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Background and Aims: Fecal biomarkers are important non-invasive markers monitoring disease activity in inflammatory bowel disease (IBD). We compared the significance of fecal eosinophil cationic protein (fECP) and fecal calprotectin (fCal).
Methods: fECP and fCal were measured in patients with Crohn's disease (CD, n = 97), ulcerative colitis (UC, n = 53), Clostridioides difficile infection (CDI, n = 9), primary food allergy (PFA, n = 11), pollen-associated food allergy (n = 25) and non-inflammatory controls (n = 78). Results were correlated with clinical and endoscopic IBD activity scores.
Results: fECP was significantly elevated in CD, UC, CDI and PFA compared to controls. fCal was significantly increased in CD, UC and CDI. fECP had lower diagnostic accuracy than fCal (area under the curve (AUC) = 0.88) in differentiating between endoscopically active and inactive patients with IBD (AUC = 0.77, ROC analysis). In contrast to fCal, fECP correlated negatively with age and levels were also elevated in clinically and endoscopically inactive patients with IBD <45 years (endoscopically inactive IBD vs controls; AUC for fECP = 0.86; AUC for fCal = 0.62). However, in those patients with low inflammatory activity (fCal <250 mg/kg), high fECP indicated the need for treatment modification or surgery (fECP <200 µg/kg = 22%; 200–600 µg/kg = 44%; >600 µg/kg = 82%) at month 48 of follow-up.
Conclusions: fECP is a diagnostic and prognostic marker in young patients with IBD in remission.
Measurements of the π±, K±, and proton double differential yields emitted from the surface of the 90-cm-long carbon target (T2K replica) were performed for the incoming 31 GeV/c protons with the NA61/SHINE spectrometer at the CERN SPS using data collected during 2010 run. The double differential π± yields were measured with increased precision compared to the previously published NA61/SHINE results, while the K± and proton yields were obtained for the first time. A strategy for dealing with the dependence of the results on the incoming proton beam profile is proposed. The purpose of these measurements is to reduce significantly the (anti)neutrino flux uncertainty in the T2K long-baseline neutrino experiment by constraining the production of (anti)neutrino ancestors coming from the T2K target.
Since Inhibitor of Apoptosis (IAP) proteins have been implicated in cellular adaptation to endoplasmic reticulum (ER) stress, we investigated the regulation of ER stress-induced apoptosis by small-molecule second mitochondria-derived activator of caspase (Smac) mimetics that antagonize IAP proteins. Here, we discover that Smac mimetic suppresses tunicamycin (TM)-induced apoptosis via resolution of the unfolded protein response (UPR) and ER stress. Smac mimetics such as BV6 selectively inhibit apoptosis triggered by pharmacological or genetic inhibition of protein N-glycosylation using TM or knockdown of DPAGT1, the enzyme that catalyzes the first step of protein N-glycosylation. In contrast, BV6 does not rescue cell death induced by other typical ER stressors (i.e., thapsigargin (TG), dithiothreitol, brefeldin A, bortezomib, or 2-deoxyglucose). The protection from TM-triggered apoptosis is found for structurally different Smac mimetics and for genetic knockdown of cellular IAP (cIAP) proteins in several cancer types, underlining the broader relevance. Interestingly, lectin microarray profiling reveals that BV6 counteracts TM-imposed inhibition of protein glycosylation. BV6 consistently abolishes TM-stimulated accumulation of ER stress markers such as glucose-regulated protein 78 (GRP78) and C/EBP homologous protein (CHOP) and reduces protein kinase RNA-like ER kinase (PERK) phosphorylation and X box-binding protein 1 (XBP1) splicing upon TM treatment. BV6-stimulated activation of nuclear factor-κB (NF-κB) contributes to the resolution of ER stress, since NF-κB inhibition by overexpression of dominant-negative IκBα superrepressor counteracts the suppression of TM-stimulated transcriptional activation of CHOP and GRP78 by BV6. Thus, our study is the first to show that Smac mimetic protects from TM-triggered apoptosis by resolving the UPR and ER stress. This provides new insights into the regulation of cellular stress responses by Smac mimetics.
Ein Zell-Atlas des kranken Herzens : Einzelzelltechniken ermöglichen neue Einsichten auf Zellebene
(2019)
Herz und Gefäße bilden ein hochkomplexes Organsystem, in dem unterschiedlichste Zellen korrekt zusammenarbeiten müssen, um alle Organe mit Blut zu versorgen. In den vergangenen Jahrzehnten hat die Herzbiologie ganze Gewebe oder Zellisolate in den Blick genommen. Doch jetzt erlauben neue Technologien, die Vielfalt der Zelltypen und ihre individuelle Antwort auf Signale bis auf die Ebene von Proteinen und Genen zu verfolgen. Forscher hoffen, kranken Herzen dadurch besser bei der Regeneration helfen zu können.
The following article attempts to clarify the ambivalent relationship that Max Horkheimer and Herbert Marcuse developed with the vitalist and phenomenological tendencies that permeated philosophy and the social sciences during the Weimar Republic. More precisely, it traces how both thinkers, in spite of acknowledging the “truth moment” contained in the criticism that the philosophical exponents of both movements (Husserl, Bergson, Dilthey) developed of 19th century positivism, also recognized in its shallow popularization the advancement of a dangerous philosophical irrationalism, suspicious of science and Enlightenment values, that would soon become an accomplice to the rise of fascism.
The procedure for the energy calibration of the high granularity electromagnetic calorimeter PHOS of the ALICE experiment is presented. The methods used to perform the relative gain calibration, to evaluate the geometrical alignment and the corresponding correction of the absolute energy scale, to obtain the nonlinearity correction coefficients and finally, to calculate the time-dependent calibration corrections, are discussed and illustrated by the PHOS performance in proton-proton (pp) collisions at √s=13 TeV. After applying all corrections, the achieved mass resolutions for π0 and η mesons for pT > 1.7 GeV/c are σmπ0 = 4.56 ± 0.03 MeV/c2 and σmη = 15.3 ± 1.0 MeV/c2, respectively.
The jet radial structure and particle transverse momentum (pT) composition within jets are presented in centrality-selected Pb–Pb collisions at √sNN = 2.76 TeV. Track-based jets, which are also called charged jets, were reconstructed with a resolution parameter of R = 0.3 at midrapidity |ηch jet| < 0.6 for transverse momenta pT, ch jet = 30–120 GeV/c. Jet–hadron correlations in relative azimuth and pseudorapidity space (Δϕ, Δη) are measured to study the distribution of the associated particles around the jet axis for different pT,assoc-ranges between 1 and 20 GeV/c. The data in Pb–Pb collisions are compared to reference distributions for pp collisions, obtained using embedded PYTHIA simulations. The number of high-pT associate particles (4 < pT,assoc < 20 GeV/c) in Pb–Pb collisions is found to be suppressed compared to the reference by 30 to 10% depending on centrality. The radial particle distribution relative to the jet axis shows a moderate modification in Pb–Pb collisions with respect to PYTHIA. High-pT associate particles are slightly more collimated in Pb–Pb collisions compared to the reference, while low-pT associate particles tend to be broadened. The results, which are presented for the first time down to pT, ch jet = 30 GeV/c in Pb–Pb collisions, are compatible with both previous jet–hadron-related measurements from the CMS Collaboration and jet shape measurements from the ALICE Collaboration at higher pT, and add further support for the established picture of in-medium parton energy loss.
Study of the Λ–Λ interaction with femtoscopy correlations in pp and p–Pb collisions at the LHC
(2019)
This work presents new constraints on the existence and the binding energy of a possible – bound state, the H-dibaryon, derived from – femtoscopic measurements by the ALICE collaboration. The results are obtained from a new measurement using the femtoscopy technique in pp collisions at √s = 13 TeV and p–Pb collisions at √sNN = 5.02 TeV, combined with previously published results from pp collisions at √s = 7 TeV. The – scattering parameter space, spanned by the inverse scattering length f −1 0 and the effective range d0, is constrained by comparing the measured – correlation function with calculations obtained within the Lednický model. The data are compatible with hypernuclei results and lattice computations, both predicting a shallow attractive interaction, and permit to test different theoretical approaches describing the – interaction. The region in the (f −1 0 ,d0) plane which would accommodate a – bound state is substantially restricted compared to previous studies. The binding energy of the possible – bound state is estimated within an effective-range expansion approach and is found to be B = 3.2+1.6 −2.4(stat)+1.8 −1.0(syst) MeV.
The ALICE collaboration performed the first rapidity-differential measurement of coherent J/ψ photoproduction in ultra-peripheral Pb–Pb collisions at a center-of-mass energy √sNN = 5.02 TeV. The J/ψ is detected via its dimuon decay in the forward rapidity region (−4.0 < y < −2.5) for events where the hadronic activity is required to be minimal. The analysis is based on an event sample corresponding to an integrated luminosity of about 750 μb−1. The cross section for coherent J/ψ production is presented in six rapidity bins. The results are compared with theoretical models for coherent J/ψ photoproduction. These comparisons indicate that gluon shadowing effects play a role in the photoproduction process. The ratio of ψ to J/ψ coherent photoproduction cross sections was measured and found to be consistent with that measured for photoproduction off protons.
Measurement of the production of charm jets tagged with D0 mesons in pp collisions at √s = 7 TeV
(2019)
The production of charm jets in proton-proton collisions at a center-of-mass energy of s√=7 TeV was measured with the ALICE detector at the CERN Large Hadron Collider. The measurement is based on a data sample corresponding to a total integrated luminosity of 6.23 nb−1, collected using a minimum-bias trigger. Charm jets are identified by the presence of a D0 meson among their constituents. The D0 mesons are reconstructed from their hadronic decay D0 →K−π+. The D0-meson tagged jets are reconstructed using tracks of charged particles (track-based jets) with the anti-kT algorithm in the jet transverse momentum range 5<pchT,jet< 30 GeV/c and pseudorapidity |ηjet| < 0.5. The fraction of charged jets containing a D0-meson increases with pchT,jet from 0.042 ± 0.004 (stat) ± 0.006 (syst) to 0.080 ± 0.009 (stat) ± 0.008 (syst). The distribution of D0-meson tagged jets as a function of the jet momentum fraction carried by the D0 meson in the direction of the jet axis (zch∥) is reported for two ranges of jet transverse momenta, 5<pchT,jet< 15 GeV/c and 15<pchT,jet< 30 GeV/c in the intervals 0.2<zch∥∥<1.0 and 0.4<zch∥∥<1.0, respectively. The data are compared with results from Monte Carlo event generators (PYTHIA 6, PYTHIA 8 and Herwig 7) and with a Next-to-Leading-Order perturbative Quantum Chromodynamics calculation, obtained with the POWHEG method and interfaced with PYTHIA 6 for the generation of the parton shower, fragmentation, hadronisation and underlying event.
We present a study of the inclusive charged-particle transverse momentum (pT) spectra as a function of charged-particle multiplicity density at mid-pseudorapidity, dNch/dη, in pp collisions at s√=5.02 and 13 TeV covering the kinematic range |η|<0.8 and 0.15<pT<20 GeV/c. The results are presented for events with at least one charged particle in |η|<1 (INEL>0). The pT spectra are reported for two multiplicity estimators covering different pseudorapidity regions. The pT spectra normalized to that for INEL>0 show little energy dependence. Moreover, the high-pT yields of charged particles increase faster than the charged-particle multiplicity density. The average pT as a function of multiplicity and transverse spherocity is reported for pp collisions at s√=13 TeV. For low- (high-) spherocity events, corresponding to jet-like (isotropic) events, the average pT is higher (smaller) than that measured in INEL>0 pp collisions. Within uncertainties, the functional form of ⟨pT⟩(Nch) is not affected by the spherocity selection. While EPOS LHC gives a good description of many features of data, PYTHIA overestimates the average pT in jet-like events.
This Letter presents the first experimental observation of the attractive strong interaction between a proton and a multistrange baryon (hyperon) Ξ−. The result is extracted from two-particle correlations of combined p−Ξ−⊕¯p−¯Ξ+ pairs measured in p−Pb collisions at √sNN=5.02 TeV at the LHC with ALICE. The measured correlation function is compared with the prediction obtained assuming only an attractive Coulomb interaction and a standard deviation in the range [3.6, 5.3] is found. Since the measured p−Ξ−⊕¯p−¯Ξ+ correlation is significantly enhanced with respect to the Coulomb prediction, the presence of an additional, strong, attractive interaction is evident. The data are compatible with recent lattice calculations by the HAL-QCD Collaboration, with a standard deviation in the range [1.8, 3.7]. The lattice potential predicts a shallow repulsive Ξ− interaction within pure neutron matter and this implies stiffer equations of state for neutron-rich matter including hyperons. Implications of the strong interaction for the modeling of neutron stars are discussed.
Production cross sections of muons from semi-leptonic decays of charm and beauty hadrons were measured at forward rapidity (2.5 < y < 4) in proton-proton (pp) collisions at a centre-of-mass energy s√ = 5.02 TeV with the ALICE detector at the CERN LHC. The results were obtained in an extended transverse momentum interval, 2 < pT< 20 GeV/c, and with an improved precision compared to previous measurements performed in the same rapidity interval at centre-of-mass energies s√ = 2.76 and 7 TeV. The pT- and y-differential production cross sections as well as the pT-differential production cross section ratios between different centre-of-mass energies and different rapidity intervals are described, within experimental and theoretical uncertainties, by predictions based on perturbative QCD.
The correlations of identical charged kaons were measured in p-Pb collisions at sNN−−−√=5.02 TeV by the ALICE experiment at the LHC. The femtoscopic invariant radii and correlation strengths were extracted from one-dimensional kaon correlation functions and were compared with those obtained in pp and Pb-Pb collisions at s√=7 TeV and sNN−−−√=2.76 TeV, respectively. The presented results also complement the identical-pion femtoscopic data published by the ALICE collaboration. The extracted radii increase with increasing charged-particle multiplicity and decrease with increasing pair transverse momentum. At comparable multiplicities, the radii measured in p-Pb collisions are found to be close to those observed in pp collisions. The obtained femtoscopic parameters are reproduced by the EPOS 3 hadronic interaction model and disfavor models with large initial size or strong collective expansion at low multiplicities.
Measurements of anisotropic flow coefficients (vn) and their cross-correlations using two- and multi-particle cumulant methods are reported in collisions of pp at s√=13 TeV, p-Pb at sNN−−−√=5.02 TeV, Xe-Xe at sNN−−−√=5.44 TeV, and Pb-Pb at sNN−−−√=5.02 TeV recorded with the ALICE detector. These measurements are performed as a function of multiplicity in the mid-rapidity region |η|<0.8 for the transverse momentum range 0.2<pT<3.0 GeV/c. An ordering of the coefficients v2>v3>v4 is found in pp and p-Pb collisions, similar to that seen in large collision systems, while a weak v2 multiplicity dependence is observed relative to nucleus--nucleus collisions in the same multiplicity range. Using the novel subevent method, v2 measured in pp and p-Pb collisions with four-particle cumulants is found to be compatible with that from six-particle cumulants. The symmetric cumulants SC(m,n) calculated with the subevent method which evaluate the correlation strength between v2n and v2m are also presented. The presented data, which add further support to the existence of long-range multi-particle azimuthal correlations in high multiplicity pp and p-Pb collisions, can neither be described by PYTHIA8 nor by IP-Glasma+MUSIC+UrQMD model calculations, and hence provide new insights into the understanding of collective effects in small collision systems.
The cross section of jets reconstructed from charged particles is measured in the transverse momentum range of 5<pT<100 GeV/c in pp collisions at the center-of-mass energy of s√=5.02 TeV with the ALICE detector. The jets are reconstructed using the anti-kT algorithm with resolution parameters R=0.2, 0.3, 0.4, and 0.6 in the pseudorapidity range |η|<0.9−R. The charged jet cross sections are compared with the leading order (LO) and to next-to-leading order (NLO) perturbative Quantum ChromoDynamics (pQCD) calculations. It was found that the NLO calculations agree better with the measurements. The cross section ratios for different resolution parameters were also measured. These ratios increase from low pT to high pT and saturate at high pT, indicating that jet collimation is larger at high pT than at low pT. These results provide a precision test of pQCD predictions and serve as a baseline for the measurement in Pb−Pb collisions at the same energy to quantify the effects of the hot and dense medium created in heavy-ion collisions at the LHC.
An improved value for the lifetime of the (anti-)hypertriton has been obtained using the data sample of Pb–Pb collisions at √sNN = 5.02 TeV collected by the ALICE experiment at the LHC. The (anti-)hypertriton has been reconstructed via its charged two-body mesonic decay channel and the lifetime has been determined from an exponential fit to the dN/d(ct) spectrum. The measured value, τ = 242+34 −38 (stat.) ± 17 (syst.) ps, is compatible with representative theoretical predictions, thus contributing to the solution of the longstanding hypertriton lifetime puzzle.
Measurement of the inclusive isolated photon production cross section in pp collisions at √s = 7 TeV
(2019)
The production cross section of inclusive isolated photons has been measured by the ALICE experiment at the CERN LHC in pp collisions at a centre-of-momentum energy of s√= 7 TeV. The measurement is performed with the electromagnetic calorimeter EMCal and the central tracking detectors, covering a range of |η|<0.27 in pseudorapidity and a transverse momentum range of 10<pγT<60 GeV/c. The result extends the pT coverage of previously published results of the ATLAS and CMS experiments at the same collision energy to smaller pT. The measurement is compared to next-to-leading order perturbative QCD calculations and to the results from the ATLAS and CMS experiments. All measurements and theory predictions are in agreement with each other.
The measurement of the production of prompt D0, D+, D*+, and D+S mesons in proton–lead (p–Pb) collisions at the centre-of-mass energy per nucleon pair of sNN−−−√ = 5.02 TeV, with an integrated luminosity of 292 ± 11 μb−1, are reported. Differential production cross sections are measured at mid-rapidity (−0.96 < ycms< 0.04) as a function of transverse momentum (pT) in the intervals 0 < pT< 36 GeV/c for D0, 1 < pT< 36 GeV/c for D+ and D*+, and 2 < pT< 24 GeV/c for D+ mesons. For each species, the nuclear modification factor RpPb is calculated as a function of pT using a proton-proton (pp) ref- erence measured at the same collision energy. The results are compatible with unity in the whole pT range. The average of the non-strange D mesons RpPb is compared with theoretical model predictions that include initial-state effects and parton transport model predictions. The pT dependence of the D0, D+, and D*+ nuclear modification factors is also reported in the interval 1 < pT< 36 GeV/c as a function of the collision centrality, and the central-to-peripheral ratios are computed from the D-meson yields measured in different centrality classes. The results are further compared with charged-particle measurements and a similar trend is observed in all the centrality classes. The ratios of the pT-differential cross sections of D0, D+, D*+, and D+S mesons are also reported. The D+S and D+ yields are compared as a function of the charged-particle multiplicity for several pT intervals. No modification in the relative abundances of the four species is observed with respect to pp collisions within the statistical and systematic uncertainties.
Inclusive J/ψ production is studied in minimum-bias proton-proton collisions at a centre-of-mass energy of s√ = 5.02 TeV by ALICE at the CERN LHC. The measurement is performed at mid-rapidity (|y| < 0.9) in the dielectron decay channel down to zero transverse momentum pT, using a data sample corresponding to an integrated luminosity of Lint = 19.4 ± 0.4 nb−1. The measured pT-integrated inclusive J/ψ production cross sec- tion is dσ/dy = 5.64 ± 0.22(stat.) ± 0.33(syst.) ± 0.12(lumi.) μb. The pT-differential cross section d2σ/dpTdy is measured in the pT range 0–10 GeV/c and compared with state-of- the-art QCD calculations. The J/ψ 〈pT〉 and ⟨p2T⟩ are extracted and compared with results obtained at other collision energies.
The measurements of the production of prompt D0, D+, D∗+, and D+s mesons in proton–proton (pp) collisions at s√=5.02 TeV with the ALICE detector at the Large Hadron Collider (LHC) are reported. D mesons were reconstructed at mid-rapidity (|y|<0.5) via their hadronic decay channels D0→K−π+, D+→K−π+π+, D∗+→D0π+→K−π+π+, D+s→ϕπ+→K+K−π+, and their charge conjugates. The production cross sections were measured in the transverse momentum interval 0<pT<36 GeV/c for D0, 1<pT<36 GeV/c for D+ and D∗+, and in 2<pT<24 GeV/c for D+s mesons. Thanks to the higher integrated luminosity, an analysis in finer pT bins with respect to the previous measurements at s√=7 TeV was performed, allowing for a more detailed description of the cross-section pT shape. The measured pT-differential production cross sections are compared to the results at s√=7 TeV and to four different perturbative QCD calculations. Its rapidity dependence is also tested combining the ALICE and LHCb measurements in pp collisions at s√=5.02 TeV. This measurement will allow for a more accurate determination of the nuclear modification factor in p–Pb and Pb–Pb collisions performed at the same nucleon–nucleon centre-of-mass energy.
First results on K/π, p/π and K/p fluctuations are obtained with the ALICE detector at the CERN LHC as a function of centrality in Pb--Pb collisions at sNN−−−√=2.76 TeV. The observable νdyn, which is defined in terms of the moments of particle multiplicity distributions, is used to quantify the magnitude of dynamical fluctuations of relative particle yields and also provides insight into the correlation between particle pairs. This study is based on a novel experimental technique, called the Identity Method, which allows one to measure the moments of multiplicity distributions in case of incomplete particle identification. The results for p/π show a change of sign in νdyn from positive to negative towards more peripheral collisions. For central collisions, the results follow the smooth trend of the data at lower energies and νdyn exhibits a change in sign for p/π and K/p.
A measurement of the production of prompt +c baryons in Pb–Pb collisions at √sNN = 5.02 TeV with the ALICE detector at the LHC is reported. The +c and − c were reconstructed at midrapidity (|y| < 0.5) via the hadronic decay channel +c → pK0 S (and charge conjugate) in the transverse momentum and centrality intervals 6 < pT < 12 GeV/c and 0–80%. The +c /D0 ratio, which is sensitive to the charm quark hadronisation mechanisms in the medium, is measured and found to be larger than the ratio measured in minimum-bias pp collisions at √s = 7 TeV and in p–Pb collisions at √sNN = 5.02 TeV. In particular, the values in p–Pb and Pb–Pb collisions differ by about two standard deviations of the combined statistical and systematic uncertainties in the common pT interval covered by the measurements in the two collision systems. The + c /D0 ratio is also compared with model calculations including different implementations of charm quark hadronisation. The measured ratio is reproduced by models implementing a pure coalescence scenario, while adding a fragmentation contribution leads to an underestimation. The + c nuclear modification factor, RAA, is also presented. The measured values of the RAA of + c , D+ s and non-strange D mesons are compatible within the combined statistical and systematic uncertainties. They show, however, a hint of a hierarchy (RD0 AA < RD+ s AA < R+ c AA ), conceivable with a contribution from coalescence mechanisms to charm hadron formation in the medium.
Two-particle correlations in high-energy collision experiments enable the extraction of particle source radii by using the Bose-Einstein enhancement of pion production at low relative momentum q ∝ 1/R. It was previously observed that in pp collisions at s√ = 7TeV the average pair transverse momentum kT range of such analyses is limited due to large background correlations which were attributed to mini-jet phenomena. To investigate this further, an event-shape dependent analysis of Bose-Einstein correlations for pion pairs is performed in this work. By categorizing the events by their transverse sphericity ST into spherical (ST > 0:7) and jet-like (ST < 0:3) events a method was developed that allows for the determination of source radii for much larger values of kT for the first time. Spherical events demonstrate little or no background correlations while jet-like events are dominated by them. This observation agrees with the hypothesis of a mini-jet origin of the non-femtoscopic background correlations and gives new insight into the physics interpretation of the kT dependence of the radii. The emission source size in spherical events shows a substantially diminished kT dependence, while jet-like events show indications of a negative trend with respect to kT in the highest multiplicity events. Regarding the emission source shape, the correlation functions for both event sphericity classes show good agreement with an exponential shape, rather than a Gaussian one.
In this letter, the production of deuterons and anti-deuterons in pp collisions at √s = 7 TeV is studied as a function of the charged-particle multiplicity density at mid-rapidity with the ALICE detector at the LHC. Production yields are measured at mid-rapidity in five multiplicity classes and as a function of the deuteron transverse momentum (pT). The measurements are discussed in the context of hadron–coalescence models. The coalescence parameter B2, extracted from the measured spectra of (anti-)deuterons and primary (anti-)protons, exhibits no significant pT-dependence for pT < 3 GeV/c, in agreement with the expectations of a simple coalescence picture. At fixed transverse momentum per nucleon, the B2 parameter is found to decrease smoothly from low multiplicity pp to Pb–Pb collisions, in qualitative agreement with more elaborate coalescence models. The measured mean transverse momentum of (anti-)deuterons in pp is not reproduced by the Blast-Wave model calculations that simultaneously describe pion, kaon and proton spectra, in contrast to central Pb–Pb collisions. The ratio between the pT-integrated yield of deuterons to protons, d/p, is found to increase with the chargedparticle multiplicity, as observed in inelastic pp collisions at different centre-of-mass energies. The d/p ratios are reported in a wide range, from the lowest to the highest multiplicity values measured in pp collisions at the LHC.
Charged-particle pseudorapidity density at mid-rapidity in p-Pb collisions at √sNN = 8.16 TeV
(2019)
The pseudorapidity density of charged particles, dNch/dη, in p–Pb collisions has been measured at a centre-of-mass energy per nucleon–nucleon pair of sNN−−−√ = 8.16 TeV at mid-pseudorapidity for non-single-diffractive events. The results cover 3.6 units of pseudorapidity, |η|<1.8. The dNch/dη value is 19.1±0.7 at |η|<0.5. This quantity divided by ⟨Npart⟩ / 2 is 4.73±0.20, where ⟨Npart⟩is the average number of participating nucleons, is 9.5% higher than the corresponding value for p–Pb collisions at sNN−−−√ = 5.02 TeV. Measurements are compared with models based on different mechanisms for particle production. All models agree within uncertainties with data in the Pb-going side, while HIJING overestimates, showing a symmetric behaviour, and EPOS underestimates the p-going side of the dNch/dη distribution. Saturation-based models reproduce the distributions well for η>−1.3. The dNch/dη is also measured for different centrality estimators, based both on the charged-particle multiplicity and on the energy deposited in the Zero-Degree Calorimeters. A study of the implications of the large multiplicity fluctuations due to the small number of participants for systems like p–Pb in the centrality calculation for multiplicity-based estimators is discussed, demonstrating the advantages of determining the centrality with energy deposited near beam rapidity.
The transverse structure of jets was studied via jet fragmentation transverse momentum (jT) distributions, obtained using two-particle correlations in proton-proton and proton-lead collisions, measured with the ALICE experiment at the LHC. The highest transverse momentum particle in each event is used as the trigger particle and the region 3 < pTt < 15GeV/c is explored in this study. The measured distributions show a clear narrow Gaussian component and a wide non-Gaussian one. Based on Pythia simulations, the narrow component can be related to non-perturbative hadronization and the wide component to quantum chromodynamical splitting. The width of the narrow component shows a weak dependence on the transverse momentum of the trigger particle, in agreement with the expectation of universality of the hadronization process. On the other hand, the width of the wide component shows a rising trend suggesting increased branching for higher transverse momentum. The results obtained in pp collisions at s√=7 TeV and in p–Pb collisions at sNN−−−√=5.02 TeV are compatible within uncertainties and hence no significant cold nuclear matter effects are observed. The results are compared to previous measurements from CCOR and PHENIX as well as to PYTHIA 8 and Herwig 7 simulations.
We present the first measurements of femtoscopic correlations between the K0 S and K± particles in pp collisions at √s = 7 TeV measured by the ALICE experiment. The observed femtoscopic correlations are consistent with final-state interactions proceeding solely via the a0(980) resonance. The extracted kaon source radius and correlation strength parameters for K0 SK− are found to be equal within the experimental uncertainties to those for K0 SK+. Results of the present study are compared with those from identical-kaon femtoscopic studies also performed with pp collisions at √s = 7 TeV by ALICE andwith a K0 SK± measurement in Pb–Pb collisions at √sNN = 2.76 TeV. Combined with the Pb–Pb results, our pp analysis is found to be compatible with th e interpretation of the a0(980) having a tetraquark structure instead of that of a diquark.
The ALICE Collaboration has measured the energy dependence of exclusive photoproduction of J/ψ vector mesons off proton targets in ultra–peripheral p–Pb collisions at a centre-of-mass energy per nucleon pair sNN−−−√=5.02 TeV. The e+e− and μ+μ− decay channels are used to measure the cross section as a function of the rapidity of the J/ψ in the range −2.5<y<2.7, corresponding to an energy in the γp centre-of-mass in the interval 40<Wγp<550 GeV. The measurements, which are consistent with a power law dependence of the exclusive J/ψ photoproduction cross section, are compared to previous results from HERA and the LHC and to several theoretical models. They are found to be compatible with previous measurements.
Comprehensive results on the production of unidentified charged particles, π±, K±, K0S, K*(892)0, p, p¯¯¯, ϕ(1020), Λ, Λ¯¯¯¯, Ξ−, Ξ¯¯¯¯+, Ω− and Ω¯¯¯¯+ hadrons in proton-proton (pp) collisions at s√ = 7 TeV at midrapidity (|y|<0.5) as a function of charged-particle multiplicity density are presented. In order to avoid auto-correlation biases, the actual transverse momentum (pT) spectra of the particles under study and the event activity are measured in different rapidity windows. In the highest multiplicity class, the charged-particle density reaches about 3.5 times the value measured in inelastic collisions. While the yield of protons normalized to pions remains approximately constant as a function of multiplicity, the corresponding ratios of strange hadrons to pions show a significant enhancement that increases with increasing strangeness content. Furthermore, all identified particle to pion ratios are shown to depend solely on charged-particle multiplicity density, regardless of system type and collision energy. The evolution of the spectral shapes with multiplicity and hadron mass shows patterns that are similar to those observed in p-Pb and Pb-Pb collisions at LHC energies. The obtained pT distributions and yields are compared to expectations from QCD-based pp event generators as well as to predictions from thermal and hydrodynamic models. These comparisons indicate that traces of a collective, equilibrated system are already present in high-multiplicity pp collisions.
The second (v2) and third (v3) flow harmonic coefficients of J/ψ mesons are measured at forward rapidity (2.5 < y < 4.0) in Pb-Pb collisions at sNN−−−√=5.02 TeV with the ALICE detector at the LHC. Results are obtained with the scalar product method and reported as a function of transverse momentum, pT, for various collision centralities. A positive value of J/ψ v3 is observed with 3.7σ significance. The measurements, compared to those of prompt D0 mesons and charged particles at mid-rapidity, indicate an ordering with vn(J/ψ) < vn(D0) < vn(h±) (n = 2, 3) at low and intermediate pT up to 6 GeV/c and a convergence with v2(J/ψ) ≈ v2(D0) ≈ v2(h±) at high pT above 6–8 GeV/c. In semi-central collisions (5–40% and 10–50% centrality intervals) at intermediate pT between 2 and 6 GeV/c, the ratio v3/v2 of J/ψ mesons is found to be significantly lower (4.6σ) with respect to that of charged particles. In addition, the comparison to the prompt D0-meson ratio in the same pT interval suggests an ordering similar to that of the v2 and v3 coefficients. The J/ψ v2 coefficient is further studied using the Event Shape Engineering technique. The obtained results are found to be compatible with the expected variations of the eccentricity of the initial-state geometry.
The production yield of prompt D mesons and their elliptic flow coefficient v2 were measured with the Event-Shape Engineering (ESE) technique applied to mid-central (10–30% and 30–50% centrality classes) Pb-Pb collisions at the centre-of-mass energy per nucleon pair sNN−−−√=5.02 TeV, with the ALICE detector at the LHC. The ESE technique allows the classification of events, belonging to the same centrality, according to the azimuthal anisotropy of soft particle production in the collision. The reported measurements give the opportunity to investigate the dynamics of charm quarks in the Quark-Gluon Plasma and provide information on their participation in the collective expansion of the medium. D mesons were reconstructed via their hadronic decays at mid-rapidity, |η| < 0.8, in the transverse momentum interval 1 < pT < 24 GeV/c. The v2 coefficient is found to be sensitive to the event-shape selection confirming a correlation between the D-meson azimuthal anisotropy and the collective expansion of the bulk matter, while the per-event D-meson yields do not show any significant modification within the current uncertainties.
We report the differential charged jet cross section and jet fragmentation distributions measured with the ALICE detector in proton-proton collisions at a centre-of-mass energy s√= 7 TeV. Jets with pseudo-rapidity |η|<0.5 are reconstructed from charged particles using the anti-kT jet finding algorithm with a resolution parameter R = 0.4. The jet cross section is measured in the transverse momentum interval 5 ≤pchjetT< 100 GeV/c. Jet fragmentation is studied measuring the scaled transverse momentum spectra of the charged constituents of jets in four intervals of jet transverse momentum between 5 GeV/c and 30 GeV/c. The measurements are compared to calculations from the PYTHIA model as well as next-to-leading order perturbative QCD calculations with POWHEG + PYTHIA8. The charged jet cross section is described by POWHEG for the entire measured range of pchjetT. For pchjetT > 40 GeV/c, the PYTHIA calculations also agree with the measured charged jet cross section. PYTHIA6 simulations describe the fragmentation distributions to 15%. Larger discrepancies are observed for PYTHIA8.
The production yield of the Λ(1520) baryon resonance is measured at mid-rapidity in Pb-Pb collisions at sNN−−−√ = 2.76 TeV with the ALICE detector at the LHC. The measurement is performed in the Λ(1520)→pK− (and charge conjugate) hadronic decay channel as a function of the transverse momentum (pT) and collision centrality. The pT-integrated production rate of Λ(1520) relative to Λ in central collisions is suppressed by about a factor of 2 with respect to peripheral collisions. This is the first observation of the suppression of a baryonic resonance at the LHC and the first 3σ evidence of Λ(1520) suppression within a single collision system. The measured Λ(1520)/Λ ratio in central collisions is smaller than the value predicted by the statistical hadronisation model calculations. The shape of the measured pT distribution and the centrality dependence of the suppression are reproduced by the EPOS3 Monte Carlo event generator. The measurement adds further support to the formation of a dense hadronic phase in the final stages of the evolution of the fireball created in heavy-ion collisions, lasting long enough to cause a significant reduction in the observable yield of short-lived resonances.
We present measurements of two-particle differential number correlation functions R2 and transverse momentum correlation functions P2, obtained from p-Pb collisions at 5.02 TeV and Pb-Pb collisions at 2.76 TeV. The results are obtained using charged particles in the pseudorapidity range |η|< 1.0, and transverse momentum range 0.2<pT<2.0 GeV/c as a function of pair separation in pseudorapidity, |Δη|, azimuthal angle, Δφ, and for several charged-particle multiplicity classes. Measurements are carried out for like-sign and unlike-sign charged-particle pairs separately and combined to obtain charge-independent and charge-dependent correlation functions. We study the evolution of the width of the near-side peak of these correlation functions with collision centrality. Additionally, we study Fourier decompositions of the correlators in Δφ as a function of the pair separation |Δη|. Significant differences in the dependence of their harmonic coefficients on multiplicity classes are found. These differences can be exploited, in theoretical models, to obtain further insight into charged-particle production and transport in heavy-ion collisions. Moreover, an upper limit of non-flow contributions to flow coefficients vn measured in Pb-Pb collisions based on the relative strength of Fourier coefficients measured in p-Pb interactions is estimated.
Charged-particle spectra at midrapidity are measured in Pb–Pb collisions at the centre-of-mass energy per nucleon–nucleon pair √sNN = 5.02 TeV and presented in centrality classes ranging from most central (0–5%) to most peripheral (95–100%) collisions. Possible medium effects are quantified using the nuclear modification factor (RAA) by comparing the measured spectra with those from proton–proton collisions, scaled by the number of independent nucleon–nucleon collisions obtained from a Glauber model. At large transverse momenta (8 < pT < 20 GeV/c), the average RAA is found to increase from about 0.15 in 0–5% central to a maximum value of about 0.8 in 75–85% peripheral collisions, beyond which it falls off strongly to below 0.2 for the most peripheral collisions. Furthermore, RAA initially exhibits a positive slope as a function of pT in the 8–20 GeV/c interval, while for collisions beyond the 80% class the slope is negative. To reduce uncertainties related to event selection and normalization, we also provide the ratio of RAA in adjacent centrality intervals. Our results in peripheral collisions are consistent with a PYTHIA-based model without nuclear modification, demonstrating that biases caused by the event selection and collision geometry can lead to the apparent suppression in peripheral collisions. This explains the unintuitive observation that RAA is below unity in peripheral Pb–Pb, but equal to unity in minimum-bias p–Pb collisions despite similar charged-particle multiplicities.
The first measurement of dielectron (e+e−) production in central (0−10%) Pb-Pb collisions at sNN−−−√ = 2.76 TeV at the LHC is presented. The dielectron invariant-mass spectrum is compared to the expected contributions from hadron decays in the invariant-mass range 0<mee<3.5 GeV/c2. The ratio of data and the cocktail of hadronic contributions without vacuum ρ0 is measured in the invariant-mass range 0.15<mee<0.7 GeV/c2, where an excess of dielectrons is observed in other experiments, and its value is 1.40±0.28 (stat.)±0.08 (syst.)±0.27 (cocktail). The dielectron spectrum measured in the invariant mass range 0<mee<1 GeV/c2 is consistent with the predictions from two theoretical model calculations that include thermal dielectron production from both partonic and hadronic phases with in-medium broadened ρ0 meson. The fraction of direct virtual photons over inclusive virtual photons is extracted for dielectron pairs with invariant mass 0.1<mee<0.3 GeV/c2, and in the transverse-momentum intervals 1<pT,ee<2 GeV/c and 2<pT,ee<4 GeV/c. The measured fraction of virtual direct photons is consistent with the measurement of real direct photons by ALICE and with the expectations from previous dielectron measurements at RHIC within the experimental uncertainties.
We report on the first femtoscopic measurement of baryon pairs, such as p−p, p−Λ, and Λ−Λ, measured by ALICE at the Large Hadron Collider (LHC) in proton-proton collisions at √s=7TeV. This study demonstrates the feasibility of such measurements in pp collisions at ultrarelativistic energies. The femtoscopy method is employed to constrain the hyperon-nucleon and hyperon-hyperon interactions, which are still rather poorly understood. A new method to evaluate the influence of residual correlations induced by the decays of resonances and experimental impurities is hereby presented. The p−p, p−Λ, and Λ−Λ correlation functions were fitted simultaneously with the help of a new tool developed specifically for the femtoscopy analysis in small colliding systems: Correlation Analysis Tool using the Schrödinger equation (CATS). Within the assumption that in pp collisions the three particle pairs originate from a common source, its radius is found to be equal to r0=1.125±0.018(stat)+0.058−0.035(syst) fm. The sensitivity of the measured p−Λ correlation is tested against different scattering parameters, which are defined by the interaction among the two particles, but the statistics is not sufficient yet to discriminate among different models. The measurement of the Λ−Λ correlation function constrains the phase space spanned by the effective range and scattering length of the strong interaction. Discrepancies between the measured scattering parameters and the resulting correlation functions at LHC and RHIC energies are discussed in the context of various models.
Angular correlations between heavy-flavour decay electrons and charged particles at mid-rapidity (|η|<0.8) are measured in p-Pb collisions at sNN−−−√ = 5.02 TeV. The analysis is carried out for the 0-20% (high) and 60-100% (low) multiplicity ranges. The jet contribution in the correlation distribution from high-multiplicity events is removed by subtracting the distribution from low-multiplicity events. An azimuthal modulation remains after removing the jet contribution, similar to previous observations in two-particle angular correlation measurements for light-flavour hadrons. A Fourier decomposition of the modulation results in a positive second-order coefficient (v2) for heavy-flavour decay electrons in the transverse momentum interval 1.5<pT<4 GeV/c in high-multiplicity events, with a significance larger than 5σ. The results are compared with those of charged particles at mid-rapidity and of inclusive muons at forward rapidity. The v2 measurement of open heavy-flavour particles at mid-rapidity in small collision systems could provide crucial information to help interpret the anisotropies observed in such systems.
The production of the ρ(770)0 meson has been measured at mid-rapidity (|y|<0.5) in pp and centrality differential Pb-Pb collisions at sNN−−−√ = 2.76 TeV with the ALICE detector at the Large Hadron Collider. The particles have been reconstructed in the ρ(770)→π+π− decay channel in the transverse momentum (pT) range 0.5−11 GeV/c. A centrality dependent suppression of the ratio of the integrated yields 2ρ(770)0/(π++π−) is observed. The ratio decreases by ∼40% from pp to central Pb-Pb collisions. A study of the pT-differential 2ρ(770)0/(π++π−) ratio reveals that the suppression occurs at low transverse momenta, pT<2 GeV/c. At higher momentum, particle ratios measured in heavy-ion and pp collisions are consistent. The observed suppression is very similar to that previously measured for the K∗(892)0/K ratio and is consistent with EPOS3 predictions that may imply that rescattering in the hadronic phase is a dominant mechanism for the observed suppression.
Measurements of inclusive and direct photon production at mid-rapidity in pp collisions at s√=2.76 and 8 TeV are presented by the ALICE experiment at the LHC. The results are reported in transverse momentum ranges of 0.4<pT<10 GeV/c and 0.3<pT<16 GeV/c, respectively. Photons are detected with the electromagnetic calorimeter~(EMCal) and via reconstruction of e+e− pairs from conversions in the ALICE detector material using the central tracking system. For the final measurement of the inclusive photon spectra the results are combined in the overlapping pT interval of both methods. Direct photon spectra, or their upper limits at 90% C.L. are extracted using the direct photon excess ratio Rγ, which quantifies the ratio of inclusive photons over decay photons generated with a decay-photon simulation. An additional hybrid method, combining photons reconstructed from conversions with those identified in the EMCal, is used for the combination of the direct photon excess ratio Rγ, as well as the extraction of direct photon spectra or their upper limits. While no significant signal of direct photons is seen over the full pT range, Rγ for pT>7 GeV/c is at least one σ above unity and consistent with expectations from next-to-leading order pQCD calculations.
Nonerythroid spectrin αII (SPTAN1) is an important cytoskeletal protein that ensures vital cellular properties including polarity and cell stabilization. In addition, it is involved in cell adhesion, cell-cell contact, and apoptosis. The detection of altered expression of SPTAN1 in tumors indicates that SPTAN1 might be involved in the development and progression of cancer. SPTAN1 has been described in cancer and therapy response and proposed as a potential marker protein for neoplasia, tumor aggressiveness, and therapeutic efficiency. On one hand, the existing data suggest that overexpression of SPTAN1 in tumor cells reflects neoplastic and tumor promoting activity. On the other hand, nuclear SPTAN1 can have tumor suppressing effects by enabling DNA repair through interaction with DNA repair proteins. Moreover, SPTAN1 cleavage products occur during apoptosis and could serve as markers for the efficacy of cancer therapy. Due to SPTAN1’s multifaceted functions and its role in adhesion and migration, SPTAN1 can influence tumor growth and progression in both positive and negative directions depending on its specific regulation. This review summarizes the current knowledge on SPTAN1 in cancer and depicts several mechanisms by which SPTAN1 could impact tumor development and aggressiveness.
Introduction: Colorectal cancers (CRCs) deficient in the DNA mismatch repair protein MutL homolog 1 (MLH1) display distinct clinicopathological features and require a different therapeutic approach compared to CRCs with MLH1 proficiency. However, the molecular basis of this fundamental difference remains elusive. Here, we report that MLH1-deficient CRCs exhibit reduced levels of the cytoskeletal scaffolding protein non-erythroid spectrin αII (SPTAN1), and that tumor progression and metastasis of CRCs correlate with SPTAN1 levels.
Methods and results: To investigate the link between MLH1 and SPTAN1 in cancer progression, a cohort of 189 patients with CRC was analyzed by immunohistochemistry. Compared with the surrounding normal mucosa, SPTAN1 expression was reduced in MLH1-deficient CRCs, whereas MLH1-proficient CRCs showed a significant upregulation of SPTAN1. Overall, we identified a strong correlation between MLH1 status and SPTAN1 expression. When comparing TNM classification and SPTAN1 levels, we found higher SPTAN1 levels in stage I CRCs, while stages II to IV showed a gradual reduction of SPTAN1 expression. In addition, SPTAN1 expression was lower in metastatic compared with non-metastatic CRCs. Knockdown of SPTAN1 in CRC cell lines demonstrated decreased cell viability, impaired cellular mobility and reduced cell-cell contact formation, indicating that SPTAN1 plays an important role in cell growth and cell attachment. The observed weakened cell-cell contact of SPTAN1 knockdown cells might indicate that tumor cells expressing low levels of SPTAN1 detach from their primary tumor and metastasize more easily.
Conclusion: Taken together, we demonstrate that MLH1 deficiency, low SPTAN1 expression, and tumor progression and metastasis are in close relation. We conclude that SPTAN1 is a candidate molecule explaining the tumor progression and metastasis of MLH1-deficient CRCs. The detailed analysis of SPTAN1 is now mandatory to substantiate its relevance and its potential value as a candidate protein for targeted therapy, and as a predictive marker of cancer aggressiveness.
Kunstfälschung und Kunstpolemik in Romanen von William Gaddis, Georges Perec und Sergio Kokis
(2019)
Fälschungen haben das Potential, die Institution der Kunst anzugreifen: Indem ein einhellig bewundertes Kunstwerk als Fälschung entlarvt wird, wird nicht nur die Autorität derer, die ihm Echtheit beschieden haben, in Frage gestellt, sondern der Kunstbetrieb als Ganzer. Man kann Fälschungen somit einen kunstpolemischen Charakter zusprechen. [...] Betrachtet man Fälschungen nicht vom moralischen oder ästhetischen Standpunkt aus, sondern als Diskursphänomen, kann man feststellen, dass sie in besonderer Weise die diskursiven Regeln anschaulich machen, die zu ihrer Akzeptanz als echte Werke führen. Im Moment der Aufdeckung der Fälschung wird deutlich, dass das, was bisher als eine Eigenschaft des Werkes betrachtet wurde, auf einer Zuschreibung beruht. [...] An den Reaktionen auf Fälschungen lassen sich daher zeit- und diskursspezifische Gegenentwürfe ablesen, welche um Begriffe kreisen wie Wahrheit, Authentizität und Originalität. [...] Der folgende Beitrag beschäftigt sich jedoch nicht mit realen Kunstfälschungen, sondern mit der Darstellung von Kunstfälschungen in der Literatur. Es wird um mehrere Beispiele für Erzählungen über Kunstfälscher gehen, ein Sujet, das besonders seit der zweiten Hälfte des 20. Jahrhunderts auffallend häufig für die Auseinandersetzung mit Kunst funktionalisiert wird und nicht so sehr zur Diskreditierung einer unlauteren Praxis.
We present the first measurement of the proton–Ω correlation function in heavy-ion collisions for the central (0–40%) and peripheral (40–80%) Au + Au collisions at √sNN = 200 GeV by the STAR experiment at the Relativistic Heavy-Ion Collider (RHIC). Predictions for the ratio of peripheral collisions to central collisions for the proton–Ω correlation function are sensitive to the presence of a nucleon– bound state. These predictions are based on the proton– interaction extracted from (2 + 1)-flavor lattice QCD calculations at the physical point. The measured ratio of the proton–Ω correlation function between the peripheral (small system) and central (large system) collisions is less than unity for relative momentum smaller than 40 MeV/c. Comparison of our measured correlation ratio with theoretical calculation slightly favors a proton– bound system with a binding energy of ∼ 27 MeV.
Quark interactions with topological gluon configurations can induce chirality imbalance and local parity violation in quantum chromodynamics. This can lead to electric charge separation along the strong magnetic field in relativistic heavy-ion collisions – the chiral magnetic effect (CME). We report measurements by the STAR collaboration of a CME-sensitive observable in p + Au and d + Au collisions at 200 GeV, where the CME is not expected, using charge-dependent pair correlations relative to a third particle. We observe strong charge-dependent correlations similar to those measured in heavy-ion collisions. This bears important implications for the interpretation of the heavy-ion data.
J/ψ suppression has long been considered a sensitive signature of the formation of the Quark-Gluon Plasma (QGP) in relativistic heavy-ion collisions. In this letter, we present the first measurement of inclusive J/ψ production at mid-rapidity through the dimuon decay channel in Au+Au collisions at √sNN = 200 GeV with the STAR experiment. These measurements became possible after the installation of the Muon Telescope Detector was completed in 2014. The J/ψ yields are measured in a wide transverse momentum (pT) range of 0.15 GeV/c to 12 GeV/c from central to peripheral collisions. They extend the kinematic reach of previous measurements at RHIC with improved precision. In the 0-10% most central collisions, the J/ψ yield is suppressed by a factor of approximately 3 for pT > 5 GeV/c relative to that in p + p collisions scaled by the number of binary nucleon-nucleon collisions. The J/ψ nuclear modification factor displays little dependence on pT in all centrality bins. Model calculations can qualitatively describe the data, providing further evidence for the color-screening effect experienced by J/ψ mesons in the QGP.
We have identified a mistake in how Fig. 1 is referenced in the text of the article Eur. Phys. J. C 77 (2017) no. 8, 569 which affected three paragraphs of the results section. The corrected three paragraphs as well as the unmodified accompanying figure are reproduced in this document with the correct labeling.
In addition, an editing issue led to a missing acknowledgements section. The missing section is reproduced at the end of this document in the manner in which it should have appeared in the published article.
The Compressed Baryonic Matter (CBM) experiment is a dedicated heavy ion collision experiment at the FAIR facility. It will be one of the first HEP experiments which works in a triggerless mode: data received in the DAQ from the detectors will not be associated with events by a hardware trigger anymore. All raw data within a giventime period will be collected continuously in containers, so-called time-slices. The task of the reconstruction algorithms is to create events out of this raw data stream. In this contribution, the optimization of the reconstruction software in the RICH detector to the free-streaming data flow is presented. The implementation of ring reconstruction algorithms which use time measurements of the hits as an additional parameter is discussed.
We present first data on sub-threshold production of Ks0 mesons and Λ hyperons in Au+Au collisions at sNN=2.4 GeV. We observe an universal 〈Apart〉 scaling of hadrons containing strangeness, independent of their corresponding production thresholds. Comparing the yields, their 〈Apart〉 scaling, and the shapes of the rapidity and the pt spectra to state-of-the-art transport model (UrQMD, HSD, IQMD) predictions, we find that none of them can simultaneously describe these observables with reasonable χ2 values.
We investigate identical pion HBT intensity interferometry in central Au+Au collisions at 1.23A GeV. High-statistics π−π− and π+π+ data are measured with HADES at SIS18/GSI. The radius parameters, derived from the correlation function depending on relative momenta in the longitudinally comoving system and parametrized as three-dimensional Gaussian distribution, are studied as function of transverse momentum. A substantial charge-sign difference of the source radii is found, particularly pronounced at low transverse momentum. The extracted source parameters agree well with a smooth extrapolation of the center-of-mass energy dependence established at higher energies, extending the corresponding excitation functions down towards a very low energy.
We present three-particle mixed-harmonic correlations 〈cos(mφa + nφb − (m + n)φc )〉 for harmonics m, n = 1 − 3 for charged particles in √sN N = 200 GeV Au+Au collisions at RHIC. These measurements provide information on the three-dimensional structure of the initial collision zone and are important for constraining models of a subsequent low-viscosity quark–gluon plasma expansion phase. We investigate correlations between the first, second and third harmonics predicted as a consequence of fluctuations in the initial state. The dependence of the correlations on the pseudorapidity separation between particles show hints of a breaking of longitudinal invariance. We compare our results to a number of state-of-the art hydrodynamic calculations with different initial states and temperature dependent viscosities. These measurements provide important steps towards constraining the temperature dependent viscosity and longitudinal structure of the initial state at RHIC.
(Coumarin‐4‐yl)methyl (c4m) and p‐hydroxyphenacyl (pHP)‐based compounds are well known for their highly efficient photoreactions, but often show limited solubility in aqueous media. To circumvent this, we synthesized and characterized the two new c4m and pHP‐based photoacid generators (PAGs), 7‐[bis(carboxymethyl)amino]‐4‐(acetoxymethyl)coumarin (c4m‐ac) and p‐hydroxyphenacyl‐2,5,8,11‐tetraoxatridecan‐13‐oate (pHP‐t), and determined their solubilities, stabilities and photolysis in aqueous media. The two compounds showed high solubilities in water of 2.77 mmol L−1±0.07 mmol L−1 (c4m‐ac) and 124.66 mmol L−1±2.1 mmol L−1 (pHP‐t). In basic conditions at pH 9, solubility increased for c4m‐ac to 646.46 mmol L−1±0.63 mmol L−1, for pHP‐t it decreased to 34.68 mmol L−1±0.62 mmol L−1. Photochemical properties of the two PAGs, such as the absorption maxima, the maximum molar absorption coefficients and the quantum yields, were found to be strongly pH‐dependent. Both PAGs showed high stabilities s24h ≥95 % in water for 24 h, but decreasing stability with increasing pH value due to hydrolysis. The present study contributes to a clearer insight into the synthesis, solubilities, stabilities, and photolysis of c4m and pHP‐based PAGs for further photochemical applications when high PAG concentrations are required, such as in polymeric foaming.
Previous studies in patients with single-sided deafness (SSD) have reported results of pitch comparisons between electric stimulation of their cochlear implant (CI) and acoustic stimulation presented to their near-normal hearing contralateral ear. These comparisons typically used sinusoids, although the percept elicited by electric stimulation may be closer to a wideband stimulus. Furthermore, it has been shown that pitch comparisons between sounds with different timbres is a difficult task and subjected to various types of range biases. The present study aims to introduce a method to minimize non-sensory biases, and to investigate the effect of different acoustic stimulus types on the frequency and variability of the electric-acoustic pitch matches. Pitch matches were collected from 13 CI users with SSD using the binary search procedure. Electric stimulation was presented at either an apical or a middle electrode position, at a rate of 800 pps. Acoustic stimulus types were sinusoids (SINE), 1/3-octave wide narrow bands of Gaussian noises (NBN), or 1/3-octave wide pulse spreading harmonic complexes (PSHC). On the one hand, NBN and PSHC are presumed to better mimic the spread of excitation produced by a single-electrode stimulation than SINE. On the other hand, SINE and PSHC contain less inherent fluctuations than NBN and may therefore provide a temporal pattern closer to that produced by a constant-amplitude electric pulse train. Analysis of mean pitch match variance showed no differences between stimulus types. However, mean pitch matches showed effects of electrode position and stimulus type, with the middle electrode always matched to a higher frequency than the apical one (p < 0.001), and significantly higher across-subject pitch matches for PSHC compared with SINE (p = 0.017). Mean pitch matches for all stimulus types were better predicted by place-dependent characteristic frequencies (CFs) based on an organ of Corti map compared with a spiral ganglion map. CF predictions were closest to pitch matches with SINE for the apical electrode position, and conversely with NBN or PSHC for the middle electrode position. These results provide evidence that the choice of acoustic stimulus type can have a significant effect on electric-acoustic pitch matching.
In diesem Beitrag wird ein hochschuldidaktisches Konzept zur Förderung des reflektierten Umgangs mit Heterogenität im schulischen Kontext unter Verwendung digitaler Lerneinheiten vorgestellt. Im Projekt "Level – Lehrkräftebildung vernetzt entwickeln" (Qualitätsoffensive Lehrerbildung BMBF, Goethe-Universität Frankfurt) wurden in den Bildungswissenschaften digitale Lerneinheiten zu den Heterogenitätsdimensionen "Geschlecht", "kultureller Hintergrund", "sozio-ökonomischer Hintergrund", "kognitiv-motivationale Lernvor-aussetzungen" und "Behinderung" konzipiert und in der universitären Lehre erprobt. Die Auswahl der erstellten Lerneinheiten begründet sich auf Ergebnissen der PISA-Studien sowie der UN-Behindertenrechtskonvention. Die Lerneinheiten werden in Blended-Learning-Szenarien eingesetzt und zielen auf den Aufbau von Fachwissen und professionellen Überzeugungen sowie Reflexivität. Auf der Grundlage individuellen Vorwissens werden von den Lernenden (videobasierte) Aufgaben bearbeitet, die der Perspektivübernahme und Selbstreflexion im Hinblick auf Kategorisierungen dienen und die Bearbeitung fachwissenschaftlicher Texte und aktueller Studien beinhalten. Arbeitsergebnisse können digital im Peer-Feedback bearbeitet sowie mit einem digitalen Portfolio verbunden werden. Das Onlineformat ermöglicht die fächer- und phasenübergreifende Nutzung durch Dozierende sowie Ausbilder_innen an Studienseminaren. Zusätzlich zu den fünf Lerneinheiten wurden eine einführende Version für Studierende und eine erweiterte Version für Lehrende erstellt, die einen Einblick in Aufbau und Struktur des Formats gibt und als "pädagogischer Doppeldecker" konzipiert ist. Die formative Evaluation mit Lehramtsstudierenden und Ausbilder_innen ergab positive Ergebnisse hinsichtlich der Einsetzbarkeit der Lerneinheiten in der Lehramtsausbildung.
Ця розмова соціяльного філософа Теодора Адорно, представника критичної теорії суспільства, з Гельмутом Бекером, політичним публіцистом і теоретиком освіти, відбулася 1966 року й була опублікована у збірці філософського-освітніх робіт Теодора Адорно, що мала назву «Виховання до повноліття». У цій розмові Адорно та Бекер критично розглянули множину аспектів тодішньої західнонімецької освіти, яка, на їхнє переконання, не виконувала власне основне завдання – своєю роботою вона не сприяла представникам західнонімецького юнацтва стати соціяльно активними людьми. За Адорно та Бекером, тодішня освіта не виховувала їх як членів демократичного суспільства, як людей, котрі мусять самостійно застосовувати власний розум у суспільстві, демократичні зміни в якому повинні мати сталий характер. Розмірковуючи про мету правильного виховання, ці німецькі інтелектуали визначили суть демократії втіленням такого політичного врядування, котре вимагає активного застосування свого розуму будь-яким членом суспільства. Таким чином, свідомість окремої людини, активізована виховним впливом на себе освіти, що розуміє правильну мету своєї роботи, здатна протистояти впливу на себе соціяльної ідеології конформістського суспільства, реальність якого має виразні ознаки культурної стаґнації. Таку людину Адорно та Бекер погодилися називали повнолітньою людиною. Однак, на їхню думку, освіта, що тримається традиційних засад виховання зумовлює формування такої раціональної адаптації людини до соціяльного світу, що лише збільшує міру її конформізму. Також вони назвали наслідком впливу цієї соціяльної ідеології на свідомість людини її нездатність триматися досвіду, отриманого нею в суспільстві, що її уречевлює. Тому ці німецькі інтелектуали звернули свою увагу на явище первинного, дошкільного виховання дитини, зауважили також й особливости періоду статевого дозрівання, запропонувавши розуміти їх можливими чинниками успішного подолання засобів традиційного виховання. Адорно та Бекер вважали, що нова освіта, здійснюючи оновлене виховання, мусить дієво застосовувати у своєму процесі спонтанність особистого мислення людини. Водночас ця єдність освіти та виховання, дієво уможливлюючи процес індивідуації окремої людини, руйнуватиме ідеологічну тенденцію збереження у вихованні принципу антиіндивідуалізму. Останнє відбуватиметься завдяки активній участи нового індивідуума, людини, яка здатна чинити свідомий опір будь-яким ідеологічним впливам на колективну свідомість суспільства.
Український переклад роботи німецького філософа-неомарксиста Теодора Адорно «Виховання після Аушвіца» присвячений 75-тій річниці визволення в’язнів нацистського концентраційного табору Аушвіц. У цій роботі, яку Теодор Адорно зачитав як доповідь на Гесенському радіо 18-го квітня 1966 року, була продовжена попередня тема особливого значення – плекання в посттоталітарному суспільстві нової, антиідеологічної освіти як засобу гуманістичного виховного впливу на нього. Теодор Адорно запропонував своїм слухачам убачати як гуманістичну потребу для посттоталітарного суспільства поширення в його культурному просторі через освіту особистого розуміння кожною людиною власної провини за трагедію Аушвіца. На переконання філософа, у такий спосіб уможливлюється відновлення цивілізованости співбуття людини та суспільства, а також це унеможливить повторення жахіть концентраційного табору Аушвіц. Иншим чинником, що має не допустити повернення злочинів Аушвіца, Теодор Адорно назвав наявність знання про ґенезу авторитарного характеру, який є соціально-психологічною причиною страждань безневинних людей. Розглянувши соціокультурні та антропологічні чинники виникнення авторитарного характеру, Адорно визначив безсумнівну психологічну залежність носіїв маніпулятивного характеру від авторитарної влади. Витоки останньої німецький філософ знаходить в наявному стані европейської культури як такої, що втратила духовну енерґію, потрібну для власних перетворень. Відповідно до своїх основних філософсько-освітніх переконань, Адорно постулював нову освіту як антиідеологічне просвітництво, як знання, яке виховує насамперед політично обізнаного молодого громадянина, як дієвий засіб, що перешкоджає поверненню авторитарної влади, а отже й повторенню Аушвіца.
Статтю «Нотатка про гуманітарну науку та освіту» німецький соціяльний філософ Теодор Адорно, представник критичної теорії суспільства, опублікував 1962 року. У цій філософсько-освітній роботі Теодор Адорно продовжив попередню тему свого критичного розгляду цілісної єдности елементів культури індустріально-масового соціуму, які сприяють утвердженню в суспільству його ідеології як цілком панівної. На переконання Теодора Адорно, сукупний вплив тих елементів, зокрема, культуріндустрії, системної філософії, науково орієнтованого пізнання тощо на колективну свідомість західних європейців виконує функцію дієвого чинника владного контролю над їхнім спільним життям. У своїх філософсько-освітніх творах Теодор Адорно здійснив також критичний напад на шкільну та університетську освіту повоєнної Західної Німеччини. Ця освіта, на думку філософа, залишається традиційно незмінною, що унеможливлює будь-які серйозні антиідеологічні перетворення в її системі. Такі зміни завдяки оновленому освітньому процесу сприяли б вихованню молодого громадянина, свідомого й активного учасника демократичних перетворень у посттоталітарному суспільстві. Однак, за Теодором Адорно, освітній процес у нереформованому університеті залишається керованим передовсім носіями сцієнтичної свідомості, що жодним чином не сприяє антиідеологічному вихованню студентів. У цій роботі Теодор Адорно зауважив особливе значення для освіти гуманітарних наук, які німецькою мовою перекладають як «науки про дух», традиційно присутніх у німецькій університетській освіті. На його переконання, гуманітарні науки, як науки про дух, через превалювання в освітньому процесі «диктату наукового ідеалу» втратили присутність у собі чинника індивідуального духу людини. Ознаками наявності того явища в університетській освіті Теодор Адорно назвав: абсолютний пріоритет серед гуманітарних студій досліджень наукового характеру, відсутність особистої педагогічної роботи викладача зі студентом-гуманітарієм, тенденція боротьби носія уречевленої наукової свідомости проти будь-якого відмінного знання, єдність соціяльного та теоретичного конформізму носія тої сцієнтичної свідомості. Як і в инших своїх філософських роботах Теодор Адорно запропонував убачати особисту діяльність людини, зумовлену силою її індивідуального духу, тим природним чинником, який здатний вести безупинну особисту боротьбу з тими неґативними явищами в освіти, що заводять на ідеологічні манівці освітній процес в університеті та в освіті загалом.
Свою роботу «Актуальність філософії» молодий філософ-неомарксист Теодор Адорно прочитав улітку 1931 року як лекцію, вступаючи на посаду приват-доцента Франкфуртського університету імені Йогана Вольфґанґа Ґете. У цій лекції Т. Адорно критично проаналізував філософію позитивізму, неокантіанство, філософію життя та феноменологічне вчення Едмунда Гуссерля, ідейно впливових течій і шкіл німецької філософії, що мали статус панівного теоретичного знання в суспільстві. Також Т. Адорно здійснив неомарксистську критику онтологічних проєктів таких німецьких філософів, як Макс Шелер та Мартін Гайдеґґер, які зазнали ідейного впливу Гуссерлевого вчення. На переконання Т. Адорно, ці онтологічні проекти через первинну присутність у них ірраціоналістичних елементів існування людини формують таку манеру суб’єктивного мислення, що не спроможне дієво поєднати його суб’єкта із зовнішньою дійсністю. Іншим об’єктом критики Т. Адорно була філософія Віденського гуртка, яка, на його переконання, хоча й переймалася розглядом людини як суб’єкта емпіричного пізнання, однак не зауважила дійсну суть його існування як історичної істоти. Неомарксист Т. Адорно запропонував убачати спільний сцієнтизм феноменології, філософії емпіріокритицизму та Віденського гуртка такою теоретичною тенденцією, котра неспроможна надавати аподиктичні відповіді на основні, сутнісні питання людського буття як історично плинного. Тим самим ця теорія доводить свою ідейну недосконалість, а також й історичну неактуальність. Виходячи зі своєї критики цієї філософії, Т. Адорно запропонував власне, неомарксистське бачення філософії, котра мусить замінити попередню філософію як панівну в суспільстві. Ця нова, матеріалістична теорія, що перебуває в буттєвому діалектичному зв’язку із соціальною практикою, має сприяти самостійному тлумаченню суб’єктом буттєвих сенсів та історичних картин, що формує за допомогою понять його розуміння соціальної дійсності як історичної, і водночас вона мусить ідейно скасовувати претензії будь-якої філософії на статус офіційної теорії. У цій лекції Т. Адорно також представив ідейний задум свого вчення про людське буття, суть якого у зміненому вигляді він пізніше експлікував у «Негативній діалектиці» (1966), своєму головному філософському творі.
Chimeric antigen receptor (CAR) T cells are in prime focus of current research in cancer immunotherapy. Facilitating CAR T cell generation is among the top goals. We have recently demonstrated direct in vivo generation of human CD19-CAR T cells by targeting CD8+ cells using lentiviral vectors (LVs). The anti-tumor potency of in vivo generated CAR T cells was assessed in human PBMC-transplanted NSG mice carrying i.v. injected CD19+ Nalm-6 tumor cells. A single injection of CD8-targeted LV delivering CD19-CAR was sufficient to completely eliminate the tumor cells from bone marrow and spleen, whereas control animals contained high levels of CD19+ cells. Tumor elimination was due to in vivo generated CAR+ cells. Notably, these were not only composed of T lymphocytes but also included CAR+ natural killer cells (NK and NKT). This is the first demonstration of tumor elimination by in vivo generated human CAR T cells.
Purpose: To evaluate if repeat Descemet membrane endothelial keratoplasty (DMEK) is appropriate to achieve functional improvements in patients with corneal decompensation from secondary graft failure after primary DMEK.
Methods: This is a retrospective monocentric cohort study including 13 eyes of 13 patients with repeat DMEK for corneal decompensation following primary DMEK. Eyes with primary DMEK only and comparable preoperative corrected distance visual acuity (CDVA) served as control. Main outcome parameter was CDVA. Secondary outcome measures were central corneal thickness (CCT), endothelial cell density, and rebubbling rate (RR).
Results: The average time interval (±SD) between primary and secondary DMEK was 12.5±6 months. Preoperative CDVA (logMAR) was 1.97±0.90 in the repeat DMEK group and 1.38±0.92 in the primary DMEK group. At 6 months, both groups showed significant improvement in visual acuity (repeat DMEK group, 0.49±0.35, P<0.01 and primary DMEK group, 0.40±0.36, P<0.01). CDVA did not differ significantly between both groups at all time points examined (1, 3, and 6 months postoperatively). Mean CCT values at 3 and 6 months postoperatively did not differ significantly between the two groups (P>0.05). The RR was
23% (n=3) in both groups.
Conclusion: Repeat DMEK is a useful therapeutic approach in the setting of corneal decompensation following primary DMEK. Functional results of repeat DMEK, visual acuity in particular, are comparable to patients with single DMEK only.
Purpose: To investigate the efficacy and safety of Descemet membrane endothelial keratoplasty (DMEK) for corneal decompensation following primary Descemet stripping automated endothelial keratoplasty (DSAEK).
Methods: This was a retrospective case series of 15 patients that underwent DMEK surgery for corneal decompensation after failed DSAEK. Main outcome parameter was corrected distance visual acuity (CDVA) after DMEK and DSAEK. Secondary outcome measures included central corneal thickness (CCT), endothelial cell density (ECD), rebubbling rate, and primary graft failure after DMEK. Explanted DSAEK grafts were evaluated by light microscopy.
Results: The mean (±SD) time period between DSAEK and DMEK surgery was 15±8 months (range, 6–31 months). Preoperative CDVA was 1.72±0.62 (logMAR). After DMEK, CDVA improved significantly to 0.78±0.48 at 1 month and to 0.23±0.24 after 12 months (P=0.022). Visual acuity data after DMEK were significantly better compared to preoperative values. The average CCT after DMEK decreased significantly from 869±210 µm (preoperative) to 505±45 µm (1 month postoperative) (P<0.001) and remained stable over 12 months. The ECD decreased from 2,589±209/mm2 (preoperative) to 1,691±589/mm2 (12 months postoperative). Rebubbling DMEK was required in three patients (=20%).
Conclusion: DMEK represents a feasible and safe procedure in achieving better functional results compared to DSAEK. Visual acuity and optical quality can be effectively reestablished after unsuccessful primary DSAEK surgery even in patients with long-standing corneal decompensation. Further investigations are required to validate the preliminary clinical findings.
Freund oder Feind?
(2019)
Bemühen wir uns um einen nüchternen Blick auf die "Fakten". Ein Hochschulprofessor betritt von Protesten begleitet einen Hörsaal, um seine Vorlesung zu halten. Aufgrund lauter Beschimpfungen und Störungen kann er diese Vorlesung nicht halten und verlässt den Campus schließlich zwei Stunden später unter Polizeischutz. Es handelt sich nicht um irgendeinen Professor, sondern um den Mann, der eine Partei gründete, vordergründig, um den Austritt Deutschlands aus der Eurozone zu erreichen und der auf der Pegida-Welle reitend eine rechtspopulistische Partei hervorbrachte, die ihre Umfragewerte von Unzufriedenheit und Enttäuschung nährt. Seit 2015 gehört er dieser Partei nicht mehr an. Samthandschuhe hat Bernd Lucke deswegen noch lange nicht verdient. Wie weit sollte aber der grundsätzlich berechtigte Protest gegen Lucke gehen?
Anaerobic ammonium oxidation (anammox) is a major process in the biogeochemical nitrogen cycle in which nitrite and ammonium are converted to dinitrogen gas and water through the highly reactive intermediate hydrazine. So far, it is unknown how anammox organisms convert the toxic hydrazine into nitrogen and harvest the extremely low potential electrons (−750 mV) released in this process. We report the crystal structure and cryo electron microscopy structures of the responsible enzyme, hydrazine dehydrogenase, which is a 1.7 MDa multiprotein complex containing an extended electron transfer network of 192 heme groups spanning the entire complex. This unique molecular arrangement suggests a way in which the protein stores and releases the electrons obtained from hydrazine conversion, the final step in the globally important anammox process.
We calculate ratios of higher-order susceptibilities quantifying fluctuations in the number of net-protons and in the net-electric charge using the Hadron Resonance Gas (HRG) model. We take into account the effect of resonance decays, the kinematic acceptance cuts in rapidity, pseudo-rapidity and transverse momentum used in the experimental analysis, as well as a randomization of the isospin of nucleons in the hadronic phase. By comparing these results to the latest experimental data from the STAR Collaboration, we determine the freeze-out conditions from net-electric charge and net-proton distributions and discuss their consistency.
This paper deals with complex prefix-particle structures like aberkennen in German. First, it presents a scheme to analyse these double complex words from a synchronic point of view. Second, it is shown for words with ab-, that this type of word formation is typical for Middle and Early Modern High German and reasons for the decrease are discussed.
Measurement of the 244Cm and 246Cm neutron-induced capture cross sections at the n_TOF facility
(2019)
The neutron capture reactions of the 244Cm and 246Cm isotopes open the path for the formation of heavier Cm isotopes and heavier elements such as Bk and Cf in a nuclear reactor. In addition, both isotopes belong to the minor actinides with a large contribution to the decay heat and to the neutron emission in irradiated fuels. There are only two previous 244Cm and 246Cm capture cross section measurements: one in 1969 using a nuclear explosion [1] and the most recent data measured at J-PARC in 2010 [2]. The data for both isotopes are very scarce due to the difficulties in performing the measurements: high intrinsic activity of the samples and limited facilities capable of providing isotopically enriched samples.
We have measured both neutron capture cross sections at the n_TOF Experimental Area 2 (EAR-2) with three C6 D6 detectors and also at Area 1 (EAR-1) with the TAC. Preliminary results assessing the quality and limitations (back-ground subtraction, measurement technique and counting statistics) of this new experimental datasets are presented and discussed.
This article unpacks Margarete Susman’s political and theological arguments at the core of her reading of the Book of Job. As I show through a reading of her oeuvre, Susman rejects political projects that she takes to be based on eschatology such as political Zionism. However, Susman should not be viewed merely as a critic of Zionism. I argue that an analysis tuned to the historical circumstances of her writing should recognize her stance on the nation-building project in Palestine as ambivalent rather than antagonistic. Susman’s conception of the Jewish spirit as rooted in self-sacrifice allows her to appreciate the national aspirations at the core of the Zionist project while rejecting Zionism’s exclusion of other Jewish national projects. I contend that Susman’s understanding of Jewish messianism as immanent rather than teleological informs her ambivalence toward Zionism as well as her original vision of Jewish political action. I argue in closing that Susman’s theodicy offers a novel vision for Jewish ethics that is not limited to the historical moment of its formulation. Susman’s theodicy also resonates within contemporary debates on Jewish diaspora in providing a non-centralized vision of Jewish national projects.
Current metabolomics approaches utilize cellular metabolite extracts, are destructive, and require high cell numbers. We introduce here an approach that enables the monitoring of cellular metabolism at lower cell numbers by observing the consumption/production of different metabolites over several kinetic data points of up to 48 hours. Our approach does not influence cellular viability, as we optimized the cellular matrix in comparison to other materials used in a variety of in‐cell NMR spectroscopy experiments. We are able to monitor real‐time metabolism of primary patient cells, which are extremely sensitive to external stress. Measurements are set up in an interleaved manner with short acquisition times (approximately 7 minutes per sample), which allows the monitoring of up to 15 patient samples simultaneously. Further, we implemented our approach for performing tracer‐based assays. Our approach will be important not only in the metabolomics fields, but also in individualized diagnostics.
Current metabolomics approaches utilize cellular metabolite extracts, are destructive, and require high cell numbers. We introduce here an approach that enables the monitoring of cellular metabolism at lower cell numbers by observing the consumption/production of different metabolites over several kinetic data points of up to 48 hours. Our approach does not influence cellular viability, as we optimized the cellular matrix in comparison to other materials used in a variety of in‐cell NMR spectroscopy experiments. We are able to monitor real‐time metabolism of primary patient cells, which are extremely sensitive to external stress. Measurements are set up in an interleaved manner with short acquisition times (approximately 7 minutes per sample), which allows the monitoring of up to 15 patient samples simultaneously. Further, we implemented our approach for performing tracer‐based assays. Our approach will be important not only in the metabolomics fields, but also in individualized diagnostics.
Leigh syndrome is one of the most common neurological phenotypes observed in pediatric mitochondrial disease presentations. It is characterized by symmetrical lesions found on neuroimaging in the basal ganglia, thalamus, and brainstem and by a loss of motor skills and delayed developmental milestones. Genetic diagnosis of Leigh syndrome is complicated on account of the vast genetic heterogeneity with >75 candidate disease-associated genes having been reported to date. Candidate genes are still emerging, being identified when “omics” tools (genomics, proteomics, and transcriptomics) are applied to manipulated cell lines and cohorts of clinically characterized individuals who lack a genetic diagnosis. NDUFAF8 is one such protein; it has been found to interact with the well-characterized complex I (CI) assembly factor NDUFAF5 in a large-scale protein-protein interaction screen. Diagnostic next-generation sequencing has identified three unrelated pediatric subjects, each with a clinical diagnosis of Leigh syndrome, who harbor bi-allelic pathogenic variants in NDUFAF8. These variants include a recurrent splicing variant that was initially overlooked due to its deep-intronic location. Subject fibroblasts were found to express a complex I deficiency, and lentiviral transduction with wild-type NDUFAF8-cDNA ameliorated both the assembly defect and the biochemical deficiency. Complexome profiling of subject fibroblasts demonstrated a complex I assembly defect, and the stalled assembly intermediates corroborate the role of NDUFAF8 in early complex I assembly. This report serves to expand the genetic heterogeneity associated with Leigh syndrome and to validate the clinical utility of orphan protein characterization. We also highlight the importance of evaluating intronic sequence when a single, definitively pathogenic variant is identified during diagnostic testing.
Environmental niche modelling is an acclaimed method for estimating species’ present or future distributions. However, in marine environments the assembly of representative data from reliable and unbiased occurrences is challenging. Here, we aimed to model the environmental niche and distribution of marine, parasitic nematodes from the Pseudoterranova decipiens complex using the software Maxent. The distribution of these potentially zoonotic species is of interest, because they infect the muscle tissue of host species targeted by fisheries. To achieve the best possible model, we used two different approaches. The land distance (LD) model was based on abiotic data, whereas the definitive host distance (DHD) model included species-specific biotic data. To assess whether DHD is a suitable descriptor for Pseudoterranova spp., the niches of the parasites and their respective definitive hosts were analysed using ecospat. The performance of LD and DHD was compared based on the variables’ contribution to the model. The DHD-model clearly outperformed the LD-model. While the LD-model gave an estimate of the parasites’ niches, it only showed the potential distribution. The DHD-model produced an estimate of the species’ realised distribution and indicated that biotic variables can help to improve the modelling of data-poor, marine species.
Compartmentalization of immune response and microbial translocation in decompensated cirrhosis
(2019)
Background: Acquired dysfunctional immunity in cirrhosis predisposes patients to frequent bacterial infections, especially spontaneous bacterial peritonitis (SBP), leading to systemic inflammation that is associated with poor outcome. But systemic inflammation can also be found in the absence of a confirmed infection. Detection of bacterial DNA has been investigated as a marker of SBP and as a predictor of prognosis. Data is, however, contradictory. Here we investigated whether levels of IL-6 and IL-8 putatively produced by myeloid cells in ascites are associated with systemic inflammation and whether inflammation depends on the presence of specific bacterial DNA.
Methods and Materials: We enrolled 33 patients with decompensated liver cirrhosis from whom we collected paired samples of blood and ascites. IL-6 and IL-8 were measured in serum samples of all patients using ELISA. In a subset of 10 representative patients, bacterial DNA was extracted from ascites and whole blood, followed by 16S rRNA gene amplicon sequencing.
Results: There were significantly higher levels of IL-6 in ascites fluid compared to blood samples in all patients. Interestingly, IL-6 levels in blood correlated tightly with disease severity and surrogates of systemic inflammation, while IL-6 levels in ascites did not. Moreover, patients with higher blood CRP levels showed greater SBP prevalence compared to patients with lower levels, despite similar positive culture results. Bacterial richness was also significantly higher in ascites compared to the corresponding patient blood. We identified differences in microbial composition and diversity between ascites and blood, but no tight relationship with surrogates of systemic inflammation could be observed.
Discussion: In decompensated cirrhosis, markers of systemic inflammation and microbiota composition seem to be dysregulated in ascites and blood. While a relationship between systemic inflammation and microbiota composition seems to exist in blood, this is not the case for ascites in our hands. These data may suggest compartmentalization of the immune response and interaction of the latter with the microbiota especially in the blood compartment.
AS WE INCREASINGLY RELY ON SEARCH ENGINES AS AN IMPORTANT SOURCE OF INFORMATION TO SUPPORT OUR DECISIONS, SEARCH ENGINES BECAME AN IMPORTANT VENUE FOR FIRMS TO ATTRACT ATTENTION AND SECURE THE LONGEVITY OF THEIR OPERATIONS. THIS ARTICLE DISCUSSES THE RESULTS OF OUR EMPIRICAL STUDIES ON HOW TO CAPTURE A FIRM’S VISIBILITY IN ORGANIC SEARCH AND HOW IT AFFECTS ITS SHORT- AND LONG-TERM FINANCIAL PERFORMANCE.
Since antiquity, poetry and music in the Near East have been interrelated and were believed to have extraordinary powers. Both the context in which oral poetry is set, and the musically induced state of enchantment or ecstasy it produces, are defined in Arabic by the word 'ṭarab'. This article aims to provide an exhaustive definition of this concept, as well as a brief introduction to the artistic domain that encompasses extemporary performance of songs/poems, from the pre-Islamic period up until our modern era. Drawing on literary excerpts, the article attempts to highlight how music, literary performance and aesthetic emotion are amalgamated through the holistic experience of 'ṭarab', which has maintained its basic features virtually unchanged from the days of Ǧāhiliyya until the golden age of Umm Kulthum.
Introduction: Observational studies have demonstrated an association between vitamin D deficiency and increased risk of morbidity and mortality in critically ill patients. Cohort studies and pilot trials have suggested promising beneficial effects of vitamin D replacement in the critical ill, at least in patients with severe vitamin D deficiency. As vitamin D is a simple, low-cost and safe intervention, it has potential to improve survival in critically ill patients.
Methods and analysis: In this randomised, placebo-controlled, double-blind, multicentre, international trial, 2400 adult patients with severe vitamin D deficiency (25-hydroxyvitamin D≤12 ng/mL) will be randomised in a 1:1 ratio by www.randomizer.at to receive a loading dose of 540 000 IU cholecalciferol within 72 hours after intensive care unit (ICU) admission, followed by 4000 IU daily for 90 days or placebo. Hypercalcaemia may occur as a side effect, but is monitored by regular checks of the calcium level. The primary outcome is all-cause mortality at 28 days after randomisation. Secondary outcomes are: ICU, hospital, 90-day and 1-year mortality; hospital and ICU length of stay, change in organ dysfunction on day 5 as measured by Sequential Organ Function Assessment (SOFA) score, number of organ failures; hospital and ICU readmission until day 90; discharge destination, self-reported infections requiring antibiotics until day 90 and health-related quality of life. Recruitment status is ongoing.
Ethics and dissemination: National ethical approval was obtained by the Ethics Committee of the University of Graz for Austria, Erasme University Brussels (Belgium) and University Hospital Frankfurt (Germany), and will further be gained according to individual national processes. On completion, results will be published in a peer-reviewed scientific journal. The study findings will be presented at national and international meetings with abstracts online.
Trial registration: NCT03188796, EudraCT-No: 2016-002460-13.
Anna Ananieva und Rolf Haaser zeigen in ihrem Beitrag über den Gymnasialreformer Hermann Köchly, mit welchen Herausforderungen der Einsatz für eine liberale Reform des Gymnasialwesens, das in den 1840er Jahren als überkommen und fragwürdig diskutiert wurde, konfrontiert war. Köchly gründete den demokratisch strukturierten Dresdener Gymnasialverein und damit einen Diskursraum, in dem schulreformerische Pläne kontrovers diskutiert werden konnten und in dem sogar Pläne eines eigenen Mustergymnasiums geschmiedet wurden, die sich wegen des Widerstands der Behörden jedoch nicht umsetzen ließen. In Dresden, das macht der Beitrag deutlich, "verschob sich sichtbar das gesellschaftliche Verständnis des Erziehungswesens von der autokratischen Zuständigkeit des Staates hin zu einer kollektiven Angelegenheit der gebildeten Öffentlichkeit, die sich keineswegs nur aus dem Bildungsbürgertum rekrutierte".
Hepatitis B virus (HBV) reactivation in immunosuppressed patients can cause considerable morbidity and mortality. The aim of our study was to evaluate factors associated with acute liver failure (ALF) in HBV reactivation. Clinical, laboratory, and virological data of 87 patients with HBV reactivation were analyzed retrospectively. Teno torque virus (TTV) plasma loads were measured as a measure of immune competence. HBV genomes isolated from 47 patients were analyzed by next-generation sequencing. A functional analysis of identified HBsAg mutants was performed. In patients with ALF the diagnosis was significantly later confirmed than in the non-ALF group. Patients diagnosed during immunosuppression had a milder clinical course compared to later diagnosed patients (p = 0.018, OR = 4.17). TTV viral loads did not differ significantly between the two groups. The HBV genomes isolated from ALF patients had higher viral complexity. A mutation in C-region of HBsAg (L216*), was associated with reduced HBsAg production and secretion. Patients diagnosed with HBV reactivation during immunosuppression had a milder clinical course compared to patients diagnosed during immune reconstitution. ALF was associated with higher viral complexity. An HBsAg mutation (L216*) was found to be more frequent in ALF patients and was associated with reduced HBsAg production and secretion.
Este artigo apresenta contribuições de Jürgen Habermas e Paulo Freire para a constituição de sujeitos crítico-reflexivos e suas implicações nos processos de ensino/pesquisa/extensão no campo dos Estudos Organizacionais. Mostramos que intersubjetividade e dialogicidade são condições para o entendimento entre sujeitos e é justamente por meio delas que ocorre sua constituição em um processo que é dialógico, pedagógico e político. Freire e Habermas oferecem elementos para desconstruir a lógica instrumental dominante e fornecem bases para a reconstrução de possibilidades inéditas/viáveis de formas de organizar e gerir. A partir disso, este artigo destaca a importância dos Estudos Organizacionais ampliarem o foco das possibilidades de ensino/pesquisa/extensão e direciona-os para um engajamento comunicativo e dialógico, ultrapassando as fronteiras das universidades. Essa reconstrução indica aos pesquisadores que participem de diferentes arenas públicas, do debate e da construção de problemas, em processos de resistência, da visibilidade e dramatização de questões problemáticas. Nos caminhos de Freire e Habermas, os Estudos Organizacionais não podem apenas desenvolver uma crítica à distância: é preciso coparticipar, co-agir, co-operar e coconstruir com os públicos em que se engajam.
This essay presents contributions by Jürgen Habermas and Paulo Freire for the constitution of critical-reflexive subjects and the implications in the teaching-research-extension processes in the field of Organizational Studies. We show that intersubjectivity and dialogicity are conditions for the understanding between subjects and it is precisely through these conditions that the subjects are constituted, in a process that is dialogical, pedagogical and political. Freire and Habermas offer elements to deconstruct dominant instrumental logic and provide the basis for the reconstruction of unprecedented-viable possibilities of ways of organizing and managing. Therefore, this article highlights the importance of Organizational Studies to broaden the focus of teaching-research-extension possibilities and directs them to a communicative and dialogic engagement, beyond the borders of universities. This reconstruction indicates that researchers participate in different public arenas, debate and build public problems, processes of resistance, visibility, and dramatization of problematic issues. Observing the contributions of Freire and Habermas, Organizational Studies as a field cannot be limited to developing a critique, from a distant point of view: it is necessary to co-participate, co-act, co-operate and co-construct with its public.
Ao considerarmos as obras que compõem a Literatura de Testemunho, podemos observar a prevalência de textos autobiográficos relatando as atrocidades da perseguição nazista e dos campos de concentração. No entanto, há também muitas obras ficcionais, de teor autobiográfico ounão, que narram tais experiências e outras relacionadas aos sofrimentos causados pelo nacional-socialismo a grandes parcelas da população europeia. Ao analisarmos a obra "Der Tod des Widersachers", de Hans Keilson, procuramos determinar os índices de ficcionalidade que a afastam de uma possível leitura autobiográfica e refletir sobre as implicações éticas e estéticas de Keilson haver ficcionalizado experiências próprias.
The impact of precipitation in shallow cumulus convection on the moisture variance and third-order moments of moisture is investigated with the help of large-eddy simulations. Three idealized simulations based on the Rain in Cumulus over the Ocean field experiment are analyzed: one nonprecipitating, on a smaller domain, and two precipitating cases, on a larger domain with different initial profiles of moisture. Results show that precipitation and the associated cloud organization lead to increased generation of higher-order moments (HOM) of moisture compared to the nonprecipitating case. To understand the physical mechanism and the role of individual processes in this increase, budgets of HOM of moisture are studied. Microphysics directly decreases the generation of HOM of moisture, but this effect is not dominant. The gradient production term is identified as the main source term in the HOM budgets. The influence of the gradient production term on moisture variance is further examined separately in cloud active and nonactive regions. The main contribution to the gradient production term comes from the smaller cloud active region because of the stronger moisture flux. Further analyses of the horizontal and vertical cross sections of moisture fluctuations show that the precipitation-induced downdrafts and updrafts are the main mechanism for the generation of moisture variance. The variance increase is linked to shallow dry downdraft regions with horizontal divergence in the subcloud layer, moist updrafts with horizontal convergence in the bulk cloud layer, and finally wider areas of horizontal divergence in the cloud inversion layer.
O presente artigo visa refletir sobre práticas didáticas comunicativas e interculturais no ensino de alemão como língua estrangeira. No sentido de trabalhar língua e cultura de maneira integrada, atentando especialmente nas necessidades comunicativas e interesse dos aprendizes, desenvolveu-se o projeto Novela, na disciplina Língua Alemã II, do curso de graduação de Letras da Universidade de São Paulo. Este projeto propôs uma releitura atual das telenovelas brasileiras, onde os aprendizes foram incentivados a produzir os episódios, narrativas sequenciais, aplicando o conhecimento de alemão adquirido e fazendo uso de materiais autênticos, tais como quadrinhos, música, conversas por SMS e WhatsApp, vídeos, entre outros. Ao abarcar todos os três aspectos delimitados por Weissenberg (2012) para um ensino focado no desenvolvimento de competências e necessidades de aprendizagem, o projeto possibilitou que os estudantes se sentissem (co)responsáveis pelo processo de aquisição e transmissão do conhecimento, tendo impactos positivos em sua motivação e senso de responsabilidade. Por fim, os resultados obtidos sugerem que tarefas que incentivam o uso de habilidades e estratégias comunicativas, além do seu potencial como ferramenta para uma aprendizagem integrativa, podem promover discussões interculturais relevantes.
Ao analisar o drama "Os bandoleiros" (1781), de Friedrich Schiller, este artigo defende a tese segundo a qual o pensamento antropológico desenvolvido à época do iluminismo tardio alemão serve de fundamento não apenas para os discursos médico e historiográfico, mas também para uma parcela significativa da produção literária do período. Para tanto, na primeira seção deste artigo, investigam-se as bases de formação da cultura letrada e, particularmente, da cultura médica alemã na segunda metade do século XVIII, bem como as discussões à época vigentes em torno do conceito de antropologia. Na segunda e na terceira seções, discutem-se as tendências da pesquisa contemporânea que exploram os pontos de contato entre o conhecimento histórico, o pensamento antropológico e a produção literária no século das Luzes. Esses passos fundamentam a tese aqui defendida e segundo a qual o modo de representação literária operado por Schiller em "Os bandoleiros" é expressão direta do projeto de compreensão - em termos antropológicos - das totalidades integradas do homem e da história da humanidade.
Background: Understanding the location and cell-type specific binding of Transcription Factors (TFs) is important in the study of gene regulation. Computational prediction of TF binding sites is challenging, because TFs often bind only to short DNA motifs and cell-type specific co-factors may work together with the same TF to determine binding. Here, we consider the problem of learning a general model for the prediction of TF binding using DNase1-seq data and TF motif description in form of position specific energy matrices (PSEMs).
Methods: We use TF ChIP-seq data as a gold-standard for model training and evaluation. Our contribution is a novel ensemble learning approach using random forest classifiers. In the context of the ENCODE-DREAM in vivo TF binding site prediction challenge we consider different learning setups.
Results: Our results indicate that the ensemble learning approach is able to better generalize across tissues and cell-types compared to individual tissue-specific classifiers or a classifier built based upon data aggregated across tissues. Furthermore, we show that incorporating DNase1-seq peaks is essential to reduce the false positive rate of TF binding predictions compared to considering the raw DNase1 signal.
Conclusions: Analysis of important features reveals that the models preferentially select motifs of other TFs that are close interaction partners in existing protein protein-interaction networks. Code generated in the scope of this project is available on GitHub: https://github.com/SchulzLab/TFAnalysis (DOI: 10.5281/zenodo.1409697).
Im Rahmen der vorliegenden Fallstudie zur Bewusstmachung der Lese- Verstehens- und Recherchekompetenz bei Studierenden des Fachbereichs Übersetzen und Dolmetschen wird der Vorschlag einer didaktischen Progression bei der Strukturalisierung des Unterrichts für literarische Übersetzung erarbeitet. Dies wird am Beispiel der türkischen Übersetzungen von Goethes Briefroman "Genç Werther'in Acıları" versucht darzustellen. Zu unterstreichen ist hier jedoch, dass die Unterrichtseinheit nicht, wie es nach übersetzungstheoretischem Ansatz zu verfolgen ist, mit der Analyse des Ausgangstextes "Die Leiden des jungen Werther" (Goethe, 1774) strukturiert ist. Diese Arbeit hat zum Ziel, den Versuch einer (in Anlehnung an die kognitions- und psychologisch wissenschaftlichen Erkenntnisse) didaktisch modellierten Vorgehensweise mehrerer aufeinanderfolgenden Unterrichtsphasen zu veranschaulichen. Der Fokus liegt jedoch hierbei auf dem Einstieg in die Unterrichtseinheit, wobei der Lese- und Verstehensprozess auf seinen Verlauf hin empirisch zu untersuchen gilt. Dazu wird die Datenerhebungsmethode angesetzt, die in der Kognitionspsychologie und der Übersetzungsprozessforschung fundiert. Die Datenauswertung erfolgt deskriptiv. Dieses Orientierungsmuster, welches zum Ziel hat, die Selbstsicherheit der Studierenden in Bezug zu unterschiedlichen Teilkompetenzen wie Lesen, Verstehen und Recherchieren, zu fördern, soll aus der Grundvorlage selbstkritischer Unterrichtserfahrung zur Durchführung des angegebenen Materials im Übersetzungsunterricht anregen.
There are 214 species of the suborder Tipulomorpha (Diptera) known from Panama. Of these, 162 species were described by the noted American entomologist, Charles Paul Alexander, from Panama during the period from 1912 through 1979. Panama hosts two of the four families found within the Tipulomorpha: Limoniidae (197 species) and Tipulidae (17 species). We have records of only three species from multiple provinces (n = 2) within Panama and 211 species from just one province. The vast majority of the latter are known from a single location within their respective provinces. There are 142 endemic species (66.4%) included in Panama’s Tipulomorpha fauna, with the remainder being found elsewhere in South America (48 species), Central America (44), Mexico (23 species), the Caribbean (14 species), and the United States (4 species). Whereas, this taxonomic group has benefited from collecting in the Canal Zone and the popular western highlands in Chiriqui Province, we know little or nothing of the distribution of species within the country, their natural history, or their relationship to water quality.
Golgi phosphoprotein 3 (GOLPH3) is a conserved protein of the Golgi apparatus that in humans has been implicated in tumorigenesis. However, the precise function of GOLPH3 in malignant transformation is still unknown. Nevertheless, clinicopathological data shows that in more than a dozen kinds of cancer, including gliomas, GOLPH3 could be found overexpressed, which correlates with poor prognosis. Experimental data shows that overexpression of GOLPH3 leads to transformation of primary cells and to tumor growth enhancement. Conversely, the knocking down of GOLPH3 in GOLPH3-overexpressing tumor cells reduces tumorigenic features, such as cell proliferation and cell migration and invasion. The cumulative evidence indicate that GOLPH3 is an oncoprotein that promotes tumorigenicity by a mechanism that impact at different levels in different types of cells, including the sorting of Golgi glycosyltransferases, signaling pathways, and the actin cytoskeleton. How GOLPH3 connects mechanistically these processes has not been determined yet. Further studies are important to have a more complete understanding of the role of GOLPH3 as oncoprotein. Given the genetic diversity in cancer, a still outstanding aspect is how in this inherent heterogeneity GOLPH3 could possibly exert its oncogenic function. We have aimed to evaluate the contribution of GOLPH3 overexpression in the malignant phenotype of different types of tumor cells. Here, we analyzed the effect on cell migration that resulted from stable, RNAi-mediated knocking down of GOLPH3 in T98G cells of glioblastoma multiforme, a human glioma cell line with unique features. We found that the reduction of GOLPH3 levels produced dramatic changes in cell morphology, involving rearrangements of the actin cytoskeleton and reduction in the number and dynamics of focal adhesions. These effects correlated with decreased cell migration and invasion due to affected persistence and directionality of cell motility. Moreover, the knocking down of GOLPH3 also caused a reduction in autoactivation of focal adhesion kinase (FAK), a cytoplasmic tyrosine kinase that regulates focal adhesions. Our data support a model in which GOLPH3 in T98G cells promotes cell migration by stimulating the activity of FAK.
Background: Posaconazole (POS) is a potent triazole antifungal agent approved in adults for treatment and prophylaxis of invasive fungal infections (IFIs). The objectives of this study were to evaluate the pharmacokinetics (PK), safety, and tolerability of POS oral suspension in pediatric subjects with neutropenia.
Methods: This was a prospective, multicenter, sequential dose-escalation study. Enrolled subjects were divided into 3 age groups: AG1, 7 to <18 years; AG2, 2 to <7 years; and AG3, 3 months to <2 years. AG1 and AG2 were divided into 3 dosage cohorts: DC1, 12 mg/kg/day divided twice daily (BID); DC2, 18 mg/kg/day BID; and DC3, 18 mg/kg/day divided thrice daily (TID). AG3 was also divided into DC1 and DC2; however, no subjects were enrolled in DC2. Subjects received 7–28 days of POS oral suspension. PK samples were collected at predefined time points. The POS PK target was predefined as ~90% of subjects with Cavg (AUC /dosing interval) between 500 and 2500 ng/mL, with an anticipated mean steady state Cavg exposure of ~1200 ng/mL.
Results: The percentage of subjects meeting the PK target was <90% across all age groups and dosage cohorts (range: 31% to 80%). The percentage of subjects that achieved the Cavg target of 500 to 2500 ng/mL on Day 7 ranged from 31% to 80%, with the lowest proportion in subjects 2 to <7 years receiving 12 mg/kg/day BID (AG2/DC1) and the highest proportion in subjects 7 to <18 years receiving 18 mg/kg/day TID (AG1/DC3). At all three dose levels (12 mg/kg/day BID, 18 mg/kg/day BID and 18 mg/kg/day TID), subjects in AG1 (7 to <18 years old) had higher mean PK exposures at steady state than those in AG2. High variability in exposures was observed in all groups. POS oral suspension was generally well tolerated and most of the reported adverse events were related to the subjects’ underlying diseases.
Conclusion: The POS PK target of 90% of subjects with Cavg between 500 and 2500 ng/mL was not achieved in any of the age groups across the different dosage cohorts. New formulations of the molecule with a greater potential to achieve the established PK target are currently under investigation.
Trial registration: ClinicalTrials.gov identifier: NCT01716234
The lateralization of neuronal processing underpinning hearing, speech, language, and music is widely studied, vigorously debated, and still not understood in a satisfactory manner. One set of hypotheses focuses on the temporal structure of perceptual experience and links auditory cortex asymmetries to underlying differences in neural populations with differential temporal sensitivity (e.g., ideas advanced by Zatorre et al. (2002) and Poeppel (2003). The Asymmetric Sampling in Time theory (AST) (Poeppel, 2003), builds on cytoarchitectonic differences between auditory cortices and predicts that modulation frequencies within the range of, roughly, the syllable rate, are more accurately tracked by the right hemisphere. To date, this conjecture is reasonably well supported, since – while there is some heterogeneity in the reported findings – the predicted asymmetrical entrainment has been observed in various experimental protocols. Here, we show that under specific processing demands, the rightward dominance disappears. We propose an enriched and modified version of the asymmetric sampling hypothesis in the context of speech. Recent work (Rimmele et al., 2018b) proposes two different mechanisms to underlie the auditory tracking of the speech envelope: one derived from the intrinsic oscillatory properties of auditory regions; the other induced by top-down signals coming from other non-auditory regions of the brain. We propose that under non-speech listening conditions, the intrinsic auditory mechanism dominates and thus, in line with AST, entrainment is rightward lateralized, as is widely observed. However, (i) depending on individual brain structural/functional differences, and/or (ii) in the context of specific speech listening conditions, the relative weight of the top-down mechanism can increase. In this scenario, the typically observed auditory sampling asymmetry (and its rightward dominance) diminishes or vanishes.
Inflammatory activation of astroglia adds to the pathology of various neurological diseases. Astrocytes respond to microglia-derived cytokines such as interleukin-1α (IL-1α) with enhanced inflammatory signaling. This provokes pro-inflammatory gene expression of, among others, the eicosanoid-generating enzyme prostaglandin endoperoxide synthase 2 (Ptgs2). Whereas metabolic regulation of innate immune cell inflammatory responses is intensely studied, pathways related to how metabolism modulates inflammatory signaling in astrocytes are underexplored. Here, we examined how mitochondrial oxidative phosphorylation affects inflammatory responses towards IL-1α and tumor necrosis factor α in neonatal rat astrocytes. Blocking respiratory complex I and III or adenosine triphosphate (ATP) synthase did not affect activation of inflammatory signaling by IL-1α, but did elicit differential effects on inflammatory gene mRNA expression. Remarkably, mRNA and protein expression of Ptgs2 by IL-1α was consistently up-regulated when oxidative phosphorylation was inhibited. The increase of Ptgs2 resulted from mRNA stabilization. Mitochondrial inhibitors also increased IL-1α-triggered secretion of eicosanoids, such as prostaglandin E2, prostaglandin F2α, and 6-keto-prostaglandin F1α, as assessed by liquid chromatography/mass spectrometry. Mechanistically, attenuating oxidative phosphorylation elevated adenosine monophosphate (AMP) and activated AMP-activated protein kinase (AMPK). AMPK silencing prevented Ptgs2 up-regulation by mitochondrial inhibitors, while AMPK activators recapitulated Ptgs2 mRNA stability regulation. Our data indicate modulation of astrocyte inflammatory responses by oxidative metabolism, with relevance towards eicosanoid production.
Hereditary Parkinson’s disease (PD) can be triggered by an autosomal dominant overdose of alpha-Synuclein (SNCA) as stressor or the autosomal recessive deficiency of PINK1 Serine/Threonine-phosphorylation activity as stress-response. We demonstrated the combination of PINK1-knockout with overexpression of SNCAA53T in double mutant (DM) mice to exacerbate locomotor deficits and to reduce lifespan. To survey posttranslational modifications of proteins underlying the pathology, brain hemispheres of old DM mice underwent quantitative label-free global proteomic mass spectrometry, focused on Ser/Thr-phosphorylations. As an exceptionally strong effect, we detected >300-fold reductions of phosphoThr1928 in MAP1B, a microtubule-associated protein, and a similar reduction of phosphoSer3781 in ANK2, an interactor of microtubules. MAP1B depletion is known to trigger perturbations of microtubular mitochondria trafficking, neurite extension, and synaptic function, so it was noteworthy that relevantly decreased phosphorylation was also detected for other microtubule and microfilament factors, namely MAP2S1801, MARK1S394, MAP1AT1794, KIF1AS1537, 4.1NS541, 4.1GS86, and ADD2S528. While the MAP1B heavy chain supports regeneration and growth cones, its light chain assists DAPK1-mediated autophagy. Interestingly, relevant phosphorylation decreases of DAPK2S299, VPS13DS2429, and VPS13CS2480 in the DM brain affected regulators of autophagy, which are implicated in PD. Overall, significant downregulations were enriched for PFAM C2 domains, other kinases, and synaptic transmission factors upon automated bioinformatics, while upregulations were not enriched for selective motifs or pathways. Validation experiments confirmed the change of LC3 processing as reflection of excessive autophagy in DM brain, and dependence of ANK2/MAP1B expression on PINK1 levels. Our new data provide independent confirmation in a mouse model with combined PARK1/PARK4/PARK6 pathology that MAP1B/ANK2 phosphorylation events are implicated in Parkinsonian neurodegeneration. These findings expand on previous observations in Drosophila melanogaster that the MAP1B ortholog futsch in the presynapse is a primary target of the PARK8 protein LRRK2, and on a report that MAP1B is a component of the pathological Lewy body aggregates in PD patient brains. Similarly, ANK2 gene locus variants are associated with the risk of PD, ANK2 interacts with PINK1/Parkin-target proteins such as MIRO1 or ATP1A2, and ANK2-derived peptides are potent inhibitors of autophagy.
Introduction: The Retro-IDEAL (ILUVIEN Implant for chronic DiabEtic MAcuLar edema) study is a retrospective study designed to assess real-world outcomes achieved with the ILUVIEN® (0.19 mg fluocinolone acetonide (FAc)) in patients with chronic diabetic macular edema (DME) in clinical practices in Germany.
Methods: This study was conducted across 16 sites in Germany and involved 81 eyes (63 patients) with persistent or recurrent DME and a prior suboptimal response to a first-line intravitreal therapy (primarily anti-VEGF intravitreal therapies).
Results: Patients were followed-up for 30.8 ± 11.3 months (mean ± standard deviation) and had a mean age of 68.0 ± 10.4 years. Best-recorded visual acuity (BRVA) improved by +5.5 letters at month 9 (P ⩽ 0.005, n=56; from a baseline of 49 letters) and this was maintained through to month 30 (P ⩽ 0.05, n = 42). There was a concurrent improvement in central macular thickness with a reduction from 502 µm at baseline to 338 µm at year 1 (P ⩽ 0.0001, n = 43). This effect was sustained to year 3 (i.e. 318 µm; P ⩽ 0.0001, n = 29). Mean intraocular pressure (IOP) remained constant between baseline and year 3 with a peak change of 1.9 mm Hg occurring at year 1. Elevated IOP was observed in a similar percentage of patients prior to (22.2% of cases) and following (27.2%) treatment with the FAc implant. In the majority of cases, these elevations were managed effectively with IOP medications.
Conclusions: Despite substantial amounts of prior intravitreal treatments – primarily with anti–vascular endothelial growth factor (VEGF) drugs – this real-world study showed that sustained structural and functional improvements can last for up to 3 years with a single FAc implant.
We tested the hypothesis that phonosemantic iconicity––i.e., a motivated resonance of sound and meaning––might not only be found on the level of individual words or entire texts, but also in word combinations such that the meaning of a target word is iconically expressed, or highlighted, in the phonetic properties of its immediate verbal context. To this end, we extracted single lines from German poems that all include a word designating high or low dominance, such as large or small, strong or weak, etc. Based on insights from previous studies, we expected to find more vowels with a relatively short distance between the first two formants (low formant dispersion) in the immediate context of words expressing high physical or social dominance than in the context of words expressing low dominance. Our findings support this hypothesis, suggesting that neighboring words can form iconic dyads in which the meaning of one word is sound-iconically reflected in the phonetic properties of adjacent words. The construct of a contiguity-based phono-semantic iconicity opens many venues for future research well beyond lines extracted from poems.
Members of conflicting groups experience threats to different identity dimensions, resulting in the need to restore the aspect of identity that was threatened. Do these needs translate into specific goals in social interactions? In the present research, we examined the hypotheses that (1) experiencing one’s ingroup as illegitimately disadvantaged or victimized arouses agentic goals (to act and appear assertive and confident) when interacting with the advantaged or victimizing group, while (2) experiencing one’s ingroup as illegitimately advantaged or perpetrating transgressions arouses communal goals (to act and appear warm and trustworthy) when interacting with the disadvantaged or victimized group. Study 1 (N = 391) generally supported both hypotheses across diverse intergroup contexts involving gender, national/ethnic, and consumer identities. Study 2 (N = 122) replicated this pattern in a context of occupational identities. Study 2 further showed that the effect of ingroup role on agentic and communal intergroup goals was not moderated by participants’ general dispositional preferences for agentic and communal goals in interpersonal interactions, thus demonstrating how ingroup role exerts a distinct and robust influence on goals for interactions with other groups. Theoretical and practical implications are discussed.
BACKGROUND: Patients with hereditary angioedema with C1 inhibitor deficiency or dysfunction have burdensome recurrent angioedema attacks. The safety, efficacy, and health-related quality of life (HRQoL) outcomes of C1 inhibitor (C1-INH) prophylaxis (intravenously administered) in patients aged 6-11 years were investigated.
METHODS: Eligible patients were enrolled in a randomized, single-blind, crossover, phase 3 trial. After a 12-week baseline observation period (BOP), patients received 500 or 1000 U C1-INH, twice weekly, for 12 weeks before crossing over to the alternate dose for 12 weeks. The primary efficacy end-point was the monthly normalized number of angioedema attacks (NNA). HRQoL was assessed using the EuroQoL 5-dimensional descriptive system youth version and visual analog scale (EQ-VAS).
RESULTS: Twelve randomized patients had a median (range) age of 10.0 (7-11) years. Mean (SD) percentage reduction in monthly NNA from BOP was 71.1% (27.1%) with 500 U and 84.5% (20.0%) with 1000 U C1-INH. Mean (SD) within-patient difference (-0.4 [0.58]) for monthly NNA with both doses was significant (P = 0.035 [90% CI, -0.706 to -0.102]). Cumulative attack severity, cumulative daily severity, and number of acute attacks treated were reduced. No serious adverse events or discontinuations occurred. Mean EQ-VAS change from BOP to week 9 of treatment (500 U C1-INH, 10.4; 1000 U C1-INH, 21.6) was greater than the minimal important difference, indicating a meaningful HRQoL change.
CONCLUSIONS: C1-INH prophylaxis was effective, safe, and well tolerated in children aged 6-11 years experiencing recurrent angioedema attacks. A post hoc analysis indicated a meaningful improvement in HRQoL with C1-INH.
TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT02052141.
Rhodopsin-based voltage imaging tools for use in muscles and neurons of Caenorhabditis elegans
(2019)
Genetically encoded voltage indicators (GEVIs) based on microbial rhodopsins utilize the voltage-sensitive fluorescence of all-trans retinal (ATR), while in electrochromic FRET (eFRET) sensors, donor fluorescence drops when the rhodopsin acts as depolarization-sensitive acceptor. In recent years, such tools have become widely used in mammalian cells but are less commonly used in invertebrate systems, mostly due to low fluorescence yields. We systematically assessed Arch(D95N), Archon, QuasAr, and the eFRET sensors MacQ-mCitrine and QuasAr-mOrange, in the nematode Caenorhabditis elegans ATR-bearing rhodopsins reported on voltage changes in body wall muscles (BWMs), in the pharynx, the feeding organ [where Arch(D95N) showed approximately 128% ΔF/F increase per 100 mV], and in neurons, integrating circuit activity. ATR fluorescence is very dim, yet, using the retinal analog dimethylaminoretinal, it was boosted 250-fold. eFRET sensors provided sensitivities of 45 to 78% ΔF/F per 100 mV, induced by BWM action potentials, and in pharyngeal muscle, measured in simultaneous optical and sharp electrode recordings, MacQ-mCitrine showed approximately 20% ΔF/F per 100 mV. All sensors reported differences in muscle depolarization induced by a voltage-gated Ca2+-channel mutant. Optogenetically evoked de- or hyperpolarization of motor neurons increased or eliminated action potential activity and caused a rise or drop in BWM sensor fluorescence. Finally, we analyzed voltage dynamics across the entire pharynx, showing uniform depolarization but compartmentalized repolarization of anterior and posterior parts. Our work establishes all-optical, noninvasive electrophysiology in live, intact C. elegans.
Optogenetic stimulation of inhibitory interneurons has become a commonly used strategy for silencing neuronal activity. This is typically achieved using transgenic mice expressing excitatory opsins in inhibitory interneurons throughout the brain, raising the question of how spatially extensive the resulting inhibition is. Here, we characterize neuronal silencing in VGAT-ChR2 mice, which express channelrhodopsin-2 in inhibitory interneurons, as a function of light intensity and distance from the light source in several cortical and subcortical regions. We show that light stimulation, even at relatively low intensities, causes inhibition not only in brain regions targeted for silencing but also in their subjacent areas. In contrast, virus-mediated expression of an inhibitory opsin enables robust silencing that is restricted to the region of opsin expression. Our results reveal important constraints on using inhibitory interneuron activation to silence neuronal activity and emphasize the necessity of carefully controlling light stimulation parameters when using this silencing strategy.