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Based on e+e− collision data corresponding to an integrated luminosity of 4.5 fb−1 collected at the center-of-mass energies between 4.600 and 4.699 GeV with the BESIII detector at BEPCII, the absolute branching fraction of the inclusive decay Λ+c→n+X, where X refers to any possible final state particles, is measured. The absolute branching fraction is determined to be B(Λ+c→n+X)=(32.4±0.7±1.5)%, where the first uncertainty is statistical and the second systematic. Assuming CP symmetry, the measurement indicates that about one-fourth of Λ+c (Λ¯−c) decay modes with a neutron (an anti-neutron) in the final state have not been observed.
Using 7.33~fb−1 of e+e− collision data collected by the BESIII detector at center-of-mass energies in the range of s√=4.128−4.226~GeV, we search for the rare decays D+s→h+(h0)e+e−, where h represents a kaon or pion. By requiring the e+e− invariant mass to be consistent with a ϕ(1020), 0.98<M(e+e−)<1.04 ~GeV/c2, the decay D+s→π+ϕ,ϕ→e+e− is observed with a statistical significance of 7.8σ, and evidence for the decay D+s→ρ+ϕ,ϕ→e+e− is found for the first time with a statistical significance of 4.4σ. The decay branching fractions are measured to be B(D+s→π+ϕ,ϕ→e+e−)=(1.17+0.23−0.21±0.03)×10−5, and B(D+s→ρ+ϕ,ϕ→e+e−)=(2.44+0.67−0.62±0.16)×10−5, where the first uncertainties are statistical and the second systematic. No significant signal for the three four-body decays of D+s→π+π0e+e−, D+s→K+π0e+e−, and D+s→K0Sπ+e+e− is observed. For D+s→π+π0e+e−, the ϕ mass region is vetoed to minimize the long-distance effects. The 90% confidence level upper limits set on the branching fractions of these decays are in the range of (7.0−8.1)×10−5.
Using 9.0 fb−1 of e+e− collision data collected at center-of-mass energies from 4.178 to 4.278 GeV with the BESIII detector at the BEPCII collider, we perform the first search for the radiative transition χc1(3872)→γψ2(3823). No χc1(3872)→γψ2(3823) signal is observed. The upper limit on the ratio of branching fractions B(χc1(3872)→γψ2(3823), ψ2(3823)→γχc1)/B(χc1(3872)→π+π−J/ψ) is set as 0.075 at the 90\% confidence level. Our result contradicts theoretical predictions under the assumption that the χc1(3872) is the pure charmonium state χc1(2P).
We study the processes e+e−→K0SD+sD∗− and e+e−→K0SD∗+sD−, as well as their charge conjugated processes, at five center-of-mass energies between 4.628~GeV and 4.699~GeV, using data samples corresponding to an integrated luminosity of 3.8 fb−1 collected by the BESIII detector at the BEPCII storage ring. Based on a partial reconstruction technique, we find evidence of a structure near the thresholds for D+sD∗− and D∗+sD− production in the K0S recoil-mass spectrum, which we refer to as the Zcs(3985)0. Fitting with a Breit-Wigner line shape, we find the mass of the structure to be (3992.2±1.7±1.6) MeV/c2 and the width to be (7.7+4.1−3.8±4.3) MeV, where the first uncertainties are statistical and the second are systematic. The significance of the Zcs(3985)0 signal is found to be 4.6σ including both the statistical and systematic uncertainty. We report the Born cross section multiplied by the branching fraction at different energy points. The mass of the Zcs(3985)0 is close to that of the Zcs(3985)+. Assuming SU(3) symmetry, the cross section of the neutral channel is consistent with that of the charged one. Hence, we conclude that the Zcs(3985)0 is the isospin partner of the Zcs(3985)+.
The singly Cabibbo-suppressed decay Λ+c→Σ−K+π+ is observed for the first time with a statistical significance of 6.4σ by using 4.5 fb−1 of e+e− collision data collected at center-of-mass energies between 4.600 and 4.699 GeV with the BESIII detector at BEPCII. The absolute branching fraction of Λ+c→Σ−K+π+ is measured to be (3.8±1.3stat±0.2syst)×10−4 in a model-independent approach. This is the first observation of a Cabibbo-suppressed Λ+c decay involving Σ− in the final state. The ratio of branching fractions between Λ+c→Σ−K+π+ and the Cabibbo-favored decay Λ+c→Σ−π+π+ is calculated to be (0.4±0.1)s2c, where sc≡sinθc=0.2248 with θc the Cabibbo mixing angle. This ratio significantly deviates from 1.0s2c and provides important information for the understanding of nonfactorization contributions in Λ+c decays.
The singly Cabibbo-suppressed decay Λ+c→Σ−K+π+ is observed for the first time with a statistical significance of 6.4σ by using 4.5 fb−1 of e+e− collision data collected at center-of-mass energies between 4.600 and 4.699 GeV with the BESIII detector at BEPCII. The absolute branching fraction of Λ+c→Σ−K+π+ is measured to be (3.8±1.3stat±0.2syst)×10−4 in a model-independent approach. This is the first observation of a Cabibbo-suppressed Λ+c decay involving Σ− in the final state. The ratio of branching fractions between Λ+c→Σ−K+π+ and the Cabibbo-favored decay Λ+c→Σ−π+π+ is calculated to be (0.4±0.1)s2c, where sc≡sinθc=0.2248 with θc the Cabibbo mixing angle. This ratio significantly deviates from 1.0s2c and provides important information for the understanding of nonfactorization contributions in Λ+c decays.
Determination of U-spin breaking parameters with an amplitude analysis of the decay D⁰ → K⁰Lπ⁺π⁻
(2022)
We present a study of the resonant structure of the decay D0→K0Lπ+π−, using quantum-correlated D0D¯0 data produced at s√=3.773 GeV. The data sample was collected by the BESIII experiment and corresponds to an integrated luminosity of 2.93 fb−1. This study is the first amplitude analysis of a decay mode involving a K0L, which also results in the first measurement of the complex U-spin breaking parameters (ρ^) related to various CP-eigenstate resonant modes through which the three-body decay proceeds. The moduli of the ρ^ parameters have central values in a wide range from 0.4 to 12.1, which indicates substantial U-spin symmetry breaking. We present the fractional resonant contributions and average strong-phase parameters over regions of phase space for both K0Sπ+π− and K0Lπ+π− modes. We also report the ratio of the branching fractions between K0Lπ+π− and K0Sπ+π− decay modes and the CP-even fraction of the K0Lπ+π− state calculated using the U-spin breaking parameters.
We report the measurement of the cross sections for e+e−→{nOCH} (nOCH stands for non-open charm hadrons) with improved precision at center-of-mass energies from 3.645 to 3.871 GeV. We observe for the first time a three-resonance structure in the energy-dependent lineshape of the cross sections, which are R(3760), R(3780) and R(3810) with significances of 9.4σ, 15.7σ, and 9.8σ, respectively. The R(3810) is observed for the first time. We found two solutions in analysis of the cross sections. For solution I [solution II], we measure the mass, the total width and the product of electronic width and nOCH decay branching fraction to be (3805.8±1.1±2.7) [(3805.8±1.1±2.7)] MeV/c2, (11.6±2.6±1.9) [(11.5±2.5±1.8)] MeV, and (10.8±3.2±2.3) [(11.0±2.9±2.4)] eV for the R(3810), respectively. In addition, we measure the branching fractions B(R(3760)→{nOCH})=(24.5±13.4±27.4)%[(6.8±5.4±7.6)%] for the first time, and B(R(3780)→{nOCH})=(11.6±5.8±7.8)%[(10.3±4.5±6.9)%]. Moreover, we determine the open-charm (OC) branching fraction B(R(3760)→{OC})=(75.5±13.4±27.4)%[(93.2±5.4±7.6)%], which supports the interpretation of R(3760) as an OC pair molecular state, but contained a simple four-quark state component. The first uncertainties are from fits to the cross sections, and the second are systematic.
We report the measurement of the inclusive cross sections for e+e−→nOCH (where nOCH denotes non-open charm hadrons) with improved precision at center-of-mass (c.m.) energies from 3.645 to 3.871 GeV. We observe three resonances: R(3760), R(3780), and R(3810) with significances of 8.1σ, 13.7σ, and 8.8σ, respectively. The R(3810) state is observed for the first time, while the R(3760) and R(3780) states are observed for the first time in the nOCH cross sections. Two sets of resonance parameters describe the energy-dependent line shape of the cross sections well. In set I [set II], the R(3810) state has mass (3805.7±1.1±2.7) [(3805.7±1.1±2.7)] MeV/c2, total width (11.6±2.9±1.9) [(11.5±2.8±1.9)] MeV, and an electronic width multiplied by the nOCH decay branching fraction of (10.9±3.8±2.5) [(11.0±3.4±2.5)] eV. In addition, we measure the branching fractions B[R(3760)→nOCH]=(25.2±16.1±30.4)%[(6.4±4.8±7.7)%] and B[R(3780)→nOCH]=(12.3±6.6±8.3)%[(10.4±4.8±7.0)%] for the first time. The R(3760) state can be interpreted as an open-charm (OC) molecular state, but containing a simple four-quark state component. The R(3810) state can be interpreted as a hadrocharmonium state.
Using a sample of (10087±44)×106 J/ψ events, which is about fifty times larger than that was previously analyzed, a further investigation on the J/ψ→γ3(π+π−) decay is performed. A significant distortion at 1.84 GeV/c2 in the line-shape of the 3(π+π−) invariant mass spectrum is observed for the first time, which is analogous to the behavior of X(1835) and could be resolved by two overlapping resonant structures, X(1840) and X(1880). The new state X(1880) is observed with a statistical significance of 14.7σ. The mass and width of X(1880) are determined to be 1882.1±1.7±0.7 MeV/c2 and 30.7±5.5±2.4 MeV, respectively, which indicates the existence of a pp¯ bound state.
Measurement of e⁺e⁻ → ΛΛ¯η from 3.5106 to 4.6988 GeV and study of ΛΛ¯ mass threshold enhancement
(2022)
Using data samples with a total integrated luminosity of approximately 18 fb−1 collected by the BESIII detector operating at the BEPCII, the process e+e−→ΛΛ¯η is studied at center-of-mass energies between 3.5106 and 4.6988 GeV. The Born cross section for the process e+e−→ΛΛ¯η is measured. No significant structure is observed in the Born cross section line shape. An enhancement near the ΛΛ¯ mass threshold is observed for the first time in the process. The structure can be described by an S-wave Breit-Wigner function. Neglecting contribution of excited Λ states and potential interferences, the mass and width are determined to be (2356±7±17) MeV/c2 and (304±28±54) MeV, respectively, where the first uncertainties are statistical and the second are systematic.
Measurement of e⁺e⁻ → ΛΛ¯η from 3.5106 to 4.6988 GeV and study of ΛΛ¯ mass threshold enhancement
(2022)
Using data samples with a total integrated luminosity of approximately 18 fb−1 collected by the BESIII detector operating at the BEPCII, the process e+e−→ΛΛ¯η is studied at center-of-mass energies between 3.5106 and 4.6988 GeV. The Born cross section for the process e+e−→ΛΛ¯η is measured. No significant structure is observed in the Born cross section line shape. An enhancement near the ΛΛ¯ mass threshold is observed for the first time in the process. The structure can be described by an S-wave Breit-Wigner function. Neglecting contribution of excited Λ states and potential interferences, the mass and width are determined to be (2356±7±17) MeV/c2 and (304±28±54) MeV, respectively, where the first uncertainties are statistical and the second are systematic.
By analyzing e+e− annihilation data corresponding to an integrated luminosity of 7.93 fb−1, collected at the center-of-mass energy of 3.773 GeV with the BESIII detector, we search for the semileptonic decays D0→K−ηe+νe, D+→K0Sηe+νe and D+→ηηe+νe for the first time. We present evidence for D0→K−ηe+νe with a significance of 3.3σ. The branching fraction of D0→K−ηe+νe is measured to be (0.84+0.29−0.34±0.22)×10−4. Here, the first uncertainties are statistical and the second ones are systematic. No significant signals are observed for the decays D+→K0Sηe+νe and D+→ηηe+νe and we set the upper limits on their branching fractions.
By analyzing e+e− annihilation data corresponding to an integrated luminosity of 7.93 fb−1, collected at the center-of-mass energy of 3.773 GeV with the BESIII detector, we search for the semileptonic decays D0→K−ηe+νe, D+→K0Sηe+νe and D+→ηηe+νe for the first time. We present evidence for D0→K−ηe+νe with a significance of 3.3σ. The branching fraction of D0→K−ηe+νe is measured to be (0.84+0.29−0.34±0.22)×10−4. %Alternatively, under the assumption that this decay is dominated by non-resonant, the branching fraction is determined to be (1.12+0.45−0.38±0.05)×10−4. Here, the first uncertainties are statistical and the second ones are systematic. No significant signals are observed for the decays D+→K0Sηe+νe and D+→ηηe+νe and we set the upper limits on their branching fractions.
By analyzing e+e− annihilation data corresponding to an integrated luminosity of 7.93 fb−1, collected at the center-of-mass energy of 3.773 GeV with the BESIII detector, we search for the semileptonic decays D0→K−ηe+νe, D+→K0Sηe+νe and D+→ηηe+νe for the first time. We present evidence for D0→K−ηe+νe with a significance of 3.3σ. The branching fraction of D0→K−ηe+νe is measured to be (0.84+0.29−0.34±0.22)×10−4. Here, the first uncertainties are statistical and the second ones are systematic. No significant signals are observed for the decays D+→K0Sηe+νe and D+→ηηe+νe and we set the upper limits on their branching fractions.
A search has been performed for the semileptonic decays D0→K0SK−e+νe, D+→K0SK0Se+νe and D+→K+K−e+νe, using 7.9 fb−1 of e+e− annihilation data collected at the center-of-mass energy s√=3.773 GeV by the BESIII detector operating at the BEPCII collider. No significant signals are observed, and upper limits are set at the 90\% confidence level of 2.13×10−5, 1.54×10−5 and 2.10×10−5 for the branching fractions of D0→K0SK−e+νe, D+→K0SK0Se+νe and D+→K+K−e+νe, respectively.
The decay D→K−π+ is studied in a sample of quantum-correlated DD¯ pairs, based on a data set corresponding to an integrated luminosity of 2.93\,fb−1 collected at the ψ(3770) resonance by the BESIII experiment. The asymmetry between CP-odd and CP-even eigenstate decays into K−π+ is determined to be AKπ=0.132±0.011±0.007, where the first uncertainty is statistical and the second is systematic. This measurement is an update of an earlier study exploiting additional tagging modes, including several decay modes involving a K0L meson. The branching fractions of the K0L modes are determined as input to the analysis in a manner that is independent of any strong phase uncertainty. Using the predominantly CP-even tag D→π+π−π0 and the ensemble of CP-odd eigenstate tags, the observable Aπππ0Kπ is measured to be 0.130±0.012±0.008. The two asymmetries are sensitive to rKπDcosδKπD, where rKπD and δKπD are the ratio of amplitudes and phase difference, respectively, between the doubly Cabibbo-suppressed and Cabibbo-favoured decays. In addition, events containing D→K−π+ tagged by D→K0S,Lπ+π− are studied in bins of phase space of the three-body decays. This analysis has sensitivity to both rKπDcosδKπD and rKπDsinδKπD. A fit to AKπ, Aπππ0Kπ and the phase-space distribution of the D→K0S,Lπ+π− tags yields δKπD=(187.6+8.9−9.7+5.4−6.4) degrees, where external constraints are applied for rKπD and other relevant parameters. This is the most precise measurement of δKπD in quantum-correlated DD¯ decays.
Using 9.0 fb−1 of e+e− collision data collected at center-of-mass energies from 4.178 to 4.278 GeV with the BESIII detector at the BEPCII collider, we perform the first search for the radiative transition χc1(3872)→γψ2(3823). No χc1(3872)→γψ2(3823) signal is observed. The upper limit on the ratio of branching fractions B(χc1(3872)→γψ2(3823),ψ2(3823)→γχc1)/B(χc1(3872)→π+π−J/ψ) is set as 0.075 at the 90\% confidence level. Our result contradicts theoretical predictions under the assumption that the χc1(3872) is the pure charmonium state χc1(2P).
We perform a study of the X(3872) lineshape using the data samples of e+e−→γX(3872), X(3872)→D0D¯0π0 and π+π−J/ψ collected with the BESIII detector. The effects of the coupled-channels and the off-shell D∗0 are included in the parameterization of the lineshape. The lineshape mass parameter is obtained to be MX=(3871.63±0.13+0.06−0.05) MeV. Two poles are found on the first and second Riemann sheets corresponding to the D∗0D¯0 branch cut. The pole location on the first sheet is much closer to the D∗0D¯0 threshold than the other, and is determined to be 7.04±0.15+0.07−0.08 MeV above the D0D¯0π0 threshold with an imaginary part −0.19±0.08+0.14−0.19 MeV.
By analyzing 7.33 fb−1 of e+e− annihilation data collected at center-of-mass energies between 4.128 and 4.226 GeV with the BESIII detector, we report the observation of the semileptonic decay D+s→η′μ+νμ, with a statistical significance larger than 10σ, and the measurements of the D+s→ημ+νμ and D+s→η′μ+νμ decay dynamics for the first time. The branching fractions of D+s→ημ+νμ and D+s→η′μ+νμ are determined to be (2.235±0.051stat±0.052syst)% and (0.801±0.055stat±0.028syst)%, respectively, with precision improved by factors of 6.0 and 6.6 compared to the previous best measurements. Combined with the results for the decays D+s→ηe+νe and D+s→η′e+νe, the ratios of the decay widths are examined both inclusively and in several ℓ+νℓ four-momentum transfer ranges. No evidence for lepton flavor universality violation is found within the current statistics. The products of the hadronic form factors fη(′)+,0(0) and the c→s Cabibbo-Kobayashi-Maskawa matrix element |Vcs| are determined. The results based on the two-parameter series expansion are fη+,0(0)|Vcs| = 0.452±0.010stat±0.007syst and fη′+,0(0)|Vcs| = 0.504±0.037stat±0.012syst, which help to constrain present models on fη(′)+,0(0). The forward-backward asymmetries are determined to be ⟨AηFB⟩=−0.059±0.031stat±0.005syst and ⟨Aη′FB⟩=−0.064±0.079stat±0.006syst for the first time, which are consistent with the theoretical calculation.
This paper reports the study of D+s→τ+ν via τ+→π+ν¯τ using a boosted decision tree method, with 7.33 fb−1 of e+e− collision data collected by the BESIII detector at center-of-mass energies between 4.128 and 4.226~GeV. The branching fraction of D+s→τ+ντ is determined to be (5.44±0.17stat±0.13syst)%. The product of the D+s decay constant fD+s and the CKM matrix element |Vcs| is fD+s|Vcs| =(248.3±3.9stat±3.1syst±1.0input) MeV. Combining with the |Vcs| value obtained from the Standard Model global fit or the fD+s from the lattice quantum chromodynamics, we determine |Vcs| = 0.993±0.015stat±0.012syst±0.004input and fD+s =(255.0±4.0stat±3.2syst±1.0input) MeV. The first uncertainty is statistical, the second one is systematic and the third one is due to the input parameters, mainly the lifetime of D+s. All results obtained in this work supersede the BESIII previous results based on 6.32 fb−1 of e+e− collision data taken at center-of-mass energies between 4.178 and 4.226~GeV.
Precise measurement of the branching fractions of of J/ψ → Λ¯π⁺Σ⁻ + c.c. and J/ψ → Λ¯π⁻Σ⁺ + c.c.
(2023)
Based on a data sample of (10087±44)×106 J/ψ events collected with the BESIII detector, the branching fraction of J/ψ→Λ¯π+Σ−+c.c. is measured to be (1.221±0.002±0.038)×10−3, and the branching fraction of its isospin partner mode J/ψ→Λ¯π−Σ++c.c. is measured to be (1.244±0.002±0.045)×10−3 with improved precision. Here the first uncertainties are statistical and the second ones systematic. The isospin symmetry of the Σ baryon in charmonium hadronic decay and the "12% rule" are tested, and no violation is found. The potential of using these channels as Σ baryon sources for nuclear physics research is studied, and the momentum and angular distributions of these sources are provided.
A light scalar X0 or vector X1 particles have been introduced as a possible explanation for the (g−2)μ anomaly and dark matter phenomena.
Using (8.998±0.039)×109 $\jpsi$ events collected by the BESIII detector, we search for a light muon philic scalar X0 or vector X1 in the processes J/ψ→μ+μ−X0,1 with X0,1 invisible decays. No obvious signal is found, and the upper limits on the coupling g′0,1 between the muon and the X0,1 particles are set to be between 1.1×10−3 and 1.0×10−2 for the X0,1 mass in the range of 1<M(X0,1)<1000 MeV/c2 at 90% confidence level.
A search has been performed for the semileptonic decays D0→K0SK−e+νe, D+→K0SK0Se+νe and D+→K+K−e+νe, using 7.9 fb−1 of e+e− annihilation data collected at the center-of-mass energy s√=3.773 GeV by the BESIII detector operating at the BEPCII collider. No significant signals are observed, and upper limits are set at the 90\% confidence level of 2.13×10−5, 1.54×10−5 and 2.10×10−5 for the branching fractions of D0→K0SK−e+νe, D+→K0SK0Se+νe and D+→K+K−e+νe, respectively.
Six C-even states, denoted as X, with quantum numbers JPC=0−+, 1±+, or 2±+, are searched for via the e+e−→γD±sD∗∓s process using (1667.39±8.84) pb−1 of e+e− collision data collected with the BESIII detector operating at the BEPCII storage ring at center-of-mass energy of s√=(4681.92±0.30) MeV. No statistically significant signal is observed in the mass range from 4.08 to 4.32 GeV/c2. The upper limits of σ[e+e−→γX]⋅B[X→D±sD∗∓s] at a 90% confidence level are determined.
Using 24.1 fb−1 of e+e− collision data collected with the BESIII detector at the BEPCII collider, the Born cross sections and effective form factors of the e+e−→Σ+Σ¯− reaction are measured. The measurements are performed at center-of-mass energies ranging from 3.510 to 4.951 GeV. No significant evidence for the decay of the charmonium(-like) states, ψ(3770), ψ(4040), ψ(4160), Y(4230), Y(4360), ψ(4415), and Y(4660), into a Σ+Σ¯− final state is observed. Consequently, upper limits for the products of the branching fractions and the electronic partial widths at the 90% confidence level are reported for these decays.
Using data samples with an integrated luminosity of 4.67 fb−1 collected by the BESIII detector operating at the BEPCII collider, we search for the process e+e−→η′ψ(2S) at center-of-mass energies from 4.66 to 4.95 GeV. No significant signal is observed, and upper limits for the Born cross sections σB(e+e−→η′ψ(2S)) at the 90\% confidence level are determined.
Using (27.12±0.14)×108 ψ(3686) events collected with the BESIII detector, we present the first observation of the decays χcJ→ΛΛ¯ω, where J=0,1,2, with statistical significances of 11.7σ,11.2σ, and 11.8σ. The branching fractions of these decays are determined to be B(χc0→ΛΛ¯ω)=(2.37±0.22±0.23)×10−4, B(χc1→ΛΛ¯ω)=(1.01±0.10±0.11)×10−4, and B(χc2→ΛΛ¯ω)=(1.40±0.13±0.17)×10−4, where the first uncertainties are statistical and the second are systematic. We observe no clear intermediate structures.
Using (2712.4 ± 14.3)×106 ψ(3686) events collected with the BESIII detector at BEPCII, a partial wave analysis of the decay ψ(3686)→ϕηη′ is performed with the covariant tensor approach. An axial-vector state with a mass near 2.3 GeV/c2 is observed for the first time. Its mass and width are measured to be 2316 ±9stat±30systMeV/c2 and 89 ±15stat±26systMeV, respectively. The product branching fractions of B(ψ(3686)→X(2300)η′)B(X(2300)→ϕη) and B(ψ(3686)→X(2300)η)B(X(2300)→ϕη′) are determined to be (4.8 ±1.3stat±0.7syst)×10−6 and (2.2 ±0.7stat±0.7syst)×10−6, respectively. The branching fraction B(ψ(3686)→ϕηη′) is measured for the first time to be (3.14±0.17stat±0.24syst)×10−5.
The first uncertainties are statistical and the second are systematic.
Search for rare decays of Dₛ⁺ to final states π⁺e⁺e⁻, ρ⁺e⁺e⁻, π⁺π⁰e⁺e⁻, K⁺π⁰e⁺e⁻, and Kₛ⁰π⁺e⁺e⁻
(2024)
Using 7.33~fb−1 of e+e− collision data collected by the BESIII detector at center-of-mass energies in the range of s√=4.128−4.226~GeV, we search for the rare decays D+s→h+(h0)e+e−, where h represents a kaon or pion. By requiring the e+e− invariant mass to be consistent with a ϕ(1020), 0.98<M(e+e−)<1.04 ~GeV/c2, the decay D+s→π+ϕ,ϕ→e+e− is observed with a statistical significance of 7.8σ, and evidence for the decay D+s→ρ+ϕ,ϕ→e+e− is found for the first time with a statistical significance of 4.4σ. The decay branching fractions are measured to be B(D+s→π+ϕ,ϕ→e+e−)=(1.17+0.23−0.21±0.03)×10−5, and B(D+s→ρ+ϕ,ϕ→e+e−)=(2.44+0.67−0.62±0.16)×10−5, where the first uncertainties are statistical and the second systematic. No significant signal for the three four-body decays of D+s→π+π0e+e−, D+s→K+π0e+e−, and D+s→K0Sπ+e+e− is observed. For D+s→π+π0e+e−, the ϕ mass region is vetoed to minimize the long-distance effects. The 90% confidence level upper limits set on the branching fractions of these decays are in the range of (7.0−8.1)×10−5.
The processes hc→γP(P=η′, η, π0) are studied with a sample of (27.12±0.14)×108 ψ(3686) events collected by the BESIII detector at the BEPCII collider. The decay hc→γη is observed for the first time with the significance of 9.0σ, and the branching fraction is determined to be (3.77±0.55±0.13±0.26)×10−4, while B(hc→γη′) is measured to be (1.40±0.11±0.04±0.10)×10−3, where the first uncertainties are statistical, the second systematic, and the third from the branching fraction of ψ(3686)→π0hc. The combination of these results allows for a precise determination of Rhc=B(hc→γη)B(hc→γη′), which is calculated to be (27.0±4.4±1.0)%. The results are valuable for gaining a deeper understanding of η−η′ mixing, and its manifestation within quantum chromodynamics. No significant signal is found for the decay hc→γπ0, and an upper limit is placed on its branching fraction of B(hc→γπ0)<5.0×10−5, at the 90% confidence level.
Based on (27.12±0.14)×108 ψ(2S) events collected with the BESIII detector, we search for the decay ηc(2S)→π+π−ηc with ηc→K0SK±π∓ and ηc→K+K−π0. No significant signal is observed, and the upper limit on the product branching fraction B(ψ(2S)→γηc(2S))×B(ηc(2S)→π+π−ηc) is determined to be 2.21×10−5 at the 90\% confidence level. In addition, the analysis of the process ψ(2S)→γηc(2S),ηc(2S)→π+π−K0SK±π∓ gives a clear ηc(2S) signal with a statistical significance of 10σ for the first time, %The product branching fraction B(ψ(2S)→γηc(2S))×B(ηc(2S)→π+π−K0SKπ) is measured to be (9.31±0.72±2.77)×10−6, and and the branching fraction B(ηc(2S)→π+π−K0SK±π∓) is determined to be (1.33±0.11±0.4±0.95)×10−2, where the first uncertainty is statistical, the second is systematic, and the third uncertainty is due to the quoted B(ψ(2S)→γηc(2S)).
Based on a sample of (448.1±2.9)×106 ψ(3686) events collected with the BESIII detector at BEPCII, the decays of ψ(3686)→K−ΛΞ¯¯¯¯++c.c. with Ξ¯¯¯¯+→Λ¯¯¯¯π+, Λ¯¯¯¯→p¯¯¯π+ are this http URL excited hyperons, Ξ(1690)− and Ξ(1820)−, are observed with large significance (≫10σ) in the K−Λ invariant mass distributions. A partial wave analysis is performed, and the spin-parities of Ξ(1690)− and Ξ(1820)− are determined to be 12− and 32−, respectively. The masses, widths, and product branching fractions of Ξ(1690)− and Ξ(1820)− are also measured.
Based on a sample of (448.1±2.9)×106 ψ(3686) events collected with the BESIII detector at BEPCII, the decays of ψ(3686)→K−ΛΞ¯¯¯¯++c.c. with Ξ¯¯¯¯+→Λ¯¯¯¯π+, Λ¯¯¯¯→p¯¯¯π+ are this http URL excited hyperons, Ξ(1690)− and Ξ(1820)−, are observed with large significance (≫10σ) in the K−Λ invariant mass distributions. A partial wave analysis is performed, and the spin-parities of Ξ(1690)− and Ξ(1820)− are determined to be 12− and 32−, respectively. The masses, widths, and product branching fractions of Ξ(1690)− and Ξ(1820)− are also measured.
The J/ψ,ψ(3686)→Σ0Σ¯0 processes and subsequent decays are studied using the world's largest J/ψ and ψ(3686) data samples collected with the BESIII detector. The strong-CP symmetry is tested in the decays of the Σ0 hyperons for the first time by measuring the decay parameters, αΣ0=−0.0017±0.0021±0.0018 and α¯Σ0=0.0021±0.0020±0.0022. The weak-CP test is performed in the subsequent decays of their daughter particles Λ and Λ¯. Also for the first time, the transverse polarizations of the Σ0 hyperons in J/ψ and ψ(3686) decays are observed with opposite directions, and the ratios between the S-wave and D-wave contributions of the J/ψ,ψ(3686)→Σ0Σ¯0 decays are obtained. These results are crucial to understand the decay dynamics of the charmonium states and the production mechanism of the Σ0−Σ¯0 pairs.
Based on (2712.4±14.3)×106 ψ(3686) events, we investigate four hadronic decay modes of the P-wave charmonium spin-singlet state hc(1P1)→h+h−π0/η (h=π or K) via the process ψ(3686)→π0hc at BESIII. The hc→π+π−π0 decay is observed with a significance of 9.6σ after taking into account systematic uncertainties. Evidences for hc→K+K−π0 and hc→K+K−η are found with significances of 3.5σ and 3.3σ, respectively, after considering the systematic uncertainties. The branching fractions of these decays are measured to be B(hc→π+π−π0)=(1.36±0.16±0.14)×10−3, B(hc→K+K−π0)=(3.26±0.84±0.36)×10−4, and B(hc→K+K−η)=(3.13±1.08±0.38)×10−4, where the first uncertainties are statistical and the second are systematic. No significant signal of hc→π+π−η is found, and the upper limit of its decay branching fraction is determined to be B(hc→π+π−η)<4.0×10−4 at 90% confidence level.
Using 7.9 fb−1 of e+e− collision data collected at s√=3.773 GeV with the BESIII detector at the BEPCII collider, we search for the massless dark photon with the flavor-changing neutral current processes D0→ωγ′ and D0→γγ′ for the first time. No significant signals are observed, and the upper limits at the 90% confidence level on the massless dark photon branching fraction are set to be 1.1×10−5 and 2.0×10−6 for D0→ωγ′ and D0→γγ′, respectively. These results provide the most stringent constraint on the new physics energy scale associated with cuγ′ coupling in the world, with the new physics energy scale related parameter |C|2+|C5|2<8.2×10−17 GeV−2 at the 90% confidence level.
The process e+e−→D∗+sD∗−s is studied with a semi-inclusive method using data samples at center-of-mass energies from threshold to 4.95 GeV collected with the BESIII detector operating at the Beijing Electron Positron Collider. The Born cross sections of the process are measured for the first time with high precision in this energy region. Two resonance structures are observed in the energy-dependent cross sections around 4.2 and 4.4 GeV. By fitting the cross sections with a coherent sum of three Breit-Wigner amplitudes and one phase-space amplitude, the two significant structures are assigned masses of (4186.5±9.0±30) MeV/c2 and (4414.5±3.2±6.0) MeV/c2, widths of (55±17±53) MeV and (122.6±7.0±8.2) MeV, where the first errors are statistical and the second ones are systematic. The inclusion of a third Breit-Wigner amplitude is necessary to describe a structure around 4.79 GeV.
Using e+e− collision data corresponding to a total integrated luminosity of 12.9 fb−1 collected with the BESIII detector at the BEPCII collider, the exclusive Born cross sections and the effective form factors of the reaction e+e−→Ξ−Ξ¯+ are measured via the single baryon-tag method at 23 center-of-mass energies between 3.510 and 4.843 GeV. Evidence for the decay ψ(3770)→Ξ−Ξ¯+ is observed with a significance of 4.5σ by analyzing the measured cross sections together with earlier BESIII results. For the other charmonium(-like) states ψ(4040), ψ(4160), Y(4230), Y(4360), ψ(4415), and Y(4660), no significant signal of their decay to Ξ−Ξ¯+ is found. For these states, upper limits of the products of the branching fraction and the electronic partial width at the 90% confidence level are provided.
The process e+e−→D∗+sD∗−s is studied with a semi-inclusive method using data samples at center-of-mass energies from threshold to 4.95 GeV collected with the BESIII detector operating at the Beijing Electron Positron Collider. The Born cross sections of the process are measured for the first time with high precision in this energy region. Two resonance structures are observed in the energy-dependent cross sections around 4.2 and 4.4 GeV. By fitting the cross sections with a coherent sum of three Breit-Wigner amplitudes and one phase-space amplitude, the two significant structures are assigned masses of (4186.5±9.0±30) MeV/c2 and (4414.5±3.2±6.0) MeV/c2, widths of (55±17±53) MeV and (122.6±7.0±8.2) MeV, where the first errors are statistical and the second ones are systematic. The inclusion of a third Breit-Wigner amplitude is necessary to describe a structure around 4.79 GeV.
Using (447.9 ± 2.3) million ψ(3686) events collected with the BESIII detector, the decays of χcJ→ϕϕ (J=0, 1, 2) have been studied via the decay ψ(3686)→γχcJ. The branching fractions of the decays χcJ→ϕϕ (J=0, 1, 2) are determined to be (8.48±0.26±0.27)×10−4, (4.36±0.13±0.18)×10−4, and (13.36±0.29±0.49)×10−4, respectively, which are the most precise measurements to date. From a helicity amplitude analysis of the process ψ(3686)→γχcJ,χcJ→ϕϕ,ϕ→K+K−, the polarization parameters of the χcJ→ϕϕ decays are determined for the first time.
Introduction: The Retro-IDEAL (ILUVIEN Implant for chronic DiabEtic MAcuLar edema) study is a retrospective study designed to assess real-world outcomes achieved with the ILUVIEN® (0.19 mg fluocinolone acetonide (FAc)) in patients with chronic diabetic macular edema (DME) in clinical practices in Germany.
Methods: This study was conducted across 16 sites in Germany and involved 81 eyes (63 patients) with persistent or recurrent DME and a prior suboptimal response to a first-line intravitreal therapy (primarily anti-VEGF intravitreal therapies).
Results: Patients were followed-up for 30.8 ± 11.3 months (mean ± standard deviation) and had a mean age of 68.0 ± 10.4 years. Best-recorded visual acuity (BRVA) improved by +5.5 letters at month 9 (P ⩽ 0.005, n=56; from a baseline of 49 letters) and this was maintained through to month 30 (P ⩽ 0.05, n = 42). There was a concurrent improvement in central macular thickness with a reduction from 502 µm at baseline to 338 µm at year 1 (P ⩽ 0.0001, n = 43). This effect was sustained to year 3 (i.e. 318 µm; P ⩽ 0.0001, n = 29). Mean intraocular pressure (IOP) remained constant between baseline and year 3 with a peak change of 1.9 mm Hg occurring at year 1. Elevated IOP was observed in a similar percentage of patients prior to (22.2% of cases) and following (27.2%) treatment with the FAc implant. In the majority of cases, these elevations were managed effectively with IOP medications.
Conclusions: Despite substantial amounts of prior intravitreal treatments – primarily with anti–vascular endothelial growth factor (VEGF) drugs – this real-world study showed that sustained structural and functional improvements can last for up to 3 years with a single FAc implant.
In den vorangehenden Kapiteln wurde die besondere Charakteristik sowie die bundes- und europaweite Bedeutung des Schutzgebietssystems um die Mansfelder Seen und vordringlich des ehemaligen Salzigen Sees herausgestellt. Es wurde ebenfalls deutlich, dass die Wiederentstehung des Salzigen Sees einen schwerwiegenden Eingriff in den bestehenden Gebietswasserhaushalt darstellt, dessen langfristige Konsequenzen noch nicht in allen Aspekten absehbar sind. Welche Auswirkungen kann dieses Vorhaben nun auf die hoch schutzwürdige Fauna und Flora haben und welche Vorkehrungen müssen getroffen werden, damit die Chancen für den Arten- und Biotopschutz, die der Wiederentstehung des Sees zweifellos innewohnen, zum Tragen kommen?
The Tarim River basin, located in Xinjiang, NW China, is the largest endorheic river basin in China and one of the largest in all of Central Asia. Due to the extremely arid climate, with an annual precipitation of less than 100 mm, the water supply along the Aksu and Tarim rivers solely depends on river water. This is linked to anthropogenic activities (e.g., agriculture) and natural and semi-natural ecosystems as both compete for water. The ongoing increase in water consumption by agriculture and other human activities in this region has been enhancing the competition for water between human needs and nature. Against this background, 11 German and 6 Chinese universities and research institutes have formed the consortium SuMaRiO (Sustainable Management of River Oases along the Tarim River; http://www.sumario.de), which aims to create a holistic picture of the availability of water resources in the Tarim River basin and the impacts on anthropogenic activities and natural ecosystems caused by the water distribution within the Tarim River basin. On the basis of the results from field studies and modeling approaches as well as from suggestions by the relevant regional stakeholders, a decision support tool (DST) will be implemented that will then assist stakeholders in balancing the competition for water, acknowledging the major external effects of water allocation to agriculture and to natural ecosystems. This consortium was formed in 2011 and is funded by the German Federal Ministry of Education and Research. As the data collection phase was finished this year, the paper presented here brings together the results from the fields from the disciplines of climate modeling, cryology, hydrology, agricultural sciences, ecology, geoinformatics, and social sciences in order to present a comprehensive picture of the effects of different water availability schemes on anthropogenic activities and natural ecosystems along the Tarim River. The second objective is to present the project structure of the whole consortium, the current status of work (i.e., major new results and findings), explain the foundation of the decision support tool as a key product of this project, and conclude with application recommendations for the region. The discharge of the Aksu River, which is the major tributary of the Tarim, has been increasing over the past 6 decades. From 1989 to 2011, agricultural area more than doubled: cotton became the major crop and there was a shift from small-scale to large-scale intensive farming. The ongoing increase in irrigated agricultural land leads to the increased threat of salinization and soil degradation caused by increased evapotranspiration. Aside from agricultural land, the major natural and semi-natural ecosystems are riparian (Tugai) forests, shrub vegetation, reed beds, and other grassland, as well as urban and peri-urban vegetation. Within the SuMaRiO cluster, focus has been set on the Tugai forests, with Populus euphratica as the dominant tree species, because these forests belong to the most productive and species-rich natural ecosystems of the Tarim River basin. At sites close to the groundwater, the annual stem diameter increments of Populus euphratica correlated with the river runoffs of the previous year. However, the natural river dynamics cease along the downstream course and thus hamper the recruitment of Populus euphratica. A study on the willingness to pay for the conservation of the natural ecosystems was conducted to estimate the concern of the people in the region and in China's capital. These household surveys revealed that there is a considerable willingness to pay for conservation of the natural ecosystems, with mitigation of dust and sandstorms considered the most important ecosystem service. Stakeholder dialogues contributed to creating a scientific basis for a sustainable management in the future.
Objectives: An increasing number of treatment-determining biomarkers has been identified in non-small cell lung cancer (NSCLC) and molecular testing is recommended to enable optimal individualized treatment. However, data on implementation of these recommendations in the “real-world” setting are scarce. This study presents comprehensive details on the frequency, methodology and results of biomarker testing of advanced NSCLC in Germany.
Patients and methods: This analysis included 3,717 patients with advanced NSCLC (2,921 non-squamous; 796 squamous), recruited into the CRISP registry at start of systemic therapy by 150 German sites between December 2015 and June 2019. Evaluated were the molecular biomarkers EGFR, ALK, ROS1, BRAF, KRAS, MET, TP53, RET, HER2, as well as expression of PD-L1.
Results: In total, 90.5 % of the patients were tested for biomarkers. Testing rates were 92.2 % (non-squamous), 70.7 % (squamous) and increased from 83.2 % in 2015/16 to 94.2% in 2019. Overall testing rates for EGFR, ALK, ROS1, and BRAF were 72.5 %, 74.5 %, 66.1 %, and 53.0 %, respectively (non-squamous). Testing rates for PD-L1 expression were 64.5 % (non-squamous), and 58.5 % (squamous). The most common testing methods were immunohistochemistry (68.5 % non-squamous, 58.3 % squamous), and next-generation sequencing (38.7 % non-squamous, 14.4 % squamous). Reasons for not testing were insufficient tumor material or lack of guideline recommendations (squamous). No alteration was found in 37.8 % (non-squamous), and 57.9 % (squamous), respectively. Most common alterations in non-squamous tumors (all patients/all patients tested for the respective biomarker): KRAS (17.3 %/39.2 %), TP53 (14.1 %/51.4 %), and EGFR (11.0 %/15.1 %); in squamous tumors: TP53 (7.0 %/69.1 %), MET (1.5 %/11.1 %), and EGFR (1.1 %/4.4 %). Median PFS (non-squamous) was 8.7 months (95 % CI 7.4–10.4) with druggable EGFR mutation, and 8.0 months (95 % CI 3.9–9.2) with druggable ALK alterations.
Conclusion: Testing rates in Germany are high nationwide and acceptable in international comparison, but still leave out a significant portion of patients, who could potentially benefit. Thus, specific measures are needed to increase implementation.
Purpose: While more advanced COVID-19 necessitates medical interventions and hospitalization, patients with mild COVID-19 do not require this. Identifying patients at risk of progressing to advanced COVID-19 might guide treatment decisions, particularly for better prioritizing patients in need for hospitalization.
Methods: We developed a machine learning-based predictor for deriving a clinical score identifying patients with asymptomatic/mild COVID-19 at risk of progressing to advanced COVID-19. Clinical data from SARS-CoV-2 positive patients from the multicenter Lean European Open Survey on SARS-CoV-2 Infected Patients (LEOSS) were used for discovery (2020-03-16 to 2020-07-14) and validation (data from 2020-07-15 to 2021-02-16).
Results: The LEOSS dataset contains 473 baseline patient parameters measured at the first patient contact. After training the predictor model on a training dataset comprising 1233 patients, 20 of the 473 parameters were selected for the predictor model. From the predictor model, we delineated a composite predictive score (SACOV-19, Score for the prediction of an Advanced stage of COVID-19) with eleven variables. In the validation cohort (n = 2264 patients), we observed good prediction performance with an area under the curve (AUC) of 0.73 ± 0.01. Besides temperature, age, body mass index and smoking habit, variables indicating pulmonary involvement (respiration rate, oxygen saturation, dyspnea), inflammation (CRP, LDH, lymphocyte counts), and acute kidney injury at diagnosis were identified. For better interpretability, the predictor was translated into a web interface.
Conclusion: We present a machine learning-based predictor model and a clinical score for identifying patients at risk of developing advanced COVID-19.
Background: Preclinical studies demonstrate synergism between cancer immunotherapy and local radiation, enhancing anti-tumor effects and promoting immune responses. BI1361849 (CV9202) is an active cancer immunotherapeutic comprising protamine-formulated, sequence-optimized mRNA encoding six non-small cell lung cancer (NSCLC)-associated antigens (NY-ESO-1, MAGE-C1, MAGE-C2, survivin, 5T4, and MUC-1), intended to induce targeted immune responses.
Methods: We describe a phase Ib clinical trial evaluating treatment with BI1361849 combined with local radiation in 26 stage IV NSCLC patients with partial response (PR)/stable disease (SD) after standard first-line therapy. Patients were stratified into three strata (1: non-squamous NSCLC, no epidermal growth factor receptor (EGFR) mutation, PR/SD after ≥4 cycles of platinum- and pemetrexed-based treatment [n = 16]; 2: squamous NSCLC, PR/SD after ≥4 cycles of platinum-based and non-platinum compound treatment [n = 8]; 3: non-squamous NSCLC, EGFR mutation, PR/SD after ≥3 and ≤ 6 months EGFR-tyrosine kinase inhibitor (TKI) treatment [n = 2]). Patients received intradermal BI1361849, local radiation (4 × 5 Gy), then BI1361849 until disease progression. Strata 1 and 3 also had maintenance pemetrexed or continued EGFR-TKI therapy, respectively. The primary endpoint was evaluation of safety; secondary objectives included assessment of clinical efficacy (every 6 weeks during treatment) and of immune response (on Days 1 [baseline], 19 and 61).
Results: Study treatment was well tolerated; injection site reactions and flu-like symptoms were the most common BI1361849-related adverse events. Three patients had grade 3 BI1361849-related adverse events (fatigue, pyrexia); there was one grade 3 radiation-related event (dysphagia). In comparison to baseline, immunomonitoring revealed increased BI1361849 antigen-specific immune responses in the majority of patients (84%), whereby antigen-specific antibody levels were increased in 80% and functional T cells in 40% of patients, and involvement of multiple antigen specificities was evident in 52% of patients. One patient had a partial response in combination with pemetrexed maintenance, and 46.2% achieved stable disease as best overall response. Best overall response was SD in 57.7% for target lesions.
Conclusion: The results support further investigation of mRNA-based immunotherapy in NSCLC including combinations with immune checkpoint inhibitors.
Trial registration: ClinicalTrials.gov identifier: NCT01915524.
The Tarim River Basin, located in Xinjiang, NW China, is the largest endorheic river basin of China and one of the largest in whole Central Asia. Due to the extremely arid climate with an annual precipitation of less than 100 mm, the water supply along the Aksu and Tarim River solely depends on river water. This applies for anthropogenic activities (e.g. agriculture) as well as for the natural ecosystems so that both compete for water. The on-going increase of water consumption by agriculture and other human activities in this region has been enhancing the competition for water between human needs and nature. Against this background, 11 German and 6 Chinese universities and research institutes formed the consortium SuMaRiO (www.sumario.de), which aims at gaining a holistic picture of the availability of water resources in the Tarim River Basin and the impacts on anthropogenic activities and natural ecosystems caused by the water distribution within the Tarim River Basin. The discharge of the Aksu River, which is the major tributary to the Tarim, has been increasing over the past 6 decades due to enhanced glacier melt. Alone from 1989 to 2011, the area under agriculture more than doubled. Thereby, cotton became the major crop and there was a shift from small-scale farming to large-scale intensive farming. The major natural ecosystems along the Aksu and Tarim River are riparian ecosystems: Riparian (Tugai) forests, shrub vegetation, reed beds, and other grassland. Within the SuMaRiO Cluster the focus was laid on the Tugai forests, with Populus euphratica as dominant tree, because the most productive and species-rich natural ecosystems can be found among those forests. On sites with groundwater distance of less than 7.5 m the annual increments correlated with river runoffs of the previous year. But, the further downstream along the Tarim River, the more the natural river dynamics ceased, which impacts on the recruitment of Populus euphratica. Household surveys revealed that there is a considerable willingness to pay for conservation of those riparian forests with the mitigation of dust and sandstorms considered as the most important ecosystem service. This interdisciplinary project will result in a decision support tool (DST), build on the participation of regional stakeholders and models based on results and field experiments. This DST finally shall assist stakeholders in balancing the water competition acknowledging the major external effects of any water allocation.
HLA-DRB1 and HLA-DQB1 genetic diversity modulates response to lithium in bipolar affective disorders
(2021)
Bipolar affective disorder (BD) is a severe psychiatric illness, for which lithium (Li) is the gold standard for acute and maintenance therapies. The therapeutic response to Li in BD is heterogeneous and reliable biomarkers allowing patients stratification are still needed. A GWAS performed by the International Consortium on Lithium Genetics (ConLiGen) has recently identified genetic markers associated with treatment responses to Li in the human leukocyte antigens (HLA) region. To better understand the molecular mechanisms underlying this association, we have genetically imputed the classical alleles of the HLA region in the European patients of the ConLiGen cohort. We found our best signal for amino-acid variants belonging to the HLA-DRB1*11:01 classical allele, associated with a better response to Li (p < 1 × 10−3; FDR < 0.09 in the recessive model). Alanine or Leucine at position 74 of the HLA-DRB1 heavy chain was associated with a good response while Arginine or Glutamic acid with a poor response. As these variants have been implicated in common inflammatory/autoimmune processes, our findings strongly suggest that HLA-mediated low inflammatory background may contribute to the efficient response to Li in BD patients, while an inflammatory status overriding Li anti-inflammatory properties would favor a weak response.
Introduction: Evidence from a number of open-label, uncontrolled studies has suggested that rituximab may benefit patients with autoimmune diseases who are refractory to standard-of-care. The objective of this study was to evaluate the safety and clinical outcomes of rituximab in several standard-of-care-refractory autoimmune diseases (within rheumatology, nephrology, dermatology and neurology) other than rheumatoid arthritis or non-Hodgkin's lymphoma in a real-life clinical setting.
Methods: Patients who received rituximab having shown an inadequate response to standard-of-care had their safety and clinical outcomes data retrospectively analysed as part of the German Registry of Autoimmune Diseases. The main outcome measures were safety and clinical response, as judged at the discretion of the investigators.
Results: A total of 370 patients (299 patient-years) with various autoimmune diseases (23.0% with systemic lupus erythematosus, 15.7% antineutrophil cytoplasmic antibody-associated granulomatous vasculitides, 15.1% multiple sclerosis and 10.0% pemphigus) from 42 centres received a mean dose of 2,440 mg of rituximab over a median (range) of 194 (180 to 1,407) days. The overall rate of serious infections was 5.3 per 100 patient-years during rituximab therapy. Opportunistic infections were infrequent across the whole study population, and mostly occurred in patients with systemic lupus erythematosus. There were 11 deaths (3.0% of patients) after rituximab treatment (mean 11.6 months after first infusion, range 0.8 to 31.3 months), with most of the deaths caused by infections. Overall (n = 293), 13.3% of patients showed no response, 45.1% showed a partial response and 41.6% showed a complete response. Responses were also reflected by reduced use of glucocorticoids and various immunosuppressives during rituximab therapy and follow-up compared with before rituximab. Rituximab generally had a positive effect on patient well-being (physician's visual analogue scale; mean improvement from baseline of 12.1 mm).
Conclusions: Data from this registry indicate that rituximab is a commonly employed, well-tolerated therapy with potential beneficial effects in standard of care-refractory autoimmune diseases, and support the results from other open-label, uncontrolled studies.
Previous studies in developing Xenopus and zebrafish reported that the phosphate transporter slc20a1a is expressed in pronephric kidneys. The recent identification of SLC20A1 as a monoallelic candidate gene for cloacal exstrophy further suggests its involvement in the urinary tract and urorectal development. However, little is known of the functional role of SLC20A1 in urinary tract development. Here, we investigated this using morpholino oligonucleotide knockdown of the zebrafish ortholog slc20a1a. This caused kidney cysts and malformations of the cloaca. Moreover, in morphants we demonstrated dysfunctional voiding and hindgut opening defects mimicking imperforate anus in human cloacal exstrophy. Furthermore, we performed immunohistochemistry of an unaffected 6-week-old human embryo and detected SLC20A1 in the urinary tract and the abdominal midline, structures implicated in the pathogenesis of cloacal exstrophy. Additionally, we resequenced SLC20A1 in 690 individuals with bladder exstrophy-epispadias complex (BEEC) including 84 individuals with cloacal exstrophy. We identified two additional monoallelic de novo variants. One was identified in a case-parent trio with classic bladder exstrophy, and one additional novel de novo variant was detected in an affected mother who transmitted this variant to her affected son. To study the potential cellular impact of SLC20A1 variants, we expressed them in HEK293 cells. Here, phosphate transport was not compromised, suggesting that it is not a disease mechanism. However, there was a tendency for lower levels of cleaved caspase-3, perhaps implicating apoptosis pathways in the disease. Our results suggest SLC20A1 is involved in urinary tract and urorectal development and implicate SLC20A1 as a disease-gene for BEEC.
Acute myeloid leukemia (AML) is characterized by uncontrolled proliferation and accumulation of immature myeloblasts, which impair normal hematopoiesis. While this definition categorizes the disease into a distinctive group, the large number of different genetic and epigenetic alterations actually suggests that AML is not a single disease, but a plethora of malignancies. Still, most AML patients are not treated with targeted medication but rather by uniform approaches such as chemotherapy. The identification of novel treatment options likely requires the identification of cancer cell vulnerabilities that take into account the different genetic and epigenetic make-up of the individual tumors. Here we show that STK3 depletion by knock-down, knock-out or chemical inhibition results in apoptotic cells death in some but not all AML cell lines and primary cells tested. This effect is mediated by a premature activation of cyclin dependent kinase 1 (CDK1) in presence of elevated cyclin B1 levels. The anti-leukemic effects seen in both bulk and progenitor AML cells suggests that STK3 might be a promising target in a subset of AML patients.
We present a systematic analysis of two-pion interferometry in Au+Au collisions at sqrt[sNN]=200GeV using the STAR detector at Relativistic Heavy Ion Collider. We extract the Hanbury-Brown and Twiss radii and study their multiplicity, transverse momentum, and azimuthal angle dependence. The Gaussianness of the correlation function is studied. Estimates of the geometrical and dynamical structure of the freeze-out source are extracted by fits with blast-wave parametrizations. The expansion of the source and its relation with the initial energy density distribution is studied.
There are strong indications that particles containing secondary organic aerosol (SOA) exhibit amorphous solid or semi-solid phase states in the atmosphere. This may facilitate deposition ice nucleation and thus influence cirrus cloud properties. However, experimental ice nucleation studies of biogenic SOA are scarce. Here, we investigated the ice nucleation ability of viscous SOA particles.
The SOA particles were produced from the ozone initiated oxidation of α-pinene in an aerosol chamber at temperatures in the range from −38 to −10 ◦C at 5–15 % relative humidity with respect to water to ensure their formation in a highly viscous phase state, i.e. semi-solid or glassy. The ice nucleation ability of SOA particles with different sizes was investigated with a new continuous flow diffusion chamber. For the first time, we observed heterogeneous ice nucleation of viscous α-pinene SOA in the deposition mode for ice saturation ratios between 1.3 and 1.4 significantly below the homogeneous freezing limit. The maximum frozen fractions found at temperatures between −36.5 and −38.3 °C ranged from 6 to 20 % and did not depend on the particle surface area. Global modelling of monoterpene SOA particles suggests that viscous biogenic SOA particles are indeed present in regions where cirrus cloud formation takes place. Hence, they could make up an important contribution to the global ice nuclei (IN) budget.
Sulphuric acid, ammonia, amines, and oxidised organics play a crucial role in nanoparticle formation in the atmosphere. In this study, we investigate the composition of nucleated nanoparticles formed from these compounds in the CLOUD (Cosmics Leaving Outdoor Droplets) chamber experiments at CERN (Centre européen pour la recherche nucléaire). The investigation was carried out via analysis of the particle hygroscopicity, ethanol affinity, oxidation state, and ion composition. Hygroscopicity was studied by a hygroscopic tandem differential mobility analyser and a cloud condensation nuclei counter, ethanol affinity by an organic differential mobility analyser and particle oxidation level by a high-resolution time-of-flight aerosol mass spectrometer. The ion composition was studied by an atmospheric pressure interface time-of-flight mass spectrometer. The volume fraction of the organics in the particles during their growth from sizes of a few nanometers to tens of nanometers was derived from measured hygroscopicity assuming the Zdanovskii–Stokes–Robinson relationship, and compared to values gained from the spectrometers. The ZSR-relationship was also applied to obtain the measured ethanol affinities during the particle growth, which were used to derive the volume fractions of sulphuric acid and the other inorganics (e.g. ammonium salts). In the presence of sulphuric acid and ammonia, particles with a mobility diameter of 150 nm were chemically neutralised to ammonium sulphate. In the presence of oxidation products of pinanediol, the organic volume fraction of freshly nucleated particles increased from 0.4 to ~0.9, with an increase in diameter from 2 to 63 nm. Conversely, the sulphuric acid volume fraction decreased from 0.6 to 0.1 when the particle diameter increased from 2 to 50 nm. The results provide information on the composition of nucleated aerosol particles during their growth in the presence of various combinations of sulphuric acid, ammonia, dimethylamine and organic oxidation products.
Under certain conditions, secondary organic aerosol (SOA) particles can exist in the atmosphere in an amorphous solid or semi-solid state. To determine their relevance to processes such as ice nucleation or chemistry occurring within particles requires knowledge of the temperature and relative humidity (RH) range for SOA to exist in these states. In the CLOUD experiment at CERN, we deployed a new in-situ optical method to detect the viscosity of α-pinene SOA particles and measured their transition from the amorphous viscous to liquid state. The method is based on the depolarising properties of laboratory-produced non-spherical SOA particles and their transformation to non-depolarising spherical liquid particles during deliquescence. We found that particles formed and grown in the chamber developed an asymmetric shape through coagulation. A transition to spherical shape was observed as the RH was increased to between 35 % at −10 ◦C and 80 % at −38 ◦C, confirming previous calculations of the viscosity transition conditions. Consequently, α-pinene SOA particles exist in a viscous state over a wide range of ambient conditions, including the cirrus region of the free troposphere. This has implications for the physical, chemical and ice-nucleation properties of SOA and SOA-coated particles in the atmosphere.
Nucleation of aerosol particles from trace atmospheric vapours is thought to provide up to half of global cloud condensation nuclei. Aerosols can cause a net cooling of climate by scattering sunlight and by leading to smaller but more numerous cloud droplets, which makes clouds brighter and extends their lifetimes. Atmospheric aerosols derived from human activities are thought to have compensated for a large fraction of the warming caused by greenhouse gases. However, despite its importance for climate, atmospheric nucleation is poorly understood. Recently, it has been shown that sulphuric acid and ammonia cannot explain particle formation rates observed in the lower atmosphere. It is thought that amines may enhance nucleation, but until now there has been no direct evidence for amine ternary nucleation under atmospheric conditions. Here we use the CLOUD (Cosmics Leaving Outdoor Droplets) chamber at CERN and find that dimethylamine above three parts per trillion by volume can enhance particle formation rates more than 1,000-fold compared with ammonia, sufficient to account for the particle formation rates observed in the atmosphere. Molecular analysis of the clusters reveals that the faster nucleation is explained by a base-stabilization mechanism involving acid–amine pairs, which strongly decrease evaporation. The ion-induced contribution is generally small, reflecting the high stability of sulphuric acid–dimethylamine clusters and indicating that galactic cosmic rays exert only a small influence on their formation, except at low overall formation rates. Our experimental measurements are well reproduced by a dynamical model based on quantum chemical calculations of binding energies of molecular clusters, without any fitted parameters. These results show that, in regions of the atmosphere near amine sources, both amines and sulphur dioxide should be considered when assessing the impact of anthropogenic activities on particle formation.
Sulphuric acid, ammonia, amines, and oxidised organics play a crucial role in nanoparticle formation in the atmosphere. In this study, we investigate the composition of nucleated nanoparticles formed from these compounds in the CLOUD chamber experiments at CERN. The investigation is carried out via analysis of the particle hygroscopicity, ethanol affinity, oxidation state, and ion composition. Hygroscopicity was studied by a hygroscopic tandem differential mobility analyser and a cloud condensation nuclei counter, ethanol affinity by an organic differential mobility analyser and particle oxidation level by a high-resolution time-of-flight aerosol mass spectrometer. The ion composition was studied by an atmospheric pressure interface time-of-flight mass spectrometer. The volume fraction of the organics in the particles during their growth from sizes of a few nanometers to tens of nanometers was derived from measured hygroscopicity assuming the Zdanovski-Stokes-Robinson relationship, and compared to values gained from the spectrometers. The ZSR-relationship was also applied to obtain the measured ethanol affinities during the particle growth, which were used to derive the volume fractions of sulphuric acid and the other inorganics (e.g. ammonium salts). In the presence of sulphuric acid and ammonia, particles with a mobility diameter of 150 nm were chemically neutralised to ammonium sulphate. In the presence of oxidation products of pinanediol, the organic volume fraction of freshly nucleated particles increased from 0.4 to ∼0.9, with an increase in diameter from 2 to 63 nm. Conversely, the sulphuric acid volume fraction decreased from 0.6 to 0.1 when the particle diameter increased from 2 to 50 nm. The results provide information on the composition of nucleated aerosol particles during their growth in the presence of various combinations of sulphuric acid, ammonia, dimethylamine and organic oxidation products.
Background: Alzheimer's disease is a common debilitating dementia with known heritability, for which 20 late onset susceptibility loci have been identified, but more remain to be discovered. This study sought to identify new susceptibility genes, using an alternative gene-wide analytical approach which tests for patterns of association within genes, in the powerful genome-wide association dataset of the International Genomics of Alzheimer's Project Consortium, comprising over 7 m genotypes from 25,580 Alzheimer's cases and 48,466 controls.
Principal findings: In addition to earlier reported genes, we detected genome-wide significant loci on chromosomes 8 (TP53INP1, p = 1.4×10−6) and 14 (IGHV1-67 p = 7.9×10−8) which indexed novel susceptibility loci.
Significance: The additional genes identified in this study, have an array of functions previously implicated in Alzheimer's disease, including aspects of energy metabolism, protein degradation and the immune system and add further weight to these pathways as potential therapeutic targets in Alzheimer's disease.
We present measurements of exclusive ensuremathπ+,0 and η production in pp reactions at 1.25GeV and 2.2GeV beam kinetic energy in hadron and dielectron channels. In the case of π+ and π0 , high-statistics invariant-mass and angular distributions are obtained within the HADES acceptance as well as acceptance-corrected distributions, which are compared to a resonance model. The sensitivity of the data to the yield and production angular distribution of Δ (1232) and higher-lying baryon resonances is shown, and an improved parameterization is proposed. The extracted cross-sections are of special interest in the case of pp → pp η , since controversial data exist at 2.0GeV; we find \ensuremathσ=0.142±0.022 mb. Using the dielectron channels, the π0 and η Dalitz decay signals are reconstructed with yields fully consistent with the hadronic channels. The electron invariant masses and acceptance-corrected helicity angle distributions are found in good agreement with model predictions.
Under certain conditions, secondary organic aerosol (SOA) particles can exist in the atmosphere in an amorphous solid or semi-solid state. To determine their relevance to processes such as ice nucleation or chemistry occurring within particles requires knowledge of the temperature and relative humidity (RH) range for SOA to exist in these states. In the Cosmics Leaving Outdoor Droplets (CLOUD) experiment at The European Organisation for Nuclear Research (CERN), we deployed a new in situ optical method to detect the viscous state of α-pinene SOA particles and measured their transition from the amorphous highly viscous state to states of lower viscosity. The method is based on the depolarising properties of laboratory-produced non-spherical SOA particles and their transformation to non-depolarising spherical particles at relative humidities near the deliquescence point. We found that particles formed and grown in the chamber developed an asymmetric shape through coagulation. A transition to a spherical shape was observed as the RH was increased to between 35 % at −10 °C and 80 % at −38 °C, confirming previous calculations of the viscosity-transition conditions. Consequently, α-pinene SOA particles exist in a viscous state over a wide range of ambient conditions, including the cirrus region of the free troposphere. This has implications for the physical, chemical, and ice-nucleation properties of SOA and SOA-coated particles in the atmosphere.
There are strong indications that particles containing secondary organic aerosol (SOA) exhibit amorphous solid or semi-solid phase states in the atmosphere. This may facilitate heterogeneous ice nucleation and thus influence cloud properties. However, experimental ice nucleation studies of biogenic SOA are scarce. Here, we investigated the ice nucleation ability of viscous SOA particles.
The SOA particles were produced from the ozone initiated oxidation of α-pinene in an aerosol chamber at temperatures in the range from −38 to −10 °C at 5–15 % relative humidity with respect to water to ensure their formation in a highly viscous phase state, i.e. semi-solid or glassy. The ice nucleation ability of SOA particles with different sizes was investigated with a new continuous flow diffusion chamber. For the first time, we observed heterogeneous ice nucleation of viscous α-pinene SOA for ice saturation ratios between 1.3 and 1.4 significantly below the homogeneous freezing limit. The maximum frozen fractions found at temperatures between −39.0 and −37.2 °C ranged from 6 to 20 % and did not depend on the particle surface area. Global modelling of monoterpene SOA particles suggests that viscous biogenic SOA particles are indeed present in regions where cirrus cloud formation takes place. Hence, they could make up an important contribution to the global ice nucleating particle budget.
Background: Although being considered as a rarely observed HIV-1 protease mutation in clinical isolates, the L76V-prevalence increased 1998-2008 in some European countries most likely due to the approval of Lopinavir, Amprenavir and Darunavir which can select L76V. Beside an enhancement of resistance, L76V is also discussed to confer hypersusceptibility to the drugs Atazanavir and Saquinavir which might enable new treatment strategies by trying to take advantage of particular mutations. Results: Based on a cohort of 47 L76V-positive patients, we examined if there might exist a clinical advantage for L76V-positive patients concerning long-term success of PI-containing regimens in patients with limited therapy options. Genotypic- and phenotypic HIV-resistance tests from 47 mostly multi-resistant, L76V-positive patients throughout Germany were accomplished retrospectively 1999-2009. Five genotype-based drug-susceptibility predictions received from online interpretation-tools for Atazanavir, Saquinavir, Amprenavir and Lopinavir, were compared to phenotype-based predictions that were determined by using a recombinant virus assay along with a Virtual Phenotype™(Virco). The clinical outcome of the L76V-adapted follow-up therapy was determined by monitoring viral load for 96 weeks. Conclusions: In this analysis, the mostly used interpretation systems overestimated the L76V-mutation concerning Atazanavir- and SQV resistance. In fact, a clear benefit in drug susceptibility for these drugs was observed in phenotype analysis after establishment of L76V. More importantly, long-term therapy success was significantly higher in patients receiving Atazanavir and/or Saquinavir plus one L76V-selecting drug compared to patients without L76V-selecting agents (p = 0.002). In case of L76V-occurrence ATV and/or SQV may represent encouraging options for patients in deep salvage situations.
Measurement of inclusive charged-particle jet production in Au+Au collisions at √sNN = 200 GeV
(2021)
The STAR Collaboration at the Relativistic Heavy Ion Collider reports the first measurement of inclusive jet production in peripheral and central Au+Au collisions at sNN−−−−√=200 GeV. Jets are reconstructed with the anti-kT algorithm using charged tracks with pseudorapidity |η|<1.0 and transverse momentum 0.2<pchT,jet<30 GeV/c, with jet resolution parameter R=0.2, 0.3, and 0.4. The large background yield uncorrelated with the jet signal is observed to be dominated by statistical phase space, consistent with a previous coincidence measurement. This background is suppressed by requiring a high-transverse-momentum (high-pT) leading hadron in accepted jet candidates. The bias imposed by this requirement is assessed, and the pT region in which the bias is small is identified. Inclusive charged-particle jet distributions are reported in peripheral and central Au+Au collisions for 5<pchT,jet<25 GeV/c and 5<pchT,jet<30 GeV/c, respectively. The charged-particle jet inclusive yield is suppressed for central Au+Au collisions, compared to both the peripheral Au+Au yield from this measurement and to the pp yield calculated using the PYTHIA event generator. The magnitude of the suppression is consistent with that of inclusive hadron production at high pT, and that of semi-inclusive recoil jet yield when expressed in terms of energy loss due to medium-induced energy transport. Comparison of inclusive charged-particle jet yields for different values of R exhibits no significant evidence for medium-induced broadening of the transverse jet profile for R<0.4 in central Au+Au collisions. The measured distributions are consistent with theoretical model calculations that incorporate jet quenching.
Simple Summary: Acute myeloid leukemia (AML) is a genetically heterogeneous disease. Clinical phenotypes of frequent mutations and their impact on patient outcome are well established. However, the role of rare mutations often remains elusive. We retrospectively analyzed 1529 newly diagnosed and intensively treated AML patients for mutations of BCOR and BCORL1. We report a distinct co-mutational pattern that suggests a role in disease progression rather than initiation, especially affecting mechanisms of DNA-methylation. Further, we found loss-of-function mutations of BCOR to be independent markers of poor outcomes in multivariable analysis. Therefore, loss-of-function mutations of BCOR need to be considered for AML management, as they may influence risk stratification and subsequent treatment allocation.
Abstract: Acute myeloid leukemia (AML) is characterized by recurrent genetic events. The BCL6 corepressor (BCOR) and its homolog, the BCL6 corepressor-like 1 (BCORL1), have been reported to be rare but recurrent mutations in AML. Previously, smaller studies have reported conflicting results regarding impacts on outcomes. Here, we retrospectively analyzed a large cohort of 1529 patients with newly diagnosed and intensively treated AML. BCOR and BCORL1 mutations were found in 71 (4.6%) and 53 patients (3.5%), respectively. Frequently co-mutated genes were DNTM3A, TET2 and RUNX1. Mutated BCORL1 and loss-of-function mutations of BCOR were significantly more common in the ELN2017 intermediate-risk group. Patients harboring loss-of-function mutations of BCOR had a significantly reduced median event-free survival (HR = 1.464 (95%-Confidence Interval (CI): 1.005–2.134), p = 0.047), relapse-free survival (HR = 1.904 (95%-CI: 1.163–3.117), p = 0.01), and trend for reduced overall survival (HR = 1.495 (95%-CI: 0.990–2.258), p = 0.056) in multivariable analysis. Our study establishes a novel role for loss-of-function mutations of BCOR regarding risk stratification in AML, which may influence treatment allocation.
Atmospheric aerosols and their effect on clouds are thought to be important for anthropogenic radiative forcing of the climate, yet remain poorly understood1. Globally, around half of cloud condensation nuclei originate from nucleation of atmospheric vapours2. It is thought that sulfuric acid is essential to initiate most particle formation in the atmosphere3,4, and that ions have a relatively minor role5. Some laboratory studies, however, have reported organic particle formation without the intentional addition of sulfuric acid, although contamination could not be excluded6,7. Here we present evidence for the formation of aerosol particles from highly oxidized biogenic vapours in the absence of sulfuric acid in a large chamber under atmospheric conditions. The highly oxygenated molecules (HOMs) are produced by ozonolysis of α-pinene. We find that ions from Galactic cosmic rays increase the nucleation rate by one to two orders of magnitude compared with neutral nucleation. Our experimental findings are supported by quantum chemical calculations of the cluster binding energies of representative HOMs. Ion-induced nucleation of pure organic particles constitutes a potentially widespread source of aerosol particles in terrestrial environments with low sulfuric acid pollution.
1H, 13C, and 15N backbone chemical shift assignments of coronavirus-2 non-structural protein Nsp10
(2020)
The international Covid19-NMR consortium aims at the comprehensive spectroscopic characterization of SARS-CoV-2 RNA elements and proteins and will provide NMR chemical shift assignments of the molecular components of this virus. The SARS-CoV-2 genome encodes approximately 30 different proteins. Four of these proteins are involved in forming the viral envelope or in the packaging of the RNA genome and are therefore called structural proteins. The other proteins fulfill a variety of functions during the viral life cycle and comprise the so-called non-structural proteins (nsps). Here, we report the near-complete NMR resonance assignment for the backbone chemical shifts of the non-structural protein 10 (nsp10). Nsp10 is part of the viral replication-transcription complex (RTC). It aids in synthesizing and modifying the genomic and subgenomic RNAs. Via its interaction with nsp14, it ensures transcriptional fidelity of the RNA-dependent RNA polymerase, and through its stimulation of the methyltransferase activity of nsp16, it aids in synthesizing the RNA cap structures which protect the viral RNAs from being recognized by the innate immune system. Both of these functions can be potentially targeted by drugs. Our data will aid in performing additional NMR-based characterizations, and provide a basis for the identification of possible small molecule ligands interfering with nsp10 exerting its essential role in viral replication.
Background & Aims: In ACLF patients, an adequate risk stratification is essential, especially for liver transplant allocation, since ACLF is associated with high short-term mortality. The CLIF-C ACLF score is the best prognostic model to predict outcome in ACLF patients. While lung failure is generally regarded as signum malum in ICU care, this study aims to evaluate and quantify the role of pulmonary impairment on outcome in ACLF patients.
Methods: In this retrospective study, 498 patients with liver cirrhosis and admission to IMC/ICU were included. ACLF was defined according to EASL-CLIF criteria. Pulmonary impairment was classified into three groups: unimpaired ventilation, need for mechanical ventilation and defined pulmonary failure. These factors were analysed in different cohorts, including a propensity score-matched ACLF cohort.
Results: Mechanical ventilation and pulmonary failure were identified as independent risk factors for increased short-term mortality. In matched ACLF patients, the presence of pulmonary failure showed the highest 28-day mortality (83.7%), whereas mortality rates in ACLF with mechanical ventilation (67.3%) and ACLF without pulmonary impairment (38.8%) were considerably lower (p < .001). Especially in patients with pulmonary impairment, the CLIF-C ACLF score showed poor predictive accuracy. Adjusting the CLIF-C ACLF score for the grade of pulmonary impairment improved the prediction significantly.
Conclusions: This study highlights that not only pulmonary failure but also mechanical ventilation is associated with worse prognosis in ACLF patients. The grade of pulmonary impairment should be considered in the risk assessment in ACLF patients. The new score may be useful in the selection of patients for liver transplantation.
Mapping cortical brain asymmetry in 17,141 healthy individuals worldwide via the ENIGMA Consortium
(2017)
Bipolar disorder (BD) is a genetically complex mental illness characterized by severe oscillations of mood and behavior. Genome-wide association studies (GWAS) have identified several risk loci that together account for a small portion of the heritability. To identify additional risk loci, we performed a two-stage meta-analysis of >9 million genetic variants in 9,784 bipolar disorder patients and 30,471 controls, the largest GWAS of BD to date. In this study, to increase power we used ~2,000 lithium-treated cases with a long-term diagnosis of BD from the Consortium on Lithium Genetics, excess controls, and analytic methods optimized for markers on the Xchromosome. In addition to four known loci, results revealed genome-wide significant associations at two novel loci: an intergenic region on 9p21.3 (rs12553324, p = 5.87×10-9; odds ratio = 1.12) and markers within ERBB2 (rs2517959, p = 4.53×10-9; odds ratio = 1.13). No significant X-chromosome associations were detected and X-linked markers explained very little BD heritability. The results add to a growing list of common autosomal variants involved in BD and illustrate the power of comparing well-characterized cases to an excess of controls in GWAS.
Measurement of inclusive charged-particle jet production in Au + Au collisions at √sNN=200 GeV
(2020)
The STAR Collaboration at the Relativistic Heavy Ion Collider reports the first measurement of inclusive jet production in peripheral and central Au+Au collisions at √𝑠𝑁𝑁=200 GeV. Jets are reconstructed with the anti-𝑘𝑇 algorithm using charged tracks with pseudorapidity |𝜂|<1.0 and transverse momentum 0.2<𝑝ch
𝑇,jet<30 GeV/𝑐, with jet resolution parameter 𝑅=0.2, 0.3, and 0.4. The large background yield uncorrelated with the jet signal is observed to be dominated by statistical phase space, consistent with a previous coincidence measurement. This background is suppressed by requiring a high-transverse-momentum (high-𝑝𝑇) leading hadron in accepted jet candidates. The bias imposed by this requirement is assessed, and the 𝑝𝑇 region in which the bias is small is identified. Inclusive charged-particle jet distributions are reported in peripheral and central Au+Au collisions for 5<𝑝ch
𝑇,jet<25 GeV/𝑐 and 5<𝑝ch
𝑇,jet<30 GeV/𝑐, respectively. The charged-particle jet inclusive yield is suppressed for central Au+Au collisions, compared to both the peripheral Au+Au yield from this measurement and to the 𝑝𝑝 yield calculated using the PYTHIA event generator. The magnitude of the suppression is consistent with that of inclusive hadron production at high 𝑝𝑇 and that of semi-inclusive recoil jet yield when expressed in terms of energy loss due to medium-induced energy transport. Comparison of inclusive charged-particle jet yields for different values of 𝑅 exhibits no significant evidence for medium-induced broadening of the transverse jet profile for 𝑅 <0.4 in central Au+Au collisions. The measured distributions are consistent with theoretical model calculations that incorporate jet quenching.
Background: Care management programmes are an effective approach to care for high risk patients with complex care needs resulting from multiple co-occurring medical and non-medical conditions. These patients are likely to be hospitalized for a potentially "avoidable" cause. Nurse-led care management programmes for high risk elderly patients showed promising results. Care management programmes based on health care assistants (HCAs) targeting adult patients with a high risk of hospitalisation may be an innovative approach to deliver cost-efficient intensified care to patients most in need. Methods: PraCMan is a cluster randomized controlled trial with primary care practices as unit of randomisation. The study evaluates a complex primary care practice-based care management of patients at high risk for future hospitalizations. Eligible patients either suffer from type 2 diabetes mellitus, chronic obstructive pulmonary disease, chronic heart failure or any combination. Patients with a high likelihood of hospitalization within the following 12 months (based on insurance data) will be included in the trial. During 12 months of intervention patients of the care management group receive comprehensive assessment of medical and non-medical needs and resources as well as regular structured monitoring of symptoms. Assessment and monitoring will be performed by trained HCAs from the participating practices. Additionally, patients will receive written information, symptom diaries, action plans and a medication plan to improve self-management capabilities. This intervention is addition to usual care. Patients from the control group receive usual care. Primary outcome is the number of all-cause hospitalizations at 12 months follow-up, assessed by insurance claims data. Secondary outcomes are health-related quality of life (SF12, EQ5D), quality of chronic illness care (PACIC), health care utilisation and costs, medication adherence (MARS), depression status and severity (PHQ-9), self-management capabilities and clinical parameters. Data collection will be performed at baseline, 12 and 24 months (12 months post-intervention). Discussion: Practice-based care management for high risk individuals involving trained HCAs appears to be a promising approach to face the needs of an aging population with increasing care demands. Trial registration: Current Controlled Trials ISRCTN56104508
Background: Complex care management is seen as an approach to face the challenges of an ageing society with increasing numbers of patients with complex care needs. The Medical Research Council in the United Kingdom has proposed a framework for the development and evaluation of complex interventions that will be used to develop and evaluate a primary care-based complex care management program for chronically ill patients at high risk for future hospitalization in Germany. Methods and design: We present a multi-method procedure to develop a complex care management program to implement interventions aimed at reducing potentially avoidable hospitalizations for primary care patients with type 2 diabetes mellitus, chronic obstructive pulmonary disease, or chronic heart failure and a high likelihood of hospitalization. The procedure will start with reflection about underlying precipitating factors of hospitalizations and how they may be targeted by the planned intervention (pre-clinical phase). An intervention model will then be developed (phase I) based on theory, literature, and exploratory studies (phase II). Exploratory studies are planned that entail the recruitment of 200 patients from 10 general practices. Eligible patients will be identified using two ways of 'case finding': software based predictive modelling and physicians' proposal of patients based on clinical experience. The resulting subpopulations will be compared regarding healthcare utilization, care needs and resources using insurance claims data, a patient survey, and chart review. Qualitative studies with healthcare professionals and patients will be undertaken to identify potential barriers and enablers for optimal performance of the complex care management program. Discussion: This multi-method procedure will support the development of a primary care-based care management program enabling the implementation of interventions that will potentially reduce avoidable hospitalizations.
We present the first measurement of fluctuations from event to event in the production of strange particles in collisions of heavy nuclei. The ratio of charged kaons to charged pions is determined for individual central Pb+Pb collisions. After accounting for the fluctuations due to detector resolution and finite number statistics we derive an upper limit on genuine non-statistical fluctuations, perhaps related to a first or second order QCD phase transition. Such fluctuations are shown to be very small.
Access to specialized care is essential for people with Parkinson´s disease (PD). Given the growing number of people with PD and the lack of general practitioners and neurologists, particularly in rural areas in Germany, specialized PD staff (PDS), such as PD nurse specialists and Parkinson Assistants (PASS), will play an increasingly important role in the care of people with PD over the coming years. PDS have several tasks, such as having a role as an educator or adviser for other health professionals or an advocate for people with PD to represent and justify their needs. PD nurse specialists have been established for a long time in the Netherlands, England, the USA, and Scandinavia. In contrast, in Germany, distinct PDS models and projects have been established. However, these projects and models show substantial heterogeneity in terms of access requirements, education, theoretical and practical skills, principal workplace (inpatient vs. outpatient), and reimbursement. This review provides an overview of the existing forms and regional models for PDS in Germany. PDS reimbursement concepts must be established that will foster an implementation throughout Germany. Additionally, development of professional roles in nursing and more specialized care in Germany is needed.
(1) Background: The aim of our study was to identify specific risk factors for fatal outcome in critically ill COVID-19 patients. (2) Methods: Our data set consisted of 840 patients enclosed in the LEOSS registry. Using lasso regression for variable selection, a multifactorial logistic regression model was fitted to the response variable survival. Specific risk factors and their odds ratios were derived. A nomogram was developed as a graphical representation of the model. (3) Results: 14 variables were identified as independent factors contributing to the risk of death for critically ill COVID-19 patients: age (OR 1.08, CI 1.06–1.10), cardiovascular disease (OR 1.64, CI 1.06–2.55), pulmonary disease (OR 1.87, CI 1.16–3.03), baseline Statin treatment (0.54, CI 0.33–0.87), oxygen saturation (unit = 1%, OR 0.94, CI 0.92–0.96), leukocytes (unit 1000/μL, OR 1.04, CI 1.01–1.07), lymphocytes (unit 100/μL, OR 0.96, CI 0.94–0.99), platelets (unit 100,000/μL, OR 0.70, CI 0.62–0.80), procalcitonin (unit ng/mL, OR 1.11, CI 1.05–1.18), kidney failure (OR 1.68, CI 1.05–2.70), congestive heart failure (OR 2.62, CI 1.11–6.21), severe liver failure (OR 4.93, CI 1.94–12.52), and a quick SOFA score of 3 (OR 1.78, CI 1.14–2.78). The nomogram graphically displays the importance of these 14 factors for mortality. (4) Conclusions: There are risk factors that are specific to the subpopulation of critically ill COVID-19 patients.
Gemas Artikel 11 der FFH-Richtlinie ist ein Monitoring des Erhaltungszustandes der Arten von gemeinschaftlicher Bedeutung durchzufuhren. Weiterhin ist nach Artikel 12 eine fortlaufende Überwachung des unbeabsichtigten Fangs oder Tötens der Anhang IV-Tierarten vorgeschrieben, worauf gegebenenfalls weiterführende Erhaltungsmaßnahmen und Forschung aufbauen sollen. Im § 40 BNatSchG wird dieses Monitoring in die Verantwortung der Bundesländer übergeben.
Faunistischer Artenschutz in Waldgebieten : dargestellt für das NSG "Borntal" im Ziegelrodaer Forst
(1999)
Das Naturschutzgebiet (NSG) "Borntal" wurde am 30. März 1961 vom Ministerium für Landwirtschaft, Erfassung und Forstwirtschaft der DDR unter Schutz gestellt. Damit wurde vor allem das Ziel verbunden, einen einmaligen Komplex naturnaher Waldgesellschaften und Standortformen, wie er in derart konzentrierter Ausprägung nirgends sonst im Ziegelrodaer Forst und dessen Umgebung zu finden ist, zu sichern. Analysen zur Bedeutung des Gebietes für die Tierwelt traten hinter diesem Aspekt stets deutlich zurück und spielten vom Zeitpunkt der Ausweisung an (Hentschel et al. 1983) bis heute (Die Naturschutzgebiete …1997) lediglich eine untergeordnete Rolle.
Schutz und Pflege von Zwergstrauchheiden in Sachsen-Anhalt : am Beispiel der "Woltersdorfer Heide"
(2001)
Im Gegensatz zu den "Feuchten Zwergstrauchheiden des nordatlantischen Raumes", welche durch eine Dominanz der Glockenheide (Erica tetralix) geprägt sind und innerhalb Deutschlands ihre Schwerpunktvorkommen im nordwestdeutschen Tiefland besitzen, sind die hier näher betrachteten "Europäischen Trockenen Heiden" (NATURA-2000-Code 4030) vor allem in Nordostdeutschland verbreitet. Die Hauptvorkommen befinden sich im Süden Mecklenburg-Vorpommerns, in Brandenburg sowie im nördlichen und mittleren Sachsen-Anhalt. Sie sind durch das Vorherrschen der Besenheide (Calluna vulgaris) gekennzeichnet, deren Wuchsorte meist durch silikatischen und oberflächlich entkalkten Untergrund sowie schlechte Nährstoff- und Wasserhaushaltsverhältnisse geprägt sind (SSYMANK et al. 1998). In Sachsen-Anhalt sind die großflächigen Heide-Vorkommen in der Regel an glazial-fluviatile Sande gebunden.
Four species of true crocodile (genus Crocodylus) have been described from the Americas. Three of these crocodile species exhibit non-overlapping distributions—Crocodylus intermedius in South America, C. moreletii along the Caribbean coast of Mesoamerica, and C. rhombifer confined to Cuba. The fourth, C. acutus, is narrowly sympatric with each of the other three species. In this study, we sampled 113 crocodiles across Crocodylus populations in Cuba, as well as exemplar populations in Belize and Florida (USA), and sequenced three regions of the mitochondrial genome (D-loop, cytochrome b, cytochrome oxidase I; 3,626 base pair long dataset) that overlapped with published data previously collected from Colombia, Jamaica, and the Cayman Islands. Phylogenetic analyses of these data revealed two, paraphyletic lineages of C. acutus. One lineage, found in the continental Americas, is the sister taxon to C. intermedius, while the Greater Antillean lineage is most closely related to C. rhombifer. In addition to the paraphyly of the two C. acutus lineages, we recovered a 5.4% estimate of Tamura-Nei genetic divergence between the Antillean and continental clades. The reconstructed paraphyly, distinct phylogenetic affinities and high genetic divergence between Antillean and continental C. acutus populations are consistent with interspecific differentiation within the genus and suggest that the current taxon recognized as C. acutus is more likely a complex of cryptic species warranting a reassessment of current taxonomy. Moreover, the inclusion, for the first time, of samples from the western population of the American crocodile in Cuba revealed evidence for continental mtDNA haplotypes in the Antilles, suggesting this area may constitute a transition zone between distinct lineages of C. acutus. Further study using nuclear character data is warranted to more fully characterize this cryptic diversity, resolve taxonomic uncertainty, and inform conservation planning in this system.
The transcriptional regulator far upstream binding protein 1 (FUBP1) is essential for fetal and adult hematopoietic stem cell (HSC) self-renewal, and the constitutive absence of FUBP1 activity during early development leads to embryonic lethality in homozygous mutant mice. To investigate the role of FUBP1 in murine embryonic stem cells (ESCs) and in particular during differentiation into hematopoietic lineages, we generated Fubp1 knockout (KO) ESC clones using CRISPR/Cas9 technology. Although FUBP1 is expressed in undifferentiated ESCs and during spontaneous differentiation following aggregation into embryoid bodies (EBs), absence of FUBP1 did not affect ESC maintenance. Interestingly, we observed a delayed differentiation of FUBP1-deficient ESCs into the mesoderm germ layer, as indicated by impaired expression of several mesoderm markers including Brachyury at an early time point of ESC differentiation upon aggregation to EBs. Coculture experiments with OP9 cells in the presence of erythropoietin revealed a diminished differentiation capacity of Fubp1 KO ESCs into the erythroid lineage. Our data showed that FUBP1 is important for the onset of mesoderm differentiation and maturation of hematopoietic progenitor cells into the erythroid lineage, a finding that is supported by the phenotype of FUBP1-deficient mice.
Improving long-term patient and graft survival after liver transplantation (LT) remains a major challenge. Compared to the early phase after LT, long-term morbidity and mortality of the recipients not only depends on complications immediately related to the graft function, infections, or rejection, but also on medical factors such as de novo malignancies, metabolic disorders (e.g., new-onset diabetes, osteoporosis), psychiatric conditions (e.g., anxiety, depression), renal failure, and cardiovascular diseases. While a comprehensive post-transplant care at the LT center and the connected regional networks may improve outcome, there is currently no generally accepted standard to the post-transplant management of LT recipients in Germany. We therefore described the structure and standards of post-LT care by conducting a survey at 12 German LT centers including transplant hepatologists and surgeons. Aftercare structures and form of cost reimbursement considerably varied between LT centers across Germany. Further discussions and studies are required to define optimal structure and content of post-LT care systems, aiming at improving the long-term outcomes of LT recipients.
The survivin suppressant YM155 is a drug candidate for neuroblastoma. Here, we tested YM155 in 101 neuroblastoma cell lines (19 parental cell lines, 82 drug-adapted sublines). Seventy seven (77) cell lines displayed YM155 IC50s in the range of clinical YM155 concentrations. ABCB1 was an important determinant of YM155 resistance. The activity of the ABCB1 inhibitor zosuquidar ranged from being similar to that of the structurally different ABCB1 inhibitor verapamil to being 65-fold higher. ABCB1 sequence variations may be responsible for this, suggesting that the design of variant-specific ABCB1 inhibitors may be possible. Further, we showed that ABCC1 confers YM155 resistance. Previously, p53 depletion had resulted in decreased YM155 sensitivity. However, TP53-mutant cells were not generally less sensitive to YM155 than TP53 wild-type cells in this study. Finally, YM155 cross-resistance profiles differed between cells adapted to drugs as similar as cisplatin and carboplatin. In conclusion, the large cell line panel was necessary to reveal an unanticipated complexity of the YM155 response in neuroblastoma cell lines with acquired drug resistance. Novel findings include that ABCC1 mediates YM155 resistance and that YM155 cross-resistance profiles differ between cell lines adapted to drugs as similar as cisplatin and carboplatin.
Purpose: To assess the levels of inflammatory and angiogenic cytokines in undiluted vitreous from treatment-naïve patients with macular edema secondary to nonischemic branch retinal vein occlusion (BRVO), with flow cytometric bead array (CBA) and to correlate the results with subjective and multiple spectral-domain optical coherence tomography (SD-OCT) parameters.
Methods: A total of 43 eyes from 43 patients (mean age 69.7 years, 23 male) were divided into groups of new, "fresh" (n = 28; mean duration after onset 4.1 months) and older BRVO (n = 15; 11.6 months). Because of macular edema, these patients underwent an intravitreal therapy combining a single-site 23 g core vitrectomy with bevacizumab and dexamethasone. Undiluted vitreous was then analyzed for interleukin-6 (IL-6), monocyte chemoattractant protein-1 (MCP-1), and vascular endothelial growth factor isoform A (VEGF-A) levels with CBA and correlated with visual acuity (VA), clinical parameters of BRVO (type and perfusion status), and morphologic parameters, such as central macular thickness, central retinal thickness, thickness of the neurosensory retina, thickness of the serous retinal detachment, and the disruption of the ellipsoid line (photoreceptor inner and outer segments) and the external limiting membrane, as measured with SD-OCT. Twenty-eight undiluted vitreous samples from patients with idiopathic, nonuveitis vitreous floaters served as the controls.
Results: The mean IL-6 was 23.2 pg/mL (standard deviation, ±48.8), MCP-1 was 602.6 (±490.3), and VEGF-A was 161.8 (±314.3), and this was higher than in the control group, which had a mean IL-6 of 6.2 ± 3.4 pg/mL (P = 0.17), MCP-1 of 253.2 ± 73.5 (P < 0.0000001), and VEGF-A of 7.0 ± 4.9 (P < 0.003). In all BRVO samples, IL-6 correlated positively with MCP-1 and VEGF-A (correlation coefficient r = 0.79 and r = 0.46, respectively). VEGF-A was the only cytokine to correlate significantly with SD-OCT parameters (thickness of the neurosensory retina r = 0.31; disruption of the ellipsoid line r = 0.33). In the older BRVO group, there was a positive correlation between cytokines (IL-6 with MCP-1, r = 0.77; Il-6 with VEGF-A, r = 0.68; MCP-1 and VEGF-A, r = 0.68), whereas only IL-6 correlated with MCP-1 in the fresh group (r = 0.8).
Conclusion: The inflammatory markers and VEGF-A were elevated in the vitreous fluid of patients with BRVO, and these correlated with one another. VEGF-A was more often correlated with the morphologic changes assessed by SD-OCT, whereas the inflammatory markers had no significant influence on SD-OCT changes.
Autophagy is a core molecular pathway for the preservation of cellular and organismal homeostasis. Pharmacological and genetic interventions impairing autophagy responses promote or aggravate disease in a plethora of experimental models. Consistently, mutations in autophagy-related processes cause severe human pathologies. Here, we review and discuss preclinical data linking autophagy dysfunction to the pathogenesis of major human disorders including cancer as well as cardiovascular, neurodegenerative, metabolic, pulmonary, renal, infectious, musculoskeletal, and ocular disorders.
The bacteriophage ΦX174 causes large pore formation in Escherichia coli and related bacteria. Lysis is mediated by the small membrane-bound toxin ΦX174-E, which is composed of a transmembrane domain and a soluble domain. The toxin requires activation by the bacterial chaperone SlyD and inhibits the cell wall precursor forming enzyme MraY. Bacterial cell wall biosynthesis is an important target for antibiotics; therefore, knowledge of molecular details in the ΦX174-E lysis pathway could help to identify new mechanisms and sites of action. In this study, cell-free expression and nanoparticle technology were combined to avoid toxic effects upon ΦX174-E synthesis, resulting in the efficient production of a functional full-length toxin and engineered derivatives. Pre-assembled nanodiscs were used to study ΦX174-E function in defined lipid environments and to analyze its membrane insertion mechanisms. The conformation of the soluble domain of ΦX174-E was identified as a central trigger for membrane insertion, as well as for the oligomeric assembly of the toxin. Stable complex formation of the soluble domain with SlyD is essential to keep nascent ΦX174-E in a conformation competent for membrane insertion. Once inserted into the membrane, ΦX174-E assembles into high-order complexes via its transmembrane domain and oligomerization depends on the presence of an essential proline residue at position 21. The data presented here support a model where an initial contact of the nascent ΦX174-E transmembrane domain with the peptidyl-prolyl isomerase domain of SlyD is essential to allow a subsequent stable interaction of SlyD with the ΦX174-E soluble domain for the generation of a membrane insertion competent toxin.
Since 2010, an intensified ambulatory cardiology care programme has been implemented in southern Germany. To improve patient management, the structure of cardiac disease management was improved, guideline-recommended care was supported, new ambulatory medical services and a morbidity-adapted reimbursement system were set up. Our aim was to determine the effects of this programme on the mortality and hospitalisation of enrolled patients with cardiac disorders. We conducted a comparative observational study in 2015 and 2016, based on insurance claims data. Overall, 13,404 enrolled patients with chronic heart failure (CHF) and 19,537 with coronary artery disease (CAD) were compared, respectively, to 8,776 and 16,696 patients that were receiving usual ambulatory cardiology care. Compared to the control group, patients enrolled in the programme had lower mortality (Hazard Ratio: 0.84; 95% CI: 0.77–0.91) and fewer all-cause hospitalisations (Rate Ratio: 0.94; 95% CI: 0.90–0.97). CHF-related hospitalisations in patients with CHF were also reduced (Rate Ratio: 0.76; 95% CI: 0.69–0.84). CAD patients showed a similar reduction in mortality rates (Hazard Ratio: 0.81; 95% CI: 0.76–0.88) and all-cause hospitalisation (Rate Ratio: 0.94; 95% CI: 0.91–0.97), but there was no effect on CAD-related hospitalisation. We conclude that intensified ambulatory care reduced mortality and hospitalisation in cardiology patients.
Following votes in the Coniacian Working Group, the Cretaceous Subcommission and the International Commission on Stratigraphy, on May 1st, 2021, the International Union of Geological Sciences voted unanimously to ratify the Global Stratotype Section and Point (GSSP) proposal for the base of the Coniacian Stage of the Upper Cretaceous Series and Cretaceous System. The lower boundary of the Coniacian Stage is placed at the base of Bed 46 of the Salzgitter-Salder section in northern Germany. The boundary is defined by the first appearance of the inoceramid bivalve species Cremnoceramus deformis erectus (Meek) and complemented by the Navigation carbon isotope event. Additional data include the bivalve genus Didymotis, foraminifera, ammonite, nannofossil and organic-walled dinoflagellate cyst events. Three auxiliary sections (Słupia Nadbrzeżna, central Poland; Střeleč, Czech Republic; El Rosario, NE Mexico) supplement the details of the boundary record in various facies, and in differing geographic and biogeographic contexts.
Background: Conversion from calcineurin inhibitor (CNI) therapy to a mammalian target of rapamycin (mTOR) inhibitor following kidney transplantation may help to preserve graft function. Data are sparse, however, concerning the impact of conversion on posttransplant diabetes mellitus (PTDM) or the progression of pre-existing diabetes.
Methods: PTDM and other diabetes-related parameters were assessed post hoc in two large open-label multicenter trials. Kidney transplant recipients were randomized (i) at month 4.5 to switch to everolimus or remain on a standard cyclosporine (CsA)-based regimen (ZEUS, n = 300), or (ii) at month 3 to switch to everolimus, remain on standard CNI therapy or convert to everolimus with reduced-exposure CsA (HERAKLES, n = 497).
Results: There were no significant differences in the incidence of PTDM between treatment groups (log rank p = 0.97 [ZEUS], p = 0.90 [HERAKLES]). The mean change in random blood glucose from randomization to month 12 was also similar between treatment groups in both trials for patients with or without PTDM, and with or without pre-existing diabetes. The change in eGFR from randomization to month 12 showed a benefit for everolimus versus comparator groups in all subpopulations, but only reached significance in larger subgroups (no PTDM or no pre-existing diabetes).
Conclusions: Within the restrictions of this post hoc analysis, including non-standardized diagnostic criteria and limited glycemia laboratory parameters, these data do not indicate any difference in the incidence or severity of PTDM with early conversion from a CsA-based regimen to everolimus, or in the progression of pre-existing diabetes.
Trial registration: clinicaltrials.gov, NCT00154310 (registered September 2005) and NCT00514514 (registered August 2007); EudraCT (2006-007021-32 and 2004-004346-40).
Non-alcoholic fatty liver disease (NAFLD) is gaining in importance and is linked to obesity. Especially,thedevelopmentoffibrosisandportalhypertensioninNAFLDpatientsrequirestreatment. Transgenic TGR(mREN2)27 rats overexpressing mouse renin spontaneously develop NAFLD with portal hypertension but without obesity. This study investigated the additional role of obesity in this model on the development of portal hypertension and fibrosis. Obesity was induced in twelve-week old TGR(mREN2)27 rats after receiving Western diet (WD) for two or four weeks. Liver fibrosis was assessed using standard techniques. Hepatic expression of transforming growth factor-β1 (TGF-β1), collagen type Iα1, α-smooth muscle actin, and the macrophage markers Emr1, as well as the chemoattractant Ccl2, interleukin-1β (IL1β) and tumor necrosis factor-α (TNFα) were analyzed. Assessment of portal and systemic hemodynamics was performed using the colored microsphere technique. Asexpected,WDinducedobesityandliverfibrosisasconfirmedbySiriusRedandOilRed O staining. The expression of the monocyte-macrophage markers, Emr1, Ccl2, IL1β and TNFα were increasedduringfeedingofWD,indicatinginfiltrationofmacrophagesintotheliver,eventhoughthis increase was statistically not significant for the EGF module-containing mucin-like receptor (Emr1) mRNA expression levels. Of note, portal pressure increased with the duration of WD compared to animals that received a normal chow. Besides obesity, WD feeding increased systemic vascular resistance reflecting systemic endothelial and splanchnic vascular dysfunction. We conclude that transgenic TGR(mREN2)27 rats are a suitable model to investigate NAFLD development with liver fibrosis and portal hypertension. Tendency towards elevated expression of Emr1 is associated with macrophage activity point to a significant role of macrophages in NAFLD pathogenesis, probably due to a shift of the renin–angiotensin system towards a higher activation of the classical pathway. The hepatic injury induced by WD in TGR(mREN2)27 rats is suitable to evaluate different stages of fibrosis and portal hypertension in NAFLD with obesity.
Broad AOX expression in a genetically tractable mouse model does not disturb normal physiology
(2017)
Plants and many lower organisms, but not mammals, express alternative oxidases (AOXs) that branch the mitochondrial respiratory chain, transferring electrons directly from ubiquinol to oxygen without proton pumping. Thus, they maintain electron flow under conditions when the classical respiratory chain is impaired, limiting excess production of oxygen radicals and supporting redox and metabolic homeostasis. AOX from Ciona intestinalis has been used to study and mitigate mitochondrial impairments in mammalian cell lines, Drosophila disease models and, most recently, in the mouse, where multiple lentivector-AOX transgenes conferred substantial expression in specific tissues. Here, we describe a genetically tractable mouse model in which Ciona AOX has been targeted to the Rosa26 locus for ubiquitous expression. The AOXRosa26 mouse exhibited only subtle phenotypic effects on respiratory complex formation, oxygen consumption or the global metabolome, and showed an essentially normal physiology. AOX conferred robust resistance to inhibitors of the respiratory chain in organello; moreover, animals exposed to a systemically applied LD50 dose of cyanide did not succumb. The AOXRosa26 mouse is a useful tool to investigate respiratory control mechanisms and to decipher mitochondrial disease aetiology in vivo.
An important question concerning inter-areal communication in the cortex is whether these interactions are synergistic, i.e. convey information beyond what can be performed by isolated signals. In other words, any two signals can either share common information (redundancy) or they can encode complementary information that is only available when both signals are considered together (synergy). Here, we dissociated cortical interactions sharing common information from those encoding complementary information during prediction error processing. To this end, we computed co-information, an information-theoretical measure that distinguishes redundant from synergistic information among brain signals. We analyzed auditory and frontal electrocorticography (ECoG) signals in five common awake marmosets performing two distinct auditory oddball tasks, and investigated to what extent event-related potentials (ERP) and broadband (BB) dynamics exhibit redundancy and synergy for auditory prediction error signals. We observed multiple patterns of redundancy and synergy across the entire cortical hierarchy with distinct dynamics. The information conveyed by ERPs and BB signals was highly synergistic even at lower stages of the hierarchy in the auditory cortex, as well as between lower and higher areas in the frontal cortex. These results indicate that the distributed representations of prediction error signals across the cortical hierarchy can be highly synergistic.