Specific CLK inhibitors from a novel chemotype for regulation of alternative splicing

There is a growing recognition of the importance of protein kinases in the control of alternative splicing. To define the underlying regulatory mechanisms, highly selective inhibitors are needed. Here, we report the discovery and characterization of the dichloroindolyl enaminonitrile KH-CB19, a potent and highly specific inhibitor of the CDC2-like kinase isoforms 1 and 4 (CLK1/CLK4). Cocrystal structures of KH-CB19 with CLK1 and CLK3 revealed a non-ATP mimetic binding mode, conformational changes in helix αC and the phosphate binding loop and halogen bonding to the kinase hinge region. KH-CB19 effectively suppressed phosphorylation of SR (serine/arginine) proteins in cells, consistent with its expected mechanism of action. Chemical inhibition of CLK1/CLK4 generated a unique pattern of splicing factor dephosphorylation and had at low nM concentration a profound effect on splicing of the two tissue factor isoforms flTF (full-length TF) and asHTF (alternatively spliced human TF).     

Pd-N to Pd-O rearrangement for a carbamate synthesis from carbon dioxide and methane: a density functional and ab initio molecular dynamics metadynamics study

We investigated the key step of Pd-N to Pd-O rearrangement from a model catalytic cycle for the activation of carbon dioxide and methane with static quantum chemical calculations and metadynamics simulation. Our calculations show that different bottlenecks appear in the catalytic cycle but that the investigated rearrangement of the Pd-N to Pd-O bounded complex has a barrier ΔG(#)/ΔF(#) of approximately 20 kJ mol?1 and is therefore accessible at ambient reaction conditions.     

Effective field theory: A modern approach to anomalous couplings

We advocate an effective field theory approach to anomalous couplings. The effective field theory approach is the natural way to extend the standard model such that the gauge symmetries are respected. It is general enough to capture any physics beyond the standard model, yet also provides guidance as to the most likely place to see the effects of new physics. The effective field theory approach also clarifies that one need not be concerned with the violation of unitarity in scattering processes at high energy. We apply these ideas to pair production of electroweak vector bosons.     

NLO event generation for chargino production at the ILC

We present a Monte Carlo event generator for simulating chargino pair production at the International Linear Collider (ILC) at next-to-leading order in the electroweak couplings. By properly resumming photons in the soft and collinear regions, we avoid negative event weights, so the program can simulate physical (unweighted) event samples. Photons are explicitly generated throughout the range where they can be experimentally resolved. Inspecting the dependence on the cutoffs separating the soft and collinear regions, we evaluate the systematic errors due to soft and collinear approximations. In the resummation approach, the residual uncertainty can be brought down to the per-mil level, coinciding with the expected statistical uncertainty at the ILC. PACS 12.15.Lk; 13.40.Ks; 13.66.Hk; 14.80.Ly     

Relaxation of spin polarized 3He by magnetized ferromagnetic contaminants

In the first in a series of three papers on wall relaxation of spin polarized ³He we have reported on a breakdown of relaxation times which is observed after exposing the ³He containing glass cells to a strong magnetizing field. In this third paper we give a quantitative analysis of this phenomenon, based on magnetic signal detection by means of SQUIDs, on the pressure dependence of relaxation times in magnetized cells, as well as on Monte Carlo simulations of ³He-relaxation in a macroscopic dipole field. Our analysis allows to identify the contaminants as being aggregates of dust-like Fe₃O₄ particles (magnetite) with a radius R ? 10 mR \approx 10~\mu m and a remanent magnetic moment of the order of m ≈O(10 ^-10 ^{-10}~ A m²). The particles are located at or close to the inner glass surface.     

Hypernuclear production in the (K, π) reaction

Cross sections for the production of hypernuclei were measured in the reaction A(K⁻, π⁻) _ΛA. on light and heavy nuclear targets, using a separated K⁻ beam at the CERN Proton Synchrotron. The pions were detected in the forward direction. The results are compared with cross sections calculated under the assumption that the reaction took place on a single neutron. The good agreement between the measured and the calculated cross sections justifies the use of the (K⁻, π⁻) reaction in order to obtain spectroscopic information on hypernuclei.     

Die Koeffizienten der Inneren Paarbildung bei den γ-Übergängen nach Co60→Ni60 und Pr142→Nd142

The coefficients ε of internal pair formation of the 1.17 and 1.33 MeV transitions in Ni⁶⁰ and of the 1.57 MeV transition in Nd¹⁴² were measured by detecting the annihilation radiation of the positrons. We obtained the values ε=(3.7±0.6)·10^?5 for Ni⁶⁰ and ε=(10.8±1.8)·10^?5 for Nd¹⁴². The results for Ni⁶⁰ are in good agreement with theoretical calculations. The 1.57 MeV transition in Nd¹⁴² is identified as electric quadrupole and the first excited level of Nd¹⁴² is determined to be 2⁺. By further measurements the partial transition from Pr¹⁴² to the first excited level of Nd¹⁴² was found to be (3.7±0.4)% per disintegration. NoK capture of Pr¹⁴² more than 2·10^?4 could be detected.