265Generation of iPSC-based cardiomyocytes for investigating mechanisms of dilated cardiomyopathy due to Lamin A/C mutations

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CaMKII inhibition rectifies arrhythmic phenotype in a patient-specific model of catecholaminergic polymorphic ventricular tachycardia

Induced pluripotent stem cells (iPSC) offer a unique opportunity for developmental studies, disease modeling and regenerative medicine approaches in humans. The aim of our study was to create an in vitro 'patient-specific cell-based system' that could facilitate the screening of new therapeutic molecules for the treatment of catecholaminergic polymorphic ventricular tachycardia (CPVT), an inherited form of fatal arrhythmia. Here, we report the development of a cardiac model of CPVT through the generation of iPSC from a CPVT patient carrying a heterozygous mutation in the cardiac ryanodine receptor gene (RyR2) and their subsequent differentiation into cardiomyocytes (CMs). Whole-cell patch-clamp and intracellular electrical recordings of spontaneously beating cells revealed the presence of delayed afterdepolarizations (DADs) in CPVT-CMs, both in resting conditions and after β-adrenergic stimulation, resembling the cardiac phenotype of the patients. Furthermore, treatment with KN-93 (2-[N-(2-hydroxyethyl)]-N-(4methoxybenzenesulfonyl)]amino-N-(4-chlorocinnamyl)-N-methylbenzylamine), an antiarrhythmic drug that inhibits Ca(2+)/calmodulin-dependent serine-threonine protein kinase II (CaMKII), drastically reduced the presence of DADs in CVPT-CMs, rescuing the arrhythmic phenotype induced by catecholaminergic stress. In addition, intracellular calcium transient measurements on 3D beating clusters by fast resolution optical mapping showed that CPVT clusters developed multiple calcium transients, whereas in the wild-type clusters, only single initiations were detected. Such instability is aggravated in the presence of isoproterenol and is attenuated by KN-93. As seen in our RyR2 knock-in CPVT mice, the antiarrhythmic effect of KN-93 is confirmed in these human iPSC-derived cardiac cells, supporting the role of this in vitro system for drug screening and optimization of clinical treatment strategies

Measurement of Time-Dependent CP-Violating Parameters in B0 -> K0S K0S decays

We report a measurement of the CP-violating parameters in B0->K0S K0S decays based on a data sample of 657 million BBbar pairs collected at the Y(4S) resonance with the Belle detector at the KEKB asymmetric-energy e+e- collider. In this study, one neutral B meson is fully reconstructed in the B0->K0S K0S decay mode, and the flavor of the accompanying B meson is identified by its decay products. The CP-violating parameters are measured from the asymmetry in the distributions of the proper-time interval between the two B decays: S = -0.38 +0.69-0.77(stat) +-0.09(syst) and A = -0.38 +-0.38(stat) +-0.05(syst).Comment: 5pages, 2figures, submitted to PR

Measurement of CP violating asymmetries in B^0 -> K^+K^- K^0_S decays with a time-dependent Dalitz approach

We report a measurement of $CP$ violating asymmetries in $B^0(\overline{B}^0) \to K^+ K^- K^0_S$ decays with a time-dependent Dalitz approach. This analysis is based on a data sample of $657\times 10^6$ $B\overline{B}$ pairs accumulated at the $\Upsilon(4S)$ resonance with the Belle detector at the KEKB asymmetric-energy $e^+e^-$ collider. As the result of an unbinned maximum likelihood fit to the selected candidates, the mixing-induced and direct $CP$ violation parameters, $\phi^{\rm eff}_1$ and ${\cal A}_{CP}$ are obtained for $B^0 \to \phi(1020) K^0_S$, $B^0 \to f_0(980) K^0_S$ and other $B^0 \to K^+ K^- K^0_S$ decays. We find four solutions that describe the data. There are \{eqnarray*} \phi_1^{\rm eff}(B^0\to \phi(1020) K^0_S) & = & (32.2 \pm 9.0 \pm 2.6 \pm 1.4)^{\circ}; \phi_1^{\rm eff}(B^0\to \phi(1020) K^0_S) & = & (26.2 \pm 8.8 \pm 2.7 \pm 1.2)^{\circ};\\ \phi_1^{\rm eff}(B^0\to \phi(1020) K^0_S) & = & (27.3 \pm 8.6 \pm 2.8 \pm 1.3)^{\circ}\; {\rm and}\\ \phi_1^{\rm eff}(B^0\to \phi(1020) K^0_S) & = & (24.3 \pm 8.0 \pm 2.9 \pm 5.2)^{\circ}.{eqnarray*}\ The values for the $CP$ violating phase in $B^0\to \phi(1020) K^0_S$ are similar but other properties of the Dalitz plot are quite different for the four solutions. These four solutions have consistent $\phi^{\rm eff}_1$ values for all three $B$ meson decay channels and none of them deviates significantly from the values measured in $B \to (c\bar{c}) K^0$ decays with the currently available statistics. In addition, we find no significant direct $CP$ violation.Comment: submitted to PR

Measurement of CP violating asymmetries in B^0 -> K^+K^- K^0_S decays with a time-dependent Dalitz approach

We report a measurement of $CP$ violating asymmetries in $B^0(\overline{B}^0) \to K^+ K^- K^0_S$ decays with a time-dependent Dalitz approach. This analysis is based on a data sample of $657\times 10^6$ $B\overline{B}$ pairs accumulated at the $\Upsilon(4S)$ resonance with the Belle detector at the KEKB asymmetric-energy $e^+e^-$ collider. As the result of an unbinned maximum likelihood fit to the selected candidates, the mixing-induced and direct $CP$ violation parameters, $\phi^{\rm eff}_1$ and ${\cal A}_{CP}$ are obtained for $B^0 \to \phi(1020) K^0_S$, $B^0 \to f_0(980) K^0_S$ and other $B^0 \to K^+ K^- K^0_S$ decays. We find four solutions that describe the data. There are \{eqnarray*} \phi_1^{\rm eff}(B^0\to \phi(1020) K^0_S) & = & (32.2 \pm 9.0 \pm 2.6 \pm 1.4)^{\circ}; \phi_1^{\rm eff}(B^0\to \phi(1020) K^0_S) & = & (26.2 \pm 8.8 \pm 2.7 \pm 1.2)^{\circ};\\ \phi_1^{\rm eff}(B^0\to \phi(1020) K^0_S) & = & (27.3 \pm 8.6 \pm 2.8 \pm 1.3)^{\circ}\; {\rm and}\\ \phi_1^{\rm eff}(B^0\to \phi(1020) K^0_S) & = & (24.3 \pm 8.0 \pm 2.9 \pm 5.2)^{\circ}.{eqnarray*}\ The values for the $CP$ violating phase in $B^0\to \phi(1020) K^0_S$ are similar but other properties of the Dalitz plot are quite different for the four solutions. These four solutions have consistent $\phi^{\rm eff}_1$ values for all three $B$ meson decay channels and none of them deviates significantly from the values measured in $B \to (c\bar{c}) K^0$ decays with the currently available statistics. In addition, we find no significant direct $CP$ violation.Comment: submitted to PR

Search for Time-Dependent CPT Violation in Hadronic and Semileptonic B Decays

We report a new sensitive search for CPT violation, which includes improved measurements of the CPT-violating parameter z and the total decay-width difference normalized to the averaged width DeltaGamma_d/Gamma_d of the two Bd mass eigenstates. The results are based on a data sample of 535 x 10^6 BBbar pairs collected at the Upsilon(4S) resonance with the Belle detector at the KEKB asymmetric-energy e^+e^- collider. We obtain Re(z) = [+1.9 +/- 3.7 (stat) +/- 3.3 (syst)] x 10^{-2}, Im(z) = [-5.7 +/- 3.3 (stat) +/- 3.3 (syst)] x 10^{-3}, and DeltaGamma_d/Gamma_d = [-1.7 +/- 1.8 (stat) +/- 1.1 (syst)] x 10^{-2}, all of which are consistent with zero. This is the most precise single measurement of these parameters in the neutral B-meson system to date.Comment: 7 pages, 3 figures, 2 tables, LaTeX; addition of supplemental information, corrections of typos, results unchange

Angular analysis of B0→K∗(892)0ℓ+ℓ−B^0 \to K^\ast(892)^0 \ell^+ \ell^-

We present a measurement of angular observables, $P_4'$, $P_5'$, $P_6'$, $P_8'$, in the decay $B^0 \to K^\ast(892)^0 \ell^+ \ell^-$, where $\ell^+\ell^-$ is either $e^+e^-$ or $\mu^+\mu^-$. The analysis is performed on a data sample corresponding to an integrated luminosity of $711~\mathrm{fb}^{-1}$ containing $772\times 10^{6}$ $B\bar B$ pairs, collected at the $\Upsilon(4S)$ resonance with the Belle detector at the asymmetric-energy $e^+e^-$ collider KEKB. Four angular observables, $P_{4,5,6,8}'$ are extracted in five bins of the invariant mass squared of the lepton system, $q^2$. We compare our results for $P_{4,5,6,8}'$ with Standard Model predictions including the $q^2$ region in which the LHCb collaboration reported the so-called $P_5'$ anomaly.Comment: Conference paper for LHC Ski 2016. SM prediction for $P_{6}'$ corrected and reference for arXiv:1207.2753 adde