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Multiple myeloma (MM) is the second most common hematologic malignancy, which is characterized by clonal proliferation of neoplastic plasma cells in the bone marrow. This microenvironment is characterized by low oxygen levels (1–6% O2), known as hypoxia. For MM cells, hypoxia is a physiologic feature that has been described to promote an aggressive phenotype and to confer drug resistance. However, studies on hypoxia are scarce and show little conformity. Here, we analyzed the mRNA expression of previously determined hypoxia markers to define the temporal adaptation of MM cells to chronic hypoxia. Subsequent analyses of the global proteome in MM cells and the stromal cell line HS-5 revealed hypoxia-dependent regulation of proteins, which directly or indirectly upregulate glycolysis. In addition, chronic hypoxia led to MM-specific regulation of nine distinct proteins. One of these proteins is the cysteine protease legumain (LGMN), the depletion of which led to a significant growth disadvantage of MM cell lines that is enhanced under hypoxia. Thus, herein, we report a methodologic strategy to examine MM cells under physiologic hypoxic conditions in vitro and to decipher and study previously masked hypoxia-specific therapeutic targets such as the cysteine protease LGMN.
We report a measurement of the observed cross sections of e+ e− → J/ψX based on 3.21 fb − 1 of data accumulated at energies from 3.645 to 3.891 GeV with the BESIII detector operated at the BEPCII collider. In analysis of the cross sections, we measured the decay branching fractions of B(ψ(3686) → J/ψX) = (64.4 ± 0.6 ± 1.6)% and B(ψ(3770) → J/ψX) = (0.5 ± 0.2 ± 0.1)% for the first time. The energy-dependent line shape of these cross sections cannot be well described by two Breit-Wigner (BW) amplitudes of the expected decays ψ (3686) → J/ψX and ψ(3770) → J/ψX. Instead, it can be better described with one more BW amplitude of the decay R(3760)→ J/ψX. Under this assumption, we extracted the R (3760) mass M R (3760 ) = 3766.2 ± 3.8 ± 0.4 MeV/c2, total width Γ tot R ( 3760 ) = 22.2 ± 5.9 ± 1.4 MeV, and product of leptonic width and decay branching fraction
ΓeeR(3760) B[R(3760) → J/ψX] = (79.4 ± 85.5 ± 11.7) eV. The significance of the R(3760) is 5.3σ. The first uncertainties of these measured quantities are from fits to the cross sections and second systematic.
Background: The human ATP-binding cassette, subfamily B, member 11 (ABCB11) gene encodes the bile salt export pump, which is exclusively expressed at the canalicular membrane of hepatocytes. A frequent variant in the coding region, c.1331 T > C, leading to the amino acid exchange p.V444A, has been associated with altered serum bile salt levels in healthy individuals and predisposes homozygous carriers of the [C] allele for obstetric cholestasis. Recently, elevated bile salt levels were shown to be significantly associated with rates and risk of cirrhosis in patients with chronic hepatitis C virus (HCV) infection treated with pegylated interferon-alpha2 and ribavirin, suggesting a potential role for bile salt levels in HCV treatment outcomes and in the fibrogenic evolution of HCV-related liver disease. The aim of this study was to investigate a possible association of ABCB11 c.1331 T > C with hepatitis C virus (HCV) infection and fibrosis stages as assessed by non-invasive transient elastography in a German cohort of patients.
Methods: ABCB11 c.1331 T > C genotype was determined by allelic discrimination assay in 649 HCV infected cases and 413 controls. Overall, 444 cases were staged for fibrotic progression by measurement of liver stiffness.
Results: Homo- or heterozygous presence of the frequent [C] allele was associated with HCV positivity (OR = 1.41, CI = 1.02 - 1.95, p = 0.037). No association was detectable between the ABCB11 c.1331 T > C genotype and increased liver stiffness.
Conclusions: Our data confirm that homozygous presence of the major [C] allele of ABCB11 c.1331 T > C is a genetic susceptibility factor for HCV infection, but not for liver fibrosis.
DNA damage in oocytes induces a switch of the quality control factor TAp63α from dimer to tetramer
(2011)
TAp63a, a homolog of the p53 tumor suppressor, is a quality control factor in the female germline. Remarkably, already undamaged oocytes express high levels of the protein, suggesting that TAp63a’s activity is under tight control of an inhibitory mechanism. Biochemical studies have proposed that inhibition requires the C-terminal transactivation inhibitory domain. However, the structural mechanism of TAp63a inhibition remains unknown. Here, we show that TAp63a is kept in an inactive dimeric state. We reveal that relief of inhibition leads to tetramer formation with ~20-fold higher DNA affinity. In vivo, phosphorylation-triggered tetramerization of TAp63a is not reversible by dephosphorylation. Furthermore, we show that a helix in the oligomerization domain of p63 is crucial for tetramer stabilization and competes with the transactivation domain for the same binding site. Our results demonstrate how TAp63a is inhibited by complex domain-domain interactions that provide the basis for regulating quality control in oocytes.
Using a data sample of e+e− collision data corresponding to an integrated luminosity of 2.93 fb−1 collected with the BESIII detector at a center-of-mass energy of s=3.773GeV, we search for the singly Cabibbo-suppressed decays D0→π0π0π0, π0π0η, π0ηη and ηηη using the double tag method. The absolute branching fractions are measured to be B(D0→π0π0π0)=(2.0±0.4±0.3)×10−4, B(D0→π0π0η)=(3.8±1.1±0.7)×10−4 and B(D0→π0ηη)=(7.3±1.6±1.5)×10−4 with the statistical significances of 4.8σ, 3.8σ and 5.5σ, respectively, where the first uncertainties are statistical and the second ones systematic. No significant signal of D0→ηηη is found, and the upper limit on its decay branching fraction is set to be B(D0→ηηη)<1.3×10−4 at the 90% confidence level.
By analyzing the large-angle Bhabha scattering events e+e− → (γ)e+e− and diphoton events e+e− → (γ)γγ for the data sets collected at center-of-mass (c.m.) energies between 2.2324 and 4.5900 GeV (131 energy points in total) with the upgraded Beijing Spectrometer (BESIII) at the Beijing Electron-Positron Collider (BEPCII), the integrated luminosities have been measured at the different c.m. energies, individually. The results are important inputs for the R value and J/ψ resonance parameter measurements.
Measurement of branching fractions for D meson decaying into ϕ meson and a pseudoscalar meson
(2019)
The four decay modes D0 → φπ0, D0 → φη, D+ → φπ+, and D+ → φK + are studied by using a data sample taken at the centre-of-mass energy √s = 3.773 GeV with the BESIII detector, corresponding to an integrated luminosity of 2.93 fb−1. The branching fractions of the first three decay modes are measured to be B(D0 → φπ0) = (1.168 ± 0.028 ± 0.028) × 10−3, B(D0 → φη) = (1.81 ± 0.46 ± 0.06) × 10−4, and B(D+ → φπ+) = (5.70 ± 0.05 ± 0.13) × 10−3, respectively, where the first uncertainties are statistical and the second are systematic. In addition, the upper limit of the branching fraction for D+ → φK+ is given to be 2.1 × 10−5 at the 90% confidence level. The ratio of B(D0 → φπ0) to B(D+ → φπ+) is calculated to be (20.49 ± 0.50 ± 0.45)%, which is consistent with the theoretical prediction based on isospin symmetry between these two decay modes.
We study the decays of J/ψ and ψ(3686) to the final states Σ(1385)0Σ¯(1385)0 and Ξ0Ξ¯0 based on a single baryon tag method using data samples of (1310.6±7.0)×106 J/ψ and (447.9±2.9)×106 ψ(3686) events collected with the BESIII detector at the BEPCII collider. The decays to Σ(1385)0Σ¯(1385)0 are observed for the first time. The measured branching fractions of J/ψ and ψ(3686)→Ξ0Ξ¯0 are in good agreement with, and much more precise, than the previously published results. The angular parameters for these decays are also measured for the first time. The measured angular decay parameter for J/ψ→Σ(1385)0Σ¯(1385)0, α=−0.64±0.03±0.10, is found to be negative, different to the other decay processes in this measurement. In addition, the "12\% rule" and isospin symmetry in the J/ψ and ψ(3686)→ΞΞ¯ and Σ(1385)Σ¯(1385) systems are tested.
Born cross sections for the processes e+e− → ωη and e+e− → ωπ0 have been determined for centerof-mass energies between 2.00 and 3.08 GeV with the BESIII detector at the BEPCII collider. The results obtained in this work are consistent with previous measurements but with improved precision. Two resonant structures are observed. In the e+e− → ωη cross sections, a resonance with a mass of (2176 ± 24 ± 3) MeV/c2 and a width of (89 ± 50 ± 5) MeV is observed with a significance of 6.2σ. Its properties are consistent with the φ(2170). In the e+e− → ωπ0 cross sections, a resonance denoted Y (2040) is observed with a significance of more than 10σ. Its mass and width are determined to be (2034 ± 13 ± 9) MeV/c2 and (234 ± 30 ± 25) MeV, respectively, where the first uncertainties are statistical and the second ones are systematic.
There has recently been a dramatic renewal of interest in hadron spectroscopy and charm physics. This renaissance has been driven in part by the discovery of a plethora of charmonium-like XYZ states at BESIII and B factories, and the observation of an intriguing proton-antiproton threshold enhancement and the possibly related X(1835) meson state at BESIII, as well as the threshold measurements of charm mesons and charm baryons.
We present a detailed survey of the important topics in tau-charm physics and hadron physics that can be further explored at BESIII during the remaining operation period of BEPCII. This survey will help in the optimization of the data-taking plan over the coming years, and provides physics motivation for the possible upgrade of BEPCII to higher luminosity.
Using 16 energy points of e+e− annihilation data collected in the vicinity of the J/ψ resonance with the BESIII detector and with a total integrated luminosity of around 100 pb−1, we study the relative phase between the strong and electromagnetic amplitudes of J/ψ decays. The relative phase between J/ψ electromagnetic decay and the continuum process (e+e− annihilation without the J/ψ resonance) is confirmed to be zero by studying the cross section lineshape of μ+μ− production. The relative phase between J/ψ strong and electromagnetic decays is then measured to be (84.9 ± 3.6)◦ or (−84.7 ± 3.1)◦ for the 2(π+π−)π0 final state by investigating the interference pattern between the J/ψ decay and the continuum process. This is the first measurement of the relative phase between J/ψ strong and electromagnetic decays into a multihadron final state using the lineshape of the production cross section. We also study the production lineshape of the multihadron final state ηπ+π− with η → π+π−π0, which provides additional information about the phase between the J/ψ electromagnetic decay amplitude and the continuum process. Additionally, the branching fraction of J/ψ → 2(π+π−)π0 is measured to be (4.73 ± 0.44)% or (4.85 ± 0.45)%, and the branching fraction of J/ψ → ηπ+π− is measured to be (3.78 ± 0.68) × 10−4. Both of them are consistent with the world average values. The quoted uncertainties include both statistical and systematic uncertainties, which are mainly caused by the low statistics.
We report the first measurement of the absolute branching fraction for Λ+c→Λμ+νμ. This measurement is based on a sample of e+e− annihilation data at a center-of-mass energy of s√=4.6 GeV collected with the BESIII detector at the BEPCII storage rings. The sample corresponds to an integrated luminosity of 567 pb−1. The branching fraction is determined to be B(Λ+c→Λμ+νμ)=(3.49±0.46(stat)±0.27(syst))%. In addition, we calculate the ratio B(Λ+c→Λμ+νμ)/B(Λ+c→Λe+νe) to be 0.96±0.16(stat)±0.04(syst).
By analyzing 2.93 fb−1 of data taken at the ψ(3770) resonance peak with the BESIII detector, we measure the branching fractions for the hadronic decays D+ → K0S K0S K +, D+ → K0S K0Sπ+, D0 → K0S K0S and D0 → K0S K0S K0S . They are determined to be B(D+ → K0S K0S K +) = (2.54 ± 0.05stat. ± 0.12sys.) × 10−3, B(D+ → K0S K0Sπ+) = (2.70 ± 0.05stat. ± 0.12sys.) × 10−3, B(D0 → K0S K0S ) = (1.67 ± 0.11stat. ± 0.11sys.) × 10−4 and B(D0 → K0S K0S K0S ) = (7.21 ± 0.33stat. ± 0.44sys.) × 10−4, where the second one is measured for the first time and the others are measured with significantly improved precision over the previous measurements.
We report the first observation of the decay Λ+c→Σ−π+π+π0, based on data obtained in e+e− annihilations with an integrated luminosity of 567~pb−1 at s√=4.6~GeV. The data were collected with the BESIII detector at the BEPCII storage rings. The absolute branching fraction B(Λ+c→Σ−π+π+π0) is determined to be (2.11±0.33(stat.)±0.14(syst.))%. In addition, an improved measurement of B(Λ+c→Σ−π+π+) is determined as (1.81±0.17(stat.)±0.09(syst.))%.
The decays of χc2→K+K−π0, KSK±π∓ and π+π−π0 are studied with the ψ(3686) data samples collected with the Beijing Spectrometer (BESIII). For the first time, the branching fractions of χc2→K∗K¯¯¯¯¯, χc2→a±2(1320)π∓/a02(1320)π0 and χc2→ρ(770)±π∓ are measured. Here K∗K¯¯¯¯¯ denotes both K∗±K∓ and K∗0K¯¯¯¯¯0+c.c., and K∗ denotes the resonances K∗(892), K∗2(1430) and K∗3(1780). The observations indicate a strong violation of the helicity selection rule in χc2 decays into vector and pseudoscalar meson pairs. The measured branching fractions of χc2→K∗(892)K¯¯¯¯¯ are more than 10 times larger than the upper limit of χc2→ρ(770)±π∓, which is so far the first direct observation of a significant U-spin symmetry breaking effect in charmonium decays.
We report the first measurements of absolute branching fractions for the W -exchange-only processes + c → 0K + and + c → (1530)0K + with the double-tag technique, by analyzing an e+e− collision data sample, that corresponds to an integrated luminosity of 567 pb−1 collected at a center-of-mass energy of 4.6 GeV by the BESIII detector. The branching fractions are measured to be B(+c → 0K +) = (5.90 ± 0.86 ± 0.39) × 10−3 and B(+c → (1530)0K +) = (5.02 ± 0.99 ± 0.31) × 10−3, where the first uncertainties are statistical and the second systematic. Our results are more precise than the previous relative measurements.
Using data samples collected with the BESIII detector at the BEPCII collider at six center-of-mass energies between 4.008 and 4.600 GeV, we observe the processes e+e− → φφω and e+e− → φφφ. The Born cross sections are measured and the ratio of the cross sections σ(e+e− → φφω)/σ(e+e− → φφφ) is estimated to be 1.75 ± 0.22 ± 0.19 averaged over six energy points, where the first uncertainty is statistical and the second is systematic. The results represent first measurements of these interactions.
The Born cross sections of the e+e− → +¯ − and e+e− → −¯ + processes are determined for centerof-mass energy from 2.3864 to 3.0200 GeV with the BESIII detector. The cross section lineshapes can be described properly by a pQCD function and the resulting ratio of effective form factors for the + and − is consistent with 3. In addition, ratios of the + electric and magnetic form factors, |GE /GM |, are obtained at three center-of-mass energies through an analysis of the angular distributions. These measurements, which are studied for the first time in the off-resonance region, provide precision experimental input for understanding baryonic structure. The observed new features of the ± form factors require more theoretical discussions for the hyperons.
Using a data sample of 448.1 × 106 ψ(3686) events collected with the BESIII detector at the BEPCII collider, we report the first observation of the electromagnetic Dalitz decay ψ(3686) → η e+e−, with significances of 7.0σ and 6.3σ when reconstructing the η meson via its decay modes η → γπ+π− and η → π+π−η (η → γγ ), respectively. The weighted average branching fraction is determined to be B(ψ(3686) → η e+e−) = (1.90 ± 0.25 ± 0.11) × 10−6, where the first uncertainty is statistical and the second systematic.
Measurements of cross section of e⁺e⁻ → pp¯π⁰ at center-of-mass energies between 4.008 and 4.600 GeV
(2017)
Based on e+e− annihilation data samples collected with the BESIII detector at the BEPCII collider at 13 center-of-mass energies from 4.008 to 4.600 GeV, measurements of the Born cross section of e+e− → pp¯π0 are performed. No significant resonant structure is observed in the measured energy dependence of the cross section. The upper limit on the Born cross section of e+e− → Y (4260) → pp¯π0 at the 90% C.L. is determined to be 0.01 pb. The upper limit on the ratio of the branching fractions B(Y (4260)→pp¯π0) B(Y (4260)→π+π− J/ψ) at the 90% C.L. is determined to be 0.02%.
The decays of χc2→K+K−π0, KSK±π∓ and π+π−π0 are studied with the ψ(3686) data samples collected with the Beijing Spectrometer (BESIII). For the first time, the branching fractions of χc2→K∗K¯¯¯¯¯, χc2→a±2(1320)π∓/a02(1320)π0 and χc2→ρ(770)±π∓ are measured. Here K∗K¯¯¯¯¯ denotes both K∗±K∓ and K∗0K¯¯¯¯¯0+c.c., and K∗ denotes the resonances K∗(892), K∗2(1430) and K∗3(1780). The observations indicate a strong violation of the helicity selection rule in χc2 decays into vector and pseudoscalar meson pairs. The measured branching fractions of χc2→K∗(892)K¯¯¯¯¯ are more than 20 times larger than that of χc2→ρ(770)±π∓, which implies the effects are largely due to U-spin symmetry breaking, rather than just isospin symmetry breaking in charmonium decays.
The decays of χc2→K+K−π0, KSK±π∓ and π+π−π0 are studied with the ψ(3686) data samples collected with the Beijing Spectrometer (BESIII). For the first time, the branching fractions of χc2→K∗K¯¯¯¯¯, χc2→a±2(1320)π∓/a02(1320)π0 and χc2→ρ(770)±π∓ are measured. Here K∗K¯¯¯¯¯ denotes both K∗±K∓ and K∗0K¯¯¯¯¯0+c.c., and K∗ denotes the resonances K∗(892), K∗2(1430) and K∗3(1780). The observations indicate a strong violation of the helicity selection rule in χc2 decays into vector and pseudoscalar meson pairs. The measured branching fractions of χc2→K∗(892)K¯¯¯¯¯ are more than 20 times larger than that of χc2→ρ(770)±π∓, which implies the effects are largely due to U-spin symmetry breaking, rather than just isospin symmetry breaking in charmonium decays.
Measurement of the e+e−→π+π− cross section between 600 and 900 MeV using initial state radiation
(2016)
We extract the e+e− →π+π− cross section in the energy range between 600 and 900 MeV, exploiting the method of initial state radiation. A data set with an integrated luminosity of 2.93 fb−1 taken at a center-of-mass energy of 3.773 GeV with the BESIII detector at the BEPCII collider is used. The cross section is measured with a systematic uncertainty of 0.9%. We extract the pion form factor |Fπ|2 as well as the contribution of the measured cross section to the leading-order hadronic vacuum polarization contribution to (g−2)μ. We find this value to be aππ,LO μ (600–900 MeV) = (368.2 ±2.5stat±3.3sys) ·10−10, which is between the corresponding values using the BaBar or KLOE data.
The decays of χc2→K+K−π0, KSK±π∓ and π+π−π0 are studied with the ψ(3686) data samples collected with the Beijing Spectrometer (BESIII). For the first time, the branching fractions of χc2→K∗K¯¯¯¯¯, χc2→a±2(1320)π∓/a02(1320)π0 and χc2→ρ(770)±π∓ are measured. Here K∗K¯¯¯¯¯ denotes both K∗±K∓ and K∗0K¯¯¯¯¯0+c.c., and K∗ denotes the resonances K∗(892), K∗2(1430) and K∗3(1780). The observations indicate a strong violation of the helicity selection rule in χc2 decays into vector and pseudoscalar meson pairs. The measured branching fractions of χc2→K∗(892)K¯¯¯¯¯ are more than 10 times larger than the upper limit of χc2→ρ(770)±π∓, which is so far the first direct observation of a significant U-spin symmetry breaking effect in charmonium decays.
Using an 𝑒+𝑒− collision data sample of 2.93 fb−1 collected at a center-of-mass energy of 3.773 GeV by the BESIII detector at BEPCII, we report the observation of 𝐷0→𝑎0(980)−𝑒+𝜈𝑒 and evidence for 𝐷+→𝑎0(980)0𝑒+𝜈𝑒 with significances of 6.4𝜎 and 2.9𝜎, respectively. The absolute branching fractions are determined to be ℬ(𝐷0→𝑎0(980)−𝑒+𝜈𝑒)×ℬ(𝑎0(980)−→𝜂𝜋−) = [1.33+0.33−0.29(stat)±0.09(syst)]×10−4 and ℬ(𝐷+→𝑎0(980)0𝑒+𝜈𝑒)×ℬ(𝑎0(980)0→𝜂𝜋0)=[1.66+0.81
−0.66(stat)±0.11(syst)]×10−4. This is the first time the 𝑎0(980) meson has been measured in a 𝐷0 semileptonic decay, which would open one more interesting page in the investigation of the nature of the puzzling 𝑎0(980) states.
The cross section of the process e+e−→K+K− is measured at a number of center-of-mass energies s√ from 2.00 to 3.08 GeV with the BESIII detector at the Beijing Electron Positron Collider (BEPCII). The results provide the best precision achieved so far. A resonant structure around 2.2 GeV is observed in the cross section line shape. A Breit-Wigner fit yields a mass of M=2239.2±7.1±11.3~and a width of Γ=139.8±12.3±20.6 MeV, where the first uncertainties are statistical and the second ones are systematic. In addition, the time-like electromagnetic form factor of the kaon is determined at the individual center-of-mass energy points.
Search for the reaction channel e⁺e⁻ → ηcηπ⁺π⁻ at center-of-mass energies from 4.23 to 4.60 GeV
(2021)
Using data collected with the BESIII detector operating at the Beijing Electron Positron Collider, we search for the process 𝑒+𝑒−→𝜂𝑐𝜂𝜋+𝜋−. The search is performed using five large datasets recorded at center-of-mass energies of 4.23, 4.26, 4.36, 4.42, and 4.60 GeV. The 𝜂𝑐 meson is reconstructed in 16 exclusive decay modes. No signal is observed in the 𝜂𝑐 mass region at any center-of-mass energy. The upper limits on the reaction cross sections are determined to be 6.2, 10.8, 27.6, 22.6 and 23.7 pb at the 90% confidence level at the center-of-mass energies listed above.
Using a sample of 106 million 𝜓(3686) decays, 𝜓(3686)→𝛾𝜒𝑐𝐽(𝐽=0,1,2) and 𝜓(3686)→𝛾𝜒𝑐𝐽,𝜒𝑐𝐽→𝛾𝐽/𝜓(𝐽=1,2) events are utilized to study inclusive 𝜒𝑐𝐽→anything, 𝜒𝑐𝐽→hadrons, and 𝐽/𝜓→anything distributions, including distributions of the number of charged tracks, electromagnetic calorimeter showers, and 𝜋0s, and to compare them with distributions obtained from the BESIII Monte Carlo simulation. Information from each Monte Carlo simulated decay event is used to construct matrices connecting the detected distributions to the input predetection “produced” distributions. Assuming these matrices also apply to data, they are used to predict the analogous produced distributions of the decay events. Using these, the charged particle multiplicities are compared with results from MARK I. Further, comparison of the distributions of the number of photons in data with those in Monte Carlo simulation indicates that G-parity conservation should be taken into consideration in the simulation.
The process 𝑒+𝑒−→𝜙𝜂′ has been studied for the first time in detail using data sample collected with the BESIII detector at the BEPCII collider at center of mass energies from 2.05 to 3.08 GeV. A resonance with quantum numbers 𝐽𝑃𝐶=1−− is observed with mass 𝑀=(2177.5±4.8(stat)±19.5(syst))MeV/𝑐2 and width Γ=(149.0±15.6(stat)±8.9(syst)) MeV with a statistical significance larger than 10𝜎, including systematic uncertainties. If the observed structure is identified with the 𝜙(2170), then the ratio of partial width between the 𝜙𝜂′ by BESIII and 𝜙𝜂 by BABAR is (ℬ𝑅𝜙𝜂Γ𝑅𝑒𝑒)/(ℬ𝑅𝜙𝜂′Γ𝑅𝑒𝑒)=0.23±0.10(stat)±0.18(syst), which is smaller than the prediction of the 𝑠¯𝑠𝑔 hybrid models by several orders of magnitude.
Using a 3.19 fb−1 data sample collected at an 𝑒+𝑒− center-of-mass energy of 𝐸cm=4.178 GeV with the BESIII detector, we measure the branching fraction of the leptonic decay 𝐷+𝑠→𝜇+𝜈𝜇 to be ℬ𝐷+𝑠→𝜇+𝜈𝜇=(5.49±0.16stat±0.15syst)×10−3. Combining our branching fraction with the masses of the 𝐷+𝑠 and 𝜇+ and the lifetime of the 𝐷+𝑠, we determine 𝑓𝐷+𝑠|𝑉𝑐𝑠|=246.2±3.6stat±3.5syst MeV. Using the 𝑐→𝑠 quark mixing matrix element |𝑉𝑐𝑠| determined from a global standard model fit, we evaluate the 𝐷+𝑠 decay constant 𝑓𝐷+𝑠=252.9±3.7stat±3.6syst MeV. Alternatively, using the value of 𝑓𝐷+𝑠 calculated by lattice quantum chromodynamics, we find |𝑉𝑐𝑠|=0.985±0.014stat±0.014syst. These values of ℬ𝐷+𝑠→𝜇+𝜈𝜇, 𝑓𝐷+𝑠|𝑉𝑐𝑠|, 𝑓𝐷+𝑠 and |𝑉𝑐𝑠| are each the most precise results to date.
Using a data sample of 448.1×106 𝜓(3686) events collected at √𝑠=3.686 GeV with the BESIII detector at the Beijing Electron-Positron Collider II, we search for the rare decay 𝐽/𝜓→𝜙𝑒+𝑒− via 𝜓(3686)→𝜋+𝜋−𝐽/𝜓. No signal events are observed and the upper limit on the branching fraction is set to be ℬ(𝐽/𝜓→𝜙𝑒+𝑒−)<1.2×10−7 at the 90% confidence level, which is still about one order of magnitude higher than the Standard Model prediction.
he process e+e−→pK0Sn¯K−+c.c. and its intermediate processes are studied for the first time, using data samples collected with the BESIII detector at BEPCII at center-of-mass energies of 3.773, 4.008, 4.226, 4.258, 4.358, 4.416, and 4.600 GeV, with a total integrated luminosity of 7.4 fb−1. The Born cross section of e+e−→pK0Sn¯K−+c.c. is measured at each center-of-mass energy, but no significant resonant structure in the measured cross-section line shape between 3.773 and 4.600 GeV is observed. No evident structure is detected in the pK−, nK0S, pK0S, nK+, pn¯, or K0SK− invariant mass distributions except for Λ(1520). The Born cross sections of e+e−→Λ(1520)n¯K0S+c.c. and e+e−→Λ(1520)p¯K++c.c. are measured, and the 90\% confidence level upper limits on the Born cross sections of e+e−→Λ(1520)Λ¯(1520) are determined at the seven center-of-mass energies.
Measurement of cross sections for e⁺e⁻ → μ⁺μ⁻ at center-of-mass energies from 3.80 to 4.60 GeV
(2020)
The observed cross sections for 𝑒+𝑒−→𝜇+𝜇− at energies from 3.8 to 4.6 GeV are measured using data samples taken with the BESIII detector operated at the BEPCII collider. We measure the muonic widths and determine the branching fractions of the charmonium states 𝜓(4040), 𝜓(4160), and 𝜓(4415) decaying to 𝜇+𝜇−, as well as making a first determination of the phase of the amplitudes. In addition, we observe evidence for a structure in the dimuon cross section near 4.220 GeV/𝑐2, which we denote as 𝑆(4220). Analyzing a coherent sum of amplitudes yields eight solutions, one of which gives a mass of 𝑀𝑆(4220) = 4216.7±8.9±4.1 MeV/𝑐2, a total width of Γtot S(4220) = 47.2±22.8±10.5 MeV, and a muonic width of Γ𝜇𝜇 𝑆(4220) = 1.53±1.26±0.54 keV, where the first uncertainties are statistical and the second systematic. The eight solutions give the central values of the mass, total width, muonic width to be, respectively, in the range from 4212.8 to 4219.4 MeV/𝑐2, from 36.4 to 49.6 MeV, and from 1.09 to 1.53 keV. The statistical significance of the 𝑆(4220) signal is 3.9𝜎. Correcting the total dimuon cross section for radiative effects yields a statistical significance for this structure of 8.1𝜎.
An amplitude analysis of the 𝐾𝑆𝐾𝑆 system produced in radiative 𝐽/𝜓 decays is performed using the (1310.6±7.0)×106 𝐽/𝜓 decays collected by the BESIII detector. Two approaches are presented. A mass-dependent analysis is performed by parametrizing the 𝐾𝑆𝐾𝑆 invariant mass spectrum as a sum of Breit-Wigner line shapes. Additionally, a mass-independent analysis is performed to extract a piecewise function that describes the dynamics of the 𝐾𝑆𝐾𝑆 system while making minimal assumptions about the properties and number of poles in the amplitude. The dominant amplitudes in the mass-dependent analysis include the 𝑓0(1710), 𝑓0(2200), and 𝑓′2(1525). The mass-independent results, which are made available as input for further studies, are consistent with those of the mass-dependent analysis and are useful for a systematic study of hadronic interactions. The branching fraction of radiative 𝐽/𝜓 decays to 𝐾𝑆𝐾𝑆 is measured to be (8.1±0.4)×10−4, where the uncertainty is systematic and the statistical uncertainty is negligible.
We report new measurements of the cross sections for the production of Dbar D final states at the ψ(3770) resonance. Our data sample consists of an integrated luminosity of 2.93 fb−1 of e+e− annihilation data produced by the BEPCII collider and collected and analyzed with the BESIII detector. We exclusively reconstruct three D0 and six D+ hadronic decay modes and use the ratio of the yield of fully reconstructed Dbar D events ("double tags") to the yield of all reconstructed D or bar D mesons ("single tags") to determine the number of D0bar D0 and D+D− events, benefiting from the cancellation of many systematic uncertainties. Combining these yields with an independent determination of the integrated luminosity of the data sample, we find the cross sections to be σ(e+e− → D0bar D0) nb and σ(e+e− → D+D−) = (2.830 ± 0.011 ± 0.026) nb, where the uncertainties are statistical and systematic, respectively.
We study the hadronic decays of Λ+c to the final states Σ+η and Σ+η′, using an e+e− annihilation data sample of 567 pb−1 taken at a center-of-mass energy of 4.6 GeV with the BESIII detector at the BEPCII collider. We find evidence for the decays Λ+c→Σ+η and Σ+η′ with statistical significance of 2.5σ and 3.2σ, respectively. Normalizing to the reference decays Λ+c→Σ+π0 and Σ+ω, we obtain the ratios of the branching fractions B(Λ+c→Σ+η)B(Λ+c→Σ+π0) and B(Λ+c→Σ+η′)B(Λ+c→Σ+ω) to be 0.35±0.16±0.03 and 0.86±0.34±0.07, respectively. The upper limits at the 90\% confidence level are set to be B(Λ+c→Σ+η)B(Λ+c→Σ+π0)<0.58 and B(Λ+c→Σ+η′)B(Λ+c→Σ+ω)<1.2. Using BESIII measurements of the branching fractions of the reference decays, we determine B(Λ+c→Σ+η)=(0.41±0.19±0.05)% (<0.68%) and B(Λ+c→Σ+η′)=(1.34±0.53±0.21)% (<1.9%). Here, the first uncertainties are statistical and the second systematic. The obtained branching fraction of Λ+c→Σ+η is consistent with the previous measurement, and the branching fraction of Λ+c→Σ+η′ is measured for the first time.
We study the electromagnetic Dalitz decay 𝐽/𝜓→𝑒+𝑒−𝜂 and search for dielectron decays of a dark gauge boson (𝛾′) in 𝐽/𝜓→𝛾′𝜂 with the two 𝜂 decay modes 𝜂→𝛾𝛾 and 𝜂→𝜋+𝜋−𝜋0 using (1310.6±7.0)×106 𝐽/𝜓 events collected with the BESIII detector. The branching fraction of 𝐽/𝜓→𝑒+𝑒−𝜂 is measured to be (1.43±0.04(stat)±0.06(syst))×10−5, with a precision that is improved by a factor of 1.5 over the previous BESIII measurement. The corresponding dielectron invariant mass dependent modulus square of the transition form factor is explored for the first time, and the pole mass is determined to be Λ=2.84±0.11(stat)±0.08(syst) GeV/𝑐2. We find no evidence of 𝛾′ production and set 90% confidence level upper limits on the product branching fraction ℬ(𝐽/𝜓→𝛾′𝜂)×ℬ(𝛾′→𝑒+𝑒−) as well as the kinetic mixing strength between the standard model photon and 𝛾′ in the mass range of 0.01≤𝑚𝛾′≤2.4 GeV/𝑐2.
Using a sample of 4.48×108 ψ(3686) events collected with the BESIII detector at the BEPCII collider, we study the two-photon decays of the pseudoscalar mesons π0, η, η′, η(1405), η(1475), η(1760), and X(1835) in J/ψ radiative decays using ψ(3686)→π+π−J/ψ events. The π0, η and η′ mesons are clearly observed in the two-photon mass spectra, and the branching fractions are determined to be B(J/ψ→γπ0→3γ)=(3.57±0.12±0.16)×10−5, B(J/ψ→γη→3γ)=(4.42±0.04±0.18)×10−4, and B(J/ψ→γη′→3γ)=(1.26±0.02±0.05)×10−4, where the first errors are statistical and the second systematic. No clear signal for η(1405), η(1475), η(1760) or X(1835) is observed in the two-photon mass spectra, and upper limits at the 90% confidence level on the product branching fractions are obtained.
Using a data sample of 448.1×106 ψ(3686) events collected at s√= 3.686 GeV with the BESIII detector at the BEPCII, we search for the rare decay J/ψ→ϕe+e− via ψ(3686)→π+π−J/ψ. No signal events are observed and the upper limit on the branching fraction is set to be B(J/ψ→ϕe+e−)<1.2×10−7 at the 90\% confidence level, which is still about one order of magnitude higher than the Standard Model prediction.
We report on new measurements of Cabibbo-suppressed semileptonic D+s decays using 3.19 fb−1 of e+e− annihilation data sample collected at a center-of-mass energy of 4.178~GeV with the BESIII detector at the BEPCII collider. Our results include branching fractions B(D+s→K0e+νe)=(3.25±0.38(stat.)±0.16(syst.))×10−3 and B(D+s→K∗0e+νe)=(2.37±0.26(stat.)±0.20(syst.))×10−3 which are much improved relative to previous measurements, and the first measurements of the hadronic form-factor parameters for these decays. For D+s→K0e+νe, we obtain f+(0)=0.720±0.084(stat.)±0.013(syst.), and for D+s→K∗0e+νe, we find form-factor ratios rV=V(0)/A1(0)=1.67±0.34(stat.)±0.16(syst.) and r2=A2(0)/A1(0)=0.77±0.28(stat.)±0.07(syst.).
Using a data sample with an integrated luminosity of 2.93 fb−1 taken at the center-of-mass energy of 3.773 GeV, we search for the Majorana neutrino (𝜈𝑚) in the lepton number violating decays 𝐷→𝐾𝜋𝑒+𝑒+. No significant signal is observed, and the upper limits on the branching fraction at the 90% confidence level are set to be ℬ(𝐷0→𝐾−𝜋−𝑒+𝑒+)<2.8×10−6, ℬ(𝐷+→𝐾0𝑆𝜋−𝑒+𝑒+)<3.3×10−6 and ℬ(𝐷+→𝐾−𝜋0𝑒+𝑒+)<8.5×10−6. The Majorana neutrino is searched for with different mass assumptions ranging from 0.25 to 1.0 GeV/𝑐2 in the decays 𝐷0→𝐾−𝑒+𝜈𝑚,𝜈𝑚→𝜋−𝑒+ and 𝐷+→𝐾0𝑆𝑒+𝜈𝑚,𝜈𝑚→𝜋−𝑒+, and the upper limits on the branching fraction at the 90% confidence level are at the level of 10−7∼10−6, depending on the mass of the Majorana neutrino. The constraints on the mixing matrix element |𝑉𝑒𝜈𝑚|2 are also evaluated.
Using a low background data sample of 9.7×105 𝐽/𝜓→𝛾𝜂′, 𝜂′→𝛾𝜋+𝜋− events, which are 2 orders of magnitude larger than those from the previous experiments, recorded with the BESIII detector at BEPCII, the decay dynamics of 𝜂′→𝛾𝜋+𝜋− are studied with both model-dependent and model-independent approaches. The contributions of 𝜔 and the 𝜌(770)−𝜔 interference are observed for the first time in the decays 𝜂′→𝛾𝜋+𝜋− in both approaches. Additionally, a contribution from the box anomaly or the 𝜌(1450) resonance is required in the model-dependent approach, while the process specific part of the decay amplitude is determined in the model-independent approach.
We report the first observation of the semimuonic decay 𝐷+→𝜔𝜇+𝜈𝜇 using an 𝑒+𝑒− collision data sample corresponding to an integrated luminosity of 2.93 fb−1 collected with the BESIII detector at a center-of-mass energy of 3.773 GeV. The absolute branching fraction of the 𝐷+→𝜔𝜇+𝜈𝜇 decay is measured to be ℬ𝐷+→𝜔𝜇+𝜈𝜇=(17.7±1.8stat±1.1syst)×10−4. Its ratio with the world average value of the branching fraction of the 𝐷+→𝜔𝑒+𝜈𝑒 decay probes lepton flavor universality and it is determined to be ℬ𝐷+→𝜔𝜇+𝜈𝜇/ℬPDG 𝐷+→𝜔𝑒+𝜈𝑒=1.05±0.14, in agreement with the standard model expectation within one standard deviation.
A partial-wave analysis of the decay 𝐽/𝜓→𝐾+𝐾−𝜋0 has been made using (223.7±1.4)×106 𝐽/𝜓 events collected with the BESIII detector in 2009. The analysis, which is performed within the isobar-model approach, reveals contributions from 𝐾*2(1430)±, 𝐾*2(1980)± and 𝐾*4(2045)± decaying to 𝐾±𝜋0. The two latter states are observed in 𝐽/𝜓 decays for the first time. Two resonance signals decaying to 𝐾+𝐾− are also observed. These contributions cannot be reliably identified and their possible interpretations are discussed. The measured branching fraction 𝐵(𝐽/𝜓→𝐾+𝐾−𝜋0) of (2.88±0.01±0.12)×10−3 is more precise than previous results. Branching fractions for the reported contributions are presented as well. The results of the partial-wave analysis differ significantly from those previously obtained by BESII and BABAR.
Based on an 𝑒+𝑒− collision data sample corresponding to an integrated luminosity of 567 pb−1 taken at the center-of-mass energy of √𝑠=4.6 GeV with the BESIII detector, we measure the absolute branching fraction of the inclusive decay Λ+𝑐→Λ+𝑋 to be ℬ(Λ+𝑐→Λ+𝑋)=(38.2+2.8−2.2±0.9)% using the double-tag method, where 𝑋 refers to any possible final state particles. In addition, we search for direct 𝐶𝑃 violation in the charge asymmetry of this inclusive decay for the first time, and obtain 𝒜𝐶𝑃≡[ℬ(Λ+𝑐→Λ+𝑋)−ℬ(¯Λ−𝑐 → ¯Λ+𝑋)]/[ℬ(Λ+𝑐→Λ+𝑋)+ℬ(¯Λ−𝑐 → ¯Λ+𝑋)]=(2.1+7.0−6.6±1.6)%, a statistically limited result with no evidence of 𝐶𝑃 violation.
The decay 𝐽/𝜓→𝛾𝛾𝜙 is studied using a sample of 1.31×109 𝐽/𝜓 events collected with the BESIII detector. Two structures around 1475 MeV/𝑐2 and 1835 MeV/𝑐2 are observed in the 𝛾𝜙 invariant mass spectrum for the first time. With a fit on the 𝛾𝜙 invariant mass, which takes into account the interference between the two structures, and a simple analysis of the angular distribution, the structure around 1475 MeV/𝑐2 is found to favor an assignment as the 𝜂(1475) and the mass and width for the structure around 1835 MeV/𝑐2 are consistent with the 𝑋(1835). The statistical significances of the two structures are 13.5𝜎 and 6.3𝜎, respectively. The results indicate that both 𝜂(1475) and 𝑋(1835) contain a sizeable 𝑠¯𝑠 component.
Using a data sample of 𝑒+𝑒− collisions corresponding to an integrated luminosity of 567 pb−1 collected at a center-of-mass energy of √𝑠=4.6 GeV with the BESIII detector, we measure the absolute branching fraction of the inclusive semileptonic Λ+𝑐 decay with a double-tag method. We obtain ℬ(Λ+𝑐→𝑋𝑒+𝜈𝑒)=(3.95±0.34±0.09)%, where the first uncertainty is statistical and the second systematic. Using the known Λ+𝑐 lifetime and the charge-averaged semileptonic decay width of nonstrange charmed mesons (𝐷0 and 𝐷+), we obtain the ratio of the inclusive semileptonic decay widths Γ(Λ+𝑐→𝑋𝑒+𝜈𝑒)/¯Γ(𝐷→𝑋𝑒+𝜈𝑒)=1.26±0.12.
Using a data sample of 448.1×106 𝜓(3686) events collected with the BESIII detector operating at the BEPCII, we perform search for the hadronic transition ℎ𝑐→𝜋+𝜋−𝐽/𝜓 via 𝜓(3686)→𝜋0ℎ𝑐. No signals of the transition are observed, and the upper limit on the product branching fraction ℬ(𝜓(3686)→𝜋0ℎ𝑐)ℬ(ℎ𝑐→𝜋+𝜋−𝐽/𝜓) at the 90% confidence level (C.L.) is determined to be 2.0×10−6. This is the most stringent upper limit to date.
We measure the Born cross sections of the process 𝑒+𝑒−→𝐾+𝐾−𝐾+𝐾− at center-of-mass (c.m.) energies, √𝑠, between 2.100 and 3.080 GeV. The data were collected using the BESIII detector at the BEPCII collider. An enhancement at √𝑠=2.232 GeV is observed, very close to the 𝑒+𝑒−→Λ¯Λ production threshold. A similar enhancement at the same c.m. energy is observed in the 𝑒+𝑒−→𝜙𝐾+𝐾− cross section. The energy dependence of the 𝐾+𝐾−𝐾+𝐾− and 𝜙𝐾+𝐾− cross sections differs significantly from that of 𝑒+𝑒−→𝜙𝜋+𝜋−.
Using 𝑒+𝑒−→Λ+𝑐¯Λ−𝑐 production from a 567 pb−1 data sample collected by BESIII at 4.6 GeV, a full angular analysis is carried out simultaneously on the four decay modes of Λ+𝑐→𝑝𝐾0𝑆, Λ𝜋+, Σ+𝜋0, and Σ0𝜋+. For the first time, the Λ+𝑐 transverse polarization is studied in unpolarized 𝑒+𝑒− collisions, where a nonzero effect is observed with a statistical significance of 2.1𝜎. The decay asymmetry parameters of the Λ+𝑐 weak hadronic decays into 𝑝𝐾0𝑆, Λ𝜋+, Σ+𝜋0 and Σ0𝜋+ are measured to be 0.18±0.43(stat)±0.14(syst), −0.80±0.11(stat)±0.02(syst), −0.57±0.10(stat)±0.07(syst), and −0.73±0.17(stat)±0.07(syst), respectively. In comparison with previous results, the measurements for the Λ𝜋+ and Σ+𝜋0 modes are consistent but with improved precision, while the parameters for the 𝑝𝐾0𝑆 and Σ0𝜋+ modes are measured for the first time.
Delayed wound repair in sepsis is associated with reduced local pro-inflammatory cytokine expression
(2013)
Sepsis is one of the main causes for morbidity and mortality in hospitalized patients. Moreover, sepsis associated complications involving impaired wound healing are common. Septic patients often require surgical interventions that in-turn may lead to further complications caused by impaired wound healing. We established a mouse model to the study delayed wound healing during sepsis distant to the septic focus point. For this reason cecal ligation and puncture (CLP) was combined with the creation of a superficial wound on the mouse ear. Control animals received the same procedure without CPL. Epithelialization was measured every second day by direct microscopic visualization up to complete closure of the wound. As interplay of TNF-α, TGF-β, matrix metalloproteinases (MMP), and tissue inhibitors of metalloproteinases (TIMP) is important in wound healing in general, TNF-α, TGF-β, MMP7, and TIMP1 were assessed immunohistochemical in samples of wounded ears harvested on days 2, 6, 10 and 16 after wounding. After induction of sepsis, animals showed a significant delay in wound epithelialization from day 2 to 12 compared to control animals. Complete wound healing was attained after mean 12.2± standard deviation (SD) 3.0 days in septic animals compared to 8.7± SD 1.7 days in the control group. Septic animals showed a significant reduction in local pro-inflammatory cytokine level of TNF-α on day 2 and day 6 as well as a reduced expression of TGF-β on day 2 in wounds. A significant lower expression of MMP7 as well as TIMP1 was also observed on day 2 after wounding. The induction of sepsis impairs wound healing distant to the septic focus point. We could demonstrate that expression of important cytokines for wound repair is deregulated after induction of sepsis. Thus restoring normal cytokine response locally in wounds could be a good strategy to enhance wound repair in sepsis.
Myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) are clonal hematopoietic stem cell diseases leading to an insufficient formation of functional blood cells. Disease-immanent factors as insufficient erythropoiesis and treatment-related factors as recurrent treatment with red blood cell transfusions frequently lead to systemic iron overload in MDS and AML patients. In addition, alterations of function and expression of proteins associated with iron metabolism might are increasingly recognized to be pathogenetic factors and potential vulnerabilities of these diseases. Iron is known to be involved in multiple intracellular and extracellular processes. It is essential for cell metabolism as well as for cell proliferation and closely linked to the formation of reactive oxygen species. Therefore, iron can influence the course of clonal myeloid disorders, the leukemic environment and the occurrence as well as the defense of infections. Imbalances of iron homeostasis may induce cell death of normal but also of malignant cells. New potential treatment strategies utilizing the importance of the iron homeostasis include iron chelation, modulation of proteins involved in iron metabolism, induction of leukemic cell death via ferroptosis and exploitation of iron proteins for the delivery of antileukemic drugs.
Here, we provide a summary of some of the latest findings about the function, the prognostic impact and potential treatment strategies of iron in patients with MDS and AML.
Wastewater-based epidemiology (WBE) has demonstrated its importance to support SARS-CoV-2 epidemiology complementing individual testing strategies. Due to their immune-evasive potential and the resulting significance for public health, close monitoring of SARS-CoV-2 variants of concern (VoC) is required to evaluate the regulation of early local countermeasures. In this study, we demonstrate a rapid workflow for wastewater-based early detection and monitoring of the newly emerging SARS-CoV-2 VoCs Omicron in the end of 2021 at the municipal wastewater treatment plant (WWTP) Emschermuendung (KLEM) in the Federal State of North-Rhine-Westphalia (NRW, Germany).
Initially, available primers detecting Omicron-related mutations were rapidly validated in a central laboratory. Subsequently, RT-qPCR analysis of purified SARS-CoV-2 RNA was performed in a decentral PCR laboratory in close proximity to KLEM. This decentralized approach enabled the early detection of K417N present in Omicron in samples collected on 8th December 2021 and the detection of further mutations (N501Y, Δ69/70) in subsequent biweekly sampling campaigns. The presence of Omicron in wastewater was confirmed by next generation sequencing (NGS) in a central laboratory with samples obtained on 14th December 2021. Moreover, the relative increase of the mutant fraction of Omicron was quantitatively monitored over time by dPCR in a central PCR laboratory starting on 12th December 2021 confirming Omicron as the dominant variant by the end of 2021.
In conclusions, WBE plays a crucial role in surveillance of SARS-CoV-2 variants and is suitable as an early warning system to identify variant emergence. In particular, the successive workflow using RT-qPCR, RT-dPCR and NGS demonstrates the strength of WBE as a versatile tool to monitor variant spreading.
Wastewater-based SARS-CoV-2 epidemiology (WBE) has been established as an important tool to support individual testing strategies. The Omicron sub-variants BA.4/BA.5 have spread globally, displacing the preceding variants. Due to the severe transmissibility and immune escape potential of BA.4/BA.5, early monitoring was required to assess and implement countermeasures in time. In this study, we monitored the prevalence of SARS-CoV-2 BA.4/BA.5 at six municipal wastewater treatment plants (WWTPs) in the Federal State of North Rhine-Westphalia (NRW, Germany) in May and June 2022. Initially, L452R-specific primers/probes originally designed for SARS-CoV-2 Delta detection were validated using inactivated authentic viruses and evaluated for their suitability for detecting BA.4/BA.5. Subsequently, the assay was used for RT-qPCR analysis of RNA purified from wastewater obtained twice a week at six WWTPs. The occurrence of L452R carrying RNA was detected in early May 2022, and the presence of BA.4/BA.5 was confirmed by variant-specific single nucleotide polymorphism PCR (SNP-PCR) targeting E484A/F486V and NGS sequencing. Finally, the mutant fractions were quantitatively monitored by digital PCR, confirming BA.4/BA.5 as the majority variant by 5 June 2022. In conclusion, the successive workflow using RT-qPCR, variant-specific SNP-PCR, and RT-dPCR demonstrates the strength of WBE as a versatile tool to rapidly monitor variants spreading independently of individual test capacities.
Wastewater-based SARS-CoV-2 epidemiology (WBE) has been established as an important tool to support individual testing strategies. Omicron sub-variants BA.4/5 have spread globally displacing the predeceasing variants. Due to the severe transmissibility and immune escape potential of BA.4/5, early monitoring was required to asses and implement countermeasures in time.
In this study, we monitored the prevalence of SARS-CoV-2 BA.4/5 at six municipal wastewater treatment plants (WWTPs) in the Federal State of North-Rhine-Westphalia (NRW, Germany) in May and June 2022. Initially, L452R-specific primers/probes originally designed for SARS-CoV-2 Delta detection were validated using inactivated authentic viruses and evaluated for their suitability to detect BA.4/5. Subsequently, the assay was used for RT-qPCR analysis of RNA purified from wastewater obtained twice a week at six WWTPs. The occurrence of L452R carrying RNA was detected in early May 2022 and the presence of BA.4/5 was confirmed by variant-specific single nucleotide polymorphism PCR (SNP-PCR) targeting E484A/F486V. Finally, the mutant fractions were quantitatively monitored by digital PCR confirming BA.4/5 as the majority variant by 5th June 2022.
In conclusions, the successive workflow using RT-qPCR, variant-specific SNP-PCR, and RT-dPCR demonstrates the strength of WBE as a versatile tool to rapidly monitor variant spreading independent of individual test capacities.
Wastewater-based SARS-CoV-2 epidemiology (WBE) has been established as an important tool to support individual testing strategies. Omicron sub-variants BA.4/5 have spread globally displacing the predeceasing variants. Due to the severe transmissibility and immune escape potential of BA.4/5, early monitoring was required to asses and implement countermeasures in time.
In this study, we monitored the prevalence of SARS-CoV-2 BA.4/5 at six municipal wastewater treatment plants (WWTPs) in the Federal State of North-Rhine-Westphalia (NRW, Germany) in May and June 2022. Initially, L452R-specific primers/probes originally designed for SARS-CoV-2 Delta detection were validated using inactivated authentic viruses and evaluated for their suitability to detect BA.4/5. Subsequently, the assay was used for RT-qPCR analysis of RNA purified from wastewater obtained twice a week at six WWTPs. The occurrence of L452R carrying RNA was detected in early May 2022 and the presence of BA.4/5 was confirmed by variant-specific single nucleotide polymorphism PCR (SNP-PCR) targeting E484A/F486V. Finally, the mutant fractions were quantitatively monitored by digital PCR confirming BA.4/5 as the majority variant by 5th June 2022.
In conclusions, the successive workflow using RT-qPCR, variant-specific SNP-PCR, and RT-dPCR demonstrates the strength of WBE as a versatile tool to rapidly monitor variant spreading independent of individual test capacities.
A wide variety of enzymatic pathways that produce specialized metabolites in bacteria, fungi and plants are known to be encoded in biosynthetic gene clusters. Information about these clusters, pathways and metabolites is currently dispersed throughout the literature, making it difficult to exploit. To facilitate consistent and systematic deposition and retrieval of data on biosynthetic gene clusters, we propose the Minimum Information about a Biosynthetic Gene cluster (MIBiG) data standard.
The bile acid activated transcription factor farnesoid X receptor (FXR) regulates numerous metabolic processes and is a rising target for the treatment of hepatic and metabolic disorders. FXR agonists have revealed efficacy in treating non-alcoholic steatohepatitis (NASH), diabetes and dyslipidemia. Here we characterize imatinib as first-in-class allosteric FXR modulator and report the development of an optimized descendant that markedly promotes agonist induced FXR activation in a reporter gene assay and FXR target gene expression in HepG2 cells. Differential effects of imatinib on agonist-induced bile salt export protein and small heterodimer partner expression suggest that allosteric FXR modulation could open a new avenue to gene-selective FXR modulators.
The last decade has seen a sharp increase in the number of scientific publications describing physiological and pathological functions of extracellular vesicles (EVs), a collective term covering various subtypes of cell-released, membranous structures, called exosomes, microvesicles, microparticles, ectosomes, oncosomes, apoptotic bodies, and many other names. However, specific issues arise when working with these entities, whose size and amount often make them difficult to obtain as relatively pure preparations, and to characterize properly. The International Society for Extracellular Vesicles (ISEV) proposed Minimal Information for Studies of Extracellular Vesicles (“MISEV”) guidelines for the field in 2014. We now update these “MISEV2014” guidelines based on evolution of the collective knowledge in the last four years. An important point to consider is that ascribing a specific function to EVs in general, or to subtypes of EVs, requires reporting of specific information beyond mere description of function in a crude, potentially contaminated, and heterogeneous preparation. For example, claims that exosomes are endowed with exquisite and specific activities remain difficult to support experimentally, given our still limited knowledge of their specific molecular machineries of biogenesis and release, as compared with other biophysically similar EVs. The MISEV2018 guidelines include tables and outlines of suggested protocols and steps to follow to document specific EV-associated functional activities. Finally, a checklist is provided with summaries of key points.
The highly infectious disease COVID-19 caused by the Betacoronavirus SARS-CoV-2 poses a severe threat to humanity and demands the redirection of scientific efforts and criteria to organized research projects. The international COVID19-NMR consortium seeks to provide such new approaches by gathering scientific expertise worldwide. In particular, making available viral proteins and RNAs will pave the way to understanding the SARS-CoV-2 molecular components in detail. The research in COVID19-NMR and the resources provided through the consortium are fully disclosed to accelerate access and exploitation. NMR investigations of the viral molecular components are designated to provide the essential basis for further work, including macromolecular interaction studies and high-throughput drug screening. Here, we present the extensive catalog of a holistic SARS-CoV-2 protein preparation approach based on the consortium’s collective efforts. We provide protocols for the large-scale production of more than 80% of all SARS-CoV-2 proteins or essential parts of them. Several of the proteins were produced in more than one laboratory, demonstrating the high interoperability between NMR groups worldwide. For the majority of proteins, we can produce isotope-labeled samples of HSQC-grade. Together with several NMR chemical shift assignments made publicly available on covid19-nmr.com, we here provide highly valuable resources for the production of SARS-CoV-2 proteins in isotope-labeled form.
Background and Objectives: Proteins of the coagulation system contribute to autoimmune inflammation in patients with multiple sclerosis (MS). On blood-brain barrier (BBB) disruption, fibrinogen enters the CNS and is rapidly converted to fibrin, unfolding pleiotropic autoimmune mechanisms. Fibrin accumulation leads to subsequent proteolytic degradation that results in D-dimer generation. The primary objective of this study was to determine intrathecal levels of D-dimer in CSF as a measure of intrathecal coagulation cascade activation and to evaluate its diagnostic utility in patients with MS in contrast to healthy subjects. Key secondary objectives included analysis of CSF D-dimer in differential diagnoses of MS and its relation to routine clinical markers of disease activity.
Methods: Patients admitted for the assessment of suspected MS were prospectively recruited from October 2017 to December 2020. Blood plasma and citrated CSF samples were analyzed using a highly sensitive luminescent oxygen channeling immunoassay. Intrathecal generation of D-dimer was analyzed by adjusting for CSF/serum albumin (Qalb) and CSF/plasma D-dimer quotients (QD-dimer), and corresponding CSF fibrinogen levels were determined. Final diagnoses after full evaluation and clinical data were recorded.
Results: Of 187 patients, 113 patients received a diagnosis of MS or clinically/radiologically isolated syndrome. We found increased intrathecal CSF D-dimer generation levels (QD-dimer/Qalb-index) for patients with relapsing-remitting MS (RRMS; n = 71, median 4.7, interquartile range [IQR] 2.5–8.0) when compared with those for disease controls (n = 22, median 2.6, IQR 2.1–4.8, p = 0.031). Absolute CSF D-dimer values correlated with CSF fibrinogen levels (r = 0.463; p < 0 .001) and CSF leukocytes (r = 0.273; p = 0.003) and were elevated in MS patients with contrast enhancement (CE) compared with MS patients without CE on MRI (n = 48, median 6 ng/mL, and IQR 3–15.25 vs n = 41, median 4 ng/mL, and IQR 2–7; p = 0.026). Exploratory subgroup analyses indicated a correlation of intrathecal inflammatory activity and CSF D-dimer levels.
Discussion: D-dimer in CSF can be reliably determined and correlates with markers of CNS inflammation and CSF fibrinogen levels. Adjusted for BBB dysfunction, CSF D-dimer may allow the identification of intrathecal coagulation cascade activation in patients with MS.
Classification of Evidence: This study provides Class I evidence that CSF D-dimer levels are elevated in patients with RRMS.
Anticoagulation with warfarin and rivaroxaban ameliorates experimental autoimmune encephalomyelitis
(2017)
Background: In multiple sclerosis, coagulation factors have been shown to modulate inflammation. In this translational study, we investigated whether long-term anticoagulation with warfarin or rivaroxaban has beneficial effects on the course of autoimmune experimental encephalomyelitis (EAE).
Methods: Female SJL/J mice treated with anticoagulants namely warfarin or rivaroxaban were immunized with PLP139–151. Stable anticoagulation was maintained throughout the entire experiment. Mice without anticoagulation treated with the vehicle only were used as controls. The neurological deficit was recorded during the course of EAE, and histopathological analyses of inflammatory lesions were performed.
Results: In preventive settings, both treatment with warfarin and rivaroxaban reduced the maximum EAE score as compared to the control group and led to a reduction of inflammatory lesions in the spinal cord. In contrast, therapeutic treatment with warfarin had no beneficial effects on the clinical course of EAE. Signs of intraparenchymal hemorrhage at the site of the inflammatory lesions were not observed.
Conclusion: We developed long-term anticoagulation models that allowed exploring the course of EAE under warfarin and rivaroxaban treatment. We found a mild preventive effect of both warfarin and rivaroxaban on neurological deficits and local inflammation, indicating a modulation of the disease induction by anticoagulation.