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The inclusive J/ψ production in Pb-Pb collisions at the center-of-mass energy per nucleon pair sNN−−−√ = 5.02 TeV, measured with the ALICE detector at the CERN LHC, is reported. The J/ψ meson is reconstructed via the dimuon decay channel at forward rapidity (2.5<y<4) down to zero transverse momentum. The suppression of the J/ψ yield in Pb-Pb collisions with respect to binary-scaled pp collisions is quantified by the nuclear modification factor (RAA). The RAA at sNN−−−√ = 5.02 TeV is presented and compared with previous measurements at sNN−−−√ = 2.76 TeV as a function of the centrality of the collision, and of the J/ψ transverse momentum and rapidity. The inclusive J/ψ RAA shows a suppression increasing toward higher pT, with a steeper dependence for central collisions. The modification of the J/ψ average pT and p2T is also studied. Comparisons with the results of models based on a transport equation and on statistical hadronization are also carried out.
Femtoscopic correlations of non-identical charged kaons (K+K−) are studied in Pb−Pb collisions at a center-of-mass energy per nucleon−nucleon collision sNN−−−√=2.76 TeV by ALICE at the LHC. One-dimensional K+K− correlation functions are analyzed in three centrality classes and eight intervals of particle-pair transverse momentum. The Lednický and Luboshitz interaction model used in the K+K− analysis includes the final-state Coulomb interactions between kaons and the final-state interaction through a0(980) and f0(980) resonances. The mass of f0(980) and coupling were extracted from the fit to K+K− correlation functions using the femtoscopic technique for the first time. The measured mass and width of the f0(980) resonance are consistent with other published measurements. The height of the ϕ(1020) meson peak present in the K+K− correlation function rapidly decreases with increasing source radius, qualitatively in agreement with an inverse volume dependence. A phenomenological fit to this trend suggests that the ϕ(1020) meson yield is dominated by particles produced directly from the hadronization of the system. The small fraction subsequently produced by FSI could not be precisely quantified with data presented in this paper and will be assessed in future work.
Two-particle transverse momentum differential correlators, recently measured in Pb-Pb collisions at LHC energies, provide an additional tool to gain insights into particle production mechanisms and infer transport properties, such as the ratio of shear viscosity to entropy density, of the medium created in Pb-Pb collisions. The longitudinal long-range correlations and the large azimuthal anisotropy measured at low transverse momenta in small collision systems, namely pp and p-Pb, at LHC energies resemble manifestations of collective behaviour. This suggests that locally equilibrated matter may be produced in these small collision systems, similar to what is observed in Pb-Pb collisions. In this work, the same two-particle transverse momentum differential correlators are exploited in pp and p-Pb collisions at s√=7 TeV and sNN−−−√=5.02 TeV, respectively, to seek evidence for viscous effects. Specifically, the strength and shape of the correlators are studied as a function of the produced particle multiplicity to identify evidence for longitudinal broadening that might reveal the presence of viscous effects in these smaller systems. The measured correlators and their evolution from pp and p-Pb to Pb-Pb collisions are additionally compared to predictions from Monte Carlo event generators, and the potential presence of viscous effects is discussed.
The measurement of the production of f0(980) in inelastic pp collisions at √s=5.02 TeV is presented. This is the first reported measurement of inclusive f0(980) yield at LHC energies. The production is measured at midrapidity, |y|<0.5, in a wide transverse momentum range, 0<pT<16 GeV/c, by reconstructing the resonance in the f0(980) →π+π− hadronic decay channel using the ALICE detector. The pT-differential yields are compared to those of pions, protons and ϕ mesons as well as to predictions from the HERWIG 7.2 QCD-inspired Monte Carlo event generator and calculations from a coalescence model that uses the AMPT model as an input. The ratio of the pT-integrated yield of f0(980) relative to pions is compared to measurements in e+e− and pp collisions at lower energies and predictions from statistical hadronisation models and HERWIG 7.2. A mild collision energy dependence of the f0(980) to pion production is observed in pp collisions from SPS to LHC energies. All considered models underpredict the pT-integrated 2f0(980)/(π+ +π−) ratio. The prediction from the canonical statistical hadronisation model assuming a zero total strangeness content of f0(980) is consistent with the data within 1.9σ and is the closest to the data. The results provide an essential reference for future measurements of the particle yield and nuclear modification in p–Pb and Pb–Pb collisions, which have been proposed to be instrumental to probe the elusive nature and quark composition of the f0(980) scalar meson.
Fluctuation measurements are important sources of information on the mechanism of particle production at LHC energies. This article reports the first experimental results on third-order cumulants of the net-proton distributions in Pb–Pb collisions at a center-of-mass energy √sNN=5.02 TeV recorded by the ALICE detector. The results on the second-order cumulants of net-proton distributions at √sNN=2.76 and 5.02 TeV are also discussed in view of effects due to the global and local baryon number conservation. The results demonstrate the presence of long-range rapidity correlations between protons and antiprotons. Such correlations originate from the early phase of the collision. The experimental results are compared with HIJING and EPOS model calculations, and the dependence of the fluctuation measurements on the phase-space coverage is examined in the context of lattice quantum chromodynamics (LQCD) and hadron resonance gas (HRG) model estimations. The measured third-order cumulants are consistent with zero within experimental uncertainties of about 4% and are described well by LQCD and HRG predictions.
The striking similarities that have been observed between high-multiplicity proton-proton (pp) collisions and heavy-ion collisions can be explored through multiplicity-differential measurements of identified hadrons in pp collisions. With these measurements, it is possible to study mechanisms such as collective flow that determine the shapes of hadron transverse momentum (pT) spectra, to search for possible modifications of the yields of short-lived hadronic resonances due to scattering effects in an extended hadron-gas phase, and to investigate different explanations provided by phenomenological models for enhancement of strangeness production with increasing multiplicity. In this paper, these topics are addressed through measurements of the K∗(892)0 and φ(1020) mesons at midrapidity in pp collisions at √s = 13 TeV as a function of the charged-particle multiplicity. The results include the pT spectra, pT-integrated yields, mean transverse momenta, and the ratios of the yields of these resonances to those of longer-lived hadrons. Comparisons with results from other collision systems and energies, as well as predictions from phenomenological models, are also discussed.
The inclusive J/ψ meson production in Pb–Pb collisions at a center-of-mass energy per nucleon–nucleon collision of sNN=5.02 TeV at midrapidity (|y|<0.9) is reported by the ALICE Collaboration. The measurements are performed in the dielectron decay channel, as a function of event centrality and J/ψ transverse momentum pT, down to pT=0. The J/ψ mean transverse momentum 〈pT〉 and rAA ratio, defined as 〈pT2〉PbPb/〈pT2〉pp, are evaluated. Both observables show a centrality dependence decreasing towards central (head-on) collisions. The J/ψ nuclear modification factor RAA exhibits a strong pT dependence with a large suppression at high pT and an increase to unity for decreasing pT. When integrating over the measured momentum range pT<10 GeV/c, the J/ψ RAA shows a weak centrality dependence. Each measurement is compared with results at lower center-of-mass energies and with ALICE measurements at forward rapidity, as well as to theory calculations. All reported features of the J/ψ production at low pT are consistent with a dominant contribution to the J/ψ yield originating from charm quark (re)combination.
This paper presents the first measurements of the charge independent (CI) and charge dependent (CD) two-particle transverse momentum correlators GCI 2 and GCD 2 in Pb–Pb collisions at √sNN = 2.76 TeV by the ALICE collaboration. The two-particle transverse momentum correlator G2 was introduced as a measure of the momentum current transfer between neighboring system cells. The correlators are measured as a function of pair separation in pseudorapidity (Δη) and azimuth (Δφ) and as a function of collision centrality. From peripheral to central collisions, the correlator GCI 2 exhibits a longitudinal broadening while undergoing a monotonic azimuthal narrowing. By contrast, GCD 2 exhibits a narrowing along both dimensions. These features are not reproduced by models such as HIJING and AMPT. However, the observed narrowing of the correlators from peripheral to central collisions is expected to result from the stronger transverse flow profiles produced in more central collisions and the longitudinal broadening is predicted to be sensitive to momentum currents and the shear viscosity per unit of entropy density η/s of the matter produced in the collisions. The observed broadening is found to be consistent with the hypothesized lower bound of η/s and is in qualitative agreement with values obtained from anisotropic flow measurements.
This Letter presents the first direct investigation of the p–0 interaction, using the femtoscopy technique in high-multiplicity pp collisions at √s = 13 TeV measured by the ALICE detector. The 0 is reconstructed via the decay channel to Λγ, and the subsequent decay of Λ to pπ−. The photon is detected via the conversion in material to e+e− pairs exploiting the capability of the ALICE detector to measure electrons at low transverse momenta. The measured p–0 correlation indicates a shallow strong interaction. The comparison of the data to several theoretical predictions obtained employing the Correlation Analysis Tool using the Schrödinger Equation (CATS) and the Lednický–Lyuboshits approach shows that the current experimental precision does not yet allow to discriminate between different models, as it is the case for the available scattering and hypernuclei data. Nevertheless, the p–0 correlation function is found to be sensitive to the strong interaction, and driven by the interplay of the different spin and isospin channels. This pioneering study demonstrates the feasibility of a femtoscopic measurement in the p–0 channel and with the expected larger data samples in LHC Run 3 and Run 4, the p–0 interaction will be constrained with high precision.
ϒ production in p–Pb interactions is studied at the centre-of-mass energy per nucleon–nucleon collision √sNN = 8.16 TeV with the ALICE detector at the CERN LHC. The measurement is performed reconstructing bottomonium resonances via their dimuon decay channel, in the centre-of-mass rapidity intervals 2.03 < ycms < 3.53 and −4.46 < ycms < −2.96, down to zero transverse momentum. In this work, results on the ϒ(1S) production cross section as a function of rapidity and transverse momentum are presented. The corresponding nuclear modification factor shows a suppression of the ϒ(1S) yields with respect to pp collisions, both at forward and backward rapidity. This suppression is stronger in the low transverse momentum region and shows no significant dependence on the centrality of the interactions. Furthermore, the ϒ(2S) nuclear modification factor is evaluated, suggesting a suppression similar to that of the ϒ(1S). A first measurement of the ϒ(3S) has also been performed. Finally, results are compared with previous ALICE measurements in p–Pb collisions at √sNN = 5.02 TeV and with theoretical calculations.
Measurements of K∗(892)0 and φ(1020) resonance production in Pb–Pb and pp collisions at √sNN = 5.02 TeV with the ALICE detector at the Large Hadron Collider are reported. The resonances are measured at midrapidity (|y| < 0.5) via their hadronic decay channels and the transverse momentum (pT) distributions are obtained for various collision centrality classes up to pT = 20 GeV/c. The pT-integrated yield ratio K∗(892)0/K in Pb–Pb collisions shows significant suppression relative to pp collisions and decreases towards more central collisions. In contrast, the φ(1020)/K ratio does not show any suppression. Furthermore, the measured K∗(892)0/K ratio in central Pb–Pb collisions is significantly suppressed with respect to the expectations based on a thermal model calculation, while the φ(1020)/K ratio agrees with the model prediction. These measurements are an experimental demonstration of rescattering of K∗(892)0 decay products in the hadronic phase of the collisions. The K∗(892)0/K yield ratios in Pb–Pb and pp collisions are used to estimate the time duration between chemical and kinetic freeze-out, which is found to be ∼ 4–7 fm/c for central collisions. The pT-differential ratios of K∗(892)0/K, φ(1020)/K, K∗(892)0/π , φ(1020)/π , p/K∗(892)0 and p/φ(1020) are also presented for Pb–Pb and pp collisions at √sNN = 5.02 TeV. These ratios show that the rescattering effect is predominantly a low-pT phenomenon.
Hadronic resonances are used to probe the hadron gas produced in the late stage of heavy-ion collisions since they decay on the same timescale, of the order of 1 to 10 fm/c, as the decoupling time of the system. In the hadron gas, (pseudo)elastic scatterings among the products of resonances that decayed before the kinetic freeze-out and regeneration processes counteract each other, the net effect depending on the resonance lifetime, the duration of the hadronic phase, and the hadronic cross sections at play. In this context, the Σ(1385)± particle is of particular interest as models predict that regeneration dominates over rescattering despite its relatively short lifetime of about 5.5 fm/c. The first measurement of the Σ(1385)± resonance production at midrapidity in Pb-Pb collisions at sNN−−−√=5.02 TeV with the ALICE detector is presented in this Letter. The resonances are reconstructed via their hadronic decay channel, Λπ, as a function of the transverse momentum (pT) and the collision centrality. The results are discussed in comparison with the measured yield of pions and with expectations from the statistical hadronization model as well as commonly employed event generators, including PYTHIA8/Angantyr and EPOS3 coupled to the UrQMD hadronic cascade afterburner. None of the models can describe the data. For Σ(1385)±, a similar behaviour as K∗(892)0 is observed in data unlike the predictions of EPOS3 with afterburner.
Inclusive ψ(2S) production is measured in p-Pb collisions at the centre-of-mass energy per nucleon-nucleon pair sNN−−−√=8.16 TeV, using the ALICE detector at the CERN LHC. The production of ψ(2S) is studied at forward (2.03<ycms<3.53) and backward (−4.46<ycms<−2.96) centre-of-mass rapidity and for transverse momentum pT < 12 GeV/c via the decay to muon pairs. In this paper, we report the integrated as well as the ycms- and pT-differential inclusive production cross sections. Nuclear effects on ψ(2S) production are studied via the determination of the nuclear modification factor that shows a strong suppression at both forward and backward centre-of-mass rapidities. Comparisons with corresponding results for inclusive J/ψ show a similar suppression for the two states at forward rapidity (p-going direction), but a stronger suppression for ψ(2S) at backward rapidity (Pb-going direction). As a function of pT, no clear dependence of the nuclear modification factor is found. The relative size of nuclear effects on ψ(2S) production compared to J/ψ is also studied via the double ratio of production cross sections [σψ(2S)/σJ/ψ]pPb/[σψ(2S)/σJ/ψ]pp between p-Pb and pp collisions. The results are compared with theoretical models that include various effects related to the initial and final state of the collision system and also with previous measurements at sNN−−−√ = 5.02 TeV.
J/ψ production as a function of charged-particle multiplicity in p–Pb collisions at √sNN = 8.16 TeV
(2020)
Inclusive J/ψ yields and average transverse momenta in p-Pb collisions at a center-of-mass energy per nucleon pair sNN−−−√ = 8.16 TeV are measured as a function of the charged-particle pseudorapidity density with ALICE. The J/ψ mesons are reconstructed at forward (2.03<ycms<3.53) and backward (−4.46<ycms<−2.96) center-of-mass rapidity in their dimuon decay channel while the charged-particle pseudorapidity density is measured around midrapidity. The J/ψ yields at forward and backward rapidity normalized to their respective average values increase with the normalized charged-particle pseudorapidity density, the former showing a weaker increase than the latter. The normalized average transverse momenta at forward and backward rapidity manifest a steady increase from low to high charged-particle pseudorapidity density with a saturation beyond the average value.
J/ψ production as a function of charged-particle multiplicity in p–Pb
collisions at √sNN = 8.16 TeV
(2021)
Inclusive J/ψ yields and average transverse momenta in p-Pb collisions at a center-of-mass energy per nucleon pair sNN−−−√ = 8.16 TeV are measured as a function of the charged-particle pseudorapidity density with ALICE. The J/ψ mesons are reconstructed at forward (2.03<ycms<3.53) and backward (−4.46<ycms<−2.96) center-of-mass rapidity in their dimuon decay channel while the charged-particle pseudorapidity density is measured around midrapidity. The J/ψ yields at forward and backward rapidity normalized to their respective average values increase with the normalized charged-particle pseudorapidity density, the former showing a weaker increase than the latter. The normalized average transverse momenta at forward and backward rapidity manifest a steady increase from low to high charged-particle pseudorapidity density with a saturation beyond the average value.
The most precise measurements to date of the 3ΛH lifetime τ and Λ separation energy BΛ are obtained using the data sample of Pb-Pb collisions at √sNN = 5.02 TeV collected by ALICE at the LHC. The 3ΛH is reconstructed via its charged two-body mesonic decay channel (3ΛH → 3He + π− and the charge-conjugate process). The measured values τ = [253 ± 11 (stat) ± 6 (syst)] ps and BΛ = [102 ± 63 (stat) ± 67 (syst)] keV are compatible with predictions from effective field theories and confirm that the 3ΛH structure is consistent with a weakly bound system.
The most precise measurements to date of the 3ΛH lifetime τ and Λ separation energy BΛ are obtained using the data sample of Pb-Pb collisions at √= 5.02 TeV collected by ALICE at the LHC. The 3ΛH is reconsNN structed via its charged two-body mesonic decay channel (3ΛH→ 3He + π− and the charge-conjugate process). The measured values τ=[253±11 (stat.)±6 (syst.)] ps and BΛ=[102±63 (stat.)±67 (syst.)] keV are compatible with predictions from effective field theories and confirm that the 3ΛH structure is consistent with a weakly-bound system.
The production of inclusive, prompt and non-prompt J/ψ was studied for the first time at midrapidity (−1.37 < ycms < 0.43) in p-Pb collisions at √sNN = 8.16 TeV with the ALICE detector at the LHC. The inclusive J/ψ mesons were reconstructed in the dielectron decay channel in the transverse momentum (pT) interval 0 < pT < 14 GeV/c and the prompt and non-prompt contributions were separated on a statistical basis for pT > 2 GeV/c. The study of the J/ψ mesons in the dielectron channel used for the first time in ALICE online single-electron triggers from the Transition Radiation Detector, providing a data sample corresponding to an integrated luminosity of 689 ± 13 μb−1. The proton-proton reference cross section for inclusive J/ψ was obtained based on interpolations of measured data at different centre-of-mass energies and a universal function describing the pT-differential J/ψ production cross sections. The pT-differential nuclear modification factors RpPb of inclusive, prompt, and non-prompt J/ψ are consistent with unity and described by theoretical models implementing only nuclear shadowing.
The production of inclusive, prompt and non-prompt J/ψ was studied for the first time at midrapidity (−1.37<ycms<0.43) in p−Pb collisions at √sNN =8.16 TeV with the ALICE detector at the LHC. The inclusive J/ψ mesons were reconstructed in the dielectron decay channel in the transverse momentum (pT) interval 0<pT<14 GeV/c and the prompt and non-prompt contributions were separated on a statistical basis for pT>2 GeV/c. The study of the J/ψ mesons in the dielectron channel used for the first time in ALICE online single-electron triggers from the Transition Radiation Detector, providing a data sample corresponding to an integrated luminosity of 689±13μb−1. The proton−proton reference cross section for inclusive J/ψ was obtained based on interpolations of measured data at different centre-of-mass energies and a universal function describing the pT-differential J/ψ production cross sections. The pT-differential nuclear modification factors RpPb of inclusive, prompt, and non-prompt J/ψ are consistent with unity and described by theoretical models implementing only nuclear shadowing.
The production of the Λ(1520) baryonic resonance has been measured at midrapidity in inelastic pp collisions at s√ = 7 TeV and in p-Pb collisions at sNN−−−√ = 5.02 TeV for non-single diffractive events and in multiplicity classes. The resonance is reconstructed through its hadronic decay channel Λ(1520) → pK− and the charge conjugate with the ALICE detector. The integrated yields and mean transverse momenta are calculated from the measured transverse momentum distributions in pp and p-Pb collisions. The mean transverse momenta follow mass ordering as previously observed for other hyperons in the same collision systems. A Blast-Wave function constrained by other light hadrons (π, K, K0S, p, Λ) describes the shape of the Λ(1520) transverse momentum distribution up to 3.5 GeV/c in p-Pb collisions. In the framework of this model, this observation suggests that the Λ(1520) resonance participates in the same collective radial flow as other light hadrons. The ratio of the yield of Λ(1520) to the yield of the ground state particle Λ remains constant as a function of charged-particle multiplicity, suggesting that there is no net effect of the hadronic phase in p-Pb collisions on the Λ(1520) yield.
The production of the Λ(1520) baryonic resonance has been measured at midrapidity in inelastic pp collisions at s√ = 7 TeV and in p-Pb collisions at sNN−−−√ = 5.02 TeV for non-single diffractive events and in multiplicity classes. The resonance is reconstructed through its hadronic decay channel Λ(1520) → pK− and the charge conjugate with the ALICE detector. The integrated yields and mean transverse momenta are calculated from the measured transverse momentum distributions in pp and p-Pb collisions. The mean transverse momenta follow mass ordering as previously observed for other hyperons in the same collision systems. A Blast-Wave function constrained by other light hadrons (π, K, K0S, p, Λ) describes the shape of the Λ(1520) transverse momentum distribution up to 3.5 GeV/c in p-Pb collisions. In the framework of this model, this observation suggests that the Λ(1520) resonance participates in the same collective radial flow as other light hadrons. The ratio of the yield of Λ(1520) to the yield of the ground state particle Λ remains constant as a function of charged-particle multiplicity, suggesting that there is no net effect of the hadronic phase in p-Pb collisions on the Λ(1520) yield.
The first evidence of spin alignment of vector mesons (K*0 and ϕ) in heavy-ion collisions at the Large Hadron Collider (LHC) is reported. The spin density matrix element ρ00 is measured at midrapidity (|y|< 0.5) in Pb-Pb collisions at a center-of-mass energy (√sNN) of 2.76 TeV
with the ALICE detector. ρ00 values are found to be less than 1/3 (1/3 implies no spin alignment) at low transverse momentum (pT<2 GeV/c) for K*0 and ϕ at a level of 3σ and 2σ, respectively. No significant spin alignment is observed for the K0S meson (spin = 0) in Pb-Pb collisions and for the vector mesons in pp collisions. The measured spin alignment is unexpectedly large but qualitatively consistent with the expectation from models which attribute it to a polarization of quarks in the presence of angular momentum in heavy-ion collisions and a subsequent hadronization by the process of recombination.
The transverse momentum (pT) differential yields of (anti-)3He and (anti-)3H measured in p-Pb collisions at sNN−−−√ = 5.02 TeV with ALICE at the Large Hadron Collider (LHC) are presented. The ratios of the pT-integrated yields of (anti-)3He and (anti-)3H to the proton yields are reported, as well as the pT dependence of the coalescence parameters B3 for (anti-)3He and (anti-)3H. For (anti-)3He, the results obtained in four classes of the mean charged-particle multiplicity density are also discussed. These results are compared to predictions from a canonical statistical hadronization model and coalescence approaches. An upper limit on the total yield of 4He¯ is determined.
The highly infectious disease COVID-19 caused by the Betacoronavirus SARS-CoV-2 poses a severe threat to humanity and demands the redirection of scientific efforts and criteria to organized research projects. The international COVID19-NMR consortium seeks to provide such new approaches by gathering scientific expertise worldwide. In particular, making available viral proteins and RNAs will pave the way to understanding the SARS-CoV-2 molecular components in detail. The research in COVID19-NMR and the resources provided through the consortium are fully disclosed to accelerate access and exploitation. NMR investigations of the viral molecular components are designated to provide the essential basis for further work, including macromolecular interaction studies and high-throughput drug screening. Here, we present the extensive catalog of a holistic SARS-CoV-2 protein preparation approach based on the consortium’s collective efforts. We provide protocols for the large-scale production of more than 80% of all SARS-CoV-2 proteins or essential parts of them. Several of the proteins were produced in more than one laboratory, demonstrating the high interoperability between NMR groups worldwide. For the majority of proteins, we can produce isotope-labeled samples of HSQC-grade. Together with several NMR chemical shift assignments made publicly available on covid19-nmr.com, we here provide highly valuable resources for the production of SARS-CoV-2 proteins in isotope-labeled form.
The current pandemic situation caused by the Betacoronavirus SARS-CoV-2 (SCoV2) highlights the need for coordinated research to combat COVID-19. A particularly important aspect is the development of medication. In addition to viral proteins, structured RNA elements represent a potent alternative as drug targets. The search for drugs that target RNA requires their high-resolution structural characterization. Using nuclear magnetic resonance (NMR) spectroscopy, a worldwide consortium of NMR researchers aims to characterize potential RNA drug targets of SCoV2. Here, we report the characterization of 15 conserved RNA elements located at the 5′ end, the ribosomal frameshift segment and the 3′-untranslated region (3′-UTR) of the SCoV2 genome, their large-scale production and NMR-based secondary structure determination. The NMR data are corroborated with secondary structure probing by DMS footprinting experiments. The close agreement of NMR secondary structure determination of isolated RNA elements with DMS footprinting and NMR performed on larger RNA regions shows that the secondary structure elements fold independently. The NMR data reported here provide the basis for NMR investigations of RNA function, RNA interactions with viral and host proteins and screening campaigns to identify potential RNA binders for pharmaceutical intervention.
Background & Aim: The resistance profile of anti-hepatitis C virus (HCV) agents used in combination is important to guide optimal treatment regimens. We evaluated baseline and treatment-emergent NS3/4A and NS5B amino-acid variants among HCV genotype (GT)-1a and -1b-infected patients treated with faldaprevir (HCV protease inhibitor), deleobuvir (HCV polymerase non-nucleoside inhibitor), and ribavirin in multiple clinical studies.
Methods: HCV NS3/4A and NS5B population sequencing (Sanger method) was performed on all baseline plasma samples (n = 1425 NS3; n = 1556 NS5B) and on post-baseline plasma samples from patients with virologic failure (n = 113 GT-1a; n = 221 GT-1b). Persistence and time to loss of resistance-associated variants (RAVs) was estimated using Kaplan–Meier analysis.
Results: Faldaprevir RAVs (NS3 R155 and D168) and deleobuvir RAVs (NS5B 495 and 496) were rare (<1%) at baseline. Virologic response to faldaprevir/deleobuvir/ribavirin was not compromised by common baseline NS3 polymorphisms (e.g. Q80K in 17.5% of GT-1a) or by NS5B A421V, present in 20% of GT-1a. In GT-1b, alanine at NS5B codon 499 (present in 15% of baseline sequences) was associated with reduced response. Treatment-emergent RAVs consolidated previous findings: NS3 R155 and D168 were key faldaprevir RAVs; NS5B A421 and P495 were key deleobuvir RAVs. Among on-treatment virologic breakthroughs, RAVs emerged in both NS3 and NS5B (>90%). Virologic relapse was associated with RAVs in both NS3 and NS5B (53% GT-1b; 52% GT-1b); some virologic relapses had NS3 RAVs only (47% GT-1a; 17% GT-1b). Median time to loss of GT-1b NS5B P495 RAVs post-treatment (5 months) was less than that of GT-1b NS3 D168 (8.5 months) and GT-1a R155 RAVs (11.5 months).
Conclusion: Faldaprevir and deleobuvir RAVs are more prevalent among virologic failures than at baseline. Treatment response was not compromised by common NS3 polymorphisms; however, alanine at NS5B amino acid 499 at baseline (wild-type in GT-1a, polymorphism in GT-1b) may reduce response to this deleobuvir-based regimen.
Multimorbidity is a health issue mostly dealt with in primary care practice. As a result of their generalist and patient-centered approach, long-lasting relationships with patients, and responsibility for continuity and coordination of care, family physicians are particularly well placed to manage patients with multimorbidity. However, conflicts arising from the application of multiple disease oriented guidelines and the burden of diseases and treatments often make consultations challenging. To provide orientation in decision making in multimorbidity during primary care consultations, we developed guiding principles and named them after the Greek mythological figure Ariadne. For this purpose, we convened a two-day expert workshop accompanied by an international symposium in October 2012 in Frankfurt, Germany. Against the background of the current state of knowledge presented and discussed at the symposium, 19 experts from North America, Europe, and Australia identified the key issues of concern in the management of multimorbidity in primary care in panel and small group sessions and agreed upon making use of formal and informal consensus methods. The proposed preliminary principles were refined during a multistage feedback process and discussed using a case example. The sharing of realistic treatment goals by physicians and patients is at the core of the Ariadne principles. These result from i) a thorough interaction assessment of the patient’s conditions, treatments, constitution, and context; ii) the prioritization of health problems that take into account the patient's preferences – his or her most and least desired outcomes; and iii) individualized management realizes the best options of care in diagnostics, treatment, and prevention to achieve the goals. Goal attainment is followed-up in accordance with a re-assessment in planned visits. The occurrence of new or changed conditions, such as an increase in severity, or a changed context may trigger the (re-)start of the process. Further work is needed on the implementation of the formulated principles, but they were recognized and appreciated as important by family physicians and primary care researchers.
SARS-CoV-2 contains a positive single-stranded RNA genome of approximately 30 000 nucleotides. Within this genome, 15 RNA elements were identified as conserved between SARS-CoV and SARS-CoV-2. By nuclear magnetic resonance (NMR) spectroscopy, we previously determined that these elements fold independently, in line with data from in vivo and ex-vivo structural probing experiments. These elements contain non-base-paired regions that potentially harbor ligand-binding pockets. Here, we performed an NMR-based screening of a poised fragment library of 768 compounds for binding to these RNAs, employing three different 1H-based 1D NMR binding assays. The screening identified common as well as RNA-element specific hits. The results allow selection of the most promising of the 15 RNA elements as putative drug targets. Based on the identified hits, we derive key functional units and groups in ligands for effective targeting of the RNA of SARS-CoV-2.
1H, 13C, and 15N backbone chemical shift assignments of coronavirus-2 non-structural protein Nsp10
(2020)
The international Covid19-NMR consortium aims at the comprehensive spectroscopic characterization of SARS-CoV-2 RNA elements and proteins and will provide NMR chemical shift assignments of the molecular components of this virus. The SARS-CoV-2 genome encodes approximately 30 different proteins. Four of these proteins are involved in forming the viral envelope or in the packaging of the RNA genome and are therefore called structural proteins. The other proteins fulfill a variety of functions during the viral life cycle and comprise the so-called non-structural proteins (nsps). Here, we report the near-complete NMR resonance assignment for the backbone chemical shifts of the non-structural protein 10 (nsp10). Nsp10 is part of the viral replication-transcription complex (RTC). It aids in synthesizing and modifying the genomic and subgenomic RNAs. Via its interaction with nsp14, it ensures transcriptional fidelity of the RNA-dependent RNA polymerase, and through its stimulation of the methyltransferase activity of nsp16, it aids in synthesizing the RNA cap structures which protect the viral RNAs from being recognized by the innate immune system. Both of these functions can be potentially targeted by drugs. Our data will aid in performing additional NMR-based characterizations, and provide a basis for the identification of possible small molecule ligands interfering with nsp10 exerting its essential role in viral replication.
Biodiversity is unevenly distributed on Earth and hotspots of biodiversity are often associated with areas that have undergone orogenic activity during recent geological history (i.e. tens of millions of years). Understanding the underlying processes that have driven the accumulation of species in some areas and not in others may help guide prioritization in conservation and may facilitate forecasts on ecosystem services under future climate conditions. Consequently, the study of the origin and evolution of biodiversity in mountain systems has motivated growing scientific interest. Despite an increasing number of studies, the origin and evolution of diversity hotspots associated with the Qinghai-Tibetan Plateau (QTP) remains poorly understood. We review literature related to the diversification of organisms linked to the uplift of the QTP. To promote hypothesis-based research, we provide a geological and palaeoclimatic scenario for the region of the QTP and argue that further studies would benefit from providing a complete set of complementary analyses (molecular dating, biogeographic, and diversification rates analyses) to test for a link between organismic diversification and past geological and climatic changes in this region. In general, we found that the contribution of biological interchange between the QTP and other hotspots of biodiversity has not been sufficiently studied to date. Finally, we suggest that the biological consequences of the uplift of the QTP would be best understood using a meta-analysis approach, encompassing studies on a variety of organisms (plants and animals) from diverse habitats (forests, meadows, rivers), and thermal belts (montane, subalpine, alpine, nival). Since the species diversity in the QTP region is better documented for some organismic groups than for others, we suggest that baseline taxonomic work should be promoted.
Ceritinib-induced regression of an insulin-like growth factor-driven neuroepithelial brain tumor
(2019)
The insulin-like growth factor (IGF) pathway plays an important role in several brain tumor entities. However, the lack of inhibitors crossing the blood–brain barrier remains a significant obstacle for clinical translation. Here, we targeted the IGF pathway using ceritinib, an off-target inhibitor of the IGF1 receptor (IGF1R) and insulin receptor (INSR), in a pediatric patient with an unclassified brain tumor and a notch receptor 1 (NOTCH1) germline mutation. Pathway analysis of the tumor revealed activation of the sonic hedgehog (SHH), the wingless and integrated-1 (WNT), the IGF, and the Notch pathway. The proliferation of the patient tumor cells (225ZL) was inhibited by arsenic trioxide (ATO), which is an inhibitor of the SHH pathway, by linsitinib, which is an inhibitor of IGF1R and INSR, and by ceritinib. 225ZL expressed INSR but not IGF1R at the protein level, and ceritinib blocked the phosphorylation of INSR. Our first personalized treatment included ATO, but because of side effects, we switched to ceritinib. After 46 days, we achieved a concentration of 1.70 µM of ceritinib in the plasma, and after 58 days, MRI confirmed that there was a response to the treatment. Ceritinib accumulated in the tumor at a concentration of 2.72 µM. Our data suggest ceritinib as a promising drug for the treatment of IGF-driven brain tumors.
Aims: To compare the effects of Ayurvedic and conventional nutritional therapy in patients with irritable bowel syndrome (IBS). Methods: Sixty-nine patients with IBS were randomized to Ayurvedic (n = 35) or conventional nutritional therapy according to the recommendations of the German Nutrition Society including the low-FODMAP diet (n = 34). Study visits took place at baseline and after 1, 3, and 6 months. The primary outcome was IBS symptom severity (IBS-SSS) after 3 months; secondary outcomes included stress (CPSS), anxiety and depression (HADS), well-being (WHO-5) and IBS-specific quality of life (IBS-QOL). A repeated measures general linear model (GLM) for intent-to-treat-analyses was applied in this explorative study. Results: After 3 months, estimated marginal means for IBS-SSS reductions were 123.8 [95% confidence interval (95% CI) = 92.8–154.9; p < 0.001] in the Ayurvedic and 72.7 (95% CI = 38.8–106.7; p < 0.001) in the conventional group. The IBS-SSS reduction was significantly higher in the Ayurveda group compared to the conventional therapy group (estimated marginal mean = 51.1; 95% CI = 3.8–98.5; p = 0.035) and clinically meaningful. Sixty-eight percentage of the variance in IBS-SSS reduction after 3 months can be explained by treatment, 6.5% by patients' expectations for their therapies and 23.4% by IBS-SSS at pre-intervention. Both therapies are equivalent in their contribution to the outcome variance. The higher the IBS-SSS score at pre-intervention and the larger the patients' expectations, the greater the IBS-SSS reduction. There were no significant group differences in any secondary outcome measures. No serious adverse events occurred in either group. Conclusion: Patients with IBS seem to benefit significantly from Ayurvedic or conventional nutritional therapy. The results warrant further studies with longer-term follow-ups and larger sample sizes. Clinical Trial Registration: https://clinicaltrials.gov/ct2/show/NCT03019861, identifier: NCT03019861.
Background: Multimorbidity is associated with negative effects both on people’s health and on healthcare systems. A key problem linked to multimorbidity is polypharmacy, which in turn is associated with increased risk of partly preventable adverse effects, including mortality. The Ariadne principles describe a model of care based on a thorough assessment of diseases, treatments (and potential interactions), clinical status, context and preferences of patients with multimorbidity, with the aim of prioritizing and sharing realistic treatment goals that guide an individualized management. The aim of this study is to evaluate the effectiveness of a complex intervention that implements the Ariadne principles in a population of young-old patients with multimorbidity and polypharmacy. The intervention seeks to improve the appropriateness of prescribing in primary care (PC), as measured by the medication appropriateness index (MAI) score at 6 and 12 months, as compared with usual care.
Methods/Design: Design: pragmatic cluster randomized clinical trial. Unit of randomization: family physician (FP). Unit of analysis: patient. Scope: PC health centres in three autonomous communities: Aragon, Madrid, and Andalusia (Spain). Population: patients aged 65–74 years with multimorbidity (≥3 chronic diseases) and polypharmacy (≥5 drugs prescribed in ≥3 months). Sample size: n = 400 (200 per study arm). Intervention: complex intervention based on the implementation of the Ariadne principles with two components: (1) FP training and (2) FP-patient interview. Outcomes: MAI score, health services use, quality of life (Euroqol 5D-5L), pharmacotherapy and adherence to treatment (Morisky-Green, Haynes-Sackett), and clinical and socio-demographic variables. Statistical analysis: primary outcome is the difference in MAI score between T0 and T1 and corresponding 95% confidence interval. Adjustment for confounding factors will be performed by multilevel analysis. All analyses will be carried out in accordance with the intention-to-treat principle.
Discussion: It is essential to provide evidence concerning interventions on PC patients with polypharmacy and multimorbidity, conducted in the context of routine clinical practice, and involving young-old patients with significant potential for preventing negative health outcomes.
Trial registration: Clinicaltrials.gov, NCT02866799
Body dysmorphic disorder (BDD), together with its subtype muscle dysmorphia (MD), has been relocated from the Somatoform Disorders category in the DSM-IV to the newly created Obsessive-Compulsive and Related Disorders category in the DSM-5. Both categorizations have been criticized, and an empirically derived classification of BDD is lacking. A community sample of N = 736 participants completed an online survey assessing different psychopathologies. Using a structural equation modeling approach, six theoretically derived models, which differed in their allocation of BDD symptoms to various factors (i.e. general psychopathology, somatoform, obsessive-compulsive and related disorders, affective, body image, and BDD model) were tested in the full sample and in a restricted sample (n = 465) which indicated primary concerns other than shape and weight. Furthermore, measurement invariance across gender was examined. Of the six models, only the body image model showed a good fit (CFI = 0.972, RMSEA = 0.049, SRMR = 0.027, TLI = 0.959), and yielded better AIC and BIC indices than the competing models. Analyses in the restricted sample replicated these findings. Analyses of measurement invariance of the body image model showed partial metric invariance across gender. The findings suggest that a body image model provides the best fit for the classification of BDD and MD. This is in line with previous studies showing strong similarities between eating disorders and BDD, including MD. Measurement invariance across gender indicates a comparable presentation and comorbid structure of BDD in males and females, which also corresponds to the equal prevalence rates of BDD across gender.
Background: Tuberous sclerosis complex (TSC), a multisystem genetic disorder, affects many organs and systems, characterized by benign growths. This German multicenter study estimated the disease-specific costs and cost-driving factors associated with various organ manifestations in TSC patients. Methods: A validated, three-month, retrospective questionnaire was administered to assess the sociodemographic and clinical characteristics, organ manifestations, direct, indirect, out-of-pocket, and nursing care-level costs, completed by caregivers of patients with TSC throughout Germany. Results: The caregivers of 184 patients (mean age 9.8 ± 5.3 years, range 0.7–21.8 years) submitted questionnaires. The reported TSC disease manifestations included epilepsy (92%), skin disorders (86%), structural brain disorders (83%), heart and circulatory system disorders (67%), kidney and urinary tract disorders (53%), and psychiatric disorders (51%). Genetic variations in TSC2 were reported in 46% of patients, whereas 14% were reported in TSC1. Mean total direct health care costs were EUR 4949 [95% confidence interval (95% CI) EUR 4088–5863, median EUR 2062] per patient over three months. Medication costs represented the largest direct cost category (54% of total direct costs, mean EUR 2658), with mechanistic target of rapamycin (mTOR) inhibitors representing the largest share (47%, EUR 2309). The cost of anti-seizure drugs (ASDs) accounted for a mean of only EUR 260 (5%). Inpatient costs (21%, EUR 1027) and ancillary therapy costs (8%, EUR 407) were also important direct cost components. The mean nursing care-level costs were EUR 1163 (95% CI EUR 1027–1314, median EUR 1635) over three months. Total indirect costs totaled a mean of EUR 2813 (95% CI EUR 2221–3394, median EUR 215) for mothers and EUR 372 (95% CI EUR 193–586, median EUR 0) for fathers. Multiple regression analyses revealed polytherapy with two or more ASDs and the use of mTOR inhibitors as independent cost-driving factors of total direct costs. Disability and psychiatric disease were independent cost-driving factors for total indirect costs as well as for nursing care-level costs. Conclusions: This study revealed substantial direct (including medication), nursing care-level, and indirect costs associated with TSC over three months, highlighting the spectrum of organ manifestations and their treatment needs in the German healthcare setting.
Autophagy is a core molecular pathway for the preservation of cellular and organismal homeostasis. Pharmacological and genetic interventions impairing autophagy responses promote or aggravate disease in a plethora of experimental models. Consistently, mutations in autophagy-related processes cause severe human pathologies. Here, we review and discuss preclinical data linking autophagy dysfunction to the pathogenesis of major human disorders including cancer as well as cardiovascular, neurodegenerative, metabolic, pulmonary, renal, infectious, musculoskeletal, and ocular disorders.
Clonal hematopoiesis of indeterminate potential (CHIP) is caused by recurrent somatic mutations leading to clonal blood cell expansion. However, direct evidence of the fitness of CHIP-mutated human hematopoietic stem cells (HSCs) in blood reconstitution is lacking. Because myeloablative treatment and transplantation enforce stress on HSCs, we followed 81 patients with solid tumors or lymphoid diseases undergoing autologous stem cell transplantation (ASCT) for the development of CHIP. We found a high incidence of CHIP (22%) after ASCT with a high mean variant allele frequency (VAF) of 10.7%. Most mutations were already present in the graft, albeit at lower VAFs, demonstrating a selective reconstitution advantage of mutated HSCs after ASCT. However, patients with CHIP mutations in DNA-damage response genes showed delayed neutrophil reconstitution. Thus, CHIP-mutated stem and progenitor cells largely gain on clone size upon ASCT-related blood reconstitution, leading to an increased future risk of CHIP-associated complications.
Late Paleozoic (Variscan) magmatism is widespread in Central Europe. The Lusatian Block is located in the NE Bohemian Massif and it is part of the Saxothuringian Zone of the Variscan orogen. It is bordered by two major NW-trending shear zones, the Intra-Sudetic Fault Zone towards NE and the Elbe Fault Zone towards SW. The scarce Variscan igneous rocks of the Lusatian Block are situated close to these faults. We investigated 19 samples from Variscan plutonic and volcanic rocks of the Lusatian Block, considering all petrological varieties (biotite-bearing granites from the Koenigshain and Stolpen plutons, amphibole-bearing granites from three boreholes, several volcanic dykes, and two volcanites from the intramontane Weissig basin). We applied whole-rock geochemistry (18 samples) and zircon evaporation dating (19 samples). From the evaporation data, we selected six representative samples for additional zircon SHRIMP and CA–ID–TIMS dating. For the Koenigshain pluton, possible protoliths were identified using whole-rock Nd-isotopes, and zircon Hf- and O-isotopes. The new age data allow a subdivision of Variscan igneous rocks in the Lusatian Block into two distinct magmatic episodes. The spatial relation of the two age groups to either the Elbe Fault Zone (298–299 Ma) or the Intra-Sudetic Fault Zone (312–313 Ma) together with reports on the fault-bound character of the dated intrusions suggests an interpretation as two major post-collisional faulting episodes. This assumption of two distinct magmatic periods is confirmed by a compilation of recently published zircon U–Pb CA–ID–TIMS data on further Variscan igneous rocks from the Saxothuringian Zone. New geochemical data allow us to exclude a dominant sedimentary protolith for the Koenigshain pluton as supposed by previous investigations. This conclusion is mainly based on new O- and Hf-isotope data on zircon and the scarcity of inherited zircons. Instead, acid or intermediate igneous rocks are supposed as the main source for these I-type granitoids from the Koenigshain pluton.
Background: Clinical trial registries increase transparency in medical research by making information and results of planned, ongoing, and completed studies publicly available. However, the registration of clinical trials remains a time-consuming manual task complicated by the fact that the same studies often need to be registered in different registries with different data entry requirements and interfaces.
Objective: This study investigates how Health Level 7 (HL7) Fast Healthcare Interoperability Resources (FHIR) may be used as a standardized format for exchanging and storing clinical trial records.
Methods: We designed and prototypically implemented an open-source central trial registry containing records from university hospitals, which are automatically exported and updated by local study management systems.
Results: We provided an architecture and implementation of a multisite clinical trials registry based on HL7 FHIR as a data storage and exchange format.
Conclusions: The results show that FHIR resources establish a harmonized view of study information from heterogeneous sources by enabling automated data exchange between trial centers and central study registries.
Kidney injury is a common complication of severe disease. Here, we report that injuries of the zebrafish embryonal kidney are rapidly repaired by a migratory response in 2-, but not in 1-day-old embryos. Gene expression profiles between these two developmental stages identify cxcl12a and myca as candidates involved in the repair process. Zebrafish embryos with cxcl12a, cxcr4b, or myca deficiency display repair abnormalities, confirming their role in response to injury. In mice with a kidney-specific knockout, Cxcl12 and Myc gene deletions suppress mitochondrial metabolism and glycolysis, and delay the recovery after ischemia/reperfusion injury. Probing these observations in zebrafish reveal that inhibition of glycolysis slows fast migrating cells and delays the repair after injury, but does not affect the slow cell movements during kidney development. Our findings demonstrate that Cxcl12 and Myc facilitate glycolysis to promote fast migratory responses during development and repair, and potentially also during tumor invasion and metastasis.
Electroencephalography (EEG) represents a widely established method for assessing altered and typically developing brain function. However, systematic studies on EEG data quality, its correlates, and consequences are scarce. To address this research gap, the current study focused on the percentage of artifact-free segments after standard EEG pre-processing as a data quality index. We analyzed participant-related and methodological influences, and validity by replicating landmark EEG effects. Further, effects of data quality on spectral power analyses beyond participant-related characteristics were explored. EEG data from a multicenter ADHD-cohort (age range 6 to 45 years), and a non-ADHD school-age control group were analyzed (ntotal = 305). Resting-state data during eyes open, and eyes closed conditions, and task-related data during a cued Continuous Performance Task (CPT) were collected. After pre-processing, general linear models, and stepwise regression models were fitted to the data. We found that EEG data quality was strongly related to demographic characteristics, but not to methodological factors. We were able to replicate maturational, task, and ADHD effects reported in the EEG literature, establishing a link with EEG-landmark effects. Furthermore, we showed that poor data quality significantly increases spectral power beyond effects of maturation and symptom severity. Taken together, the current results indicate that with a careful design and systematic quality control, informative large-scale multicenter trials characterizing neurophysiological mechanisms in neurodevelopmental disorders across the lifespan are feasible. Nevertheless, results are restricted to the limitations reported. Future work will clarify predictive value.
We report on HCFC-22 data acquired by the Michelson Interferometer for Passive Atmospheric Sounding (MIPAS) in the reduced spectral resolution nominal observation mode. The data cover the period from January 2005 to April 2012 and the altitude range from the upper troposphere (above cloud top altitude) to about 50 km. The profile retrieval was performed by constrained nonlinear least squares fitting of modelled spectra to the measured limb spectral radiances. The spectral ν4-band at 816.5 ± 13 cm−1 was used for the retrieval. A Tikhonov-type smoothing constraint was applied to stabilise the retrieval. In the lower stratosphere, we find a global volume mixing ratio of HCFC-22 of about 185 pptv in January 2005. The rate of linear growth in the lower latitudes lower stratosphere was about 6 to 7 pptv year−1 in the period 2005–2012. The profiles obtained were compared with ACE-FTS satellite data v3.5, as well as with MkIV balloon profiles and cryosampler balloon measurements. Between 13 and 22 km, average agreement within −3 to +5 pptv (MIPAS – ACE) with ACE-FTS v3.5 profiles is demonstrated. Agreement with MkIV solar occultation balloon-borne measurements is within 10–20 pptv below 30 km and worse above, while in situ cryosampler balloon measurements are systematically lower over their full altitude range by 15–50 pptv below 24 km and less than 10 pptv above 28 km. MIPAS HCFC-22 time series below 10 km altitude are shown to agree mostly well to corresponding time series of near-surface abundances from the NOAA/ESRL and AGAGE networks, although a more pronounced seasonal cycle is obvious in the satellite data. This is attributed to tropopause altitude fluctuations and subsidence of polar winter stratospheric air into the troposphere. A parametric model consisting of constant, linear, quasi-biennial oscillation (QBO) and several sine and cosine terms with different periods has been fitted to the temporal variation of stratospheric HCFC-22 for all 10°-latitude/1-to-2-km-altitude bins. The relative linear variation was always positive, with relative increases of 40–70 % decade−1 in the tropics and global lower stratosphere, and up to 120 % decade−1 in the upper stratosphere of the northern polar region and the southern extratropical hemisphere. Asian HCFC-22 emissions have become the major source of global upper tropospheric HCFC-22. In the upper troposphere, monsoon air, rich in HCFC-22, is instantaneously mixed into the tropics. In the middle stratosphere, between 20 and 30 km, the observed trend is inconsistent with the trend at the surface (corrected for the age of stratospheric air), hinting at circulation changes. There exists a stronger positive trend in HCFC-22 in the Southern Hemisphere and a more muted positive trend in the Northern Hemisphere, implying a potential change in the stratospheric circulation over the observation period.
We report on HCFC-22 data acquired by the Michelson Interferometer for Passive Atmospheric Sounding (MIPAS) in reduced spectral resolution nominal mode in the period from January 2005 to April 2012 from version 5.02 level-1b spectral data and covering an altitude range from the upper troposphere (above cloud top altitude) to about 50 km. The profile retrieval was performed by constrained nonlinear least squares fitting of measured limb spectral radiances to modelled spectra. The spectral v4-band at 816.5 ± 13 cm-1 was used for the retrieval. A Tikhonov-type smoothing constraint was applied to stabilise the retrieval. In the lower stratosphere, we find a global volume mixing ratio of HCFC-22 of about 185 pptv in January 2005. The linear growth rate in the lower latitudes lower stratosphere was about 6 to 7 pptv yr-1 in the period 2005–2012. The obtained profiles were compared with ACE-FTS satellite data v3.5, as well as with MkIV balloon profiles and in situ cryosampler balloon measurements. Between 13 and 22 km, average agreement within -3 to +5 pptv (MIPAS–ACE) with ACE-FTS v3.5 pro files is demonstrated. Agreement with MkIV solar occultation balloon-borne measurements is within 10–20 pptv below 30 km and worse above, while in situ cryosampler balloon measurements are systematically lower over their full altitude range by 15– 50 pptv below 24 km and less than 10 pptv above 28 km. Obtained MIPAS HCFC-22 time series below 10 km altitude are shown to agree mostly well to corresponding time series of near-surface abundances from NOAA/ESRL and AGAGE networks, although a more pronounced seasonal cycle is obvious in the satellite data, probably due to tropopause altitude fluctuations and subsidence of polar winter stratospheric air into the troposphere. A parametric model consisting of constant, linear, quasi-biennial oscillation (QBO) and several sine and cosine terms with different periods has been fitted to the temporal variation of stratospheric HCFC-22 for all 10° latitude/1 to 2 km altitude bins. The relative linear variation was always positive, with relative increases of 40–70%decade-1 in the tropics and global lower stratosphere, and up to 120%decade-1 in the upper stratosphere of the northern polar region and the southern extratropical hemisphere. In the middle stratosphere between 20 and 30 km, the observed trend is not consistent with the age of stratospheric air-corrected trend at ground, but stronger positive at the Southern Hemisphere and less strong increasing in the Northern Hemisphere, hinting towards changes in the stratospheric circulation over the observation period.
Purpose: The aim of this study is to record material- and surface-dependent heat dissipation during the process of inserting implants into native animal bone. Materials and Methods: Implants made of titanium and zirconium that were identical in macrodesign were inserted under controlled conditions into a bovine rib tempered to 37 °C. The resulting surface temperature was measured on two bone windows by an infrared camera. The results of the six experimental groups, ceramic machined (1), sandblasted (2), and sandblasted and acid-etched surfaces (3) versus titanium implants with the corresponding surfaces (4, 5, and 6) were statistically tested. Results: The average temperature increase, 3 mm subcrestally at ceramic implants, differed with high statistical significance (p = 7.163 × 10−9, resulting from group-adjusted linear mixed-effects model) from titanium. The surface texture of ceramic implants shows a statistical difference between group 3 (15.44 ± 3.63 °C) and group 1 (19.94 ± 3.28 °C) or group 2 (19.39 ± 5.73 °C) surfaces. Within the titanium implants, the temperature changes were similar for all surfaces. Conclusion: Within the limits of an in vitro study, the high temperature rises at ceramic versus titanium implants should be limited by a very slow insertion velocity.
The Altenberg–Teplice Volcanic Complex (ATVC) is a large ~ NNW–SSE trending volcano-plutonic system in the southern part of the Eastern Erzgebirge (northern Bohemian Massif, south-eastern Germany and northern Czech Republic). This study presents high precision U–Pb CA-ID-TIMS zircon ages for the pre-caldera volcano-sedimentary Schönfeld–Altenberg Complex and various rocks of the caldera stage: the Teplice rhyolite, the microgranite ring dyke, and the Sayda-Berggießhübel dyke swarm. These data revealed a prolonged time gap of ca. 7–8 Myr between the pre-caldera stage (Schönfeld–Altenberg Complex) and the climactic caldera stage. The volcanic rocks of the Schönfeld–Altenberg Complex represent the earliest volcanic activity in the Erzgebirge and central Europe at ca. 322 Ma. The subsequent Teplice rhyolite was formed during a relatively short time interval of only 1–2 Myr (314–313 Ma). During the same time interval (314–313 Ma), the microgranite ring dyke intruded at the rim of the caldera structure. In addition, one dyke of the Sayda-Berggiesshübel dyke swarm was dated at ca. 314 Ma, while another yielded a younger age (ca. 311 Ma). These data confirm the close genetic and temporal relationship of the Teplice rhyolite, the microgranite ring dyke, and (at least part of) the Sayda-Berggießhübel dyke swarm. Remarkably, the caldera formation in the south of the Eastern Erzgebirge (caldera stage of ATVC: 314–313 Ma) and that in the north (Tharandt Forest caldera: 314–312 Ma) occurred during the same time. These data document a large ~ 60 km NNW–SSE trending magmatic system in the whole Eastern Erzgebirge. For the first time, Hf-O-isotope zircon data was acquired on the ring dyke from the ATVC rocks to better characterize its possible sources. The homogeneous Hf-O-isotope zircon data from the microgranite ring dyke require preceding homogenization of basement rocks. Some small-scale melts that were produced during Variscan amphibolite-facies metamorphism show similar Hf-O-isotope characteristics and can therefore be considered as the most probable source for the microgranite ring dyke melt. In addition, a second source with low oxygen isotope ratios (e.g. basic rocks) probably contributed to the melt and possibly triggered the climactic eruption of the Teplice rhyolite as well as the crystal-rich intrusion of the ring dyke.
Background: The impact of MRI-lesion targeted (TB) and systematic biopsy (SB) Gleason score (GS) as a predictor for final pathological GS still remains unclear. Methods: All patients with TB + SB, and subsequent radical prostatectomy (RP) between 01/2014-12/2020 were analyzed. Rank correlation coefficient predicted concordance with pathological GS for patients’ TB and SB GS, as well as for the combined effect of SB + TB. Results: Of 159 eligible patients, 77% were biopsy naïve. For SB taken in addition to TB, a Spearman’s correlation of +0.33 was observed regarding final GS. Rates of concordance, upgrading, and downgrading were 37.1, 37.1 and 25.8%, respectively. For TB, a +0.52 correlation was computed regarding final GS. Rates of concordance, upgrading and downgrading for TB biopsy GS were 45.9, 33.3, and 20.8%, respectively. For the combination of SB + TB, a correlation of +0.59 was observed. Rates of concordance, upgrading and downgrading were 49.7, 15.1 and 35.2%, respectively. The combined effect of SB + TB resulted in a lower upgrading rate, relative to TB and SB (both p < 0.001), but a higher downgrading rate, relative to TB (p < 0.01). Conclusions: GS obtained from TB provided higher concordance and lower upgrading and downgrading rates, relative to SB GS with regard to final pathology. The combined effect of SB + TB led to the highest concordance rate and the lowest upgrading rate.
We report here the nuclear magnetic resonance 19F screening of 14 RNA targets with different secondary and tertiary structure to systematically assess the druggability of RNAs. Our RNA targets include representative bacterial riboswitches that naturally bind with nanomolar affinity and high specificity to cellular metabolites of low molecular weight. Based on counter-screens against five DNAs and five proteins, we can show that RNA can be specifically targeted. To demonstrate the quality of the initial fragment library that has been designed for easy follow-up chemistry, we further show how to increase binding affinity from an initial fragment hit by chemistry that links the identified fragment to the intercalator acridine. Thus, we achieve low-micromolar binding affinity without losing binding specificity between two different terminator structures.
The German Cancer Consortium ('Deutsches Konsortium für Translationale Krebsforschung', DKTK) is a long-term cancer consortium, bringing together the German Cancer Research Center (DKFZ), Germany's largest life science research center, and the leading University Medical Center-based Comprehensive Cancer Centers (CCCs) at seven sites across Germany. DKTK was founded in 2012 following international peer review and has positioned itself since then as the leading network for translational cancer research in Germany. DKTK is long term funded by the German Ministry of Research and Education and the federal states of each DKTK partner site. DKTK acts at the interface between basic and clinical cancer research, one major focus being to generate suitable multisite cooperation structures and provide the basis for including higher numbers of patients and facilitate effective collaborative forward and reverse translational cancer research. The consortium addresses areas of high scientific and medical relevance and develops critical infrastructures, for example, for omics technologies, clinical and research big data exchange and analysis, imaging, and clinical grade drug manufacturing. Moreover, DKTK provides a very attractive environment for interdisciplinary and interinstitutional training and career development for clinician and medical scientists.
Background: The approval of everolimus (EVE) for the treatment of angiomyolipoma (2013), subependymal giant cell astrocytoma (2013) and drug-refractory epilepsy (2017) in patients with tuberous sclerosis complex (TSC) represents the first disease-modifying treatment option available for this rare and complex genetic disorder. Objective: The objective of this study was to analyse the use, efficacy, tolerability and treatment retention of EVE in patients with TSC in Germany from the patient’s perspective. Methods: A structured cross-age survey was conducted at 26 specialised TSC centres in Germany and by the German TSC patient advocacy group between February and July 2019, enrolling children, adolescents and adult patients with TSC. Results: Of 365 participants, 36.7% (n = 134) reported the current or past intake of EVE, including 31.5% (n = 115) who were taking EVE at study entry. The mean EVE dosage was 6.1 ± 2.9 mg/m2 (median: 5.6 mg/m2, range 2.0–15.1 mg/m2) in children and adolescents and 4 ± 2.1 mg/m2 (median: 3.7 mg/m2, range 0.8–10.1 mg/m2) in adult patients. An early diagnosis of TSC, the presence of angiomyolipoma, drug-refractory epilepsy, neuropsychiatric manifestations, subependymal giant cell astrocytoma, cardiac rhabdomyoma and overall multi-organ involvement were associated with the use of EVE as a disease-modifying treatment. The reported efficacy was 64.0% for angiomyolipoma (75% in adult patients), 66.2% for drug-refractory epilepsy, and 54.4% for subependymal giant cell astrocytoma. The overall retention rate for EVE was 85.8%. The retention rates after 12 months of EVE therapy were higher among adults (93.7%) than among children and adolescents (88.7%; 90.5% vs 77.4% after 24 months; 87.3% vs 77.4% after 36 months). Tolerability was acceptable, with 70.9% of patients overall reporting adverse events, including stomatitis (47.0%), acne-like rash (7.7%), increased susceptibility to common infections and lymphoedema (each 6.0%), which were the most frequently reported symptoms. With a total score of 41.7 compared with 36.8 among patients not taking EVE, patients currently being treated with EVE showed an increased Liverpool Adverse Event Profile. Noticeable deviations in the sub-items ‘tiredness’, ‘skin problems’ and ‘mouth/gum problems’, which are likely related to EVE-typical adverse effects, were more frequently reported among patients taking EVE. Conclusions: From the patients’ perspective, EVE is an effective and relatively well-tolerated disease-modifying treatment option for children, adolescents and adults with TSC, associated with a high long-term retention rate that can be individually considered for each patient. Everolimus therapy should ideally be supervised by a centre experienced in the use of mechanistic target of rapamycin inhibitors, and adverse effects should be monitored on a regular basis.
The Kinase Chemogenomic Set (KCGS): an open science resource for kinase vulnerability identification
(2021)
We describe the assembly and annotation of a chemogenomic set of protein kinase inhibitors as an open science resource for studying kinase biology. The set only includes inhibitors that show potent kinase inhibition and a narrow spectrum of activity when screened across a large panel of kinase biochemical assays. Currently, the set contains 187 inhibitors that cover 215 human kinases. The kinase chemogenomic set (KCGS), current Version 1.0, is the most highly annotated set of selective kinase inhibitors available to researchers for use in cell-based screens.
The Kinase Chemogenomic Set (KCGS): An open science resource for kinase vulnerability identification
(2019)
We describe the assembly and annotation of a chemogenomic set of protein kinase inhibitors as an open science resource for studying kinase biology. The set only includes inhibitors that show potent kinase inhibition and a narrow spectrum of activity when screened across a large panel of kinase biochemical assays. Currently, the set contains 187 inhibitors that cover 215 human kinases. The kinase chemogenomic set (KCGS) is the most highly annotated set of selective kinase inhibitors available to researchers for use in cell-based screens.
Introduction: Older patients with multimorbidity, polypharmacy and related complex care needs represent a growing proportion of the population and a challenge for healthcare systems. Particularly in transitional care (hospital admission and hospital discharge), medical errors, inappropriate treatment, patient concerns and lack of confidence in healthcare are major problems that may arise from a lack of information continuity. The aim of this study is to develop an intervention to improve informational continuity of care at the interface between general practice and hospital care.
Methods and analysis: A qualitative approach will be used to develop our participatory intervention. Overall, 32 semistructured interviews with relevant stakeholders will be conducted and analysed. The stakeholders will include healthcare professionals from the outpatient setting (general practitioners, healthcare assistants, ambulatory care nurses) and the inpatient setting (clinical doctors, nurses, pharmacists, clinical information scientists) as well as patients and informal caregivers. At a series of workshops based on the results of the stakeholder analyses, we aim to develop a participatory intervention that will then be implemented in a subsequent pilot study. The same stakeholder groups will be invited for participation in the workshops.
Ethics and dissemination: Ethical approval for this study was waived by the Ethics Committee of Goethe University Frankfurt because of the nature of the proposed study. Written informed consent will be obtained from all study participants prior to participation. Results will be tested in a pilot study and disseminated at (inter)national conferences and via publication in peer-reviewed journals.