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The STAR Collaboration reports measurements of the transverse single-spin asymmetry (TSSA) of inclusive 𝜋0 at center-of-mass energies (√𝑠) of 200 GeV and 500 GeV in transversely polarized proton-proton collisions in the pseudo-rapidity region 2.7 to 4.0. The results at the two different energies show a continuous increase of the TSSA with Feynman-𝑥, and, when compared to previous measurements, no dependence on √𝑠 from 19.4 GeV to 500 GeV is found. To investigate the underlying physics leading to this large TSSA, different topologies have been studied. 𝜋0 with no nearby particles tend to have a higher TSSA than inclusive 𝜋0. The TSSA for inclusive electromagnetic jets, sensitive to the Sivers effect in the initial state, is substantially smaller, but shows the same behavior as the inclusive 𝜋0 asymmetry as a function of Feynman-𝑥. To investigate final-state effects, the Collins asymmetry of 𝜋0 inside electromagnetic jets has been measured. The Collins asymmetry is analyzed for its dependence on the 𝜋0 momentum transverse to the jet thrust axis and its dependence on the fraction of jet energy carried by the 𝜋0. The asymmetry was found to be small in each case for both center-of-mass energies. All the measurements are compared to QCD-based theoretical calculations for transverse-momentum-dependent parton distribution functions and fragmentation functions. Some discrepancies are found, which indicates new mechanisms might be involved.
With the introduction of the virtual allocation crossmatch in the Eurotransplant (ET) region in 2023, the determination of unacceptable antigen mismatches (UAM) in kidney transplant recipients is of utmost importance for histocompatibility laboratories and transplant centers. Therefore, a joined working group of members from the German Society for Immunogenetics (Deutsche Gesellschaft für Immungenetik, DGI) and the German Transplantation Society (Deutsche Transplantationsgesellschaft, DTG) revised and updated the previous recommendations from 2015 in light of recently published evidence. Like in the previous version, a wide range of topics is covered from technical issues to clinical risk factors. This review summarizes the evidence about the prognostic value of contemporary methods for HLA antibody detection and identification, as well as the impact of UAM on waiting time, on which these recommendations are based. As no clear criteria could be determined to differentiate potentially harmful from harmless HLA antibodies, the general recommendation is to assign all HLA against which plausible antibodies are found as UAM. There is, however, a need for individualized solutions for highly immunized patients. These revised recommendations provide a list of aspects that need to be considered when assigning UAM to enable a fair and comprehensible procedure and to harmonize risk stratification prior to kidney transplantation between transplant centers.
The rare decay 𝜂′→𝜋+𝜋−𝑒+𝑒− is studied using a sample of 1.3×109 𝐽/𝜓 events collected with the BESIII detector at BEPCII in 2009 and 2012. The branching fraction is measured with improved precision to be (2.42±0.05stat±0.08syst)×10−3. Due to the inclusion of new data, this result supersedes the last BESIII result on this branching fraction. In addition, the 𝐶𝑃-violating asymmetry in the angle between the decay planes of the 𝜋+𝜋−-pair and the 𝑒+𝑒−-pair is investigated. A measurable value would indicate physics beyond the standard model; the result is 𝒜𝐶𝑃=(2.9±3.7stat±1.1syst)%, which is consistent with the standard model expectation of no 𝐶𝑃-violation. The precision is comparable to the asymmetry measurement in the 𝐾0𝐿→𝜋+𝜋−𝑒+𝑒− decay where the observed (14±2)% effect is driven by a standard model mechanism.
Search for the reaction channel e⁺e⁻ → ηcηπ⁺π⁻ at center-of-mass energies from 4.23 to 4.60 GeV
(2021)
Using data collected with the BESIII detector operating at the Beijing Electron Positron Collider, we search for the process 𝑒+𝑒−→𝜂𝑐𝜂𝜋+𝜋−. The search is performed using five large datasets recorded at center-of-mass energies of 4.23, 4.26, 4.36, 4.42, and 4.60 GeV. The 𝜂𝑐 meson is reconstructed in 16 exclusive decay modes. No signal is observed in the 𝜂𝑐 mass region at any center-of-mass energy. The upper limits on the reaction cross sections are determined to be 6.2, 10.8, 27.6, 22.6 and 23.7 pb at the 90% confidence level at the center-of-mass energies listed above.
Using a sample of 1.31×109 𝐽/𝜓 events collected with the BESIII detector, we perform a study of 𝐽/𝜓→𝛾𝜂𝜂𝜂′ to search for the 𝑋(2370) and 𝜂𝑐 in the 𝜂𝜂𝜂′ invariant mass distribution. No significant signal for the 𝑋(2370) is observed, and we set an upper limit for the product branching fraction of ℬ(𝐽/𝜓→𝛾𝑋(2370)·ℬ(𝑋(2370)→𝜂𝜂𝜂′)<9.2×10−6 at the 90% confidence level. A clear 𝜂𝑐 signal is observed for the first time, yielding a product branching fraction of ℬ(𝐽/𝜓→𝛾𝜂𝑐)·ℬ(𝜂𝑐→𝜂𝜂𝜂′)=(4.86±0.62(stat)±0.45(sys))×10−5.
Observation of η′ → π⁺π⁻μ⁺μ⁻
(2021)
Using (1310.6±7.0)×106 𝐽/𝜓 events acquired with the BESIII detector at the BEPCII storage rings, the decay 𝜂′→𝜋+𝜋−𝜇+𝜇− is observed for the first time with a significance of 8𝜎 via the process 𝐽/𝜓→𝛾𝜂′. We measure the branching fraction of 𝜂′→𝜋+𝜋−𝜇+𝜇− to be ℬ(𝜂′→𝜋+𝜋−𝜇+𝜇−)=(1.97±0.33(stat)±0.19(syst))×10−5, where the first and second uncertainties are statistical and systematic, respectively
he Born cross sections for the process 𝑒+𝑒−→𝜂′𝜋+𝜋− at different center-of-mass energies between 2.00 and 3.08 GeV are reported with improved precision from an analysis of data samples collected with the BESIII detector operating at the BEPCII storage ring. An obvious structure is observed in the Born cross section line shape. Fit as a Breit-Wigner resonance, it has a statistical significance of 6.3𝜎 and a mass and width of 𝑀=(2111±43±25) MeV/𝑐2 and Γ=(135±34±30) MeV, where the uncertainties are statistical and systematic, respectively. These measured resonance parameters agree with the measurements of BABAR in 𝑒+𝑒−→𝜂′𝜋+𝜋− and BESIII in 𝑒+𝑒−→𝜔𝜋0 within two standard deviations.
The Born cross sections for the process e+e−→η′π+π− at different center-of-mass energies between 2.00 and 3.08 GeV are reported with improved precision from an analysis of data samples collected with the BESIII detector operating at the BEPCII storage ring. An obvious structure is observed in the Born cross section line shape. Fit as a Breit-Wigner resonance, it has a statistical significance of 6.3σ and a mass and width of M=(2111±43±25)~MeV/c2 and Γ=(135±34±30)~MeV, where the uncertainties are statistical and systematic, respectively. These measured resonance parameters agree with the measurements of BABAR in e+e−→η′π+π− and BESIII in e+e−→ωπ0 within two standard deviations.
The Born cross sections for the process e+e−→η′π+π− at different center-of-mass energies between 2.00 and 3.08~GeV are reported with improved precision from an analysis of data samples collected with the BESIII detector operating at the BEPCII storage ring. An obvious structure is observed in the Born cross section line shape. Fit as a Breit-Wigner resonance, it has a statistical significance of 6.3σ and a mass and width of M=(2108±46±25)~MeV/c2 and Γ=(138±36±30)~MeV, where the uncertainties are statistical and systematic, respectively. These measured resonance parameters agree with the measurements of BABAR in e+e−→η′π+π− and BESIII in e+e−→ωπ0 within two standard deviations.
We report a study of the processes of e+e−→K+(D−sD∗0+D∗−sD0) based on e+e− annihilation samples collected with the BESIII detector operating at BEPCII at five center-of-mass energies ranging from 4.628 to 4.698 GeV with a total integrated luminosity of 3.7 fb−1. An excess over the known contributions of the conventional charmed mesons is observed near the D−sD∗0 and D∗−sD0 mass thresholds in the K+ recoil-mass spectrum for events collected at s√=4.681 GeV. The structure matches a mass-dependent-width Breit-Wigner line shape, whose pole mass and width are determined as (3982.5+1.8−2.6±2.1) MeV/c2 and (12.8+5.3−4.4±3.0) MeV, respectively. The first uncertainties are statistical and the second are systematic. The significance of the resonance hypothesis is estimated to be 5.3 σ over the contributions only from the conventional charmed mesons. This is the first candidate of the charged hidden-charm tetraquark with strangeness, decaying into D−sD∗0 and D∗−sD0. However, the properties of the excess need further exploration with more statistics.
Observation of a near-threshold structure in the K⁺ recoil-mass spectra in e⁺e⁻ → K⁺(Dₛ⁻D*⁰+Dₛ*⁻D⁰)
(2021)
We report a study of the processes of 𝑒+𝑒−→𝐾+𝐷−𝑠𝐷*0 and 𝐾+𝐷*−𝑠𝐷0 based on 𝑒+𝑒− annihilation samples collected with the BESIII detector operating at BEPCII at five center-of-mass energies ranging from 4.628 to 4.698 GeV with a total integrated luminosity of 3.7 fb−1. An excess of events over the known contributions of the conventional charmed mesons is observed near the 𝐷−𝑠𝐷*0 and 𝐷*−𝑠𝐷0 mass thresholds in the 𝐾+ recoil-mass spectrum for events collected at √𝑠=4.681 GeV. The structure matches a mass-dependent-width Breit-Wigner line shape, whose pole mass and width are determined as (3982.5+1.8
−2.6±2.1) MeV/𝑐2 and (12.8+5.3−4.4±3.0) MeV, respectively. The first uncertainties are statistical and the second are systematic. The significance of the resonance hypothesis is estimated to be 5.3 𝜎 over the contributions only from the conventional charmed mesons. This is the first candidate for a charged hidden-charm tetraquark with strangeness, decaying into 𝐷−𝑠𝐷*0 and 𝐷*−𝑠𝐷0. However, the properties of the excess need further exploration with more statistics.
In this work we investigate the existence of bound states for doubly heavy tetraquark systems Q¯Q¯′qq′ in a full lattice-QCD computation, where heavy bottom quarks are treated in the framework of non-relativistic QCD. We focus on three systems with quark content b¯b¯ud, b¯b¯us and b¯c¯ud. We show evidence for the existence of b¯b¯ud and b¯b¯us bound states, while no binding appears to be present for b¯c¯ud. For the bound four-quark states we also discuss the importance of various creation operators and give an estimate of the meson-meson and diquark-antidiquark percentages.
We report high-precision measurements of the longitudinal double-spin asymmetry, 𝐴𝐿𝐿, for midrapidity inclusive jet and dijet production in polarized 𝑝𝑝 collisions at a center-of-mass energy of √𝑠=200 GeV. The new inclusive jet data are sensitive to the gluon helicity distribution, Δ𝑔(𝑥,𝑄2), for gluon momentum fractions in the range from 𝑥≃0.05 to 𝑥≃0.5, while the new dijet data provide further constraints on the 𝑥 dependence of Δ𝑔(𝑥,𝑄2). The results are in good agreement with previous measurements at √𝑠=200 GeV and with recent theoretical evaluations of prior world data. Our new results have better precision and thus strengthen the evidence that Δ𝑔(𝑥,𝑄2) is positive for 𝑥>0.05.
Search for the lepton number violating decay Σ⁻ → pe⁻e⁻ and the rare inclusive decay Σ⁻ → Σ⁺X
(2021)
Using a data sample of (1310.6±7.0)×106 𝐽/𝜓 events taken with the BESIII detector at the center-of-mass energy of 3.097 GeV, we search for the first time for the lepton number violating decay Σ−→𝑝𝑒−𝑒− and the rare inclusive decay Σ−→Σ+𝑋, where 𝑋 denotes any possible particle combination. The Σ− candidates are tagged in 𝐽/𝜓→¯Σ(1385)+Σ− decays. No signal candidates are found, and the upper limits on the branching fractions at the 90% confidence level are determined to be ℬ(Σ−→𝑝𝑒−𝑒−)<6.7×10−5 and ℬ(Σ−→Σ+𝑋)<1.2×10−4.
Using 10.1 × 109 J/ψ events produced by the Beijing Electron Positron Collider (BEPCII) at a center-of-mass energy √s = 3.097 GeV and collected with the BESIII detector, we present a search for the rare semi-leptonic decay J/ψ → D−e+νe + c.c. No excess of signal above background is observed, and an upper limit on the branching fraction B(J/ψ → D−e +νe + c.c.) < 7.1 × 10−8 is obtained at 90% confidence level. This is an improvement of more than two orders of magnitude over the previous best limit.
Using 6.32 fb−1 of 𝑒+𝑒− collision data collected by the BESIII detector at the center-of-mass energies between 4.178 and 4.226 GeV, an amplitude analysis of the 𝐷+𝑠→𝐾0𝑆𝐾−𝜋+𝜋+ decays is performed for the first time to determine the intermediate-resonant contributions. The dominant component is the 𝐷+𝑠→𝐾*(892)+¯𝐾*(892)0 decay with a fraction of (40.6±2.9stat±4.9sys)%. Our results of the amplitude analysis are used to obtain a more precise measurement of the branching fraction of the 𝐷+𝑠→𝐾0𝑆𝐾−𝜋+𝜋+ decay, which is determined to be (1.46±0.05stat±0.05sys)%.
Using a total of 5.25 fb−1 of e+e− collision data with center-of-mass energies from 4.236 to 4.600 GeV, we report the first observation of the process e+e− → ηψ(2S) with a statistical significance of 4.9 standard deviations. The data sets were collected by the BESIII detector operating at the BEPCII storage ring. We measure the yield of events integrated over center-of-mass energies and also present the energy dependence of the measured cross section.
The decays D → K−π+π+π− and D → K−π+π 0 are studied in a sample of quantum-correlated DD¯ pairs produced through the process e+e− → ψ(3770) → DD¯, exploiting a data set collected by the BESIII experiment that corresponds to an integrated luminosity of 2.93 fb−1 . Here D indicates a quantum superposition of a D0 and a D¯ 0 meson. By reconstructing one neutral charm meson in a signal decay, and the other in the same or a different final state, observables are measured that contain information on the coherence factors and average strong-phase differences of each of the signal modes. These parameters are critical inputs in the measurement of the angle γ of the Unitarity Triangle in B− → DK− decays at the LHCb and Belle II experiments. The coherence factors are determined to be RK3π = 0.52+0.12−0.10 and RKππ0 = 0.78 ± 0.04, with values for the average strong-phase differences that are δ K3π D = (167+31−19)◦ and δKππ0D = (196+14−15◦ , where the uncertainties include both statistical and systematic contributions. The analysis is re-performed in four bins of the phase-space of the D → K−π+π+π− to yield results that will allow for a more sensitive measurement of γ with this mode, to which the BESIII inputs will contribute an uncertainty of around 6◦.
We report new measurements of the branching fraction ℬ(𝐷+𝑠→ℓ+𝜈), where ℓ+ is either 𝜇+ or 𝜏+(→𝜋+¯𝜈𝜏), based on 6.32 fb−1 of electron-positron annihilation data collected by the BESIII experiment at six center-of-mass energy points between 4.178 and 4.226 GeV. Simultaneously floating the 𝐷+𝑠→𝜇+𝜈𝜇 and 𝐷+𝑠→𝜏+𝜈𝜏 components yields ℬ(𝐷+𝑠→𝜏+𝜈𝜏)=(5.21±0.25±0.17)×10−2, ℬ(𝐷+𝑠→𝜇+𝜈𝜇)=(5.35±0.13±0.16)×10−3, and the ratio of decay widths 𝑅=Γ(𝐷+𝑠→𝜏+𝜈𝜏)Γ(𝐷+𝑠→𝜇+𝜈𝜇)=9.73+0.61−0.58±0.36, where the first uncertainties are statistical and the second systematic. No evidence of 𝐶𝑃 asymmetry is observed in the decay rates 𝐷±𝑠→𝜇±𝜈𝜇 and 𝐷±𝑠→𝜏±𝜈𝜏: 𝐴𝐶𝑃(𝜇±𝜈)=(−1.2±2.5±1.0)% and 𝐴𝐶𝑃(𝜏±𝜈)=(+2.9±4.8±1.0)%. Constraining our measurement to the Standard Model expectation of lepton universality (𝑅=9.75), we find the more precise results ℬ(𝐷+𝑠→𝜏+𝜈𝜏)=(5.22±0.10±0.14)×10−2 and 𝐴𝐶𝑃(𝜏±𝜈𝜏)=(−0.1±1.9±1.0)%. Combining our results with inputs external to our analysis, we determine the 𝑐→¯𝑠 quark mixing matrix element, 𝐷+𝑠 decay constant, and ratio of the decay constants to be |𝑉𝑐𝑠|=0.973±0.009±0.014, 𝑓𝐷+𝑠=249.9±2.4±3.5 MeV, and 𝑓𝐷+𝑠/𝑓𝐷+=1.232±0.035, respectively.
Using 2.93 fb−1 of e+e− collision data taken with the BESIII detector at a center-of-mass energy of 3.773 GeV, the observation of the D0→K1(1270)−e+νe semileptonic decay is presented. The statistical significance of the decay D0→K1(1270)−e+νe is greater than 10σ. The branching fraction of D0→K1(1270)−e+νe is measured to be (1.09±0.13+0.09−0.16±0.12)×10−3. Here, the first uncertainty is statistical, the second is systematic, and the third originates from the assumed branching fraction of K1(1270)−→K−π+π−. The fraction of longitudinal polarization in D0→K1(1270)−e+νe is determined for the first time to be 0.50±0.19stat±0.08syst.
Using 2.93 fb−1 of e+e− collision data taken with the BESIII detector at a center-of-mass energy of 3.773 GeV, the observation of the D0→K1(1270)−e+νe semileptonic decay is presented. The statistical significance of the decay D0→K1(1270)−e+νe is greater than 10σ. The branching fraction of D0→K1(1270)−e+νe is measured to be (1.09±0.13+0.09−0.13±0.12)×10−3. Here, the first uncertainty is statistical, the second is systematic, and the third originates from the assumed branching fraction of K1(1270)−→K−π+π−.
Born cross sections for the processes e+e− → ωη and e+e− → ωπ0 have been determined for centerof-mass energies between 2.00 and 3.08 GeV with the BESIII detector at the BEPCII collider. The results obtained in this work are consistent with previous measurements but with improved precision. Two resonant structures are observed. In the e+e− → ωη cross sections, a resonance with a mass of (2176 ± 24 ± 3) MeV/c2 and a width of (89 ± 50 ± 5) MeV is observed with a significance of 6.2σ. Its properties are consistent with the φ(2170). In the e+e− → ωπ0 cross sections, a resonance denoted Y (2040) is observed with a significance of more than 10σ. Its mass and width are determined to be (2034 ± 13 ± 9) MeV/c2 and (234 ± 30 ± 25) MeV, respectively, where the first uncertainties are statistical and the second ones are systematic.
The Born cross sections of the e+e− → +¯ − and e+e− → −¯ + processes are determined for centerof-mass energy from 2.3864 to 3.0200 GeV with the BESIII detector. The cross section lineshapes can be described properly by a pQCD function and the resulting ratio of effective form factors for the + and − is consistent with 3. In addition, ratios of the + electric and magnetic form factors, |GE /GM |, are obtained at three center-of-mass energies through an analysis of the angular distributions. These measurements, which are studied for the first time in the off-resonance region, provide precision experimental input for understanding baryonic structure. The observed new features of the ± form factors require more theoretical discussions for the hyperons.
We report an amplitude analysis and branching fraction measurement of 𝐷+
𝑠→𝐾+𝐾−𝜋+ decay using a data sample of 3.19 fb−1 recorded with BESIII detector at a center-of-mass energy of 4.178 GeV. We perform a model-independent partial wave analysis in the low 𝐾+𝐾− mass region to determine the 𝐾+𝐾− S-wave line shape, followed by an amplitude analysis of our very pure high-statistics sample. With the detection efficiency based on the amplitude analysis results, the absolute branching fraction is measured to be ℬ(𝐷+𝑠→𝐾+𝐾−𝜋+)=(5.47±0.08stat±0.13sys)%.
We report an amplitude analysis and branching fraction measurement of D+s→K+K−π+ decay using a data sample of 3.19 fb−1 recorded with BESIII detector at a center-of-mass energy of 4.178 GeV.
We perform a model-independent partial wave analysis in the low K+K− mass region to determine the K+K− S-wave lineshape, followed by an amplitude analysis of our very pure high-statistics sample.
The amplitude analysis provides an accurate determination of the detection efficiency allowing us to measure the branching fraction B(D+s→K+K−π+)=(5.47±0.08stat±0.13sys)%.
Using a data sample corresponding to an integrated luminosity of 2.93 fb−1 collected at a center-of-mass energy s√=3.773 GeV by the BESIII detector, the decay D0→ωϕ is observed for the first time. The branching fraction is measured to be (6.48±0.96±0.38)×10−4 with a significance of 6.3σ, where the first and second uncertainties are statistical and systematic, respectively. An angular analysis reveals that the ϕ and ω mesons from the D0→ωϕ decay are transversely polarized.
Using a data sample corresponding to an integrated luminosity of 2.93 fb−1 collected at a center-of-mass energy s√=3.773 GeV by the BESIII detector, the decay D0→ωϕ is observed for the first time. The branching fraction is measured to be (6.48±0.96±0.38)×10−4 with a significance of 6.3σ, where the first and second uncertainties are statistical and systematic, respectively. An angular analysis reveals that the ϕ and ω mesons from the D0→ωϕ decay are transversely polarized, which is inconsistent with current theoretical expectations and challenges our understanding of the underlying dynamics in charm meson decays.
Using a data sample corresponding to an integrated luminosity of 2.93 fb−1 collected at a center-of-mass energy s√=3.773 GeV by the BESIII detector, the decay D0→ωϕ is observed for the first time. The branching fraction is measured to be (6.48±0.96±0.40)×10−4 with a significance of 6.3σ, where the first and second uncertainties are statistical and systematic, respectively. An angular analysis reveals that the ϕ and ω mesons from the D0→ωϕ decay are transversely polarized. The 95% confidence level upper limit on longitudinal polarization fraction is set to be less than 0.24, which is inconsistent with current theoretical expectations and challenges our understanding of the underlying dynamics in charm meson decays.
Using data samples with a total integrated luminosity of 20.1 fb−1 collected by the BESIII detector operating at the BEPCII collider, the cross section of the process 𝑒+𝑒−→𝜋+𝜋−𝜓(3686) is measured at center-of-mass energies between 4.0076 and 4.6984 GeV. The measured cross section is consistent with previous results, and with much improved precision. A fit to the measured energy-dependent cross section, which includes three Breit-Wigner functions and a nonresonant contribution, confirms the existence of the charmonium-like states 𝑌(4220), 𝑌(4390), and 𝑌(4660). This is the first observation of the 𝑌(4660) at the BESIII experiment.
Using (10.087±0.044)×109 𝐽/𝜓 events collected by the Beijing Spectrum III (BESIII) detector at the Beijing Electron Positron Collider II (BEPCII) collider, we search for the hyperon semileptonic decay Ξ−→Ξ0𝑒−¯𝜈𝑒. No significant signal is observed and the upper limit on the branching fraction ℬ(Ξ−→Ξ0𝑒−¯𝜈𝑒) is set to be 2.59×10−4 at 90% confidence level. This result is one order of magnitude more strict than the previous best limit.
Using inclusive decays of the J/ψ, a precise determination of the number of J/ψ events collected with the BESIII detector is performed. For the two data sets taken in 2009 and 2012, the numbers of J/ψ events are recalculated to be (224.0±1.3)×106 and (1088.5±4.4)×106 respectively, which are in good agreement with the previous measurements. For the J/ψ sample taken in 2017--2019, the number of events is determined to be (8774.0±39.4)×106. The total number of J/ψ events collected with the BESIII detector is determined to be (10087±44)×106, where the uncertainty is dominated by systematic effects and the statistical uncertainty is negligible.
A search for the charged lepton flavor violating decay 𝐽/𝜓→𝑒±𝜏∓ with 𝜏∓→𝜋∓𝜋0𝜈𝜏 is performed with about 10×109 𝐽/𝜓 events collected with the BESIII detector at the BEPCII. No significant signal is observed, and an upper limit is set on the branching fraction ℬ(𝐽/𝜓→𝑒±𝜏∓)<7.5×10−8 at the 90% confidence level. This improves the previously published limit by two orders of magnitude.
During the 2016-17 and 2018-19 running periods, the BESIII experiment collected 7.5~fb−1 of e+e− collision data at center-of-mass energies ranging from 4.13 to 4.44 GeV. These data samples are primarily used for the study of excited charmonium and charmoniumlike states. By analyzing the di-muon process e+e−→(γISR/FSR)μ+μ−, we measure the center-of-mass energies of the data samples with a precision of 0.6 MeV. Through a run-by-run study, we find that the center-of-mass energies were stable throughout most of the data-taking period.
During the 2016-17 and 2018-19 running periods, the BESIII experiment collected 7.5~fb−1 of e+e− collision data at center-of-mass energies ranging from 4.13 to 4.44 GeV. These data samples are primarily used for the study of excited charmonium and charmoniumlike states. By analyzing the di-muon process e+e−→(γISR/FSR)μ+μ−, we measure the center-of-mass energies of the data samples with a precision of 0.6 MeV. Through a run-by-run study, we find that the center-of-mass energies were stable throughout most of the data-taking period.
During the 2016-17 and 2018-19 running periods, the BESIII experiment collected 7.5~fb−1 of e+e− collision data at center-of-mass energies ranging from 4.13 to 4.44 GeV. These data samples are primarily used for the study of excited charmonium and charmoniumlike states. By analyzing the di-muon process e+e−→(γISR/FSR)μ+μ−, we measure the center-of-mass energies of the data samples with a precision of 0.6 MeV. Through a run-by-run study, we find that the center-of-mass energies were stable throughout most of the data-taking period.
During the 2016-17 and 2018-19 running periods, the BESIII experiment collected 7.5~fb−1 of e+e− collision data at center-of-mass energies ranging from 4.13 to 4.44 GeV. These data samples are primarily used for the study of excited charmonium and charmoniumlike states. By analyzing the di-muon process e+e−→(γISR/FSR)μ+μ−, we measure the center-of-mass energies of the data samples with a precision of 0.6 MeV. Through a run-by-run study, we find that the center-of-mass energies were stable throughout most of the data-taking period.
During the 2016-17 and 2018-19 running periods, the BESIII experiment collected 7.5 fb -1 of e+e− collision data at center-of-mass energies ranging from 4.13 to 4.44 GeV. These data samples are primarily used for the study of excited charmonium and charmoniumlike states. By analyzing the di-muon process e+e− (γISR/FSR)µ -> +µ-, we measure the center-of-mass energies of the data samples with a precision of 0.6 MeV. Through a run-by-run study, we find that the center-of-mass energies were stable throughout most of the data-collection period.
Argonaute 2 (AGO2) is an indispensable component of the RNA-induced silencing complex, operating at the translational or posttranscriptional level. It is compartmentalized into structures such as GW- and P-bodies, stress granules and adherens junctions as well as the midbody. Here we show using immunofluorescence, image and bioinformatic analysis and cytogenetics that AGO2 also resides in membrane protrusions such as open- and close-ended tubes. The latter are cytokinetic bridges where AGO2 colocalizes at the midbody arms with cytoskeletal components such as α-Τubulin and Aurora B, and various kinases. AGO2, phosphorylated on serine 387, is located together with Dicer at the midbody ring in a manner dependent on p38 MAPK activity. We further show that AGO2 is stress sensitive and important to ensure the proper chromosome segregation and cytokinetic fidelity. We suggest that AGO2 is part of a regulatory mechanism triggered by cytokinetic stress to generate the appropriate micro-environment for local transcript homeostasis.
In Ref. [1] the BESIII collaboration published a cross section measurement of the process e+e− → π+π− in the energy range between 600 and 900 MeV. In this corrigendum, we report a corrected evaluation of the statistical errors in terms of a fully propagated covariance matrix. The correction also yields a reduced statistical uncertainty for the hadronic vacuum polarization contribution to the anomalous magnetic moment of the muon, which now reads as aππ,LO μ (600 − 900 MeV) = (368.2 ± 1.5stat ± 3.3syst) × 10−10. The central values of the cross section measurement and of aππ,LO μ , as well as the systematic uncertainties remain unchanged.
Oncogenic transformation of lung epithelial cells is a multi-step process, frequently starting with the inactivation of tumor suppressors and subsequent activating mutations in proto-oncogenes, such as members of the PI3K or MAPK family. Cells undergoing transformation have to adjust to changes, such as metabolic requirements. This is achieved, in part, by modulating the protein abundance of transcription factors, which manifest these adjustments. Here, we report that the deubiquitylase USP28 enables oncogenic reprogramming by regulating the protein abundance of proto-oncogenes, such as c-JUN, c-MYC, NOTCH and ΔNP63, at early stages of malignant transformation. USP28 is increased in cancer compared to normal cells due to a feed-forward loop, driven by increased amounts of oncogenic transcription factors, such as c-MYC and c-JUN. Irrespective of oncogenic driver, interference with USP28 abundance or activity suppresses growth and survival of transformed lung cells. Furthermore, inhibition of USP28 via a small molecule inhibitor reset the proteome of transformed cells towards a ‘pre-malignant’ state, and its inhibition cooperated with clinically established compounds used to target EGFRL858R, BRAFV600E or PI3KH1047R driven tumor cells. Targeting USP28 protein abundance already at an early stage via inhibition of its activity therefore is a feasible strategy for the treatment of early stage lung tumours and the observed synergism with current standard of care inhibitors holds the potential for improved targeting of established tumors.
DNA methylation profiles of aggressive behavior may capture lifetime cumulative effects of genetic, stochastic, and environmental influences associated with aggression. Here, we report the first large meta-analysis of epigenome-wide association studies (EWAS) of aggressive behavior (N = 15,324 participants). In peripheral blood samples of 14,434 participants from 18 cohorts with mean ages ranging from 7 to 68 years, 13 methylation sites were significantly associated with aggression (alpha = 1.2 × 10−7; Bonferroni correction). In cord blood samples of 2425 children from five cohorts with aggression assessed at mean ages ranging from 4 to 7 years, 83% of these sites showed the same direction of association with childhood aggression (r = 0.74, p = 0.006) but no epigenome-wide significant sites were found. Top-sites (48 at a false discovery rate of 5% in the peripheral blood meta-analysis or in a combined meta-analysis of peripheral blood and cord blood) have been associated with chemical exposures, smoking, cognition, metabolic traits, and genetic variation (mQTLs). Three genes whose expression levels were associated with top-sites were previously linked to schizophrenia and general risk tolerance. At six CpGs, DNA methylation variation in blood mirrors variation in the brain. On average 44% (range = 3–82%) of the aggression–methylation association was explained by current and former smoking and BMI. These findings point at loci that are sensitive to chemical exposures with potential implications for neuronal functions. We hope these results to be a starting point for studies leading to applications as peripheral biomarkers and to reveal causal relationships with aggression and related traits.
Tuberous sclerosis complex (TSC) is a rare genetic disease that is, besides cutaneous and visceral organ manifestations, typically associated with a severe, usually drug refractory epilepsy at a very early stage of the disease. Due to its direct effect on the mTOR signaling pathway dysregulated by TSC and its synergistic effects on other organ manifestations, the rapamycin derivative everolimus (EVE) is increasingly being used. The aim of this systematic review is to evaluate the efficacy, safety and tolerability of EVE in patients with TSC-associated, refractory epilepsy.
The hydrothermal vent tubeworm Riftia pachyptila hosts a single 16S rRNA phylotype of intracellular sulfur-oxidizing symbionts, which vary considerably in cell morphology and exhibit a remarkable degree of physiological diversity and redundancy, even in the same host. To elucidate whether multiple metabolic routes are employed in the same cells or rather in distinct symbiont subpopulations, we enriched symbionts according to cell size by density gradient centrifugation. Metaproteomic analysis, microscopy, and flow cytometry strongly suggest that Riftia symbiont cells of different sizes represent metabolically dissimilar stages of a physiological differentiation process: While small symbionts actively divide and may establish cellular symbiont-host interaction, large symbionts apparently do not divide, but still replicate DNA, leading to DNA endoreduplication. Moreover, in large symbionts, carbon fixation and biomass production seem to be metabolic priorities. We propose that this division of labor between smaller and larger symbionts benefits the productivity of the symbiosis as a whole.
We investigate the possible formation of a Bose-Einstein condensed phase of pions in the early Universe at nonvanishing values of lepton flavor asymmetries. A hadron resonance gas model with pion interactions, based on first-principle lattice QCD simulations at nonzero isospin density, is used to evaluate cosmic trajectories at various values of electron, muon, and tau lepton asymmetries that satisfy the available constraints on the total lepton asymmetry. The cosmic trajectory can pass through the pion condensed phase if the combined electron and muon asymmetry is sufficiently large: |le+lμ|≳0.1, with little sensitivity to the difference le−lμ between the individual flavor asymmetries. Future constraints on the values of the individual lepton flavor asymmetries will thus be able to either confirm or rule out the condensation of pions during the cosmic QCD epoch. We demonstrate that the pion condensed phase leaves an imprint both on the spectrum of primordial gravitational waves and on the mass distribution of primordial black holes at the QCD scale, e.g., the black hole binary of recent LIGO event GW190521 can be formed in that phase.
Hintergrund: Die chirurgische Facharztweiterbildung erfordert neben dem Erlernen theoretischen Wissens ebenfalls den Erwerb praktisch-chirurgischer Kompetenzen. Eine Alternative zur Aus- und Weiterbildung am Patienten stellen simulationsbasierte Lehrkonzepte dar. Ziel der vorliegenden Studie ist die Analyse der Verteilung und des Einsatzes chirurgischer Simulatoren in deutschen Kliniken.
Methoden: Die Datenanalyse erfolgte auf Basis eines individuellen Onlinefragebogens mit insgesamt 19 standardisierten Fragen. Dieser wurde über die E‑Mail-Verteiler der deutschen chirurgischen Fachgesellschaften an die leitenden chirurgischen Klinikärzte versendet.
Ergebnisse: Insgesamt 267 vollständige Antwortdatensätze wurden analysiert (Rücklaufquote 12,0 %). 84,0 % der Teilnehmer gaben ihre Tätigkeit an einem Lehrkrankenhaus an. Zum Zeitpunkt der Untersuchung waren 143 chirurgische Simulatoren an 35,0 % der in die Auswertung eingeschlossenen Kliniken vorhanden. Regional zeigten sich deutliche Unterschiede zwischen den einzelnen Bundesländern. 21,1 % der Teilnehmer, an deren Klinik kein Simulator zur Verfügung steht, planten eine Neubeschaffung. Studierende (41,1 %) und Ärzte in Weiterbildung (ÄiW, 32,5 %) nutzten das Simulationstraining am häufigsten. Eine Integration in die chirurgische Weiterbildung bestand zu 81,8 % nicht. 94,0 % der beteiligten Kliniken zeigten Interesse an einer zukünftigen Integration in die chirurgische Facharztweiterbildung.
Schlussfolgerung: Die vorliegenden Ergebnisse bestätigen die besondere Bedeutung des simulationsbasierten Trainings für die chirurgische Weiterbildung an deutschen Kliniken. Gleichzeitig bestehen deutliche Informationsdefizite über das Nutzungsverhalten sowie eine defizitär empfundene Integration des Simulationstrainings in die chirurgische Weiterbildung.
Thermally stable and highly conductive SAMs on Ag substrate — the impact of the anchoring group
(2021)
Self-assembled monolayers (SAMs) on metal substrates are an important part of modern interfacial chemistry and nanotechnology. The robustness of SAMs strongly depends on their thermal stability, which, together with electric conductivity, crucial for their applications in molecular/organic electronics. In this context, using a multidisciplinary approach, the structure, stability, and conductivity properties of conjugated aromatic SAMs featuring the naphthalene backbone and S, Se, or COO group, mediating bonding to the Ag substrate are addressed. Whereas thermal stability of these SAMs exhibits a strong dependence on anchoring group, their conductivity is similar, which is rationalized by tentative model considering redistribution of charge density along the molecular framework. The thermal stability of model naphthalenethiol SAM, emphasized by desorption energy of ≈1.69 eV, is better than that of typical N-heterocyclic carbene (NHC) monolayers considered currently as the most stable SAMs on metal substrates. However, in contrast to NHC SAMs, which are highly insulating, the naphtalene-based SAM, with S, Se or COO anchoring groups, are highly conductive, even in comparison with analogous oligophenyl SAMs (by a factor of 10). A unique combination of the ultimate thermal stability and superior conductivity for the naphthalenethiol SAM on Ag makes it highly attractive for applications.
The Born cross sections and effective form factors for process 𝑒+𝑒−→Ξ−¯Ξ+ are measured at eight center-of-mass energies between 2.644 and 3.080 GeV, using a total integrated luminosity of 363.9 pb−1 𝑒+𝑒− collision data collected with the BESIII detector at BEPCII. After performing a fit to the Born cross section of 𝑒+𝑒−→Ξ−¯Ξ+, no significant threshold effect is observed.
Highlights
• Prevalence of probable DS identified from German healthcare data: 4.7 per 100,000.
• Healthcare costs: €11,048 per patient-year, mostly inpatient care 47%, medication 26%.
• Costs and hospitalizations greater in patients with rescue medication than without.
• Mean (SD) of 5.0 (2.5) different ASMs prescribed per patient over study period.
• Patients with probable DS had significantly higher mortality risk vs. controls (11.88% vs. 1.19%).
Abstract
Objective: Ten-year retrospective study to assess burden of illness in patients with probable Dravet syndrome (DS) identified from German healthcare data.
Methods: In the absence of an International Classification of Diseases code, patients with probable DS were identified using a selection algorithm considering diagnoses and drug prescriptions. Primary analyses were prevalence and demographics; secondary analyses included healthcare costs, annual hospitalization rate (AHR) and length of stay (LOS), medication use, and mortality.
Results: In the final study year, 64 patients with probable DS (mean [range] age: 33.2 [3–82] years; male: 48%) were identified. Prevalence: 4.7 per 100,000 people. During the study, 160 patients with probable DS were identified and followed up for 1,261 patient-years. Mean cost of healthcare was €11,048 per patient-year (PPY), mostly attributable to inpatient care (47%), medication (26%), and services and devices (19%). Annual healthcare costs were significantly greater for those with prescribed rescue medication (15% of patient-years) vs. without (€16,123 vs. €10,125 PPY, p < 0.001). Mean (standard deviation [SD]) AHR and LOS were 1.1 (1.7) and 17.5 (33.5) days PPY. AHR was significantly greater in patients with prescribed rescue medication vs. without (1.6 [2.0] vs. 1.0 [1.6] PPY, p < 0.001). Mean (SD) number of antiseizure medications prescribed was 2.6 (1.2) PPY and 5.0 (2.5) over the entire observable time for each patient. Mortality rate was significantly higher for probable DS vs. matched controls (11.88% [19 events] vs. 1.19% [172 events], p < 0.001).
Conclusion: Probable DS is associated with substantial healthcare costs in Germany.
From early to middle childhood, brain regions that underlie memory consolidation undergo profound maturational changes. However, there is little empirical investigation that directly relates age-related differences in brain structural measures to the memory consolidation processes. The present study examined system-level memory consolidations of intentionally studied object-location associations after one night of sleep (short delay) and after two weeks (long delay) in normally developing 5-to-7-year-old children (n = 50) and young adults (n = 39). Behavioural differences in memory consolidation were related to structural brain measures. Our results showed that children, in comparison to young adults, consolidate correctly learnt object-location associations less robustly over short and long delay. Moreover, using partial least squares correlation method, a unique multivariate profile comprised of specific neocortical (prefrontal, parietal, and occipital), cerebellar, and hippocampal subfield structures was found to be associated with variation in short-delay memory consolidation. A different multivariate profile comprised of a reduced set of brain structures, mainly consisting of neocortical (prefrontal, parietal, and occipital), and selective hippocampal subfield structures (CA1-2 and subiculum) was associated with variation in long-delay memory consolidation. Taken together, the results suggest that multivariate structural pattern of unique sets of brain regions are related to variations in short- and long-delay memory consolidation across children and young adults.
RESEARCH HIGHLIGHTS
Short- and long-delay memory consolidation is less robust in children than in young adults
* Short-delay brain profile comprised of hippocampal, cerebellar, and neocortical brain regions
* Long-delay brain profile comprised of neocortical and selected hippocampal brain regions.
* Brain profiles differ between children and young adults.
The Board of Directors of the German Society of Epileptology and the committee on epilepsy and syncope of the German Society of Neurology have reviewed the current data on vaccination to prevent coronavirus disease 2019 (COVID-19) and vaccination prioritization in people with epilepsy and provide a summary and recommendations.
Owing to their morphological complexity and dense network connections, neurons modify their proteomes locally, using mRNAs and ribosomes present in the neuropil (tissue enriched for dendrites and axons). Although ribosome biogenesis largely takes place in the nucleus and perinuclear region, neuronal ribosomal protein (RP) mRNAs have been frequently detected remotely, in dendrites and axons. Here, using imaging and ribosome profiling, we directly detected the RP mRNAs and their translation in the neuropil. Combining brief metabolic labeling with mass spectrometry, we found that a group of RPs rapidly associated with translating ribosomes in the cytoplasm and that this incorporation was independent of canonical ribosome biogenesis. Moreover, the incorporation probability of some RPs was regulated by location (neurites vs. cell bodies) and changes in the cellular environment (following oxidative stress). Our results suggest new mechanisms for the local activation, repair and/or specialization of the translational machinery within neuronal processes, potentially allowing neuronal synapses a rapid means to regulate local protein synthesis.
Owing to their morphological complexity and dense network connections, neurons modify their proteomes locally, using mRNAs and ribosomes present in the neuropil (tissue enriched for dendrites and axons). Although ribosome biogenesis largely takes place in the nucleus and perinuclear region, neuronal ribosomal protein (RP) mRNAs have been frequently detected remotely, in dendrites and axons. Here, using imaging and ribosome profiling, we directly detected the RP mRNAs and their translation in the neuropil. Combining brief metabolic labeling with mass spectrometry, we found that a group of RPs quickly associated with translating ribosomes in the cytoplasm and that this incorporation is independent of canonical ribosome biogenesis. Moreover, the incorporation probability of some RPs was regulated by location (neurites vs. cell bodies) and changes in the cellular environment (in response to oxidative stress). Our results suggest new mechanisms for the local activation, repair and/or specialization of the translational machinery within neuronal processes, potentially allowing remote neuronal synapses a rapid solution to the relatively slow and energy-demanding requirement of nuclear ribosome biogenesis.
Influence of macrophage polarization on the effectiveness of surgical therapy of peri-implantitis
(2021)
Purpose: To evaluate the influence of macrophage expression and polarization on the effectiveness of surgical therapy of peri-implantitis over a 6 month follow-up.
Methods: A total of fourteen patients (n = 14 implants) diagnosed with peri-implantitis underwent access flap surgery, granulation tissue removal, implantoplasty, and augmentation at intra-bony components using a natural derived bone mineral and application of a native collagen membrane during a standardized surgical procedure. Granulation tissue biopsies were prepared for immunohistochemical characterization and macrophage polarization assessment. M1 and M2 phenotype expression was identified and quantified through immunohistochemical markers and histomorphometrical analyses. Clinical evaluation and data collection were performed initially and after a healing period of 6 months. Statistical analyses were performed to associate infiltrated area, macrophage, and M1/M2 phenotype influence on peri-implant tissue healing parameters after a 6-month follow-up.
Results: Mean infiltrated compartment (ICT) values occupied a total percentage of 70.3% ± 13.0 in the analyzed granulation tissue biopsies. Macrophages occupied a mean area of 15.3% ± 7.0. M1 and M2 phenotypes were present in 7.1 ± 4.1% and 5.5 ± 3.7%, respectively. No statistically significant difference was observed between M1 and M2% expression (p = 0.16). The mean M1/ M2 ratio amounted to 1.5 ± 0.8. Surgical therapy was associated with statistically significant reductions in mean bleeding on probing (BOP), probing depth (PD) and suppuration (SUPP) scores at 6 months (p < 0.05). Linear regression analyses revealed a significant correlation between macrophage expression (CD68%) and changes in PD scores and M1 (%) expression and changes in mucosal recession (MR) scores at 6 months.
Conclusions: The present data suggest that macrophages might influence peri-implant tissue healing mechanisms following surgical therapy of peri-implantitis over a short-term period. Particularly, changes in PD and MR scores were statistically significantly associated with macrophage expression and phenotype.
Fendrr synergizes with Wnt signalling to regulate fibrosis related genes during lung development
(2021)
Long non-coding RNAs are a very versatile class of molecules that can have important roles in regulating a cells function, including regulating other genes on the transcriptional level. One of these mechanisms is that RNA can directly interact with DNA thereby recruiting additional components such as proteins to these sites via a RNA:dsDNA triplex formation. We genetically deleted the triplex forming sequence (FendrrBox) from the lncRNA Fendrr in mice and find that this FendrrBox is partially required for Fendrr function in vivo. We find that the loss of the triplex forming site in developing lungs causes a dysregulation of gene programs, associated with lung fibrosis. A set of these genes contain a triplex site directly at their promoter and are expressed in fibroblasts. We find that Fendrr with the Wnt signaling pathway regulates these genes, implicating that Fendrr synergizes with Wnt signaling in lung fibrosis.
Background: During the current second wave of COVID-19, the radiologists are expected to face great challenges in differentiation between COVID-19 and other virulent influenza viruses, mainly H1N1. Accordingly, this study was performed in order to find any differentiating CT criteria that would help during the expected clinical overlap during the current Influenza season.
Results: This study was retrospectively conducted during the period from June till November 2020, on acute symptomatic 130 patients with no history of previous pulmonary diseases; 65 patients had positive PCR for COVID-19 including 50 mild patients and 15 critical or severe patients; meanwhile, the other 65 patients had positive PCR for H1N1 including 50 mild patients and 15 critical or severe patients. They included 74 males and 56 females (56.9%:43.1%). Their age ranged 14–90 years (mean age 38.9 ± 20.3 SD). HRCT findings were analyzed by four expert consultant radiologists in consensus. All patients with COVID-19 showed parenchymal or alveolar HRCT findings; only one of them had associated airway involvement. Among the 65 patients with H1N1; 56 patients (86.2%) had parenchymal or alveolar HRCT findings while six patients (9.2%) presented only by HRCT signs of airway involvement and three patients (4.6%) had mixed parenchymal and airway involvement. Regarding HRCT findings of airway involvement (namely tree in bud nodules, air trapping, bronchial wall thickening, traction bronchiectasis, and mucous plugging), all showed significant p value (ranging from 0.008 to 0.04). On the other hand, HRCT findings of parenchymal or alveolar involvement (mainly ground glass opacities) showed no significant relation.
Conclusion: HRCT can help in differentiation between non-severe COVID-19 and H1N1 based on signs of airway involvement.
EphrinB2 and GRIP1 stabilize mushroom spines during denervation-induced homeostatic plasticity
(2021)
Highlights
• Denervation induces mushroom spine loss and AMPAR redistribution to the surface
• GRIP1 and ephrinB2 mediate homeostatic mechanisms after lesion
• Stimulation with the ephrinB2 receptor EphB4 promotes a surface shift of AMPARs
• AMPARs surface shift restores impaired spine recovery after lesion in GRIP1 mutants
Summary
Despite decades of work, much remains elusive about molecular events at the interplay between physiological and structural changes underlying neuronal plasticity. Here, we combined repetitive live imaging and expansion microscopy in organotypic brain slice cultures to quantitatively characterize the dynamic changes of the intracellular versus surface pools of GluA2-containing α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) across the different dendritic spine types and the shaft during hippocampal homeostatic plasticity. Mechanistically, we identify ephrinB2 and glutamate receptor interacting protein (GRIP) 1 as mediating AMPAR relocation to the mushroom spine surface following lesion-induced denervation. Moreover, stimulation with the ephrinB2 specific receptor EphB4 not only prevents the lesion-induced disappearance of mushroom spines but is also sufficient to shift AMPARs to the surface and rescue spine recovery in a GRIP1 dominant-negative background. Thus, our results unravel a crucial role for ephrinB2 during homeostatic plasticity and identify a potential pharmacological target to improve dendritic spine plasticity upon injury.
Background/Objective: Evidence-based clinical pathways can be a useful tool for guideline implementation. However, there seem to be barriers to the use of clinical pathways. The aim of the present questionnaire survey was to assess the perceived usability of the clinical pathway “Overweight/obesity in children and adolescents at primary care level” and to identify factors promoting and hindering the use of the clinical pathway.
Methods: In January 2020, an online questionnaire survey was sent out to 3,916 general practitioners and 470 pediatricians in Austria. The data collected were analysed descriptively.
Results: A total of 148 people took part in the questionnaire survey (response rate 3.7 %). The majority of respondents indicated that they, in general, perceive evidence-based clinical pathways as helpful (90 %) and also make use of them (57 %). Few respondents (9 %) felt well-informed about new clinical pathways developed in Austria. Most of the respondents considered the clinical pathway “Overweight/obesity in children and adolescents at primary care level” as a useful support (60 %), as a reference work (72 %) or as a facilitator for justifying their approach to their patients (68 %). However, a large proportion of the respondents stated that the clinical pathway is not easily applicable in everyday practice. The three most frequently cited barriers to using the clinical pathway were lack of time resources, lack of structures and lack of financial incentives. Other display and access options (e. g., individualisation, integration into practice software) were most frequently cited as factors that might promote the use of the pathway.
Conclusion: Although the majority of the respondents had positive expectations regarding the use of the clinical pathway “Overweight/obesity in children and adolescents at primary care level”, many of them still perceived its usability in everyday clinical practice as difficult. The necessary next steps to improve the use of evidence-based clinical pathways seem to be: an economic and practicable design, easy accessibility of clinical pathways and the creation of framework conditions that facilitate their use in everyday practice.
In the past two decades, an increasing body of studies has been published on the intersex phenomenon in separate-sexed crustaceans from marine and freshwater ecosystems. Various causes are being considered that could have an influence on the occurrence of intersex. Besides genetic factors, environmental conditions such as photoperiodicity, temperature, salinity and parasitism, but also environmental pollution with endocrine disrupting chemicals (EDCs) are discussed. As part of a long-term monitoring (2012 – 2020) in north-west Brittany, we recorded the occurrence of intersex in the marine amphipod Echinogammarus marinus. We quantified the intersex incidence at marine and estuarine sites and analyzed the incidence in relation to the endocrine potential of the sediments. Intersex occurred with mean frequencies between 0.87% and 12%. It was striking that the incidence of intersex increased with increasing distance from the sea. Since the highest incidence was observed at the range boundary of this stenohaline species, we assume that intersex is triggered by endocrine potential and increasing stress due to increasing freshwater content − and thus an interplay of different environmental factors.
Recombinant DNA technology is an essential area of life engineering. The main aim of research in this field is to experimentally explore the possibilities of repairing damaged human DNA, healing or enhancing future human bodies. Based on ethnographic research in a Czech biochemical laboratory, the article explores biotechnological corporealities and their specific ontology through dealings with bio-objects, the bodywork of scientists. Using the complementary concepts of utopia and heterotopia, the text addresses the situation of bodies and bio-objects in a laboratory. Embodied utopias are analyzed as material semiotic phenomena that are embodied by scientists in their visions and emotions and that are related to potential bodies and to future, not-yet-actualized embodiments. As a counterpart to this, the text explores embodied heterotopias, which are always the other spaces, like biotechnological bio-objects that are simulated in computers or stored in special solutions.
We consider a linear ill-posed equation in the Hilbert space setting. Multiple independent unbiased measurements of the right-hand side are available. A natural approach is to take the average of the measurements as an approximation of the right-hand side and to estimate the data error as the inverse of the square root of the number of measurements. We calculate the optimal convergence rate (as the number of measurements tends to infinity) under classical source conditions and introduce a modified discrepancy principle, which asymptotically attains this rate.
A single wavelength heterodyne interferometer has been set up to investigate the free electron density integrated axially along the line of sight (line density) in a theta-pinch plasma to determine its applicability as a plasma target for ion beam stripping. The maximal line density reached in this experiment was (3.57 ± 0.28) × 1018 cm−2 at 80 Pa and 20 kV. The findings demonstrate the pulsed character of the line density and its increase by raising the load voltage and the working gas pressure. Additionally, the results were compared with spectroscopic free electron density estimations, which were carried out by Hβ -line broadening and peak separation. The time behavior of the line density indicates that its peak value is delayed by about 10 μs compared to the spectroscopic results. This effect is due to the formation of an extended, magnetically compressed plasma column in the vicinity of the current maximum, although the highest volumetric free electron density is reached near the current zero crossing. Since the line density is an essential parameter in describing the stripping capabilities of the plasma target, the interferometric diagnostic is superior to a spectroscopic diagnostic, because it directly provides integrated values along the line of sight. Furthermore, the measurements of the line density in this experiment partially show nonphysical negative values, which is due to gaseous effects and residual shot vibrations.
The adult human body contains about 4 g of iron. About 1–2 mg of iron is absorbed every day, and in healthy individuals, the same amount is excreted. We describe a patient who presents with severe iron deficiency anemia with hemoglobin levels below 6 g/dL and ferritin levels below 30 ng/mL. Although red blood cell concentrates and intravenous iron have been substituted every month for years, body iron stores remain depleted. Diagnostics have included several esophago-gastro-duodenoscopies, colonoscopies, MRI of the liver, repetitive bone marrow biopsies, psychological analysis, application of radioactive iron to determine intact erythropoiesis, and measurement of iron excretion in urine and feces. Typically, gastrointestinal bleeding is a major cause of iron loss. Surprisingly, intestinal iron excretion in stool in the patient was repetitively increased, without gastrointestinal bleeding. Furthermore, whole exome sequencing was performed in the patient and additional family members to identify potential causative genetic variants that may cause intestinal iron loss. Under different inheritance models, several rare mutations were identified, two of which (in CISD1 and KRI1) are likely to be functionally relevant. Intestinal iron loss in the current form has not yet been described and is, with high probability, the cause of the severe iron deficiency anemia in this patient.
Gram-negative Tripartite Resistance Nodulation and cell Division (RND) superfamily efflux pumps confer various functions, including multidrug and bile salt resistance, quorum-sensing, virulence and can influence the rate of mutations on the chromosome. Multidrug RND efflux systems are often characterized by a wide substrate specificity. Similarly to many other RND efflux pump systems, AcrAD-TolC confers resistance toward SDS, novobiocin and deoxycholate. In contrast to the other pumps, however, it in addition confers resistance against aminoglycosides and dianionic β-lactams, such as sulbenicillin, aztreonam and carbenicillin. Here, we could show that AcrD from Salmonella typhimurium confers resistance toward several hitherto unreported AcrD substrates such as temocillin, dicloxacillin, cefazolin and fusidic acid. In order to address the molecular determinants of the S. typhimurium AcrD substrate specificity, we conducted substitution analyses in the putative access and deep binding pockets and in the TM1/TM2 groove region. The variants were tested in E. coli ΔacrBΔacrD against β-lactams oxacillin, carbenicillin, aztreonam and temocillin. Deep binding pocket variants N136A, D276A and Y327A; access pocket variant R625A; and variants with substitutions in the groove region between TM1 and TM2 conferred a sensitive phenotype and might, therefore, be involved in anionic β-lactam export. In contrast, lower susceptibilities were observed for E. coli cells harbouring deep binding pocket variants T139A, D176A, S180A, F609A, T611A and F627A and the TM1/TM2 groove variant I337A. This study provides the first insights of side chains involved in drug binding and transport for AcrD from S. typhimurium.
Dealing with potential stress in species that have high husbandry requirements, such as elephants, is a challenge for zoos. The objective of the present study was to determine whether positive reinforcement training (PRT) and exposure to a novel object (NOV) for enrichment induced a salivary cortisol response indicative of activation of the hypothalamic–pituitary–adrenal (HPA) axis and which factors determine individual variation in this regard in captive African elephants. We repeatedly sampled the saliva of ten animals (three zoos) for the analysis of cortisol (SACort) before and up to 60 min (in 10–15 min intervals) after the onset of PRT (three repeats) or NOV (nine repeats), which lasted 10 min. There was considerable individual variation in SACort in response to PRT or NOV. Using mixed models, we were able to control these and to reveal that PRT was associated with high SACort before and relatively low SACort after PRT, while NOV induced a moderate SACort increase. The individual differences in SACort were related to age and sex (NOV), while the effects of zoo, handling method (free vs. protected contact) and reproductive and social status were variable. We conclude that positive affective states, such as anticipation or arousal, should be taken into account when interpreting the differences in the SACort responses between PRT and NOV. In addition, understanding the individuality of stress will support management decisions aimed at promoting captive elephant welfare.
In recent decades, mass spectrometry has moved more than ever before into the front line of protein-centered research. After being established at the qualitative level, the more challenging question of quantification of proteins and peptides using mass spectrometry has become a focus for further development. In this chapter, we discuss and review actual strategies and problems of the methods for the quantitative analysis of peptides, proteins, and finally proteomes by mass spectrometry. The common themes, the differences, and the potential pitfalls of the main approaches are presented in order to provide a survey of the emerging field of quantitative, mass spectrometry-based proteomics.
Biallelic pathogenic variants in CLPP, encoding mitochondrial matrix peptidase ClpP, cause a rare autosomal recessive condition, Perrault syndrome type 3 (PRLTS3). It is characterized by primary ovarian insufficiency and early sensorineural hearing loss, often associated with progressive neurological deficits. Mouse models showed that accumulations of (i) its main protein interactor, the substrate-selecting AAA+ ATPase ClpX, (ii) mitoribosomes, and (iii) mtDNA nucleoids are the main cellular consequences of ClpP absence. However, the sequence of these events and their validity in human remain unclear. Here, we studied global proteome profiles to define ClpP substrates among mitochondrial ClpX interactors, which accumulated consistently in ClpP-null mouse embryonal fibroblasts and brains. Validation work included novel ClpP-mutant patient fibroblast proteomics. ClpX co-accumulated in mitochondria with the nucleoid component POLDIP2, the mitochondrial poly(A) mRNA granule element LRPPRC, and tRNA processing factor GFM1 (in mouse, also GRSF1). Only in mouse did accumulated ClpX, GFM1, and GRSF1 appear in nuclear fractions. Mitoribosomal accumulation was minor. Consistent accumulations in murine and human fibroblasts also affected multimerizing factors not known as ClpX interactors, namely, OAT, ASS1, ACADVL, STOM, PRDX3, PC, MUT, ALDH2, PMPCB, UQCRC2, and ACADSB, but the impact on downstream metabolites was marginal. Our data demonstrate the primary impact of ClpXP on the assembly of proteins with nucleic acids and show nucleoid enlargement in human as a key consequence.
The accumulation of functionally impaired mitochondria is a key event in aging. Previous works with the fungal aging model Podospora anserina demonstrated pronounced age-dependent changes of mitochondrial morphology and ultrastructure, as well as alterations of transcript and protein levels, including individual proteins of the oxidative phosphorylation (OXPHOS). The identified protein changes do not reflect the level of the whole protein complexes as they function in-vivo. In the present study, we investigated in detail the age-dependent changes of assembled mitochondrial protein complexes, using complexome profiling. We observed pronounced age-depen-dent alterations of the OXPHOS complexes, including the loss of mitochondrial respiratory supercomplexes (mtRSCs) and a reduction in the abundance of complex I and complex IV. Additionally, we identified a switch from the standard complex IV-dependent respiration to an alternative respiration during the aging of the P. anserina wild type. Interestingly, we identified proteasome components, as well as endoplasmic reticulum (ER) proteins, for which the recruitment to mitochondria appeared to be increased in the mitochondria of older cultures. Overall, our data demonstrate pronounced age-dependent alterations of the protein complexes involved in energy transduction and suggest the induction of different non-mitochondrial salvage pathways, to counteract the age-dependent mitochondrial impairments which occur during aging.
Efficient processing of visual environment necessitates the integration of incoming sensory evidence with concurrent contextual inputs and mnemonic content from our past experiences. To delineate how this integration takes place in the brain, we studied modulations of feedback neural patterns in non-stimulated areas of the early visual cortex in humans (i.e., V1 and V2). Using functional magnetic resonance imaging and multivariate pattern analysis, we show that both, concurrent contextual and time-distant mnemonic information, coexist in V1/V2 as feedback signals. The extent to which mnemonic information is reinstated in V1/V2 depends on whether the information is retrieved episodically or semantically. These results demonstrate that our stream of visual experience contains not just information from the visual surrounding, but also memory-based predictions internally generated in the brain.
We use holography to study the dynamics of a strongly-coupled gauge theory in four-dimensional de Sitter space with Hubble rate H. The gauge theory is non-conformal with a characteristic mass scale M. We solve Einstein’s equations numerically and determine the time evolution of homogeneous gauge theory states. If their initial energy density is high compared with H4 then the early-time evolution is well described by viscous hydrodynamics with a non-zero bulk viscosity. At late times the dynamics is always far from equilibrium. The asymptotic late-time state preserves the full de Sitter symmetry group and its dual geometry is a domain-wall in AdS5. The approach to this state is characterised by an emergent relation of the form P = w ℰ that is different from the equilibrium equation of state in flat space. The constant w does not depend on the initial conditions but only on H/M and is negative if the ratio H/M is close to unity. The event and the apparent horizons of the late-time solution do not coincide with one another, reflecting its non-equilibrium nature. In between them lies an “entanglement horizon” that cannot be penetrated by extremal surfaces anchored at the boundary, which we use to compute the entanglement entropy of boundary regions. If the entangling region equals the observable universe then the extremal surface coincides with a bulk cosmological horizon that just touches the event horizon, while for larger regions the extremal surface probes behind the event horizon.
As cryo-EM approaches the physical resolution limits imposed by electron optics and radiation damage, it becomes increasingly urgent to address the issues that impede high-resolution structure determination of biological specimens. One of the persistent problems has been beam-induced movement, which occurs when the specimen is irradiated with high-energy electrons. Beam-induced movement results in image blurring and loss of high-resolution information. It is particularly severe for biological samples in unsupported thin films of vitreous water. By controlled devitrification of conventionally plunge-frozen samples, the suspended film of vitrified water was converted into cubic ice, a polycrystalline, mechanically stable solid. It is shown that compared with vitrified samples, devitrification reduces beam-induced movement in the first 5 e Å−2 of an exposure by a factor of ∼4, substantially enhancing the contribution of the initial, minimally damaged frames to a structure. A 3D apoferritin map reconstructed from the first frames of 20 000 particle images of devitrified samples resolved undamaged side chains. Devitrification of frozen-hydrated specimens helps to overcome beam-induced specimen motion in single-particle cryo-EM, as a further step towards realizing the full potential of cryo-EM for high-resolution structure determination.
We use the quantum null energy condition in strongly coupled two-dimensional field theories (QNEC2) as diagnostic tool to study a variety of phase structures, including crossover, second and first order phase transitions. We find a universal QNEC2 constraint for first order phase transitions with kinked entanglement entropy and discuss in general the relation between the QNEC2-inequality and monotonicity of the Casini-Huerta c-function. We then focus on a specific example, the holographic dual of which is modelled by three-dimensional Einstein gravity plus a massive scalar field with one free parameter in the self-interaction potential. We study translation invariant stationary states dual to domain walls and black branes. Depending on the value of the free parameter we find crossover, second and first order phase transitions between such states, and the c-function either flows to zero or to a finite value in the infrared. We present evidence that evaluating QNEC2 for ground state solutions allows to predict the existence of phase transitions at finite temperature.
Holography has provided valuable insights into the time evolution of strongly coupled gauge theories in a fixed spacetime. However, this framework is insufficient if this spacetime is dynamical. We present a novel scheme to evolve a four-dimensional, strongly interacting gauge theory coupled to four-dimensional dynamical gravity in the semiclassical regime. We use holography to evolve the quantum gauge theory stress tensor. The four-dimensional metric evolves according to the four-dimensional Einstein equations coupled to the expectation value of the stress tensor. We focus on Friedmann-Lemaître-Robertson-Walker geometries and evolve far-from-equilibrium initial states that lead to asymptotically expanding, flat or collapsing Universes.
We use the quantum null energy condition in strongly coupled two-dimensional field theories (QNEC2) as diagnostic tool to study a variety of phase structures, including crossover, second and first order phase transitions. We find a universal QNEC2 constraint for first order phase transitions with kinked entanglement entropy and discuss in general the relation between the QNEC2-inequality and monotonicity of the Casini-Huerta c-function. We then focus on a specific example, the holographic dual of which is modelled by three-dimensional Einstein gravity plus a massive scalar field with one free parameter in the self-interaction potential. We study translation invariant stationary states dual to domain walls and black branes. Depending on the value of the free parameter we find crossover, second and first order phase transitions between such states, and the c-function either flows to zero or to a finite value in the infrared. Strikingly, evaluating QNEC2 for ground state solutions allows to predict the existence of phase transitions at finite temperature.
We present a novel framework for the equation of state of dense and hot Quantum Chromodynamics (QCD), which focuses on the region of the phase diagram relevant for neutron star mergers and core-collapse supernovae. The model combines predictions from the gauge/gravity duality with input from lattice field theory, QCD perturbation theory, chiral effective theory and statistical modeling. It is therefore, by construction, in good agreement with theoretical constraints both at low and high densities and temperatures. The main ingredients of our setup are the non-perturbative V-QCD model based on the gauge/gravity duality, a van der Waals model for nucleon liquid, and the DD2 version of the Hempel-Schaffner-Bielich statistical model of nuclear matter. By consistently combining these models, we also obtain a description for the nuclear to quark matter phase transition and its critical endpoint. The parameter dependence of the model is represented by three (soft, intermediate and stiff) variants of the equation of state, all of which agree with observational constraints from neutron stars and their mergers. We discuss resulting constraints for the equation of state, predictions for neutron stars and the location of the critical point.
We present the first holographic simulations of non-equilibrium steady state formation in strongly coupled N=4 SYM theory in 3+1 dimensions. We initially join together two thermal baths at different temperatures and chemical potentials and compare the subsequent evolution of the combined system to analytic solutions of the corresponding Riemann problem and to numeric solutions of ideal and viscous hydrodynamics. The time evolution of the energy density that we obtain holographically is consistent with the combination of a shock and a rarefaction wave: A shock wave moves towards the cold bath, and a smooth broadening wave towards the hot bath. Between the two waves emerges a steady state with constant temperature and flow velocity, both of which are accurately described by a shock+rarefaction wave solution of the Riemann problem. In the steady state region, a smooth crossover develops between two regions of different charge density. This is reminiscent of a contact discontinuity in the Riemann problem. We also obtain results for the entanglement entropy of regions crossed by shock and rarefaction waves and find both of them to closely follow the evolution of the energy density.
We present the first holographic simulations of non-equilibrium steady state formation in strongly coupled N=4 SYM theory in 3+1 dimensions. We initially join together two thermal baths at different temperatures and chemical potentials and compare the subsequent evolution of the combined system to analytic solutions of the corresponding Riemann problem and to numeric solutions of ideal and viscous hydrodynamics. The time evolution of the energy density that we obtain holographically is consistent with the combination of a shock and a rarefaction wave: A shock wave moves towards the cold bath, and a smooth broader wave towards the hot bath. Between the two waves emerges a steady state with constant temperature and flow velocity, both of which are accurately described by a shock+rarefaction wave solution of the Riemann problem. In the steady state region develops a smooth crossover between two regions of different charge densities that diffuses on a timescale proportional to t√ and is reminiscent of a contact discontinuity in the Riemann problem. We also obtain results for the entanglement entropy of regions crossed by shock and rarefaction waves and find both of them to closely follow the evolution of the energy density.
Objective: To analyze the influence of biopsy Gleason score on the risk for lymph node invasion (LNI) during pelvic lymph node dissection (PLND) in patients undergoing radical prostatectomy (RP) for intermediate-risk prostate cancer (PCa).
Materials and Methods: We retrospectively analyzed 684 patients, who underwent RP between 2014 and June 2020 due to PCa. Univariable and multivariable logistic regression, as well as binary regression tree models were used to assess the risk of positive LNI and evaluate the need of PLND in men with intermediate-risk PCa.
Results: Of the 672 eligible patients with RP, 80 (11.9%) men harbored low-risk, 32 (4.8%) intermediate-risk with international society of urologic pathologists grade (ISUP) 1 (IR-ISUP1), 215 (32.0%) intermediate-risk with ISUP 2 (IR-ISUP2), 99 (14.7%) intermediate-risk with ISUP 3 (IR-ISUP3), and 246 (36.6%) high-risk PCa. Proportions of LNI were 0, 3.1, 3.7, 5.1, and 24.0% for low-risk, IR-ISUP1, IR-ISUP 2, IR-ISUP-3, and high-risk PCa, respectively (p < 0.001). In multivariable analyses, after adjustment for patient and surgical characteristics, IR-ISUP1 [hazard ratio (HR) 0.10, p = 0.03], IR-ISUP2 (HR 0.09, p < 0.001), and IR-ISUP3 (HR 0.18, p < 0.001) were independent predictors for lower risk of LNI, compared with men with high-risk PCa disease.
Conclusions: The international society of urologic pathologists grade significantly influence the risk of LNI in patients with intermediate- risk PCa. The risk of LNI only exceeds 5% in men with IR-ISUP3 PCa. In consequence, the need for PLND in selected patients with IR-ISUP 1 or IR-ISUP2 PCa should be critically discussed.
Trajectories of internalizing disorders and behavioral addictions are still largely unknown. Research shows that both disorders are highly comorbid. Previous longitudinal studies have focused on associations between internalizing disorders and behavioral addictions using screening instruments. Our aim was to develop and examine a theory-based model of trajectories, according to which internalizing disorders foster symptoms of Internet use disorders, mediated by a reward deprivation and maladaptive emotion regulation. We applied clinically relevant measures for depression and social anxiety in a prospective longitudinal study with a 12-month follow-up investigation. On the basis of an at-risk population of 476 students (mean age = 14.99 years, SD = 1.99), we investigated the predictive influence of clinically relevant depression and social anxiety at baseline (t1) on Internet use disorder symptoms at 12-month follow-up (t2) using multiple linear regression analyses. Our results showed that both clinically relevant depression and social anxiety significantly predicted symptom severity of Internet use disorders one year later after controlling for baseline symptoms of Internet use disorders, gender and age. These results remained robust after including both depression and social anxiety simultaneously in the model, indicating an independent influence of both predictors on Internet use disorder symptoms. The present study enhances knowledge going beyond a mere association between internalizing disorders and Internet use disorders. To our knowledge, this is the first study investigating clinically relevant depression and social anxiety to predict future Internet use disorder symptoms at 12-month follow-up. In line with our model of trajectories, a significant temporal relationship between clinically relevant internalizing disorders and Internet use disorder symptoms at 12-month follow-up was confirmed. Further studies should investigate the mediating role of reward deprivation and maladaptive emotion regulation, as postulated in our model. One implication of these findings is that clinicians should pay particular attention to the increased risk of developing behavioral addictions for adolescents with depression and social anxiety.
Interest is an important factor for successful learning that has been the subject of intensive research for decades. Although interest in nature is of great importance for environmental education, to date there is no valid and reliable measurement tool. Therefore, the purpose of this study was to develop and test a scale for interest in nature, the Nature Interest Scale (NIS). In study 1, nine items were selected based on the three dimensions of the psychological interest construct to represent interest in nature. The factor structure of this new measurement instrument, was tested using confirmatory factor analyses. The results show that the instrument represents the three dimensions of the interest construct well. In study 2 the validity (discriminant and convergent validity) as well as the reliability (internal consistency, composite reliability, test-retest reliability) of the NIS were demonstrated. In study 3, the applicability of the NIS was tested with a different target group, students with learning disabilities. The results of this factor analysis also confirm the factor structure of the scale. Thus, this study provides a valid and reliable measurement tool for individual interest in nature that can be used for future research.
Endogenous nitro-fatty acids (NFA) are potent electrophilic lipid mediators that exert biological effects in vitro and in vivo via selective covalent modification of thiol-containing target proteins. The cytoprotective, anti-inflammatory, and anti-tumorigenic effects of NFA in animal models of disease caused by targeted protein nitroalkylation are a valuable basis for the development of future anti-phlogistic and anti-neoplastic drugs. Considering the complexity of diseases and accompanying comorbidities there is an urgent need for clinically effective multifunctional drugs. NFA are composed of a fatty acid backbone containing a nitroalkene moiety triggering Michael addition reactions. However, less is known about the target-specific structure–activity relationships and selectivities comparing different NFA targets. Therefore, we analyzed 15 NFA derivatives and compared them with the lead structure 9-nitro-oleic acid (9NOA) in terms of their effect on NF-κB (nuclear factor kappa B) signaling inhibition, induction of Nrf-2 (nuclear factor erythroid 2-related factor 2) gene expression, sEH (soluble epoxide hydrolase), LO (lipoxygenase), and COX-2 (cyclooxygenase-2) inhibition, and their cytotoxic effects on colorectal cancer cells. Minor modifications of the Michael acceptor position and variation of the chain length led to drugs showing increased target preference or enhanced multi-targeting, partly with higher potency than 9NOA. This study is a significant step forward to better understanding the biology of NFA and their enormous potential as scaffolds for designing future anti-inflammatory drugs.
The complex and adaptive nature of malignant neoplasm constitute a major challenge for the development of effective anti-oncogenic therapies. Emerging evidence has uncovered the pivotal functions exerted by the small leucine-rich proteoglycans, decorin and biglycan, in affecting tumor growth and progression. In their soluble forms, decorin and biglycan act as powerful signaling molecules. By receptor-mediated signal transduction, both proteoglycans modulate key processes vital for tumor initiation and progression, such as autophagy, inflammation, cell-cycle, apoptosis, and angiogenesis. Despite of their structural homology, these two proteoglycans interact with distinct cell surface receptors and thus modulate distinct signaling pathways that ultimately affect cancer development. In this review, we summarize growing evidence for the complex roles of decorin and biglycan signaling in tumor biology and address potential novel therapeutic implications.
Effect of chemotherapy on overall survival in contemporary metastatic prostate cancer patients
(2021)
Introduction: Randomized clinical trials demonstrated improved overall survival in chemotherapy exposed metastatic prostate cancer patients. However, real-world data validating this effect with large scale epidemiological data sets are scarce and might not agree with trials. We tested this hypothesis.
Materials and Methods: We identified de novo metastatic prostate cancer patients within the Surveillance, Epidemiology, and End Results (SEER) database (2014-2015). Kaplan-Meier plots and Cox regression models tested for overall survival differences between chemotherapy-exposed patients vs chemotherapy-naïve patients. All analyses were repeated in propensity-score matched cohorts. Additionally, landmark analyses were applied to account for potential immortal time bias.
Results: Overall, 4295 de novo metastatic prostate cancer patients were identified. Of those, 905 (21.1%) patients received chemotherapy vs 3390 (78.9%) did not. Median overall survival was not reached at 30 months follow-up. Chemotherapy-exposed patients exhibited significantly better overall survival (61.6 vs 54.3%, multivariable HR:0.82, CI: 0.72-0.96, p=0.01) at 30 months compared to their chemotherapy-naïve counterparts. These findings were confirmed in propensity score matched analyses (multivariable HR: 0.77, CI:0.66-0.90, p<0.001). Results remained unchanged after landmark analyses were applied in propensity score matched population.
Conclusions: In this contemporary real-world population-based cohort, chemotherapy for metastatic prostate cancer patients was associated with better overall survival. However, the magnitude of overall survival benefit was not comparable to phase 3 trials.
Introduction: To evaluate the oncological outcome of high dose rate (HDR) brachytherapy (BRT) as monotherapy for clinically localised prostate cancer (PCA).
Material and Methods: Between January 2002 and February 2004, 141 consecutive patients with clinically localised PCA were treated with HDR-BRT monotherapy. The cohort comprised 103 (73%) low-, 32 (22.7%) intermediate- and 6 (4.3%) high risk patients according to D’Amico classification or 104 (73.8%) low-, 24 (17.0%) intermediate favourable-, 12 (8.5%) intermediate unfavourable- and one (0.7%) very high risk patient according to National Comprehensive Cancer Network (NCCN) one. Patients received four fractions of 9.5 Gy delivered within a single implant up to a total physical dose of 38 Gy. Catheter-implantation was transrectal ultrasound-based whereas treatment planning CT-based. Thirty-three patients (23.4%) received ADT neoadjuvantly and continued concurrently with BRT. Biochemical relapse-free survival (BRFS) was defined according to the Phoenix Consensus Criteria and genitourinary (GU)/gastrointestinal (GI) toxicity evaluated using the Common Toxicity Criteria for Adverse Events version 5.0.
Results: Median age at treatment and median follow-up time was 67.2 and 15.2 years, respectively. Twenty-three (16.3%) patients experienced a biochemical relapse and 5 (3.5%) developed distant metastases, with only one patient dying of PCA. The BRFS was 85.1% at 15 years and 78.7% at 18 years. The corresponding overall survival, metastases-free survival, and prostate cancer specific mortality at 15- and 18-years was 73.9%/59.1%, 98.3%/90.6%, and 100%/98.5% respectively. Late grade 3 GI and GU toxicity was 4.2% and 5.6% respectively. Erectile dysfunction grade 3 was reported by 27 (19%) patients. From the prognostic factors evaluated, tumor stage (≤T2b compared to ≥T2c) along with the risk group (low-intermediate vs. high) when using the D’Amico classification but not when the NCCN one was taken into account, correlated significantly with BRFS.
Conclusion: Our long-term results confirm HDR-BRT to be a safe and effective monotherapeutic treatment modality for low- and intermediate risk PCA.
Biological as well as advanced artificial intelligences (AIs) need to decide which goals to pursue. We review nature's solution to the time allocation problem, which is based on a continuously readjusted categorical weighting mechanism we experience introspectively as emotions. One observes phylogenetically that the available number of emotional states increases hand in hand with the cognitive capabilities of animals and that raising levels of intelligence entail ever larger sets of behavioral options. Our ability to experience a multitude of potentially conflicting feelings is in this view not a leftover of a more primitive heritage, but a generic mechanism for attributing values to behavioral options that can not be specified at birth. In this view, emotions are essential for understanding the mind. For concreteness, we propose and discuss a framework which mimics emotions on a functional level. Based on time allocation via emotional stationarity (TAES), emotions are implemented as abstract criteria, such as satisfaction, challenge and boredom, which serve to evaluate activities that have been carried out. The resulting timeline of experienced emotions is compared with the “character” of the agent, which is defined in terms of a preferred distribution of emotional states. The long-term goal of the agent, to align experience with character, is achieved by optimizing the frequency for selecting individual tasks. Upon optimization, the statistics of emotion experience becomes stationary.
The analysis of ethanol and of its congeners in blood plays an important role in forensic cases, especially when allegations are made that alcohol has been consumed after an accident. In alcoholic beverages, congener alcohols are by-products and are generated during fermentation. The assay of these compounds in serum samples and beverages has been previously performed using headspace-gas chromatography-flame ionization detection methods (HS-GC-FID). As an alternative, a robust headspace-gas chromatography-mass spectrometry (HS-GC-MS) procedure was developed and validated, which has the following advantages:
- Simultaneous determination of ethanol, congener alcohols and other
endogenous substances.
- Reduction of matrix interference by increasing selectivity and
specificity.
- Clear separation of the positional isomers 3-methyl-1-butanol and
2-methyl-1-butanol.
Peracarid data were collected in the Southern Ocean and South Atlantic Ocean. Sampling was performed during nine different expeditions on board of RRS James Clark Ross and RV Polarstern, using epibenthic sledges (EBS) at depth ranging between 160–6348 m at 109 locations. The correlation between environmental variables and peracarid abundance was investigated. Abundance data comprise a total of 128570 peracarids (52366 were amphipods, 28516 were cumaceans, 36142 isopods, 5676 mysidaceans and 5870 were tanaidaceans). The presented data are useful to investigate the composition and abundance patterns of peracarid orders at a wide depth range and spatial scale in the Southern Ocean. They can also be reused to compare their abundance with that of other taxa in broader ecological surveys.
The Q80K polymorphism in the NS3-4A protease of the hepatitis C virus is associated with treatment failure of direct-acting antiviral agents. This polymorphism is highly prevalent in genotype 1a infections and stably transmitted between hosts. Here, we investigated the underlying molecular mechanisms of evolutionarily conserved coevolving amino acids in NS3-Q80K and revealed potential implications of epistatic interactions in immune escape and variants persistence. Using purified protein, we characterized the impact of epistatic amino acid substitutions on the physicochemical properties and peptide cleavage kinetics of the NS3-Q80K protease. We found that Q80K destabilized the protease protein fold (p < 0.0001). Although NS3-Q80K showed reduced peptide substrate turnover (p < 0.0002), replicative fitness in an H77S.3 cell culture model of infection was not significantly inferior to the WT virus. Epistatic substitutions at residues 91 and 174 in NS3-Q80K stabilized the protein fold (p < 0.0001) and leveraged the WT protease stability. However, changes in protease stability inversely correlated with enzymatic activity. In infectious cell culture, these secondary substitutions were not associated with a gain of replicative fitness in NS3-Q80K variants. Using molecular dynamics, we observed that the total number of residue contacts in NS3-Q80K mutants correlated with protein folding stability. Changes in the number of contacts reflected the compensatory effect on protein folding instability by epistatic substitutions. In summary, epistatic substitutions in NS3-Q80K contribute to viral fitness by mechanisms not directly related to RNA replication. By compensating for protein-folding instability, epistatic interactions likely protect NS3-Q80K variants from immune cell recognition.
We extend the canonical income process with persistent and transitory risk to cyclical shock distributions with left-skewness and excess kurtosis. We estimate our income process by GMM for US household data. We find countercyclical variance and procyclical skewness of persistent shocks. All shock distributions are highly leptokurtic. The tax and transfer system reduces dispersion and left-skewness. We then show that in a standard incomplete-markets life-cycle model, first, higherorder risk has sizable welfare implications, which depend on risk attitudes; second, it matters quantitatively for the welfare costs of cyclical idiosyncratic risk; third, it has non-trivial implications for self-insurance against shocks.
We consider an additively time-separable life-cycle model for the family of power period utility functions u such that u0(c) = c−θ for resistance to inter-temporal substitution of θ > 0. The utility maximization problem over life-time consumption is dynamically inconsistent for almost all specifications of effective discount factors. Pollak (1968) shows that the savings behavior of a sophisticated agent and her naive counterpart is always identical for a logarithmic utility function (i.e., for θ = 1). As an extension of Pollak’s result we show that the sophisticated agent saves a greater (smaller) fraction of her wealth in every period than her naive counterpart whenever θ > 1 (θ < 1) irrespective of the specification of discount factors. We further show that this finding extends to an environment with risky returns and dynamically inconsistent Epstein-Zin-Weil preferences.
Using a structural life-cycle model and data on school visits from Safegraph and school closures from Burbio, we quantify the heterogeneous impact of school closures during the Corona crisis on children affected at different ages and coming from households with different parental characteristics. Our data suggests that secondary schools were closed for in-person learning for longer periods than elementary schools (implying that younger children experienced less school closures than older children), and that private schools experienced shorter closures than public schools, and schools in poorer U.S. counties experienced shorter school closures. We then extend the structural life cycle model of private and public schooling investments studied in Fuchs-Schündeln, Krueger, Ludwig, and Popova (2021) to include the choice of parents whether to send their children to private schools, empirically discipline it with data on parental investments from the PSID, and then feed into the model the school closure measures from our empirical analysis to quantify the long-run consequences of the Covid-19 school closures on the cohorts of children currently in school. Future earnings- and welfare losses are largest for children that started public secondary schools at the onset of the Covid-19 crisis. Comparing children from the topto children from the bottom quartile of the income distribution, welfare losses are ca. 0.8 percentage points larger for the poorer children if school closures were unrelated to income. Accounting for the longer school closures in richer counties reduces this gap by about 1/3. A policy intervention that extends schools by 3 months (6 weeks in the next two summers) generates significant welfare gains for the children and raises future tax revenues approximately sufficient to pay for the cost of this schooling expansion.
Using a structural life-cycle model, we quantify the heterogeneous impact of school closures during the Corona crisis on children affected at different ages and coming from households with different parental characteristics. In the model, public investment through schooling is combined with parental time and resource investments in the production of child human capital at different stages in the children’s development process. We quantitatively characterize the long-term consequences from a Covid-19 induced loss of schooling, and find average losses in the present discounted value of lifetime earnings of the affected children of close to 1%, as well as welfare losses equivalent to about 0.6% of permanent consumption. Due to self-productivity in the human capital production function, skill attainment at a younger stage of the life cycle raises skill attainment at later stages, and thus younger children are hurt more by the school closures than older children. We find that parental reactions reduce the negative impact of the school closures, but do not fully offset it. The negative impact of the crisis on children’s welfare is especially severe for those with parents with low educational attainment and low assets. The school closures themselves are primarily responsible for the negative impact of the Covid-19 shock on the long-run welfare of the children, with the pandemic-induced income shock to parents playing a secondary role.
We characterize the optimal linear tax on capital in an Overlapping Generations model with two period lived households facing uninsurable idiosyncratic labor income risk. The Ramsey government internalizes the general equilibrium effects of private precautionary saving on factor prices and taxes capital unless the weight on future generations in the social welfare function is sufficiently high. For logarithmic utility a complete analytical solution of the Ramsey problem exhibits an optimal aggregate saving rate that is independent of income risk, whereas the optimal time-invariant tax on capital implementing this saving rate is increasing in income risk. The optimal saving rate is constant along the transition and its sign depends on the magnitude of risk and on the Pareto weight of future generations. If the Ramsey tax rate that maximizes steady state utility is positive, then implementing this tax rate permanently induces a Pareto-improving transition even if the initial equilibrium capital stock is below the golden rule.
Background: Genome sequencing of all known eukaryotes on Earth promises unprecedented advances in biological sciences and in biodiversity-related applied fields such as environmental management and natural product research. Advances in long-read DNA sequencing make it feasible to generate high-quality genomes for many non–genetic model species. However, long-read sequencing today relies on sizable quantities of high-quality, high molecular weight DNA, which is mostly obtained from fresh tissues. This is a challenge for biodiversity genomics of most metazoan species, which are tiny and need to be preserved immediately after collection. Here we present de novo genomes of 2 species of submillimeter Collembola. For each, we prepared the sequencing library from high molecular weight DNA extracted from a single specimen and using a novel ultra-low input protocol from Pacific Biosciences. This protocol requires a DNA input of only 5 ng, permitted by a whole-genome amplification step.
Results: The 2 assembled genomes have N50 values >5.5 and 8.5 Mb, respectively, and both contain ∼96% of BUSCO genes. Thus, they are highly contiguous and complete. The genomes are supported by an integrative taxonomy approach including placement in a genome-based phylogeny of Collembola and designation of a neotype for 1 of the species. Higher heterozygosity values are recorded in the more mobile species. Both species are devoid of the biosynthetic pathway for β-lactam antibiotics known in several Collembola, confirming the tight correlation of antibiotic synthesis with the species way of life.
Conclusions: It is now possible to generate high-quality genomes from single specimens of minute, field-preserved metazoans, exceeding the minimum contig N50 (1 Mb) required by the Earth BioGenome Project.
Evaluation of 2‑methoxyestradiol serum levels as a potential prognostic marker in malignant melanoma
(2021)
Experimental findings indicated that 2‑methoxyestradiol (2‑ME), an endogenous metabolite of 17β‑estradiol, may exhibit anti‑tumorigenic properties in various types of tumour, such as melanoma and endometrial carcinoma. In patients with endometrial cancer, the serum levels of 2‑ME are decreased compared with those in healthy controls, and this finding has been associated with a poor outcome. The aim of the present study was to examine whether the serum levels of 2‑ME are decreased in patients with melanoma, and whether this decrease may be correlated with disease stage and, therefore, serve as a prognostic indicator. ELISA was used to detect serum levels of 2‑ME in patients with stage I‑IV malignant melanoma (MM). A cohort of 78 patients with MM was analysed, along with 25 healthy controls, among whom 15 were women in the second trimester of pregnancy (positive control). As expected, significantly elevated levels of serum 2‑ME were observed in pregnant control patients compared with those in patients with MM and healthy controls. There was no observed correlation between 2‑ME serum levels in patients with MM and disease stage, tumour thickness, lactate dehydrogenase or S100 calcium‑binding protein B levels. In addition, the 2‑ME levels of patients with MM did not differ significantly from those of normal healthy controls. Overall, the findings of the present study indicated that the 2‑ME serum levels in patients with MM were not decreased, and there was no correlation with early‑ or advanced‑stage disease. Therefore, in contrast to published results on endometrial cancer, endogenous serum 2‑ME levels in MM were not found to be correlated with tumour stage and did not appear to be a suitable prognostic factor in MM.