Big conductance calcium-activated potassium channel openers control spasticity without sedation.

BACKGROUND AND PURPOSE: Our initial aim was to generate cannabinoid agents that control spasticity, occurring as a consequence of multiple sclerosis (MS), whilst avoiding the sedative side effects associated with cannabis. VSN16R was synthesized as an anandamide (endocannabinoid) analogue in an anti-metabolite approach to identify drugs that target spasticity. EXPERIMENTAL APPROACH: Following the initial chemistry, a variety of biochemical, pharmacological and electrophysiological approaches, using isolated cells, tissue-based assays and in vivo animal models, were used to demonstrate the activity, efficacy, pharmacokinetics and mechanism of action of VSN16R. Toxicological and safety studies were performed in animals and humans. KEY RESULTS: VSN16R had nanomolar activity in tissue-based, functional assays and dose-dependently inhibited spasticity in a mouse experimental encephalomyelitis model of MS. This effect occurred with over 1000-fold therapeutic window, without affecting normal muscle tone. Efficacy was achieved at plasma levels that are feasible and safe in humans. VSN16R did not bind to known CB1 /CB2 /GPPR55 cannabinoid-related receptors in receptor-based assays but acted on a vascular cannabinoid target. This was identified as the major neuronal form of the big conductance, calcium-activated potassium (BKCa ) channel. Drug-induced opening of neuronal BKCa channels induced membrane hyperpolarization, limiting excessive neural-excitability and controlling spasticity. CONCLUSIONS AND IMPLICATIONS: We identified the neuronal form of the BKCa channel as the target for VSN16R and demonstrated that its activation alleviates neuronal excitability and spasticity in an experimental model of MS, revealing a novel mechanism to control spasticity. VSN16R is a potential, safe and selective ligand for controlling neural hyper-excitability in spasticity

Results of Molecular Monitoring in Posttransplant Period by Means of Series Investigation of WT1 Gene Expression in Patients with Acute Myeloid Leukemia

Aim. To demonstrate diagnostic and prognostic significance of series measurement of WT1 expression in patients with acute myeloid leukemia (AML) after allogenic hematopoietic stem cell transplantation (allo-HSCT). Materials & Methods. The clinical trial included 88 AML patients (38 females (43 %) and 50 males (57 %) aged 2–68, median 30 years). All the patients received allo-HSCT. Bone marrow was aspirated before (D0) and after HSCT (D+30, D+60, and D+100). Results. The univariate analysis showed statistically significant differences in 2-year overall survival with respect to the following factors: with and without remission at the moment of HSCT (p 250 copies before HSCT (p < 0.001) and at time points D+60 (p = 0.012), and D+100 (p < 0.001). Multivariate analysis revealed similar statistical significance of differences among patients transplanted in remission (p = 0.041) and with cGVHD (p = 0.03). In univariate analysis statistically significant differences in 2-year event-free survival (EFS) were found: a) in patients with allo-HSCT, either in remission or not (p < 0.001); b) using HSC, but not bone marrow, as transplant source (p < 0.026); c) with normal or high WT1 expression at the stage of HSCT (p < 0.001) and at time point D+100 (p < 0.001); d) using HSC from related or unrelated donor (p = 0.006); e) in patients with cGVHD (p = 0.05). In multivariate analysis independent positive effect on EFS was observed only in patients with normal WT1 expression at D+100 (p = 0.011) and with cGVHD (p = 0.038). Cumulative incidence of posttransplant relapse (PTR) in AML patients with normal or high WT1 expression at the stage of HSCT within the 2-year follow-up was significantly different (28.2 vs. 58.9 %; p = 0.002), also in measurements of this parameter at D+60 and D+100 (p = 0.015 and p < 0.001, respectively). In 1/4 of patients cytological relapses (cPTR) appeared considerably later than molecular relapses (mPTR), i.e. 13–489 days later (median 35 days), which is accounted for by early preventive therapy aimed at cPTR prophylaxis against the background of already recorded mPTR. According to our data, GVHD plays a crucial role in cPTR management. Conclusion. Phenomenon of WT1 expression normalization after allo-HSCT in AML patients proves to have a high diagnostic and prognostic significance. Introduction of this approach into clinical practice seems highly advisable for national oncohematological centers

Small Polarons in Transition Metal Oxides

The formation of polarons is a pervasive phenomenon in transition metal oxide compounds, with a strong impact on the physical properties and functionalities of the hosting materials. In its original formulation the polaron problem considers a single charge carrier in a polar crystal interacting with its surrounding lattice. Depending on the spatial extension of the polaron quasiparticle, originating from the coupling between the excess charge and the phonon field, one speaks of small or large polarons. This chapter discusses the modeling of small polarons in real materials, with a particular focus on the archetypal polaron material TiO2. After an introductory part, surveying the fundamental theoretical and experimental aspects of the physics of polarons, the chapter examines how to model small polarons using first principles schemes in order to predict, understand and interpret a variety of polaron properties in bulk phases and surfaces. Following the spirit of this handbook, different types of computational procedures and prescriptions are presented with specific instructions on the setup required to model polaron effects.Comment: 36 pages, 12 figure

An improved limit for Gamma(ee) of X(3872) and Gamma(ee) measurement of psi(3686)

Using the data sets taken at center-of-mass energies above 4 GeV by the BESIII detector at the BEPCII storage ring, we search for the reaction e(+)e(-) -> gamma(ISR) X(3872) -> gamma(ISR)pi(+)pi(-) J/psi via the Initial State Radiation technique. The production of a resonance with quantum numbers J(PC) = 1(++) such as the X(3872) via single photon e(+)e(-) annihilation is forbidden, but is allowed by a next-to-leading order box diagram. We do not observe a significant signal of X(3872), and therefore give an upper limit for the electronic width times the branching fraction Gamma B-X(3872)(ee)(X(3872) -> pi(+)pi(-) J/psi) <0.13 eVat the 90% confidence level. This measurement improves upon existing limits by a factor of 46. Using the same final state, we also measure the electronic width of the psi(3686) to be Gamma(psi)(ee)(3686) ee = 2213 +/- 18(stat) +/- 99(sys) eV. (C) 2015 The Authors. Published by Elsevier B.V

Search for C-parity violation in J/ψ→γγJ/ \psi \to \gamma\gamma and γϕ \gamma \phi

Using $1.06\times10^8$ $\psi(3686)$ events recorded in $e^{+}e^{-}$ collisions at $\sqrt{s}=$ 3.686 GeV with the BESIII at the BEPCII collider, we present searches for C-parity violation in $J/\psi \to \gamma\gamma$ and $\gamma \phi$ decays via $\psi(3686) \to J/\psi \pi^+\pi^-$. No significant signals are observed in either channel. Upper limits on the branching fractions are set to be $\mathcal{B}(J/\psi \to \gamma\gamma) < 2.7 \times 10^{-7}$ and $\mathcal{B}(J/\psi \to \gamma\phi) < 1.4 \times 10^{-6}$ at the 90\% confidence level. The former is one order of magnitude more stringent than the previous upper limit, and the latter represents the first limit on this decay channel.Comment: 7 pages, 2 figure

Precision Measurement of the Mass of the τ\tau Lepton

An energy scan near the $\tau$ pair production threshold has been performed using the BESIII detector. About $24$ pb$^{-1}$ of data, distributed over four scan points, was collected. This analysis is based on $\tau$ pair decays to $ee$, $e\mu$, $eh$, $\mu\mu$, $\mu h$, $hh$, $e\rho$, $\mu\rho$ and $\pi\rho$ final states, where $h$ denotes a charged $\pi$ or $K$. The mass of the $\tau$ lepton is measured from a maximum likelihood fit to the $\tau$ pair production cross section data to be $m_{\tau} = (1776.91\pm0.12 ^{+0.10}_{-0.13}$) MeV/$c^2$, which is currently the most precise value in a single measurement.Comment: 13 pages, 7 figure

Search for the radiative transitions ψ(3770)→γηc\psi(3770)\to\gamma\eta_c and γηc(2S)\gamma\eta_c(2S)

By using a 2.92 fb$^{-1}$ data sample taken at $\sqrt{s} = 3.773$ GeV with the BESIII detector operating at the BEPCII collider, we search for the radiative transitions $\psi(3770)\to\gamma\eta_c$ and $\gamma\eta_c(2S)$ through the hadronic decays $\eta_c(\eta_c(2S))\to K^0_SK^\pm\pi^\mp$. No significant excess of signal events above background is observed. We set upper limits at a 90% confidence level for the product branching fractions to be $\mathcal{B}(\psi(3770)\to\gamma\eta_c)\times \mathcal{B}(\eta_c\to K^0_SK^\pm\pi^\mp) < 1.6\times10^{-5}$ and $\mathcal{B}(\psi(3770)\to\gamma\eta_c(2S))\times \mathcal{B}(\eta_c(2S)\to K^0_SK^\pm\pi^\mp) < 5.6\times10^{-6}$. Combining our result with world-average values of $\mathcal{B}(\eta_c(\eta_c(2S))\to K^0_SK^\pm\pi^\mp)$, we find the branching fractions $\mathcal{B}(\psi(3770)\to\gamma\eta_c) < 6.8\times10^{-4}$ and $\mathcal{B}(\psi(3770)\to\gamma\eta_c(2S)) < 2.0\times10^{-3}$ at a 90% confidence level.Comment: 10 pages, 4 figure

Measurement of the proton form factor by studying e+e−→ppˉe^{+} e^{-}\rightarrow p\bar{p}

Using data samples collected with the BESIII detector at the BEPCII collider, we measure the Born cross section of $e^{+}e^{-}\rightarrow p\bar{p}$ at 12 center-of-mass energies from 2232.4 to 3671.0 MeV. The corresponding effective electromagnetic form factor of the proton is deduced under the assumption that the electric and magnetic form factors are equal $(|G_{E}|= |G_{M}|)$. In addition, the ratio of electric to magnetic form factors, $|G_{E}/G_{M}|$, and $|G_{M}|$ are extracted by fitting the polar angle distribution of the proton for the data samples with larger statistics, namely at $\sqrt{s}=$ 2232.4 and 2400.0 MeV and a combined sample at $\sqrt{s}$ = 3050.0, 3060.0 and 3080.0 MeV, respectively. The measured cross sections are in agreement with recent results from BaBar, improving the overall uncertainty by about 30\%. The $|G_{E}/G_{M}|$ ratios are close to unity and consistent with BaBar results in the same $q^{2}$ region, which indicates the data are consistent with the assumption that $|G_{E}|=|G_{M}|$ within uncertainties.Comment: 13 pages, 24 figure

Observation of the ψ(13D2)\psi(1^3D_2) state in e+e−→π+π−γχc1e^+e^-\to\pi^+\pi^-\gamma\chi_{c1} at BESIII

We report the observation of the $X(3823)$ in the process $e^+e^-\to \pi^+\pi^-X(3823) \to \pi^+\pi^-\gamma\chi_{c1}$ with a statistical significance of $6.2\sigma$, in data samples at center-of-mass energies $\sqrt{s}=$4.230, 4.260, 4.360, 4.420 and 4.600~GeV collected with the BESIII detector at the BEPCII electron positron collider. The measured mass of the $X(3823)$ is $(3821.7\pm 1.3\pm 0.7)$~MeV/$c^2$, where the first error is statistical and the second systematic, and the width is less than $16$~MeV at the 90\% confidence level. The products of the Born cross sections for $e^+e^-\to \pi^+\pi^-X(3823)$ and the branching ratio $\mathcal{B}[X(3823)\to \gamma\chi_{c1,c2}]$ are also measured. These measurements are in good agreement with the assignment of the $X(3823)$ as the $\psi(1^3D_2)$ charmonium state.Comment: 7 pages, 3 figures, version to appear in Phys. Rev. Let