Scale setting for Nf=3+1N_f=3+1 QCD

We present the scale setting for a new set of gauge configurations generated with $N_f=3+1$ Wilson quarks with a non-perturbatively determined clover coefficient in a massive O($a$) improvement scheme. The three light quarks are degenerate, with the sum of their masses being equal to its value in nature and the charm quark has its physical mass. We use open boundary conditions in time direction to avoid the problem of topological freezing at small lattice spacings and twisted-mass reweighting for improved stability of the simulations. The decoupling of charm at low energy allows us to set the scale by measuring the value of the low-energy quantity $t_0^\star/a^2$, which is the flow scale $t_0$ at our mass point, and comparing it to an $N_f=2+1$ result in physical units. We present the details of the algorithmic setup and tuning procedure and give the bare parameters of ensembles with two lattice spacings a=0.054 fm and a=0.043 fm. We discuss finite volume effects and lattice artifacts and present physical results for the charmonium spectrum. In particular the hyperfine splitting between the $\eta_c$ and $J/\psi$ mesons agrees very well with its physical value.Comment: 25 pages, 9 figures. Version accepted for publication in the European Physical Journal

Identifizierung und Charakterisierung eines spezifischen Liganden für das Alzheimer Amyloidβ\beta-Peptid (Aβ\beta)

Alzheimer's Disease (AD) is a progressive neurodegenerative disorder. Extracellular amyloid plaques in the brain are one of the main histopathological hallmarks of this disease. The amyloid-cascade-hypothesis" assigns the amyloid-$\beta$-peptide (A$\beta$) a central role in the pathogenesis of AD. lt is assumed that progressive accumulation of A$\beta$ initiates a complex multicellular cascade that includes neuritic dystrophy, microgliosis, astrocytosis, neuronal dysfunction and loss of synapsis. The consequences ofthis multicellular cascade are impaired amnestic and cognitive functions of patients suffered by AD. Based an this hypothesis, diagnostic and therapeutic strategies targeting A$\beta$ and A$\beta$ fibrils are being pursued. In the present dissertation peptides consisting of D-amino acids (D-peptides) should be identified that bind to A$\beta$ with high specifity. D-peptides are thought to be protease-resistant and less immunogenic than the respective L-enantimer (Schumacher et al., 1996). A screening of a randomized 12mer peptide library presented an bacteriophage M13 for binding to A$\beta_{l-42}$ consisting of D-amino acids as target was performed. After four rounds of selection and amplification different peptides were selected. The amino acid sequence of Q S H Y R H I S P A Q V (all amino acids in one-letter-code) was obtained in 20 of 39 selected peptides. The mirror image of this dominating peptide (D-peptide) binds to synthetic A$\beta_{1-42}$ consisting of L-amino acids as shown by fluorescence spectroscopy titration experiments. An estimation of the dissociation equilibrium constant (KD) with non-linear regression produced a value in the micromolar range. Binding of D-Pepl to natural A$\beta$ was verified through in-vitro-targeting of A$\beta$ precipitations in tissue sections derived from patients that suffered from AD. Amyloid precipitations in tissue sections of patients that suffered from other amyloidosis disorders were not marked by D-Pepl. In cytotoxicity tests, it has been demonstrated that the D-peptide has a positive effect an the cytotoxicity of A$\beta$. The influence depends an the concentration of the D-peptide and the fibril formation state of A$\beta$. The results of the cytotoxicity assays could not be explained based an the nucleations-elongations-modell by Lansbury et al. (consisting of two steps: building of a aggregation nucleus and elongation of fibrils) (Jarrett et al., 1993 ; Jarrett and Lansbury, 1993; Harper and Lansbury, 1997). An interpretation of all results of the cytotoxicity tests becomes possible by consideration of an extended model by Harper et al. which adjuLansbury, 1993; Harper and Lansbury, 1997). An interpretation of all results of the cytotoxicity tests becomes possible by consideration of an extended model by Harper et al.. which adjusts protofilaments (Harper et al., 1999). Thereby an influence of D-Pepl to the aggregation of ALansbury, 1993; Harper and Lansbury, 1997). An interpretation of all results of the cytotoxicity tests becomes possible by consideration of an extended model by Harper et al.. which adjusts protofilaments (Harper et al., 1999). Thereby an influence of D-Pepl to the aggregation of $\beta$ as well as different mechanisms for toxicity of protofilaments and fibrils was assumed

ELISA.

<p>Optical density (OD) at 450 nm measured at 2.5 h of pNPP incubation. OD for the different compounds at different concentrations is given. A and B illustrate the ability of the compounds to recognize Aβ fibrils. They indicate two series of experiments performed with following compounds A: ACI-80-Kφ to ACI-86-Kφ. ACI-80 without φ-label was run as a control. B: ACI-87-Kφ to ACI-89-Kφ, as well as fluorinated derivatives. ACI-80-Kφ, ACI-82-Kφ and ACI-83-Kφ were included as controls. C and D illustrate the ability of the compounds to recognize peptide film which largely consists of Aβ monomers.</p

Surface plasmon resonance analysis of the interaction between immobilized Aβ1–42 fibrils and ACI-80-Kφ and various derivatives (Kφ presents a lysine (K) covalently linked to a fluorescein isothiocyanate (φ).

<p>ACI-80 derivatives were solved in running buffer (PBS, pH 7.4). The injected volume of ACI-80 derivatives was 10 µl of a 50 µg/ml concentration using a flow rate of 5 µl/min. The response of ACI-80-Kφ in resonance units [RU] was defined as 100%. Values >100% denote increased Aβ interaction of the ACI-80 derivative in comparison to ACI-80-Kφ. All derivatives were φ-labeled. Only the variations in comparison to ACI-80-Kφ are indicated in the figure.</p

List of investigated D-enantiomeric peptide compounds.

<p>Modifications in the original amino acid sequence of ACI-80 are printed in bold. Amino acid residues are given in the one-letter-code. All amino-acids are D-enantiomers. Kφ presents a lysine (K) linked to a fluorescein isothiocyanate (φ).</p

Results for compound – Aβ fibril interactions obtained with the heterogeneous ligand model.

<p>Results for compound – Aβ fibril interactions obtained with the heterogeneous ligand model.</p

ELISA: Mean binding values for compounds with concentration of 10 µg/ml.

<p>All values were compared to that of ACI-80-Kφ. Compound binding to compound film, containing predominantly monomers and to fibrils was measured. Average values of two or three experiments unless marked otherwise. *value of one single experiment only. Kφ presents a lysine (K) linked to a fluorescein isothiocyanate (φ).</p

Photomicroscope images of mouse brain sections (female APP (V717I) × PS1 (A246E), age 24.3 months) in light microscope.

<p>Overview (left panel) and higher magnification (right panel). The brain slices were incubated with ACI-89-Kφ-peptide binding to plaques was visualized using an anti-fluorecein isothiocyanate 1 antibody and alkaline phosphatase as chromogenic detection. This revealed the high sensitivity of this method and the presence of abundant plaques in the tg mouse brain.</p