collider (LHC) is presented for inelastic proton–proton collisions at a centre-of-mass energy of 7 TeV. The transverse momentum (pT) distributions were studied at mid-rapidity (|y|<0.5) in the range of 0.6<pT<8.5 GeV/c for Ξ− and Ξ¯+ baryons, and in the range of 0.8<pT<5 GeV/c for Ω− and Ω¯+. Baryons and antibaryons were measured as separate particles and we find that the baryon to antibaryon ratio of both particle species is consistent with unity over the entire range of the measurement. The statistical precision of the current data has allowed us to measure a difference between the mean pT of Ξ− (Ξ¯+) and Ω− (Ω¯+). Particle yields, mean pT, and the spectra in the intermediate pT range are not well described by the PYTHIA Perugia 2011 tune Monte Carlo event generator, which has been tuned to reproduce the early LHC data. The discrepancy is largest for Ω− (Ω¯+). This PYTHIA tune approaches the pT spectra of Ξ− and Ξ¯+ baryons below pT<0.85 GeV/c and describes the Ξ− and Ξ¯+ spectra above pT>6.0 GeV/c. We also illustrate the difference between the experimental data and model by comparing the corresponding ratios of (Ω−+Ω¯+)/(Ξ−+Ξ¯+) as a function of transverse mass.
Heavy flavour decay muon production at forward rapidity in proton–proton collisions at √s=7 TeV
(2012)
The production of muons from heavy flavour decays is measured at forward rapidity in proton–proton collisions at √s=7 TeV collected with the ALICE experiment at the LHC. The analysis is carried out on a data sample corresponding to an integrated luminosity Lint=16.5 nb−1. The transverse momentum and rapidity differential production cross sections of muons from heavy flavour decays are measured in the rapidity range 2.5<y<4, over the transverse momentum range 2<pt<12 GeV/c. The results are compared to predictions based on perturbative QCD calculations.
The ALICE Zero Degree Calorimeter system (ZDC) is composed of two identical sets of calorimeters, placed at opposite sides with respect to the interaction point, 114 meters away from it, complemented by two small forward electromagnetic calorimeters (ZEM). Each set of detectors consists of a neutron (ZN) and a proton (ZP) ZDC. They are placed at zero degrees with respect to the LHC axis and allow to detect particles emitted close to beam direction, in particular neutrons and protons emerging from hadronic heavy-ion collisions (spectator nucleons) and those emitted from electromagnetic processes. For neutrons emitted by these two processes, the ZN calorimeters have nearly 100% acceptance.
During the √sNN = 2.76 TeV Pb-Pb data-taking, the ALICE Collaboration studied forward neutron emission with a dedicated trigger, requiring a minimum energy deposition in at least one of the two ZN. By exploiting also the information of the two ZEM calorimeters it has been possible to separate the contributions of electromagnetic and hadronic processes and to study single neutron vs. multiple neutron emission.
The measured cross sections of single and mutual electromagnetic dissociation of Pb nuclei at √sNN = 2.76 TeV, with neutron emission, are σsingle EMD = 187:4 ± 0.2 (stat.)−11.2+13.2 (syst.) b and σmutual EMD = 5.7 ± 0.1 (stat.) ±0.4 (syst.) b, respectively [1]. This is the first measurement of electromagnetic dissociation of 208Pb nuclei at the LHC energies, allowing a test of electromagnetic dissociation theory in a new energy regime. The experimental results are compared to the predictions from a relativistic electromagnetic dissociation model.
Inclusive transverse momentum spectra of primary charged particles in Pb–Pb collisions at √sNN=2.76 TeV have been measured by the ALICE Collaboration at the LHC. The data are presented for central and peripheral collisions, corresponding to 0–5% and 70–80% of the hadronic Pb–Pb cross section. The measured charged particle spectra in |η|<0.8 and 0.3<pT<20 GeV/c are compared to the expectation in pp collisions at the same sNN, scaled by the number of underlying nucleon–nucleon collisions. The comparison is expressed in terms of the nuclear modification factor RAA. The result indicates only weak medium effects (RAA≈0.7) in peripheral collisions. In central collisions, RAA reaches a minimum of about 0.14 at pT=6–7 GeV/c and increases significantly at larger pT. The measured suppression of high-pT particles is stronger than that observed at lower collision energies, indicating that a very dense medium is formed in central Pb–Pb collisions at the LHC.
Measurements of the sphericity of primary charged particles in minimum bias proton--proton collisions at s√=0.9, 2.76 and 7 TeV with the ALICE detector at the LHC are presented. The observable is linearized to be collinear safe and is measured in the plane perpendicular to the beam direction using primary charged tracks with pT≥0.5 GeV/c in |η|≤0.8. The mean sphericity as a function of the charged particle multiplicity at mid-rapidity (Nch) is reported for events with different pT scales ("soft" and "hard") defined by the transverse momentum of the leading particle. In addition, the mean charged particle transverse momentum versus multiplicity is presented for the different event classes, and the sphericity distributions in bins of multiplicity are presented. The data are compared with calculations of standard Monte Carlo event generators. The transverse sphericity is found to grow with multiplicity at all collision energies, with a steeper rise at low Nch, whereas the event generators show the opposite tendency. The combined study of the sphericity and the mean pT with multiplicity indicates that most of the tested event generators produce events with higher multiplicity by generating more back-to-back jets resulting in decreased sphericity (and isotropy). The PYTHIA6 generator with tune PERUGIA-2011 exhibits a noticeable improvement in describing the data, compared to the other tested generators.
Suppression of high transverse momentum D mesons in central Pb-Pb collisions at √sNN = 2.76 TeV
(2012)
The production of the prompt charm mesons D0, D+, D∗+, and their antiparticles, was measured with the ALICE detector in Pb-Pb collisions at the LHC, at a centre-of-mass energy sNN−−−−√=2.76 TeV per nucleon--nucleon collision. The pT-differential production yields in the range 2<pT<16 GeV/c at central rapidity, |y|<0.5, were used to calculate the nuclear modification factor RAA with respect to a proton-proton reference obtained from the cross section measured at s√=7 TeV and scaled to s√=2.76 TeV. For the three meson species, RAA shows a suppression by a factor 3-4, for transverse momenta larger than 5 GeV/c in the 20% most central collisions. The suppression is reduced for peripheral collisions.
The ALICE experiment has measured the inclusive J/ψ production in Pb-Pb collisions at sNN−−−√=2.76 TeV down to zero transverse momentum in the rapidity range 2.5<y<4. A suppression of the inclusive J/ψ yield in Pb-Pb is observed with respect to the one measured in pp collisions scaled by the number of binary nucleon-nucleon collisions. The nuclear modification factor, integrated over the 0-80% most central collisions, is 0.545±0.032(stat.)±0.083(syst.) and does not exhibit a significant dependence on the collision centrality. These features appear significantly different from measurements at lower collision energies. Models including J/ψ production from charm quarks in a deconfined partonic phase can describe our data.
The ALICE experiment has measured the inclusive J/psi production in Pb-Pb collisions at sqrt(sNN) = 2.76 TeV down to zero transverse momentum in the rapidity range 2.5 < y < 4. A suppression of the inclusive J/psi yield in Pb-Pb is observed with respect to the one measured in pp collisions scaled by the number of binary nucleon-nucleon collisions. The nuclear modification factor, integrated over the 0%-80% most central collisions, is 0.545+/-0.032(stat)+/-0.083(syst) and does not exhibit a significant dependence on the collision centrality. These features appear significantly different from measurements at lower collision energies. Models including J/psi production from charm quarks in a deconfined partonic phase can describe our data.
The ALICE experiment has measured the inclusive J/ψ production in Pb-Pb collisions at sNN−−−√=2.76 TeV down to zero transverse momentum in the rapidity range 2.5<y<4. A suppression of the inclusive J/ψ yield in Pb-Pb is observed with respect to the one measured in pp collisions scaled by the number of binary nucleon-nucleon collisions. The nuclear modification factor, integrated over the 0-80% most central collisions, is 0.545±0.032(stat.)±0.083(syst.) and does not exhibit a significant dependence on the collision centrality. These features appear significantly different from measurements at lower collision energies. Models including J/ψ production from charm quarks in a deconfined partonic phase can describe our data.
The ALICE experiment has measured the inclusive J/psi production in Pb-Pb collisions at sqrt(sNN) = 2.76 TeV down to pt = 0 in the rapidity range 2.5 < y < 4. A suppression of the inclusive J/psi yield in Pb-Pb is observed with respect to the one measured in pp collisions scaled by the number of binary nucleon-nucleon collisions. The nuclear modification factor, integrated over the 0%-80% most central collisions, is 0.545 +/- 0.032 (stat.) +/- 0.084 (syst.) and does not exhibit a significant dependence on the collision centrality. These features appear significantly different from lower energy measurements. Models including J/psi production from charm quarks in a deconfined partonic phase can describe our data.
In psychiatry, there has been a growing focus on identifying at-risk populations. For schizophrenia, these efforts have led to the development of early recognition and intervention measures. Despite a similar disease burden, the populations at risk of bipolar disorder have not been sufficiently characterized. Within the BipoLife consortium, we used magnetic resonance imaging (MRI) data from a multicenter study to assess structural gray matter alterations in N = 263 help-seeking individuals from seven study sites. We defined the risk using the EPIbipolar assessment tool as no-risk, low-risk, and high-risk and used a region-of-interest approach (ROI) based on the results of two large-scale multicenter studies of bipolar disorder by the ENIGMA working group. We detected significant differences in the thickness of the left pars opercularis (Cohen’s d = 0.47, p = 0.024) between groups. The cortex was significantly thinner in high-risk individuals compared to those in the no-risk group (p = 0.011). We detected no differences in the hippocampal volume. Exploratory analyses revealed no significant differences in other cortical or subcortical regions. The thinner cortex in help-seeking individuals at risk of bipolar disorder is in line with previous findings in patients with the established disorder and corresponds to the region of the highest effect size in the ENIGMA study of cortical alterations. Structural alterations in prefrontal cortex might be a trait marker of bipolar risk. This is the largest structural MRI study of help-seeking individuals at increased risk of bipolar disorder.
The highly infectious disease COVID-19 caused by the Betacoronavirus SARS-CoV-2 poses a severe threat to humanity and demands the redirection of scientific efforts and criteria to organized research projects. The international COVID19-NMR consortium seeks to provide such new approaches by gathering scientific expertise worldwide. In particular, making available viral proteins and RNAs will pave the way to understanding the SARS-CoV-2 molecular components in detail. The research in COVID19-NMR and the resources provided through the consortium are fully disclosed to accelerate access and exploitation. NMR investigations of the viral molecular components are designated to provide the essential basis for further work, including macromolecular interaction studies and high-throughput drug screening. Here, we present the extensive catalog of a holistic SARS-CoV-2 protein preparation approach based on the consortium’s collective efforts. We provide protocols for the large-scale production of more than 80% of all SARS-CoV-2 proteins or essential parts of them. Several of the proteins were produced in more than one laboratory, demonstrating the high interoperability between NMR groups worldwide. For the majority of proteins, we can produce isotope-labeled samples of HSQC-grade. Together with several NMR chemical shift assignments made publicly available on covid19-nmr.com, we here provide highly valuable resources for the production of SARS-CoV-2 proteins in isotope-labeled form.
The inclusive charged particle transverse momentum distribution is measured in proton–proton collisions at s=900 GeV at the LHC using the ALICE detector. The measurement is performed in the central pseudorapidity region (|η|<0.8) over the transverse momentum range 0.15<pT<10 GeV/c. The correlation between transverse momentum and particle multiplicity is also studied. Results are presented for inelastic (INEL) and non-single-diffractive (NSD) events. The average transverse momentum for |η|<0.8 is 〈pT〉INEL=0.483±0.001 (stat.)±0.007 (syst.) GeV/c and 〈pT〉NSD=0.489±0.001 (stat.)±0.007 (syst.) GeV/c, respectively. The data exhibit a slightly larger 〈pT〉 than measurements in wider pseudorapidity intervals. The results are compared to simulations with the Monte Carlo event generators PYTHIA and PHOJET.
Quasifree one-proton knockout reactions have been employed in inverse kinematics for a systematic study of the structure of stable and exotic oxygen isotopes at the R3B/LAND setup with incident beam energies in the range of 300–450 MeV/u. The oxygen isotopic chain offers a large variation of separation energies that allows for a quantitative understanding of single-particle strength with changing isospin asymmetry. Quasifree knockout reactions provide a complementary approach to intermediate-energy one-nucleon removal reactions. Inclusive cross sections for quasifree knockout reactions of the type AO(p,2p)A−1N have been determined and compared to calculations based on the eikonal reaction theory. The reduction factors for the single-particle strength with respect to the independent-particle model were obtained and compared to state-of-the-art ab initio predictions. The results do not show any significant dependence on proton-neutron asymmetry.
The neutron-unbound isotope 13Be has been studied in several experiments using different reactions, different projectile energies, and different experimental setups. There is, however, no real consensus in the interpretation of the data, in particular concerning the structure of the low-lying excited states. Gathering new experimental information, which may reveal the 13Be structure, is a challenge, particularly in light of its bridging role between 12Be, where the N = 8 neutron shell breaks down, and the Borromean halo nucleus 14Be. The purpose of the present study is to investigate the role of bound excited states in the reaction product 12Be after proton knockout from 14B, by measuring coincidences between 12Be, neutrons, and γ rays originating from de-excitation of states fed by neutron decay of 13Be. The 13Be isotopes were produced in proton knockout from a 400 MeV/nucleon 14B beam impinging on a CH2 target. The 12 Be-n relative-energy spectrum d σ /d Ef n was obtained from coincidences between 12Be(g.s.) and a neutron, and also as threefold coincidences by adding γ rays, from the de-excitation of excited states in 12Be. Neutron decay from the first 5/2+ state in 13Be to the 2+ state in 12Be at 2.11 MeV is confirmed. An energy independence of the proton-knockout mechanism is found from a comparison with data taken with a 35 MeV/nucleon 14B beam. A low-lying p-wave resonance in 13Be(1/2−) is confirmed by comparing proton- and neutron-knockout data from 14B and 14Be.
Tolerizing CTL by sustained hepatic PD-L1 expression provides a new therapy spproach in mouse sepsis
(2019)
Cytotoxic T lymphocyte (CTL) activation contributes to liver damage during sepsis, but the mechanisms involved are largely unknown. Understanding the underlying principle will permit interference with CTL activation and thus, provide a new therapeutic option.
Methods: To elucidate the mechanism leading to CTL activation we used the Hepa1-6 cell line in vitro and the mouse model of in vivo polymicrobial sepsis, following cecal-ligation and -puncture (CLP) in wildtype, myeloid specific NOX-2, global NOX2 and NOX4 knockout mice, and their survival as a final readout. In this in vivo setting, we also determined hepatic mRNA and protein expression as well as clinical parameters of liver damage - aspartate- and alanine amino-transaminases. Hepatocyte specific overexpression of PD-L1 was achieved in vivo by adenoviral infection and transposon-based gene transfer using hydrodynamic injection.
Results: We observed downregulation of PD-L1 on hepatocytes in the murine sepsis model. Adenoviral and transposon-based gene transfer to restore PD-L1 expression, significantly improved survival and reduced the release of liver damage, as PD-L1 is a co-receptor that negatively regulates T cell function. Similar protection was observed during pharmacological intervention using recombinant PD-L1-Fc. N-acetylcysteine blocked the downregulation of PD-L1 suggesting the involvement of reactive oxygen species. This was confirmed in vivo, as we observed significant upregulation of PD-L1 expression in NOX4 knockout mice, following sham operation, whereas its expression in global as well as myeloid lineage NOX2 knockout mice was comparable to that in the wild type animals. PD-L1 expression remained high following CLP only in total NOX2 knockouts, resulting in significantly reduced release of liver damage markers.
Conclusion: These results suggest that, contrary to common assumption, maintaining PD-L1 expression on hepatocytes improves liver damage and survival of mice during sepsis. We conclude that administering recombinant PD-L1 or inhibiting NOX2 activity might offer a new therapeutic option in sepsis.
During winter 2015/2016, the Arctic stratosphere was characterized by extraordinarily low temperatures in connection with a very strong polar vortex and with the occurrence of extensive polar stratospheric clouds. From mid-December 2015 until mid-March 2016, the German research aircraft HALO (High Altitude and Long-Range Research Aircraft) was deployed to probe the lowermost stratosphere in the Arctic region within the POLSTRACC (Polar Stratosphere in a Changing Climate) mission. More than 20 flights have been conducted out of Kiruna, Sweden, and Oberpfaffenhofen, Germany, covering the whole winter period. Besides total reactive nitrogen (NOy), observations of nitrous oxide, nitric acid, ozone, and water were used for this study. Total reactive nitrogen and its partitioning between the gas and particle phases are key parameters for understanding processes controlling the ozone budget in the polar winter stratosphere. The vertical redistribution of total reactive nitrogen was evaluated by using tracer–tracer correlations (NOy–N2O and NOy–O3). The trace gases are well correlated as long as the NOy distribution is controlled by its gas-phase production from N2O. Deviations of the observed NOy from this correlation indicate the influence of heterogeneous processes. In early winter no such deviations have been observed. In January, however, air masses with extensive nitrification were encountered at altitudes between 12 and 15 km. The excess NOy amounted to about 6 ppb. During several flights, along with gas-phase nitrification, indications for extensive occurrence of nitric acid containing particles at flight altitude were found. These observations support the assumption of sedimentation and subsequent evaporation of nitric acid-containing particles, leading to redistribution of total reactive nitrogen at lower altitudes. Remnants of nitrified air masses have been observed until mid-March. Between the end of February and mid-March, denitrified air masses have also been observed in connection with high potential temperatures. This indicates the downward transport of air masses that have been denitrified during the earlier winter phase. Using tracer–tracer correlations, missing total reactive nitrogen was estimated to amount to 6 ppb. Further, indications of transport and mixing of these processed air masses outside the vortex have been found, contributing to the chemical budget of the winter lowermost stratosphere. Observations within POLSTRACC, at the bottom of the vortex, reflect heterogeneous processes from the overlying Arctic winter stratosphere. The comparison of the observations with CLaMS model simulations confirm and complete the picture arising from the present measurements. The simulations confirm that the ensemble of all observations is representative of the vortex-wide vertical NOy redistribution.
Large-scale molecular profiling studies in recent years have shown that central nervous system (CNS) tumors display a much greater heterogeneity in terms of molecularly distinct entities, cellular origins and genetic drivers than anticipated from histological assessment. DNA methylation profiling has emerged as a useful tool for robust tumor classification, providing new insights into these heterogeneous molecular classes. This is particularly true for rare CNS tumors with a broad morphological spectrum, which are not possible to assign as separate entities based on histological similarity alone. Here, we describe a molecularly distinct subset of predominantly pediatric CNS neoplasms (n = 60) that harbor PATZ1 fusions. The original histological diagnoses of these tumors covered a wide spectrum of tumor types and malignancy grades. While the single most common diagnosis was glioblastoma (GBM), clinical data of the PATZ1-fused tumors showed a better prognosis than typical GBM, despite frequent relapses. RNA sequencing revealed recurrent MN1:PATZ1 or EWSR1:PATZ1 fusions related to (often extensive) copy number variations on chromosome 22, where PATZ1 and the two fusion partners are located. These fusions have individually been reported in a number of glial/glioneuronal tumors, as well as extracranial sarcomas. We show here that they are more common than previously acknowledged, and together define a biologically distinct CNS tumor type with high expression of neural development markers such as PAX2, GATA2 and IGF2. Drug screening performed on the MN1:PATZ1 fusion-bearing KS-1 brain tumor cell line revealed preliminary candidates for further study. In summary, PATZ1 fusions define a molecular class of histologically polyphenotypic neuroepithelial tumors, which show an intermediate prognosis under current treatment regimens.
Background: Atypical EGFR mutations occur in 10%-30% of non-small-cell lung cancer (NSCLC) patients with EGFR mutations and their sensitivity to classical epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKI) is highly heterogeneous. Patients harboring one group of uncommon, recurrent EGFR mutations (G719X, S768I, L861Q) respond to EGFR-TKI. Exon 20 insertions are mostly insensitive to EGFR-TKI but display sensitivity to exon 20 inhibitors. Clinical outcome data of patients with very rare point and compound mutations upon systemic treatments are still sparse to date.
Patients and methods: In this retrospective, multicenter study of the national Network Genomic Medicine (nNGM) in Germany, 856 NSCLC cases with atypical EGFR mutations including co-occurring mutations were reported from 12 centers. Clinical follow-up data after treatment with different EGFR-TKIs, chemotherapy and immune checkpoint inhibitors were available from 260 patients. Response to treatment was analyzed in three major groups: (i) uncommon mutations (G719X, S7681, L861Q and combinations), (ii) exon 20 insertions and (iii) very rare EGFR mutations (very rare single point mutations, compound mutations, exon 18 deletions, exon 19 insertions).
Results: Our study comprises the largest thus far reported real-world cohort of very rare EGFR single point and compound mutations treated with different systemic treatments. We validated higher efficacy of EGFR-TKI in comparison to chemotherapy in group 1 (uncommon), while most exon 20 insertions (group 2) were not EGFR-TKI responsive. In addition, we found TKI sensitivity of very rare point mutations (group 3) and of complex EGFR mutations containing exon 19 deletions or L858R mutations independent of the combination partner. Notably, treatment responses in group 3 (very rare) were highly heterogeneous. Co-occurring TP53 mutations exerted a non-significant trend for a detrimental effect on outcome in EGFR-TKI-treated patients in groups 2 and 3 but not in group 1.
Conclusions: Based on our findings, we propose a novel nNGM classification of atypical EGFR mutations.
About half of present-day cloud condensation nuclei originate from atmospheric nucleation, frequently appearing as a burst of new particles near midday1. Atmospheric observations show that the growth rate of new particles often accelerates when the diameter of the particles is between one and ten nanometres2,3. In this critical size range, new particles are most likely to be lost by coagulation with pre-existing particles4, thereby failing to form new cloud condensation nuclei that are typically 50 to 100 nanometres across. Sulfuric acid vapour is often involved in nucleation but is too scarce to explain most subsequent growth5,6, leaving organic vapours as the most plausible alternative, at least in the planetary boundary layer7,8,9,10. Although recent studies11,12,13 predict that low-volatility organic vapours contribute during initial growth, direct evidence has been lacking. The accelerating growth may result from increased photolytic production of condensable organic species in the afternoon2, and the presence of a possible Kelvin (curvature) effect, which inhibits organic vapour condensation on the smallest particles (the nano-Köhler theory)2,14, has so far remained ambiguous. Here we present experiments performed in a large chamber under atmospheric conditions that investigate the role of organic vapours in the initial growth of nucleated organic particles in the absence of inorganic acids and bases such as sulfuric acid or ammonia and amines, respectively. Using data from the same set of experiments, it has been shown15 that organic vapours alone can drive nucleation. We focus on the growth of nucleated particles and find that the organic vapours that drive initial growth have extremely low volatilities (saturation concentration less than 10−4.5 micrograms per cubic metre). As the particles increase in size and the Kelvin barrier falls, subsequent growth is primarily due to more abundant organic vapours of slightly higher volatility (saturation concentrations of 10−4.5 to 10−0.5 micrograms per cubic metre). We present a particle growth model that quantitatively reproduces our measurements. Furthermore, we implement a parameterization of the first steps of growth in a global aerosol model and find that concentrations of atmospheric cloud concentration nuclei can change substantially in response, that is, by up to 50 per cent in comparison with previously assumed growth rate parameterizations.
The last decade has seen a sharp increase in the number of scientific publications describing physiological and pathological functions of extracellular vesicles (EVs), a collective term covering various subtypes of cell-released, membranous structures, called exosomes, microvesicles, microparticles, ectosomes, oncosomes, apoptotic bodies, and many other names. However, specific issues arise when working with these entities, whose size and amount often make them difficult to obtain as relatively pure preparations, and to characterize properly. The International Society for Extracellular Vesicles (ISEV) proposed Minimal Information for Studies of Extracellular Vesicles (“MISEV”) guidelines for the field in 2014. We now update these “MISEV2014” guidelines based on evolution of the collective knowledge in the last four years. An important point to consider is that ascribing a specific function to EVs in general, or to subtypes of EVs, requires reporting of specific information beyond mere description of function in a crude, potentially contaminated, and heterogeneous preparation. For example, claims that exosomes are endowed with exquisite and specific activities remain difficult to support experimentally, given our still limited knowledge of their specific molecular machineries of biogenesis and release, as compared with other biophysically similar EVs. The MISEV2018 guidelines include tables and outlines of suggested protocols and steps to follow to document specific EV-associated functional activities. Finally, a checklist is provided with summaries of key points.
Two-particle correlation functions of negative hadrons over wide phase space, and transverse mass spectra of negative hadrons and deuterons near mid-rapidity have been measured in central Pb+Pb collisions at 158 GeV per nucleon by the NA49 experiment at the CERN SPS. A novel Coulomb correction procedure for the negative two-particle correlations is employed making use of the measured oppositely charged particle correlation. Within an expanding source scenario these results are used to extract the dynamic characteristics of the hadronic source, resolving the ambiguities between the temperature and transverse expansion velocity of the source, that are unavoidable when single and two particle spectra are analysed separately. The source shape, the total duration of the source expansion, the duration of particle emission, the freeze-out temperature and the longitudinal and transverse expansion velocities are deduced.
We report measurements of Xi and Xi-bar hyperon absolute yields as a function of rapidity in 158 GeV/c Pb+Pb collisions. At midrapidity, dN/dy = 2.29 +/- 0.12 for Xi, and 0.52 +/- 0.05 for Xi-bar, leading to the ratio of Xi-bar/Xi = 0.23 +/- 0.03. Inverse slope parameters fitted to the measured transverse mass spectra are of the order of 300 MeV near mid-rapidity. The estimated total yield of Xi particles in Pb+Pb central interactions amounts to 7.4 +/- 1.0 per collision. Comparison to Xi production in properly scaled p+p reactions at the same energy reveals a dramatic enhancement (about one order of magnitude) of Xi production in Pb+Pb central collisions over elementary hadron interactions.
The directed and elliptic flow of protons and charged pions has been observed from the semi-central collisions of a 158 GeV/nucleon Pb beam with a Pb target. The rapidity and transverse momentum dependence of the flow has been measured. The directed flow of the pions is opposite to that of the protons but both exhibit negative flow at low pt. The elliptic flow of both is fairly independent of rapidity but rises with pt. PACS numbers: 25.75.-q, 25.75.Ld
Using the NA49 main TPC, the central production of hyperons has been measured in CERN SPS Pb - Pb collisions at 158 GeV c-1. The preliminary ratio, studied at 2.0 < y < 2.6 and 1 < pT < 3 GeV c-1, equals ~ (13 ± 4)% (systematic error only). It is compatible, within errors, with the previously obtained ratios for central S + S [1], S + W [2], and S + Au [3] collisions. The fit to the transverse momentum distribution resulted in an inverse slope parameter T of 297 MeV. At this level of statistics we do not see any noticeable enhancement of hyperon production with the increased volume (and, possibly, degree of equilibration) of the system from S + S to Pb + Pb. This result is unexpected and counterintuitive, and should be further investigated. If confirmed, it will have a significant impact on our understanding of mechanisms leading to the enhanced strangeness production in heavy-ion collisions.
Preliminary data on phi production in central Pb + Pb collisions at 158 GeV per nucleon are presented, measured by the NA49 experiment in the hadronic decay channel phi - K+K-. At mid-rapidity, the kaons were separated from pions and protons by combining dE/dx and time-of-flight information; in the forward rapidity range only dE/dx identification was used to obtain the rapidity distribution and a rapidity-integrated mt-spectrum. The mid-rapidity yield obtained was dN/dy = 1.85 ± 0.3 per event; the total phi multiplicity was estimated to be 5.0 ± 0.7 per event. Comparison with published pp data shows a slight, but not very significant strangeness enhancement.
The large acceptance TPCs of the NA49 spectrometer allow for a systematic multidimensional study of two-particle correlations in different part of phase space. Results from Bertsch-Pratt and Yano-Koonin-Podgoretskii parametrizations are presented differentially in transverse pair momentum and pair rapidity. These studies give an insight into the dynamical space-time evolution of relativistic Pb+Pb collisions, which is dominated by longitudinal expansion.
Lambda and Antilambda reconstruction in central Pb+Pb collisions using a time projection chamber
(1997)
The large acceptance time projection chambers of the NA49 experiment are used to record the trajectory of charged particles from Pb + Pb collisions at 158 GeV per nucleon. Neutral strange hadrons have been reconstructed from their charged decay products. To obtain distributions of Λ, and Ks0 in discrete bins of rapidity, y, and transverse momentum, pT, calculations have been performed to determine the acceptance of the detector and the efficiency of the reconstruction software as a function of both variables. The lifetime distributions obtained give values of cτ = 7.8 ± 0.6 cm for Λ and cτ = 2.5 ± 0.3 cm for Ks0, consistent with data book values.
The transverse momentum and rapidity distributions of negative hadrons and participant protons have been measured for central 32S+ 32S collisions at plab=200 GeV/c per nucleon. The proton mean rapidity shift < Delta y>~1.6 and mean transverse momentum <pT>~0.6 GeV/c are much higher than in pp or peripheral AA collisions and indicate an increase in the nuclear stopping power. All pT spectra exhibit similar source temperatures. Including previous results for K0s Lambda , and Lambda -bar, we account for all important contributions to particle production.
The NA35 experiment has collected a high statistics set of momentum analyzed negative hadrons near and forward of midrapidity for central collisions of 200A GeV/c 32S+S, Cu, Ag, and Au. Using momentum space correlations to study the size of the source of particle production, the transverse source radii are found to decrease by ~40% at midrapidity and ~20% at forward rapidity while the longitudinal radius RL is found to decrease by ~50% as pT increases over the interval 50<pT<600 MeV/c. Calculations using a microscopic phase space approach (relativistic quantum molecular dynamics) reproduce the observed trends of the data. PACS: 25.75.+r
Pattern recognition approaches to the analysis of neuroimaging data have brought new applications such as the classification of patients and healthy controls within reach. In our view, the reliance on expensive neuroimaging techniques which are not well tolerated by many patient groups and the inability of most current biomarker algorithms to accommodate information about prior class frequencies (such as a disorder's prevalence in the general population) are key factors limiting practical application. To overcome both limitations, we propose a probabilistic pattern recognition approach based on cheap and easy-to-use multi-channel near-infrared spectroscopy (fNIRS) measurements. We show the validity of our method by applying it to data from healthy controls (n = 14) enabling differentiation between the conditions of a visual checkerboard task. Second, we show that high-accuracy single subject classification of patients with schizophrenia (n = 40) and healthy controls (n = 40) is possible based on temporal patterns of fNIRS data measured during a working memory task. For classification, we integrate spatial and temporal information at each channel to estimate overall classification accuracy. This yields an overall accuracy of 76% which is comparable to the highest ever achieved in biomarker-based classification of patients with schizophrenia. In summary, the proposed algorithm in combination with fNIRS measurements enables the analysis of sub-second, multivariate temporal patterns of BOLD responses and high-accuracy predictions based on low-cost, easy-to-use fNIRS patterns. In addition, our approach can easily compensate for variable class priors, which is highly advantageous in making predictions in a wide range of clinical neuroimaging applications. Hum Brain Mapp, 2013. © 2012 Wiley Periodicals, Inc.
Consensus on definition and severity grading of lymphatic complications after kidney transplantation
(2020)
Background: The incidence of lymphatic complications after kidney transplantation varies considerably in the literature. This is partly because a universally accepted definition has not been established. This study aimed to propose an acceptable definition and severity grading system for lymphatic complications based on their management strategy.
Methods: Relevant literature published in MEDLINE and Web of Science was searched systematically. A consensus for definition and a severity grading was then sought between 20 high-volume transplant centres.
Results: Lymphorrhoea/lymphocele was defined in 32 of 87 included studies. Sixty-three articles explained how lymphatic complications were managed, but none graded their severity. The proposed definition of lymphorrhoea was leakage of more than 50 ml fluid (not urine, blood or pus) per day from the drain, or the drain site after removal of the drain, for more than 1 week after kidney transplantation. The proposed definition of lymphocele was a fluid collection of any size near to the transplanted kidney, after urinoma, haematoma and abscess have been excluded. Grade A lymphatic complications have a minor and/or non-invasive impact on the clinical management of the patient; grade B complications require non-surgical intervention; and grade C complications require invasive surgical intervention.
Conclusion: A clear definition and severity grading for lymphatic complications after kidney transplantation was agreed. The proposed definitions should allow better comparisons between studies.
Introduction: The neurobiological mechanisms behind panic disorder with agoraphobia (PD/AG) are not completely explored. The functional A/T single nucleotide polymorphism (SNP) rs324981 in the neuropeptide S receptor gene (NPSR1) has repeatedly been associated with panic disorder and might partly drive function respectively dysfunction of the neural “fear network”. We aimed to investigate whether the NPSR1 T risk allele was associated with malfunctioning in a fronto-limbic network during the anticipation and perception of agoraphobia-specific stimuli.
Method: 121 patients with PD/AG and 77 healthy controls (HC) underwent functional magnetic resonance imaging (fMRI) using the disorder specific “Westphal-Paradigm”. It consists of neutral and agoraphobia-specific pictures, half of the pictures were cued to induce anticipatory anxiety.
Results: Risk allele carriers showed significantly higher amygdala activation during the perception of agoraphobia-specific stimuli than A/A homozygotes. A linear group x genotype interaction during the perception of agoraphobia-specific stimuli showed a strong trend towards significance. Patients with the one or two T alleles displayed the highest and HC with the A/A genotype the lowest activation in the inferior orbitofrontal cortex (iOFC).
Discussion: The study demonstrates an association of the NPSR1rs324981 genotype and the perception of agoraphobia-specific stimuli. These results support the assumption of a fronto-limbic dysfunction as an intermediate phenotype of PD/AG.
Aims: We investigated N471D WASH complex subunit strumpellin (Washc5) knock-in and Washc5 knock-out mice as models for hereditary spastic paraplegia type 8 (SPG8). Methods: We generated heterozygous and homozygous N471D Washc5 knock-in mice and subjected them to a comprehensive clinical, morphological and laboratory parameter screen, and gait analyses. Brain tissue was used for proteomic analysis. Furthermore, we generated heterozygous Washc5 knock-out mice. WASH complex subunit strumpellin expression was determined by qPCR and immunoblotting. Results: Homozygous N471D Washc5 knock-in mice showed mild dilated cardiomyopathy, decreased acoustic startle reactivity, thinner eye lenses, increased alkaline phosphatase and potassium levels and increased white blood cell counts. Gait analyses revealed multiple aberrations indicative of locomotor instability. Similarly, the clinical chemistry, haematology and gait parameters of heterozygous mice also deviated from the values expected for healthy animals, albeit to a lesser extent. Proteomic analysis of brain tissue depicted consistent upregulation of BPTF and downregulation of KLHL11 in heterozygous and homozygous knock-in mice. WASHC5-related protein interaction partners and complexes showed no change in abundancies. Heterozygous Washc5 knock-out mice showing normal WASHC5 levels could not be bred to homozygosity. Conclusions: While biallelic ablation of Washc5 was prenatally lethal, expression of N471D mutated WASHC5 led to several mild clinical and laboratory parameter abnormalities, but not to a typical SPG8 phenotype. The consistent upregulation of BPTF and downregulation of KLHL11 suggest mechanistic links between the expression of N471D mutated WASHC5 and the roles of both proteins in neurodegeneration and protein quality control, respectively.
Increased sympathetic noradrenergic signaling is crucially involved in fear and anxiety as defensive states. MicroRNAs regulate dynamic gene expression during synaptic plasticity and genetic variation of microRNAs modulating noradrenaline transporter gene (SLC6A2) expression may thus lead to altered central and peripheral processing of fear and anxiety. In silico prediction of microRNA regulation of SLC6A2 was confirmed by luciferase reporter assays and identified hsa-miR-579-3p as a regulating microRNA. The minor (T)-allele of rs2910931 (MAFcases = 0.431, MAFcontrols = 0.368) upstream of MIR579 was associated with panic disorder in patients (pallelic = 0.004, ncases = 506, ncontrols = 506) and with higher trait anxiety in healthy individuals (pASI = 0.029, pACQ = 0.047, n = 3112). Compared to the major (A)-allele, increased promoter activity was observed in luciferase reporter assays in vitro suggesting more effective MIR579 expression and SLC6A2 repression in vivo (p = 0.041). Healthy individuals carrying at least one (T)-allele showed a brain activation pattern suggesting increased defensive responding and sympathetic noradrenergic activation in midbrain and limbic areas during the extinction of conditioned fear. Panic disorder patients carrying two (T)-alleles showed elevated heart rates in an anxiety-provoking behavioral avoidance test (F(2, 270) = 5.47, p = 0.005). Fine-tuning of noradrenaline homeostasis by a MIR579 genetic variation modulated central and peripheral sympathetic noradrenergic activation during fear processing and anxiety. This study opens new perspectives on the role of microRNAs in the etiopathogenesis of anxiety disorders, particularly their cardiovascular symptoms and comorbidities.
In den vergangenen Jahren gab es verschiedene Initiativen, die auf die unzureichende Fördersituation der Schadstoffbezogenen Umweltwissenschaften in der Bundesrepublik Deutschland aufmerksam gemacht haben. Um eine objektive Analyse über die Fördersituation der Ökotoxikologie und Umweltchemie in Deutschland zu erhalten, wurde eine anonyme Online-Befragung ausgearbeitet. Mit Unterstützung der Society of Environmental Toxicology and Chemistry (SETAC) – German Language Branch und der Gesellschaft Deutscher Chemiker (GDCh) – Fachgruppe für Umweltchemie und Ökotoxikologie wurde eine Einladung zur Teilnahme an der Befragung an alle Mitglieder dieser beiden maßgeblichen Verbände der Ökotoxikologie und Umweltchemie im deutschsprachigen Raum versendet. Nur leitende Mitarbeiter aus den Bereichen Forschung, Behörden und Industrie sollten an der Befragung teilnehmen. Die Befragung gliedert sich in eine Sektion zur sozioökonomischen Charakterisierung der Teilnehmer, eine zur Förderung der Forschung durch die DFG und eine zur Förderung durch andere Geldgeber. Insgesamt haben 71 Wissenschaftler und Wissenschaftlerinnen in leitenden Positionen aus verschiedenen Sparten an der Befragung teilgenommen. Die Ergebnisse zeigen, dass die Teilnehmer als sehr leistungsstark eingestuft werden können. 48,5 % der Befragten hatten bereits einen Antrag bei der DFG gestellt. Ein Drittel der Befragten gaben an, eine Förderung durch die DFG erhalten zu haben. 64 % sind mit der Förderung Schadstoffbezogener Umweltwissenschaften durch die DFG nicht zufrieden, nur 7 % sind zufrieden. Es zeigte sich, dass die Anträge insgesamt sehr heterogen auf verschiedene Fachbereiche der DFG verteilt sind. Geowissenschaften, Wasserforschung und Chemie nehmen die ersten Ränge ein, vor Biologie und Ökologie. Im Gegensatz dazu gaben 91,2 % der Befragten an, dass Sie bereits Drittmittelanträge bei anderen Förderinstitutionen (außer der DFG) gestellt haben, und 83,6 % wurden bereits entsprechende Drittmittelanträge bewilligt. 62,3 % der Befragten sind der Meinung, dass sich die Fördersituation für die Schadstoffbezogenen Umweltwissenschaften in den letzten Jahren insgesamt verschlechtert oder sogar deutlich verschlechtert hat. Der überwiegende Anteil der Befragten (60,9 %) ist mit der Fördersituation durch Drittmittelgeber unzufrieden, nur 10,9 % sind damit zufrieden. Auf die Frage „Ist die Forschungsförderung im europäischen Ausland insgesamt besser als in Deutschland?“ antworteten 30 % mit „ja“, 9 % mit „nein“ und 61 % mit „ich weiß nicht“. Zusammenfassend ergab die Befragung, dass die Fördersituation der Ökotoxikologie und Umweltchemie in Deutschland insgesamt als steigerungsbedürftig, bei der DFG jedoch als problematisch zu bewerten ist. Die auffällige Unterrepräsentation der DFG im Vergleich zu anderen Drittmittelgebern verdeutlicht, dass die wichtigste Förderinstitution Deutschlands den Bedürfnissen der Schadstoffbezogenen Umweltwissenschaften nicht hinreichend Rechnung trägt. Insbesondere die Antworten auf die offenen Fragen bezüglich Verbesserungsmöglichkeiten der Forschungsförderung sollten als Grundlage für einen offenen Dialog der Schadstoffbezogenen Umweltforschung mit den Drittmittelgebern DFG, BMBF und DBU bzw. den entsprechenden Institutionen in CH und A genutzt werden.
We retrospectively investigated histopathological growth patterns in individuals with advanced nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) treated within the randomized HD18 study. In all, 35/60 patients (58%) presented with atypical growth patterns. Patients with atypical growth patterns more often had stage IV disease (P = 0·0354) and splenic involvement (P = 0·0048) than patients with typical growth patterns; a positive positron emission tomography after two cycles of chemotherapy (PET-2) tended to be more common (P = 0·1078). Five-year progression-free survival [hazard ratio (HR) = 0·86; 95% confidence interval (CI) = 0·49–1·47] and overall survival (HR = 0·85; 95% CI = 0·49–1·51) did not differ between the groups after study treatment with PET-2-guided escalated BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisone). Thus, advanced NLPHL is often associated with atypical growth patterns but their prognostic impact is compensated by PET-2-guided escalated BEACOPP.
Nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) can present with different histopathological growth patterns. The impact of these histopathological growth patterns on relapse characteristics is unknown. We therefore analyzed paired biopsies obtained at initial diagnosis and relapse from 33 NLPHL patients who had received first‐line treatment within German Hodgkin Study Group (GHSG) trial protocols, and from a second cohort of 41 relapsed NLPHL patients who had been treated outside GHSG studies. Among the 33 GHSG patients, 21 patients presented with a typical growth pattern at initial diagnosis, whereas 12 patients had a variant histology. The histopathological growth patterns at initial diagnosis and at relapse were consistent in 67% of cases. A variant histology at initial diagnosis was associated with a shorter median time to lymphoma recurrence (2.8 vs 5.2 years; P = .0219). A similar tendency towards a shorter median time to lymphoma recurrence was observed for patients presenting with a variant histology at relapse, irrespective of the growth pattern at initial diagnosis. Results obtained from the 41 NLPHL patients who had been treated outside GHSG studies were comparable (median time to lymphoma recurrence for variant histology vs typical growth pattern at initial diagnosis: 1.5 vs 7.0 years). In conclusion, the histopathological growth pattern remains consistent at relapse in the majority of NLPHL cases, and has major impact on the time of relapse.
Non-standard errors
(2021)
In statistics, samples are drawn from a population in a data-generating process (DGP). Standard errors measure the uncertainty in sample estimates of population parameters. In science, evidence is generated to test hypotheses in an evidence-generating process (EGP). We claim that EGP variation across researchers adds uncertainty: non-standard errors. To study them, we let 164 teams test six hypotheses on the same sample. We find that non-standard errors are sizeable, on par with standard errors. Their size (i) co-varies only weakly with team merits, reproducibility, or peer rating, (ii) declines significantly after peer-feedback, and (iii) is underestimated by participants.
Introduction: Esophageal atresia with or without tracheoesophageal fistula (EA/TEF) occurs approximately 1 in 3.500 live births representing the most common malformation of the upper digestive tract. Only half a century ago, EA/TEF was fatal among affected newborns suggesting that the steady birth prevalence might in parts be due to mutational de novo events in genes involved in foregut development.
Methods: To identify mutational de novo events in EA/TEF patients, we surveyed the exome of 30 case-parent trios. Identified and confirmed de novo variants were prioritized using in silico prediction tools. To investigate the embryonic role of genes harboring prioritized de novo variants we performed targeted analysis of mouse transcriptome data of esophageal tissue obtained at the embryonic day (E) E8.5, E12.5, and postnatal.
Results: In total we prioritized 14 novel de novo variants in 14 different genes (APOL2, EEF1D, CHD7, FANCB, GGT6, KIAA0556, NFX1, NPR2, PIGC, SLC5A2, TANC2, TRPS1, UBA3, and ZFHX3) and eight rare de novo variants in eight additional genes (CELSR1, CLP1, GPR133, HPS3, MTA3, PLEC, STAB1, and PPIP5K2). Through personal communication during the project, we identified an additional EA/TEF case-parent trio with a rare de novo variant in ZFHX3. In silico prediction analysis of the identified variants and comparative analysis of mouse transcriptome data of esophageal tissue obtained at E8.5, E12.5, and postnatal prioritized CHD7, TRPS1, and ZFHX3 as EA/TEF candidate genes. Re-sequencing of ZFHX3 in additional 192 EA/TEF patients did not identify further putative EA/TEF-associated variants.
Conclusion: Our study suggests that rare mutational de novo events in genes involved in foregut development contribute to the development of EA/TEF.
The SARS-CoV-2 (SCoV-2) virus is the causative agent of the ongoing COVID-19 pandemic. It contains a positive sense single-stranded RNA genome and belongs to the genus of Betacoronaviruses. The 5′- and 3′-genomic ends of the 30 kb SCoV-2 genome are potential antiviral drug targets. Major parts of these sequences are highly conserved among Betacoronaviruses and contain cis-acting RNA elements that affect RNA translation and replication. The 31 nucleotide (nt) long highly conserved stem-loop 5a (SL5a) is located within the 5′-untranslated region (5′-UTR) important for viral replication. SL5a features a U-rich asymmetric bulge and is capped with a 5′-UUUCGU-3′ hexaloop, which is also found in stem-loop 5b (SL5b). We herein report the extensive 1H, 13C and 15N resonance assignment of SL5a as basis for in-depth structural studies by solution NMR spectroscopy.
The bromodomain and PHD-finger containing transcription factor (BPTF) is part of the nucleosome remodeling factor (NURF) complex and has been implicated in multiple cancer types. Here, we report the discovery of a potent and selective chemical probe targeting the bromodomain of BPTF with an attractive pharmacokinetic profile enabling cellular and in vivo experiments in mice. Microarray-based transcriptomics in presence of the probe in two lung cancer cell lines revealed only minor effects on the transcriptome. Profiling against a panel of cancer cell lines revealed that the antiproliferative effect does not correlate with BPTF dependency score in depletion screens. Both observations and the multi-domain architecture of BPTF suggest that depleting the protein by proteolysis targeting chimeras (PROTACs) could be a promising strategy to target cancer cell proliferation. We envision that the presented chemical probe and the related negative control will enable the research community to further explore scientific hypotheses with respect to BPTF bromodomain inhibition.
We report on HCFC-22 data acquired by the Michelson Interferometer for Passive Atmospheric Sounding (MIPAS) in reduced spectral resolution nominal mode in the period from January 2005 to April 2012 from version 5.02 level-1b spectral data and covering an altitude range from the upper troposphere (above cloud top altitude) to about 50 km. The profile retrieval was performed by constrained nonlinear least squares fitting of measured limb spectral radiances to modelled spectra. The spectral v4-band at 816.5 ± 13 cm-1 was used for the retrieval. A Tikhonov-type smoothing constraint was applied to stabilise the retrieval. In the lower stratosphere, we find a global volume mixing ratio of HCFC-22 of about 185 pptv in January 2005. The linear growth rate in the lower latitudes lower stratosphere was about 6 to 7 pptv yr-1 in the period 2005–2012. The obtained profiles were compared with ACE-FTS satellite data v3.5, as well as with MkIV balloon profiles and in situ cryosampler balloon measurements. Between 13 and 22 km, average agreement within -3 to +5 pptv (MIPAS–ACE) with ACE-FTS v3.5 pro files is demonstrated. Agreement with MkIV solar occultation balloon-borne measurements is within 10–20 pptv below 30 km and worse above, while in situ cryosampler balloon measurements are systematically lower over their full altitude range by 15– 50 pptv below 24 km and less than 10 pptv above 28 km. Obtained MIPAS HCFC-22 time series below 10 km altitude are shown to agree mostly well to corresponding time series of near-surface abundances from NOAA/ESRL and AGAGE networks, although a more pronounced seasonal cycle is obvious in the satellite data, probably due to tropopause altitude fluctuations and subsidence of polar winter stratospheric air into the troposphere. A parametric model consisting of constant, linear, quasi-biennial oscillation (QBO) and several sine and cosine terms with different periods has been fitted to the temporal variation of stratospheric HCFC-22 for all 10° latitude/1 to 2 km altitude bins. The relative linear variation was always positive, with relative increases of 40–70%decade-1 in the tropics and global lower stratosphere, and up to 120%decade-1 in the upper stratosphere of the northern polar region and the southern extratropical hemisphere. In the middle stratosphere between 20 and 30 km, the observed trend is not consistent with the age of stratospheric air-corrected trend at ground, but stronger positive at the Southern Hemisphere and less strong increasing in the Northern Hemisphere, hinting towards changes in the stratospheric circulation over the observation period.
The transport of air masses originating from the Asian monsoon anticyclone into the extratropical upper troposphere and lower stratosphere (Ex-UTLS) above potential temperatures Θ = 380K was identified during the HALO aircraft mission TACTS in August and September 2012. In-situ measurements of CO, O3 and N2O during TACTS Flight 2 on the 30 August 2012 show the irreversible mixing of aged with younger (originating from the troposphere) stratospheric air masses within the Ex-UTLS. Backward trajectories calculated with the trajetory module of the CLaMS model indicate that these tropospherically affected air masses originate from the Asian monsoon anticyclone. From the monsoon circulation region these air masses are quasi-isentropically transported above Θ = 380 K into the Ex-UTLS where they subsequently mix with stratospheric air masses. The overall trace gas distribution measured during TACTS shows that this transport pathway has a significant impact on the Ex-UTLS during boreal summer and autumn. This leads to an intensification of the tropospheric influence on the Ex-UTLS with ∆Θ > 30 K (relative to the tropopause) within three weeks during the TACTS mission. In the same time period a weakening of the tropospheric influence on the lowermost stratosphere (LMS) is determined. Therefore, the study shows that the transport of air masses originating from the Asian summer monsoon region within the lower stratosphere above Θ = 380K is of major importance for the change of the chemical composition of the Ex-UTLS from summer to autumn.
The transport of air masses originating from the Asian monsoon anticyclone into the extratropical upper troposphere and lower stratosphere (Ex-UTLS) above potential temperatures Θ = 380 K was identified during the HALO aircraft mission TACTS in August and September 2012. In situ measurements of CO, O3 and N2O during TACTS flight 2 on 30 August 2012 show the irreversible mixing of aged stratospheric air masses with younger (recently transported from the troposphere) ones within the Ex-UTLS. Backward trajectories calculated with the trajectory module of CLaMS indicate that these tropospherically affected air masses originate from the Asian monsoon anticyclone. These air masses are subsequently transported above potential temperatures Θ = 380 K from the monsoon circulation region into the Ex-UTLS, where they subsequently mix with stratospheric air masses. The overall trace gas distribution measured during TACTS shows that this transport pathway had affected the chemical composition of the Ex-UTLS during boreal summer and autumn 2012. This leads to an intensification of the tropospheric influence on the extratropical lower stratosphere with PV > 8 pvu within 3 weeks during the TACTS mission. During the same time period a weakening of the tropospheric influence on the lowermost stratosphere (LMS) is determined. The study shows that the transport of air masses originating from the Asian summer monsoon region within the lower stratosphere affects the change in the chemical composition of the Ex-UTLS over Europe and thus contributes to the flushing of the LMS during summer 2012.
We report on HCFC-22 data acquired by the Michelson Interferometer for Passive Atmospheric Sounding (MIPAS) in the reduced spectral resolution nominal observation mode. The data cover the period from January 2005 to April 2012 and the altitude range from the upper troposphere (above cloud top altitude) to about 50 km. The profile retrieval was performed by constrained nonlinear least squares fitting of modelled spectra to the measured limb spectral radiances. The spectral ν4-band at 816.5 ± 13 cm−1 was used for the retrieval. A Tikhonov-type smoothing constraint was applied to stabilise the retrieval. In the lower stratosphere, we find a global volume mixing ratio of HCFC-22 of about 185 pptv in January 2005. The rate of linear growth in the lower latitudes lower stratosphere was about 6 to 7 pptv year−1 in the period 2005–2012. The profiles obtained were compared with ACE-FTS satellite data v3.5, as well as with MkIV balloon profiles and cryosampler balloon measurements. Between 13 and 22 km, average agreement within −3 to +5 pptv (MIPAS – ACE) with ACE-FTS v3.5 profiles is demonstrated. Agreement with MkIV solar occultation balloon-borne measurements is within 10–20 pptv below 30 km and worse above, while in situ cryosampler balloon measurements are systematically lower over their full altitude range by 15–50 pptv below 24 km and less than 10 pptv above 28 km. MIPAS HCFC-22 time series below 10 km altitude are shown to agree mostly well to corresponding time series of near-surface abundances from the NOAA/ESRL and AGAGE networks, although a more pronounced seasonal cycle is obvious in the satellite data. This is attributed to tropopause altitude fluctuations and subsidence of polar winter stratospheric air into the troposphere. A parametric model consisting of constant, linear, quasi-biennial oscillation (QBO) and several sine and cosine terms with different periods has been fitted to the temporal variation of stratospheric HCFC-22 for all 10°-latitude/1-to-2-km-altitude bins. The relative linear variation was always positive, with relative increases of 40–70 % decade−1 in the tropics and global lower stratosphere, and up to 120 % decade−1 in the upper stratosphere of the northern polar region and the southern extratropical hemisphere. Asian HCFC-22 emissions have become the major source of global upper tropospheric HCFC-22. In the upper troposphere, monsoon air, rich in HCFC-22, is instantaneously mixed into the tropics. In the middle stratosphere, between 20 and 30 km, the observed trend is inconsistent with the trend at the surface (corrected for the age of stratospheric air), hinting at circulation changes. There exists a stronger positive trend in HCFC-22 in the Southern Hemisphere and a more muted positive trend in the Northern Hemisphere, implying a potential change in the stratospheric circulation over the observation period.
Knowledge about the biogeographic affinities of the world’s tropical forests helps to better understand regional differences in forest structure, diversity, composition, and dynamics. Such understanding will enable anticipation of region-specific responses to global environmental change. Modern phylogenies, in combination with broad coverage of species inventory data, now allow for global biogeographic analyses that take species evolutionary distance into account. Here we present a classification of the world’s tropical forests based on their phylogenetic similarity. We identify five principal floristic regions and their floristic relationships: (i) Indo-Pacific, (ii) Subtropical, (iii) African, (iv) American, and (v) Dry forests. Our results do not support the traditional neo- versus paleotropical forest division but instead separate the combined American and African forests from their Indo-Pacific counterparts. We also find indications for the existence of a global dry forest region, with representatives in America, Africa, Madagascar, and India. Additionally, a northern-hemisphere Subtropical forest region was identified with representatives in Asia and America, providing support for a link between Asian and American northern-hemisphere forests.
The nucleosynthesis of elements beyond iron is dominated by neutron captures in the s and r processes. However, 32 stable, proton-rich isotopes cannot be formed during those processes, because they are shielded from the s-process flow and r-process β-decay chains. These nuclei are attributed to the p and rp process.
For all those processes, current research in nuclear astrophysics addresses the need for more precise reaction data involving radioactive isotopes. Depending on the particular reaction, direct or inverse kinematics, forward or time-reversed direction are investigated to determine or at least to constrain the desired reaction cross sections.
The Facility for Antiproton and Ion Research (FAIR) will offer unique, unprecedented opportunities to investigate many of the important reactions. The high yield of radioactive isotopes, even far away from the valley of stability, allows the investigation of isotopes involved in processes as exotic as the r or rp processes.
The balance function is a new observable based on the principle that charge is locally conserved when particles are pair produced. Balance functions have been measured for charged particle pairs and identified charged pion pairs in Au+Au collisions at sqrt[sNN]=130 GeV at the Relativistic Heavy Ion Collider using STAR. Balance functions for peripheral collisions have widths consistent with model predictions based on a superposition of nucleon-nucleon scattering. Widths in central collisions are smaller, consistent with trends predicted by models incorporating late hadronization.
Azimuthal anisotropy (v2) and two-particle angular correlations of high pT charged hadrons have been measured in Au+Au collisions at sqrt[sNN]=130 GeV for transverse momenta up to 6 GeV/c, where hard processes are expected to contribute significantly. The two-particle angular correlations exhibit elliptic flow and a structure suggestive of fragmentation of high pT partons. The monotonic rise of v2(pT) for pT<2 GeV/c is consistent with collective hydrodynamical flow calculations. At pT>3 GeV/c, a saturation of v2 is observed which persists up to pT=6 GeV/c.
Azimuthal anisotropy (v2) and two-particle angular correlations of high pT charged hadrons have been measured in Au+Au collisions at sqrt[sNN]=130 GeV for transverse momenta up to 6 GeV/c, where hard processes are expected to contribute significantly. The two-particle angular correlations exhibit elliptic flow and a structure suggestive of fragmentation of high pT partons. The monotonic rise of v2(pT) for pT<2 GeV/c is consistent with collective hydrodynamical flow calculations. At pT>3 GeV/c, a saturation of v2 is observed which persists up to pT=6 GeV/c.
Elliptic flow holds much promise for studying the early-time thermalization attained in ultrarelativistic nuclear collisions. Flow measurements also provide a means of distinguishing between hydrodynamic models and calculations which approach the low density (dilute gas) limit. Among the effects that can complicate the interpretation of elliptic flow measurements are azimuthal correlations that are unrelated to the reaction plane (nonflow correlations). Using data for Au + Au collisions at sqrt[sNN]=130 GeV from the STAR time projection chamber, it is found that four-particle correlation analyses can reliably separate flow and nonflow correlation signals. The latter account for on average about 15% of the observed second-harmonic azimuthal correlation, with the largest relative contribution for the most peripheral and the most central collisions. The results are also corrected for the effect of flow variations within centrality bins. This effect is negligible for all but the most central bin, where the correction to the elliptic flow is about a factor of 2. A simple new method for two-particle flow analysis based on scalar products is described. An analysis based on the distribution of the magnitude of the flow vector is also described.
We report the first observation of K*(892)0--> pi K in relativistic heavy ion collisions. The transverse momentum spectrum of (K*0+K*0)/2 from central Au+Au collisions at sqrt[sNN]=130 GeV is presented. The ratios of the K*0 yield derived from these data to the yields of negative hadrons, charged kaons, and phi mesons have been measured in central and minimum bias collisions and compared with model predictions and comparable e+e-, pp, and p-barp results. The data indicate no dramatic reduction of K*0 production in relativistic heavy ion collisions despite expected losses due to rescattering effects.
The STAR Collaboration reports the first observation of exclusive rho 0 photoproduction, AuAu-->AuAu rho 0, and rho 0 production accompanied by mutual nuclear Coulomb excitation, AuAu-->Au [star] Au [star] rho 0, in ultraperipheral heavy-ion collisions. The rho 0 have low transverse momenta, consistent with coherent coupling to both nuclei. The cross sections at sqrt[sNN]=130 GeV agree with theoretical predictions treating rho 0 production and Coulomb excitation as independent processes.
We report STAR results on the azimuthal anisotropy parameter v2 for strange particles K0S, Lambda , and Lambda -bar at midrapidity in Au+Au collisions at sqrt[sNN]=130 GeV at the Relativistic Heavy Ion Collider. The value of v2 as a function of transverse momentum, pt, of the produced particle and collision centrality is presented for both particles up to pt~3.0 GeV/c. A strong pt dependence in v2 is observed up to 2.0 GeV/c. The v2 measurement is compared with hydrodynamic model calculations. The physics implications of the pt integrated v2 magnitude as a function of particle mass are also discussed.
Inclusive transverse momentum distributions of charged hadrons within 0.2<pT<6.0 GeV/c have been measured over a broad range of centrality for Au+Au collisions at sqrt[sNN]=130 GeV. Hadron yields are suppressed at high pT in central collisions relative to peripheral collisions and to a nucleon-nucleon reference scaled for collision geometry. Peripheral collisions are not suppressed relative to the nucleon-nucleon reference. The suppression varies continuously at intermediate centralities. The results indicate significant nuclear medium effects on high-pT hadron production in heavy-ion collisions at high energy.
We report the first measurement of strange ( Lambda ) and antistrange ( Lambda -bar) baryon production from sqrt[sNN]=130 GeV Au+Au collisions at the Relativistic Heavy Ion Collider (RHIC). Rapidity density and transverse mass distributions at midrapidity are presented as a function of centrality. The yield of Lambda and Lambda -bar hyperons is found to be approximately proportional to the number of negative hadrons. The production of Lambda -bar hyperons relative to negative hadrons increases very rapidly with transverse momentum. The magnitude of the increase cannot be described by existing hadronic string fragmentation models alone.
Two-pion correlation functions in Au+Au collisions at sqrt[sNN] = 130 GeV have been measured by the STAR (solenoidal tracker at RHIC) detector. The source size extracted by fitting the correlations grows with event multiplicity and decreases with transverse momentum. Anomalously large sizes or emission durations, which have been suggested as signals of quark-gluon plasma formation and rehadronization, are not observed. The Hanbury Brown-Twiss parameters display a weak energy dependence over a broad range in sqrt[sNN].
The first measurements of light antinucleus production in Au+Au collisions at the Relativistic Heavy-Ion Collider are reported. The observed production rates for d-bar and 3He-bar are much larger than in lower energy nucleus-nucleus collisions. A coalescence model analysis of the yields indicates that there is little or no increase in the antinucleon freeze-out volume compared to collisions at CERN SPS energy. These analyses also indicate that the 3He-bar freeze-out volume is smaller than the d-bar freeze-out volume.
We present the first measurement of midrapidity vector meson phi production in Au+Au collisions at RHIC (sqrt[sNN]=130 GeV) from the STAR detector. For the 11% highest multiplicity collisions, the slope parameter from an exponential fit to the transverse mass distribution is T=379±50(stat)±45(syst) MeV, the yield dN/dy=5.73±0.37(stat)±0.69(syst) per event, and the ratio N phi /Nh- is found to be 0.021±0.001(stat)±0.004(syst). The measured ratio N phi /Nh- and T for the phi meson at midrapidity do not change for the selected multiplicity bins.
Elliptic flow from nuclear collisions is a hadronic observable sensitive to the early stages of system evolution. We report first results on elliptic flow of charged particles at midrapidity in Au+Au collisions at sqrt[sNN] = 130 GeV using the STAR Time Projection Chamber at the Relativistic Heavy Ion Collider. The elliptic flow signal, v2, averaged over transverse momentum, reaches values of about 6% for relatively peripheral collisions and decreases for the more central collisions. This can be interpreted as the observation of a higher degree of thermalization than at lower collision energies. Pseudorapidity and transverse momentum dependence of elliptic flow are also presented.
The on-surface synthesis of bisheptahelicene by Ullmann coupling of 9-bromoheptahelicene on Au(111) and its temperature-induced dehydrogenation is studied using temperature-programmed reaction spectroscopy and time-of-flight secondary ion mass spectrometry. Specific dehydrogenation products of bisheptahelicene after loss of 6, 8 and 10 hydrogen atoms are identified, corresponding to molecules having undergone Diels–Alder transformations and intramolecular C–C coupling reactions. By combining with atomic hydrogen produced by dehydrogenation, the Ullmann coupling side-product bromine desorbs as HBr. H2 desorption emerges only after all Br has desorbed. Such characteristic behavior is explained by a kinetic model which explicitly considers the coverage of transient atomic H on the surface. Heating experiments performed with saturated layers of different Br-containing molecules reveal that the onset of HBr desorption depends strictly on the dehydrogenation step and therefore on the structure of the molecules.
Background: Regulatory T cells (Treg) expressing the transcription factor forkhead-box protein P3 (Foxp3) have been identified to counteract anti-tumor immune responses during tumor progression. Besides, Foxp3 presentation by cancer cells itself may also allow them to evade from effector T-cell responses, resulting in a survival benefit of the tumor. For colorectal cancer (CRC) the clinical relevance of Foxp3 has not been evaluated in detail. Therefore the aim of this study was to study its impact in colorectal cancer (CRC).
Methods and Findings: Gene and protein analysis of tumor tissues from patients with CRC was performed to quantify the expression of Foxp3 in tumor infiltrating Treg and colon cancer cells. The results were correlated with clinicopathological parameters and patients overall survival. Serial morphological analysis demonstrated Foxp3 to be expressed in cancer cells. High Foxp3 expression of the cancer cells was associated with poor prognosis compared to patients with low Foxp3 expression. In contrast, low and high Foxp3 level in tumor infiltrating Treg cells demonstrated no significant differences in overall patient survival.
Conclusions: Our findings strongly suggest that Foxp3 expression mediated by cancer cells rather than by Treg cells contribute to disease progression.
The Tarim River basin, located in Xinjiang, NW China, is the largest endorheic river basin in China and one of the largest in all of Central Asia. Due to the extremely arid climate, with an annual precipitation of less than 100 mm, the water supply along the Aksu and Tarim rivers solely depends on river water. This is linked to anthropogenic activities (e.g., agriculture) and natural and semi-natural ecosystems as both compete for water. The ongoing increase in water consumption by agriculture and other human activities in this region has been enhancing the competition for water between human needs and nature. Against this background, 11 German and 6 Chinese universities and research institutes have formed the consortium SuMaRiO (Sustainable Management of River Oases along the Tarim River; http://www.sumario.de), which aims to create a holistic picture of the availability of water resources in the Tarim River basin and the impacts on anthropogenic activities and natural ecosystems caused by the water distribution within the Tarim River basin. On the basis of the results from field studies and modeling approaches as well as from suggestions by the relevant regional stakeholders, a decision support tool (DST) will be implemented that will then assist stakeholders in balancing the competition for water, acknowledging the major external effects of water allocation to agriculture and to natural ecosystems. This consortium was formed in 2011 and is funded by the German Federal Ministry of Education and Research. As the data collection phase was finished this year, the paper presented here brings together the results from the fields from the disciplines of climate modeling, cryology, hydrology, agricultural sciences, ecology, geoinformatics, and social sciences in order to present a comprehensive picture of the effects of different water availability schemes on anthropogenic activities and natural ecosystems along the Tarim River. The second objective is to present the project structure of the whole consortium, the current status of work (i.e., major new results and findings), explain the foundation of the decision support tool as a key product of this project, and conclude with application recommendations for the region. The discharge of the Aksu River, which is the major tributary of the Tarim, has been increasing over the past 6 decades. From 1989 to 2011, agricultural area more than doubled: cotton became the major crop and there was a shift from small-scale to large-scale intensive farming. The ongoing increase in irrigated agricultural land leads to the increased threat of salinization and soil degradation caused by increased evapotranspiration. Aside from agricultural land, the major natural and semi-natural ecosystems are riparian (Tugai) forests, shrub vegetation, reed beds, and other grassland, as well as urban and peri-urban vegetation. Within the SuMaRiO cluster, focus has been set on the Tugai forests, with Populus euphratica as the dominant tree species, because these forests belong to the most productive and species-rich natural ecosystems of the Tarim River basin. At sites close to the groundwater, the annual stem diameter increments of Populus euphratica correlated with the river runoffs of the previous year. However, the natural river dynamics cease along the downstream course and thus hamper the recruitment of Populus euphratica. A study on the willingness to pay for the conservation of the natural ecosystems was conducted to estimate the concern of the people in the region and in China's capital. These household surveys revealed that there is a considerable willingness to pay for conservation of the natural ecosystems, with mitigation of dust and sandstorms considered the most important ecosystem service. Stakeholder dialogues contributed to creating a scientific basis for a sustainable management in the future.
Diffusion tensor imaging (DTI) based assessment of white matter fiber tract integrity can support the diagnosis of Alzheimer’s disease (AD). The use of DTI as a biomarker, however, depends on its applicability in a multicenter setting accounting for effects of different MRI scanners. We applied multivariate machine learning (ML) to a large multicenter sample from the recently created framework of the European DTI study on Dementia (EDSD). We hypothesized that ML approaches may amend effects of multicenter acquisition. We included a sample of 137 patients with clinically probable AD (MMSE 20.6±5.3) and 143 healthy elderly controls, scanned in nine different scanners. For diagnostic classification we used the DTI indices fractional anisotropy (FA) and mean diffusivity (MD) and, for comparison, gray matter and white matter density maps from anatomical MRI. Data were classified using a Support Vector Machine (SVM) and a Naïve Bayes (NB) classifier. We used two cross-validation approaches, (i) test and training samples randomly drawn from the entire data set (pooled cross-validation) and (ii) data from each scanner as test set, and the data from the remaining scanners as training set (scanner-specific cross-validation). In the pooled cross-validation, SVM achieved an accuracy of 80% for FA and 83% for MD. Accuracies for NB were significantly lower, ranging between 68% and 75%. Removing variance components arising from scanners using principal component analysis did not significantly change the classification results for both classifiers. For the scanner-specific cross-validation, the classification accuracy was reduced for both SVM and NB. After mean correction, classification accuracy reached a level comparable to the results obtained from the pooled cross-validation. Our findings support the notion that machine learning classification allows robust classification of DTI data sets arising from multiple scanners, even if a new data set comes from a scanner that was not part of the training sample.
We report first results on elliptic flow of identified particles at midrapidity in Au+Au collisions at sqrt[sNN] = 130 GeV using the STAR TPC at RHIC. The elliptic flow as a function of transverse momentum and centrality differs significantly for particles of different masses. This dependence can be accounted for in hydrodynamic models, indicating that the system created shows a behavior consistent with collective hydrodynamical flow. The fit to the data with a simple model gives information on the temperature and flow velocities at freeze-out.
The minimum-bias multiplicity distribution and the transverse momentum and pseudorapidity distributions for central collisions have been measured for negative hadrons ( h-) in Au+Au interactions at sqrt[sNN] = 130 GeV. The multiplicity density at midrapidity for the 5% most central interactions is dNh-/d eta | eta = 0 = 280±1(stat)±20(syst), an increase per participant of 38% relative to pp-bar collisions at the same energy. The mean transverse momentum is 0.508±0.012 GeV/c and is larger than in central Pb+Pb collisions at lower energies. The scaling of the h- yield per participant is a strong function of pperp. The pseudorapidity distribution is almost constant within | eta |<1.
We report the first measurement of inclusive antiproton production at midrapidity in Au+Au collisions at sqrt[sNN] = 130 GeV by the STAR experiment at RHIC. The antiproton transverse mass distributions in the measured transverse momentum range of 0.25<pperp<0.95 GeV/c are found to fall less steeply for more central collisions. The extrapolated antiproton rapidity density is found to scale approximately with the negative hadron multiplicity density.
We report results on the ratio of midrapidity antiproton-to-proton yields in Au+Au collisions at sqrt[sNN] = 130 GeV per nucleon pair as measured by the STAR experiment at RHIC. Within the rapidity and transverse momentum range of | y|<0.5 and 0.4<pt<1.0 GeV/c, the ratio is essentially independent of either transverse momentum or rapidity, with an average of 0.65±0.01(stat)±0.07(syst) for minimum bias collisions. Within errors, no strong centrality dependence is observed. The results indicate that at this RHIC energy, although the p-p-bar pair production becomes important at midrapidity, a significant excess of baryons over antibaryons is still present.
Nowadays, several options are available to treat patients with conductive or mixed hearing loss. Whenever surgical intervention is not possible or contra-indicated, and amplification by a conventional hearing device (e.g., behind-the-ear device) is not feasible, then implantable hearing devices are an indispensable next option. Implantable bone-conduction devices and middle-ear implants have advantages but also limitations concerning complexity/invasiveness of the surgery, medical complications, and effectiveness. To counsel the patient, the clinician should have a good overview of the options with regard to safety and reliability as well as unequivocal technical performance data. The present consensus document is the outcome of an extensive iterative process including ENT specialists, audiologists, health-policy scientists, and representatives/technicians of the main companies in this field. This document should provide a first framework for procedures and technical characterization to enhance effective communication between these stakeholders, improving health care.
Background: Preclinical studies demonstrate synergism between cancer immunotherapy and local radiation, enhancing anti-tumor effects and promoting immune responses. BI1361849 (CV9202) is an active cancer immunotherapeutic comprising protamine-formulated, sequence-optimized mRNA encoding six non-small cell lung cancer (NSCLC)-associated antigens (NY-ESO-1, MAGE-C1, MAGE-C2, survivin, 5T4, and MUC-1), intended to induce targeted immune responses.
Methods: We describe a phase Ib clinical trial evaluating treatment with BI1361849 combined with local radiation in 26 stage IV NSCLC patients with partial response (PR)/stable disease (SD) after standard first-line therapy. Patients were stratified into three strata (1: non-squamous NSCLC, no epidermal growth factor receptor (EGFR) mutation, PR/SD after ≥4 cycles of platinum- and pemetrexed-based treatment [n = 16]; 2: squamous NSCLC, PR/SD after ≥4 cycles of platinum-based and non-platinum compound treatment [n = 8]; 3: non-squamous NSCLC, EGFR mutation, PR/SD after ≥3 and ≤ 6 months EGFR-tyrosine kinase inhibitor (TKI) treatment [n = 2]). Patients received intradermal BI1361849, local radiation (4 × 5 Gy), then BI1361849 until disease progression. Strata 1 and 3 also had maintenance pemetrexed or continued EGFR-TKI therapy, respectively. The primary endpoint was evaluation of safety; secondary objectives included assessment of clinical efficacy (every 6 weeks during treatment) and of immune response (on Days 1 [baseline], 19 and 61).
Results: Study treatment was well tolerated; injection site reactions and flu-like symptoms were the most common BI1361849-related adverse events. Three patients had grade 3 BI1361849-related adverse events (fatigue, pyrexia); there was one grade 3 radiation-related event (dysphagia). In comparison to baseline, immunomonitoring revealed increased BI1361849 antigen-specific immune responses in the majority of patients (84%), whereby antigen-specific antibody levels were increased in 80% and functional T cells in 40% of patients, and involvement of multiple antigen specificities was evident in 52% of patients. One patient had a partial response in combination with pemetrexed maintenance, and 46.2% achieved stable disease as best overall response. Best overall response was SD in 57.7% for target lesions.
Conclusion: The results support further investigation of mRNA-based immunotherapy in NSCLC including combinations with immune checkpoint inhibitors.
Trial registration: ClinicalTrials.gov identifier: NCT01915524.
This paper presents an analysis of the recent tropospheric molecular hydrogen (H2) budget with a particular focus on soil uptake and surface emissions. A variational inversion scheme is combined with observations from the RAMCES and EUROHYDROS atmospheric networks, which include continuous measurements performed between mid-2006 and mid-2009. Net H2 surface flux, soil uptake distinct from surface emissions and finally, soil uptake, biomass burning, anthropogenic emissions and N2 fixation-related emissions separately were inverted in several scenarios. The various inversions generate an estimate for each term of the H2 budget. The net H2 flux per region (High Northern Hemisphere, Tropics and High Southern Hemisphere) varies between −8 and 8 Tg yr−1. The best inversion in terms of fit to the observations combines updated prior surface emissions and a soil deposition velocity map that is based on soil uptake measurements. Our estimate of global H2 soil uptake is −59 ± 4.0 Tg yr−1. Forty per cent of this uptake is located in the High Northern Hemisphere and 55% is located in the Tropics. In terms of surface emissions, seasonality is mainly driven by biomass burning emissions. The inferred European anthropogenic emissions are consistent with independent H2 emissions estimated using a H2/CO mass ratio of 0.034 and CO emissions considering their respective uncertainties. To constrain a more robust partition of H2 sources and sinks would need additional constraints, such as isotopic measurements.