Small-molecule conversion of toxic oligomers to nontoxic β-sheet-rich amyloid fibrils

Several lines of evidence indicate that prefibrillar assemblies of amyloid-{beta} (A{beta}) polypeptides, such as soluble oligomers or protofibrils, rather than mature, end-stage amyloid fibrils cause neuronal dysfunction and memory impairment in Alzheimer's disease. These findings suggest that reducing the prevalence of transient intermediates by small molecule-mediated stimulation of amyloid polymerization might decrease toxicity. Here we demonstrate the acceleration of A{beta} fibrillogenesis through the action of the orcein-related small molecule O4, which directly binds to hydrophobic amino acid residues in A{beta} peptides and stabilizes the self-assembly of seeding-competent, {beta}-sheet-rich protofibrils and fibrils. Notably, the O4-mediated acceleration of amyloid fibril formation efficiently decreases the concentration of small, toxic A{beta} oligomers in complex, heterogeneous aggregation reactions. In addition, O4 treatment suppresses inhibition of long-term potentiation by A{beta} oligomers in hippocampal brain slices. These results support the hypothesis that small, diffusible prefibrillar amyloid species rather than mature fibrillar aggregates are toxic for mammalian cells

First observation of the decay Bˉs0→D0K∗0\bar{B}^0_s \to D^0 K^{*0} and a measurement of the ratio of branching fractions B(Bˉs0→D0K∗0)B(Bˉ0→D0ρ0)\frac{{\cal B}(\bar{B}^0_s \to D^0 K^{*0})}{{\cal B}(\bar{B}^0 \to D^0 \rho^0)}

The first observation of the decay $\bar{B}^0_s \to D^0 K^{*0}$ using $pp$ data collected by the LHCb detector at a centre-of-mass energy of 7 TeV, corresponding to an integrated luminosity of 36 pb$^{-1}$, is reported. A signal of $34.4 \pm 6.8$ events is obtained and the absence of signal is rejected with a statistical significance of more than nine standard deviations. The $\bar{B}^0_s \to D^0 K^{*0}$ branching fraction is measured relative to that of $\bar{B}^0 \to D^0 \rho^0$: $\frac{{\cal B}(\bar{B}^0_s \to D^0 K^{*0})}{{\cal B}(\bar{B}^0 \to D^0 \rho^0)} = 1.48 \pm 0.34 \pm 0.15 \pm 0.12$, where the first uncertainty is statistical, the second systematic and the third is due to the uncertainty on the ratio of the $B^0$ and $B^0_s$ hadronisation fractions.Comment: 10 pages, 3 figures, submitted to Phys. Lett. B; ISSN 0370-269

Observation of CP violation in B+ to DK+ decays

An analysis of B+ to DK+ and B+ to Dpi+ decays is presented where the D meson is reconstructed in the two-body final states: K+pi-, K+K-, pi+pi- and pi+K-. Using 1.0 fb-1 of LHCb data, measurements of several observables are made including the first observation of the suppressed mode B+ to DK+, D to pi+K-. CP violation in B+ to DK+ decays is observed with 5.8 sigma significance

Search for the Xb and other hidden-beauty states in the π+π−ϒ(1S) channel at ATLAS

This Letter presents a search for a hidden-beauty counterpart of the X(3872) in the mass ranges of 10.05–10.31 GeV and 10.40–11.00 GeV, in the channel Xb→π+π−ϒ(1S)(→μ+μ−), using 16.2 fb−1 of pp   collision data collected by the ATLAS detector at the LHC. No evidence for new narrow states is found, and upper limits are set on the product of the Xb cross section and branching fraction, relative to those of the ϒ(2S), at the 95% confidence level using the CLS approach. These limits range from 0.8% to 4.0%, depending on mass. For masses above 10.1 GeV, the expected upper limits from this analysis are the most restrictive to date. Searches for production of the ϒ(13DJ), , and states also reveal no significant signals

Observation of ηc(2S)→ppˉ\eta_{c}(2S) \to p \bar p and search for X(3872)→ppˉX(3872) \to p \bar p decays

The first observation of the decay $\eta_{c}(2S) \to p \bar p$ is reported using proton-proton collision data corresponding to an integrated luminosity of $3.0\rm \, fb^{-1}$ recorded by the LHCb experiment at centre-of-mass energies of 7 and 8 TeV. The $\eta_{c}(2S)$ resonance is produced in the decay $B^{+} \to [c\bar c] K^{+}$. The product of branching fractions normalised to that for the $J/\psi$ intermediate state, ${\cal R}_{\eta_{c}(2S)}$, is measured to be \begin{align*} {\cal R}_{\eta_{c}(2S)}\equiv\frac{{\mathcal B}(B^{+} \to \eta_{c}(2S) K^{+}) \times {\mathcal B}(\eta_{c}(2S) \to p \bar p)}{{\mathcal B}(B^{+} \to J/\psi K^{+}) \times {\mathcal B}(J/\psi\to p \bar p)} =~& (1.58 \pm 0.33 \pm 0.09)\times 10^{-2}, \end{align*} where the first uncertainty is statistical and the second systematic. No signals for the decays $B^{+} \to X(3872) (\to p \bar p) K^{+}$ and $B^{+} \to \psi(3770) (\to p \bar p) K^{+}$ are seen, and the 95\% confidence level upper limits on their relative branching ratios are % found to be ${\cal R}_{X(3872)}<0.25\times10^{-2}$ and ${\cal R}_{\psi(3770))}<0.10$. In addition, the mass differences between the $\eta_{c}(1S)$ and the $J/\psi$ states, between the $\eta_{c}(2S)$ and the $\psi(2S)$ states, and the natural width of the $\eta_{c}(1S)$ are measured as \begin{align*} M_{J/\psi} - M_{\eta_{c}(1S)} =~& 110.2 \pm 0.5 \pm 0.9 \rm \, MeV, M_{\psi(2S)} -M_{\eta_{c}(2S)} =~ & 52.5 \pm 1.7 \pm 0.6 \rm \, MeV, \Gamma_{\eta_{c}(1S)} =~& 34.0 \pm 1.9 \pm 1.3 \rm \, MeV. \end{align*}Comment: 16 pages, 2 figures All figures and tables, along with any supplementary material and additional information, are available at https://lhcbproject.web.cern.ch/lhcbproject/Publications/LHCbProjectPublic/LHCb-PAPER-2016-016.htm

Measurement of CPCP asymmetries in D±→η′π±D^{\pm}\rightarrow \eta^{\prime} \pi^{\pm} and Ds±→η′π±D_s^{\pm}\rightarrow \eta^{\prime} \pi^{\pm} decays

See paper for full list of authors - All figures and tables, along with any supplementary material and additional information, are available at https://lhcbproject.web.cern.ch/lhcbproject/Publications/LHCbProjectPublic/LHCb-PAPER-2016-041.html - Submitted to Phys. Lett. BInternational audienceA search for CP violation in D±→η′π± and D±s→η′π± decays is performed using proton-proton collision data, corresponding to an integrated luminosity of 3 fb−1, recorded by the LHCb experiment at centre-of-mass energies of 7 and 8 TeV. The measured CP-violating charge asymmetries are ACP(D±→η′π±)=(−0.61±0.72±0.55±0.12)% and ACP(D±s→η′π±)=(−0.82±0.36±0.24±0.27)%, where the first uncertainties are statistical, the second systematic, and the third are the uncertainties on the ACP(D±→K0Sπ±) and ACP(D±s→ϕπ±) measurements used for calibration. The results represent the most precise measurements of these asymmetries to date

Quantification of protein backbone hydrogen-deuterium exchange rates by solid state NMR spectroscopy.

We present the quantification of backbone amide hydrogen-deuterium exchange rates (HDX) for immobilized proteins. The experiments make use of the deuterium isotope effect on the amide nitrogen chemical shift, as well as on proton dilution by deuteration. We find that backbone amides in the microcrystalline &alpha;-spectrin SH3 domain exchange rather slowly with the solvent (with exchange rates negligible within the individual (15)N-T (1) timescales). We observed chemical exchange for 6 residues with HDX exchange rates in the range from 0.2 to 5 s(-1). Backbone amide (15)N longitudinal relaxation times that we determined previously are not significantly affected for most residues, yielding no systematic artifacts upon quantification of backbone dynamics (Chevelkov et al. 2008b). Significant exchange was observed for the backbone amides of R21, S36 and K60, as well as for the sidechain amides of N38, N35 and for W41&epsilon;. These residues could not be fit in our previous motional analysis, demonstrating that amide proton chemical exchange needs to be considered in the analysis of protein dynamics in the solid-state, in case D(2)O is employed as a solvent for sample preparation. Due to the intrinsically long (15)N relaxation times in the solid-state, the approach proposed here can expand the range of accessible HDX rates in the intermediate regime that is not accessible so far with exchange quench and MEXICO type experiments

Solid state NMR study on the structure and dynamics of graphite electrodes in sodium ion batteries with solvent co intercalation

The possibility to co intercalate sodium ions together with various glymes in graphite enables its use as a negative electrode material in sodium ion batteries SIBs . However, the storage mechanism and local interactions appearing during this reaction still needs further clarification. 1 H, 13 C and 23 Na ex situ solid state NMR ss NMR experiments are performed to obtain insights into the storage mechanism depending on the state of charge SOC and the electrolyte solvent used. Distinct differences could be seen depending on the SOC, indicating a possible change of the solvation shell, differences in the mobility as well as a phase transition at the plateau. Furthermore, exchange experiments reveal information on the sodium ion transport process in the graphitic lattice. The inferior cycling performance of triglyme 3G compared to diglyme 2G and pentaglyme 5G is also reflected in the ss NMR spectra, showing a reduced mobility and stronger interactions between sodium ions, 3G and graphite already at room temperature R

Cryogenic solid state NMR studies of fibrils of the Alzheimer&#39;s disease amyloid-&beta; peptide: Perspectives for DNP.

Dynamic Nuclear Polarization solid-state NMR holds the potential to enable a dramatic increase in sensitivity by exploiting the large magnetic moment of the electron. However, applications to biological solids are hampered in uniformly isotopically enriched biomacromolecules due to line broadening which yields a limited spectral resolution at cryogenic temperatures. We show here that high magnetic fields allow to overcome the broadening of resonance lines often experienced at liquid nitrogen temperatures. For a fibril sample of the Alzheimer&#39;s disease &beta;-amyloid peptide, we find similar line widths at low temperature and at room temperature. The presented results open new perspectives for structural investigations in the solid-state