siRNA-mediated off-target gene silencing triggered by a 7 nt complementation

A growing body of evidence suggests that siRNA could generate off-target effects through different mechanisms. However, the full impact of off-target gene regulation on phenotypic induction and accordingly on data interpretation in the context of large-scale siRNA library screen has not been reported. Here we report on off-target gene silencing effects observed in a large-scale knockdown experiment designed to identify novel regulators of the HIF-1 pathway. All of the three ‘top hits’ from our screen have been demonstrated to result from off-target gene silencing. Two of the three ‘siRNA hits’ were found to directly trigger down-regulation of hif-1α mRNA through a 7 nt motif, AGGCAGT, that is present in both the hif-1α mRNA and the siRNAs. Further analysis revealed that the generation of off-target gene silencing via this 7 nt motif depends on the characteristics of the target mRNA, including the sequence context surrounding the complementary region, the position of the complementary region in the mRNA and the copy number of the complementary region. Interestingly, the off-target siRNA against hif-1α was also shown to trigger mRNA degradation with high probability of other genes that possess multiple copies of the AGGCAGT motif in the 3′-untranslated region. Lessons learned from this study will be a valuable asset to aid in designing siRNAs with more stringent target selectivity and improving ‘hits-follow-up’ strategies for future large-scale knockdown experiments

Pore water exchange-driven inorganic carbon export from intertidal salt marshes

© The Author(s), 2021. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in Tamborski, J. J., Eagle, M., Kurylyk, B. L., Kroeger, K. D., Wang, Z. A., Henderson, P., & Charette: 1774-1792, https://doi.org/10.1002/lno.11721.Respiration in intertidal salt marshes generates dissolved inorganic carbon (DIC) that is exported to the coastal ocean by tidal exchange with the marsh platform. Understanding the link between physical drivers of water exchange and chemical flux is a key to constraining coastal wetland contributions to regional carbon budgets. The spatial and temporal (seasonal, annual) variability of marsh pore water exchange and DIC export was assessed from a microtidal salt marsh (Sage Lot Pond, Massachusetts). Spatial variability was constrained from 224Ra : 228Th disequilibria across two hydrologic units within the marsh sediments. Disequilibrium between the more soluble 224Ra and its sediment-bound parent 228Th reveals significant pore water exchange in the upper 5 cm of the marsh surface (0–36 L m−2 d−1) that is most intense in low marsh elevation zones, driven by tidal overtopping. Surficial sediment DIC transport ranges from 0.0 to 0.7 g C m−2 d−1. The sub-surface sediment horizon intersected by mean low tide was disproportionately impacted by tidal pumping (20–80 L m−2 d−1) and supplied a seasonal DIC flux of 1.7–5.4 g C m−2 d−1. Export exceeded 10 g C m−2 d−1 for another marsh unit, demonstrating that fluxes can vary substantially across salt marshes under similar conditions within the same estuary. Seasonal and annual variability in marsh pore water exchange, constrained from tidal time-series of radium isotopes, was driven in part by variability in mean sea level. Rising sea levels will further inundate high marsh elevation zones, which may lead to greater DIC export.This research was undertaken thanks in part to funding from the Canada First Research Excellence Fund, through the Ocean Frontier Institute. Additional funding was provided by the U.S. Geological Survey (USGS) Coastal & Marine Geology Program and the USGS Land Change Science Program's LandCarbon program

Temperature and magnetic field dependence of the lattice constant in spin-Peierls cuprate CuGeO_3 studied by capacitance dilatometry in fields up to 16 Tesla

We present high resolution measurements of the thermal expansion coefficient and the magnetostriction along the a-axis of CuGeO_3 in magnetic fields up to 16 Tesla. From the pronounced anomalies of the lattice constant a occurring for both temperature and field induced phase transitions clear structural differences between the uniform, dimerized, and incommensurate phases are established. A precise field temperature phase diagram is derived and compared in detail with existing theories. Although there is a fair agreement with the calculations within the Cross Fisher theory, some significant and systematic deviations are present. In addition, our data yield a high resolution measurement of the field and temperature dependence of the spontaneous strain scaling with the spin-Peierls order parameter. Both the zero temperature values as well as the critical behavior of the order parameter are nearly field independent in the dimerized phase. A spontaneous strain is also found in the incommensurate high field phase, which is significantly smaller and shows a different critical behavior than that in the low field phase. The analysis of the temperature dependence of the spontaneous strain yields a pronounced field dependence within the dimerized phase, whereas the temperature dependence of the incommensurate lattice modulation compares well with that of the dimerization in zero magnetic field.Comment: 25 pages, 15 Figs., to appear in Phys. Rev. B55 (Vol.5

Measurement of eta_c(1S), eta_c(2S) and non-resonant eta' pi+ pi- production via two-photon collisions

We report the measurement of gamma gamma to eta_c(1S), eta_c(2S) to eta' pi+ pi- with eta' decays to gamma rho and eta pi+ pi- using 941 fb^{-1} of data collected with the Belle detector at the KEKB asymmetric-energy e+e- collider. The eta_c(1S) mass and width are measured to be M = [2984.6\pm0.7 (stat.)\pm2.2 (syst.)] MeV/c^{2} and \Gamma = [30.8^{+2.3}_{-2.2}~(stat.) \pm 2.5~(syst.)] MeV, respectively. First observation of eta_c(2S) to eta' pi+ pi- with a significance of 5.5sigma including systematic error is obtained, and the eta_c(2S) mass is measured to be M = [3635.1\pm3.7~(stat.)\pm2.9~(syst.)] MeV/c^{2}. The products of the two-photon decay width and branching fraction (B) of decays to eta'pi+ pi- are determined to be \Gamma_{gamma gamma}B = [65.4\pm2.6~(stat.)\pm6.9~(syst.)] eV for eta_c(1S) and [5.6^{+1.2}_{-1.1}~(stat.)\pm1.1~(syst.)] eV for eta_c(2S). A new decay mode for the eta_c(1S) to eta'f_0(2080) with f_0(2080) to pi+ pi- is observed with a statistical significance of 20sigma. The f_0(2080) mass and width are determined to be M = [2083^{+63}_{-66}~(stat.)\pm 32~(syst.)] MeV/c^{2} and \Gamma = [178^{+60}_{-178}~(stat.) \pm 55~(syst.)] MeV. The cross sections for gamma gamma to eta' pi+ pi- and eta'f_{2}(1270) are measured for the first time.Comment: 19 pages, 14 figure

Measurement of the τ\tau lepton polarization and R(D∗)R(D^*) in the decay Bˉ→D∗τ−νˉτ\bar{B} \rightarrow D^* \tau^- \bar{\nu}_\tau with one-prong hadronic τ\tau decays at Belle

With the full data sample of $772 \times 10^6$ $B{\bar B}$ pairs recorded by the Belle detector at the KEKB electron-positron collider, the decay $\bar{B} \rightarrow D^* \tau^- \bar{\nu}_\tau$ is studied with the hadronic $\tau$ decays $\tau^- \rightarrow \pi^- \nu_\tau$ and $\tau^- \rightarrow \rho^- \nu_\tau$. The $\tau$ polarization $P_\tau(D^*)$ in two-body hadronic $\tau$ decays is measured, as well as the ratio of the branching fractions $R(D^{*}) = \mathcal{B}(\bar {B} \rightarrow D^* \tau^- \bar{\nu}_\tau) / \mathcal{B}(\bar{B} \rightarrow D^* \ell^- \bar{\nu}_\ell)$, where $\ell^-$ denotes an electron or a muon. Our results, $P_\tau(D^*) = -0.38 \pm 0.51 {\rm (stat)} ^{+0.21}_{-0.16} {\rm (syst)}$ and $R(D^*) = 0.270 \pm 0.035{\rm (stat)} ^{+0.028}_{-0.025}{\rm (syst)}$, are consistent with the theoretical predictions of the Standard Model. The polarization values of $P_\tau(D^*) > +0.5$ are excluded at the 90\% confidence level.Comment: 17 pages, 11 figures, submitted to Physical Review

Measurement of Branching Fractions of Hadronic Decays of the Ωc0\Omega_c^0 Baryon

Using a data sample of 980 ${\rm fb}^{-1}$ of $e^+e^-$ annihilation data taken with the Belle detector operating at the KEKB asymmetric-energy $e^+e^-$ collider, we report the results of a study of the decays of the $\Omega_c^0$ charmed baryon into hadronic final states. We report the most precise measurements to date of the relative branching fractions of the $\Omega_c^0$ into $\Omega^-\pi^+\pi^0$, $\Omega^-\pi^+\pi^-\pi^+$, $\Xi^-K^-\pi^+\pi^+$, and $\Xi^0K^-\pi^+$, as well as the first measurements of the branching fractions of the $\Omega_c^0$ into $\Xi^-\bar{K}^0\pi^+$, $\Xi^0\bar{K}^0$, and $\Lambda \bar{K}^0\bar{K}^0$, all with respect to the $\Omega^-\pi^+$ decay. In addition, we investigate the resonant substructure of these modes. Finally, we present a limit on the branching fraction for the decay $\Omega_c^0\to\Sigma^+K^-K^-\pi^+$

Outcomes and toxicity of allogeneic hematopoietic cell transplantation in chronic myeloid leukemia patients previously treated with second-generation tyrosine kinase inhibitors : a prospective non-interventional study from the Chronic Malignancy Working Party of the EBMT

Allogeneic hematopoietic cell transplantation (allo-HCT) remains a treatment option for patients with chronic myeloid leukemia (CML) who fail to respond to tyrosine kinase inhibitors (TKIs). While imatinib seems to have no adverse impact on outcomes after transplant, little is known on the effects of prior use of second-generation TKI (2GTKI). We present the results of a prospective non-interventional study performed by the EBMT on 383 consecutive CML patients previously treated with dasatinib or nilotinib undergoing allo-HCT from 2009 to 2013. The median age was 45 years (18-68). Disease status at transplant was CP1 in 139 patients (38%), AP or >CP1 in 163 (45%), and BC in 59 (16%). The choice of 2GTKI was: 40% dasatinib, 17% nilotinib, and 43% a sequential treatment of dasatinib and nilotinib with or without bosutinib/ponatinib. With a median follow-up of 37 months (1-77), 8% of patients developed either primary or secondary graft failure, 34% acute and 60% chronic GvHD. There were no differences in post-transplant complications between the three different 2GTKI subgroups. Non-relapse mortality was 18% and 24% at 12 months and at 5 years, respectively. Relapse incidence was 36%, overall survival 56% and relapse-free survival 40% at 5 years. No differences in post-transplant outcomes were found between the three different 2GTKI subgroups. This prospective study demonstrates the feasibility of allo-HCT in patients previously treated with 2GTKI with a post-transplant complications rate comparable to that of TKI-naive or imatinib-treated patients.Peer reviewe

Inclusive study of bottomonium production in association with an η\eta meson in e+e−e^+e^- annihilations near Υ(5S)\Upsilon(5S)

We study bottomonium production in association with an $\eta$ meson in $e^+e^-$ annihilations near the $\Upsilon(5S)$, at a center of mass energy of $\sqrt{s}=10.866\,$GeV. The results are based on the $121.4\,$fb$^{-1}$ data sample collected by the Belle experiment at the asymmetric energy KEKB collider. Only the $\eta$ meson is reconstructed and the missing-mass spectrum of $\eta$ candidates is investigated. We observe the $e^+e^-\to\eta\Upsilon_J(1D)$ process and find evidence for the $e^+e^-\to\eta\Upsilon(2S)$ process, while no significant signals of $\Upsilon(1S)$, $h_b(1P)$, nor $h_b(2P)$ are found. Cross sections for the studied processes are reported.Comment: Submitted to EPJ-

Measurement of the CKM Matrix Element ∣Vcb∣|V_{cb}| from B0→D∗−ℓ+νℓB^{0} \to D^{*-} \ell^+ \nu_\ell at Belle

We present a new measurement of the CKM matrix element $|V_{cb}|$ from $B^{0} \to D^{*-} \ell^+ \nu_\ell$ decays, reconstructed with the full Belle data set of $711 \, \rm fb^{-1}$ integrated luminosity. Two form factor parameterizations, originally conceived by the Caprini-Lellouch-Neubert (CLN) and the Boyd, Grinstein and Lebed (BGL) groups, are used to extract the product $\mathcal{F}(1)\eta_{\rm EW}|V_{cb}|$ and the decay form factors, where $\mathcal{F}(1)$ is the normalization factor and $\eta_{\rm EW}$ is a small electroweak correction. In the CLN parameterization we find $\mathcal{F}(1)\eta_{\rm EW}|V_{cb}| = (35.06 \pm 0.15 \pm 0.56) \times 10^{-3}$, $\rho^{2}=1.106 \pm 0.031 \pm 0.007$, $R_{1}(1)=1.229 \pm 0.028 \pm 0.009$, $R_{2}(1)=0.852 \pm 0.021 \pm 0.006$. For the BGL parameterization we obtain $\mathcal{F}(1)\eta_{\rm EW}|V_{cb}|= (34.93 \pm 0.23 \pm 0.59)\times 10^{-3}$, which is consistent with the World Average when correcting for $\mathcal{F}(1)\eta_{\rm EW}$. The branching fraction of $B^{0} \to D^{*-} \ell^+ \nu_\ell$ is measured to be $\mathcal{B}(B^{0}\rightarrow D^{*-}\ell^{+}\nu_{\ell}) = (4.90 \pm 0.02 \pm 0.16)\%$. We also present a new test of lepton flavor universality violation in semileptonic $B$ decays, $\frac{{\cal B }(B^0 \to D^{*-} e^+ \nu)}{{\cal B }(B^0 \to D^{*-} \mu^+ \nu)} = 1.01 \pm 0.01 \pm 0.03~$. The errors correspond to the statistical and systematic uncertainties respectively. This is the most precise measurement of $\mathcal{F}(1)\eta_{\rm EW}|V_{cb}|$ and form factors to date and the first experimental study of the BGL form factor parameterization in an experimental measurement