Optimisation of BACE1 inhibition of tripartite structures by modification of membrane anchors, spacers and pharmacophores – development of potential agents for the treatment of Alzheimer's disease

Systematic variation of membrane anchor, spacer and pharmacophore building blocks leads to an optimisation of the inhibitory effect of tripartite structures towards BACE1-induced cleavage of the amyloid precursor protein (APP).Dieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFG-geförderten) Allianz- bzw. Nationallizenz frei zugänglich

The versatile functions of complement C3-derived ligands

The complement system is a major component of immune defense. Activation of the complement cascade by foreign substances and altered self-structures may lead to the elimination of the activating agent, and during the enzymatic cascade, several biologically active fragments are generated. Most immune regulatory effects of complement are mediated by the activation products of C3, the central component. The indispensable role of C3 in opsonic phagocytosis as well as in the regulation of humoral immune response is known for long, while the involvement of complement in T-cell biology have been revealed in the past few years. In this review, we discuss the immune modulatory functions of C3-derived fragments focusing on their role in processes which have not been summarized so far. The importance of locally synthesized complement will receive special emphasis, as several immunological processes take place in tissues, where hepatocyte-derived complement components might not be available at high concentrations. We also aim to call the attention to important differences between human and mouse systems regarding C3-mediated processes. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Lt

Magnetic dipole excitations of 50^{50}Cr

The low-lying $M1$-strength of the open-shell nucleus $^{50}$Cr has been studied with the method of nuclear resonance fluorescence up to 9.7 MeV, using bremsstrahlung at the superconducting Darmstadt linear electron accelerator S-DALINAC and Compton backscattered photons at the High Intensity $\gamma$-ray Source (HI$\gamma$S) facility between 6 and 9.7 MeV of the initial photon energy. Fifteen $1^{+}$ states have been observed between 3.6 and 9.7 MeV. Following our analysis, the lowest $1^{+}$ state at 3.6 MeV can be considered as an isovector orbital mode with some spin admixture. The obtained results generally match the estimations and trends typical for the scissors-like mode. Detailed calculations within the Skyrme Quasiparticle Random-Phase-Approximation method and the Large-Scale Shell Model justify our conclusions. The calculated distributions of the orbital current for the lowest $1^{+}$-state suggest the schematic view of Lipparini and Stringari (isovector rotation-like oscillations inside the rigid surface) rather than the scissors-like picture of Lo Iudice and Palumbo. The spin M1 resonance is shown to be mainly generated by spin-flip transitions between the orbitals of the $fp$-shell.Comment: Accepted in PRC as a regular articl

Dipole response of Rb-87 and its impact on the Rb-86(n, gamma) Rb-87 cross section

Background: Detailed information on the low-lying dipole response in atomic nuclei along isotonic or isotopic chains is well suited to systematically investigate the structure and evolution of the pygmy dipole resonance (PDR). Moreover, the dipole strength below and around the neutron separation energy S-n has impact on statistical model calculations for nucleosynthesis processes. Purpose: The photon strength function (PSF) of Rb-87, which is directly connected to the photoabsorption cross section, is a crucial input for statistical model calculations constraining the Maxwellian-averaged cross section (MACS) of the neutron capture of the unstable s-process branching-point nucleus Rb-86. Within this work, the photoabsorption cross section is investigated. Methods: The photoabsorption cross section of the N = 50 nucleus Rb-87 was determined from photon-scattering experiments via the nuclear resonance fluorescence (NRF) technique. Bremsstrahlung beams at the gamma ELBE facility in conjunction with monoenergetic photon beams at the HI gamma S facility were used to determine the integrated cross sections I-s of isolated states as well as the averaged cross section as function of the excitation energy. Decays to the ground state were disentangled from decays to first low-lying excited states. Statistical and experimental approaches for the gamma-decay properties at various excitation energies were applied. The linearly polarized photon beams at HI gamma S provide information on the ratio of electric and magnetic type of radiation. Results: Within this work, more than 200 ground-state decays and associated levels in Rb-87 were identified. Moreover, transitions below the sensitivity limit of the state-by-state analysis were taken into account via a statistical approach from the bremsstrahlung data as well as model-independently from the HI gamma S data. The photoabsorption cross sections at various excitation energies were determined. The dipole response between 6 and 10 MeV of Rb-87 is in agreement with assuming contributions of electric multipolarity, only. Conclusions: The photoabsorption cross section of Rb-87 does not contradict with the trend of decreasing E1 strength with increasing proton number along the N = 50 isotonic chain but might also be associated with a constant trend. The experimental gamma decay at various excitation energies of the HI gamma S data supports the statistical approach but does not provide a stringent proof due to the limited sensitivity in the decay channels. The additional E1 strength observed in the present experiments significantly enhances the MACSs compared only to recent microscopic HFB+QRPA (Hartree-Fock-Bogoliubov plus quasiparticle random-phase approximation) calculations using the D1M interaction. Moreover, theoretical estimations provided by the KADoNiS project could be significantly improved

Photo-response of the N=Z nucleus 24Mg

AbstractThe electric E1 and magnetic M1 dipole responses of the $$N=Z$$ N = Z nucleus $$^{24}$$ 24 Mg were investigated in an inelastic photon scattering experiment. The 13.0 MeV electrons, which were used to produce the unpolarised bremsstrahlung in the entrance channel of the $$^{24}$$ 24 Mg($$\gamma ,\gamma ^{\prime }$$ γ , γ ′ ) reaction, were delivered by the ELBE accelerator of the Helmholtz-Zentrum Dresden-Rossendorf. The collimated bremsstrahlung photons excited one $$J^{\pi }=1^-$$ J π = 1 - , four $$J^{\pi }=1^+$$ J π = 1 + , and six $$J^{\pi }=2^+$$ J π = 2 + states in $$^{24}$$ 24 Mg. De-excitation $$\gamma$$ γ rays were detected using the four high-purity germanium detectors of the $$\gamma$$ γ ELBE setup, which is dedicated to nuclear resonance fluorescence experiments. In the energy region up to 13.0 MeV a total $$B(M1)\uparrow = 2.7(3)~\mu _N^2$$ B ( M 1 ) ↑ = 2.7 ( 3 ) μ N 2 is observed, but this $$N=Z$$ N = Z nucleus exhibits only marginal E1 strength of less than $$\sum B(E1)\uparrow \le 0.61 \times 10^{-3}$$ ∑ B ( E 1 ) ↑ ≤ 0.61 × 10 - 3  e$$^2 \,$$ 2 fm$$^2$$ 2 . The $$B(\varPi 1, 1^{\pi }_i \rightarrow 2^+_1)/B(\varPi 1, 1^{\pi }_i \rightarrow 0^+_{gs})$$ B ( Π 1 , 1 i π → 2 1 + ) / B ( Π 1 , 1 i π → 0 gs + ) branching ratios in combination with the expected results from the Alaga rules demonstrate that K is a good approximative quantum number for $$^{24}$$ 24 Mg. The use of the known $$\rho ^2(E0, 0^+_2 \rightarrow 0^+_{gs})$$ ρ 2 ( E 0 , 0 2 + → 0 gs + ) strength and the measured $$B(M1, 1^+ \rightarrow 0^+_2)/B(M1, 1^+ \rightarrow 0^+_{gs})$$ B ( M 1 , 1 + → 0 2 + ) / B ( M 1 , 1 + → 0 gs + ) branching ratio of the 10.712 MeV $$1^+$$ 1 + level allows, in a two-state mixing model, an extraction of the difference $$\varDelta \beta _2^2$$ Δ β 2 2 between the prolate ground-state structure and shape-coexisting superdeformed structure built upon the 6432-keV $$0^+_2$$ 0 2 + level.</jats:p

Integrated geophysical-petrological modeling of the lithosphere and sublithospheric upper mantle: Methodology and applications

A combined geophysical-petrological methodology to study the thermal, compositional, density, and seismological structure of lithospheric/sublithospheric domains is presented. A new finite-element code (LitMod) is used to produce 2-D forward models from the surface to the 410-km discontinuity. The code combines data from petrology, mineral physics, and geophysical observables within a self-consistent framework. The final result is a lithospheric/sublithospheric model that simultaneously fits all geophysical observables and consequently reduces the uncertainties associated with the modeling of these observables alone or in pairs, as is commonly done. The method is illustrated by applying it to both oceanic and continental domains. We show that anelastic attenuation and uncertainties in seismic data make it unfeasible to identify compositional variations in the lithospheric mantle from seismic studies only. In the case of oceanic lithosphere, plates with thermal thicknesses of 105 ± 5 km satisfy geophysical and petrological constraints. We find that Vp are more sensitive to phase transitions than Vs, particularly in the case of the spinel-garnet transition. A low-velocity zone with absolute velocities and gradients comparable to those observed below ocean basins is an invariable output of our oceanic models, even when no melt effects are included. In the case of the Archean subcontinental lithospheric mantle, we show that ‘‘typical’’ depleted compositions (and their spatial distribution) previously thought to be representative of these mantle sections are compatible neither with geophysical nor with petrological data. A cratonic keel model consisting of (1) strongly depleted material (i.e., dunitic/harzburgitic) in the first 100–160 km depth and (2) less depleted (approximately isopycnic) lower section extending down to 220–300 km depth is necessary to satisfy elevation, geoid, SHF, seismic velocities, and petrological constraints. This highly depleted (viscous) upper layer, and its chemical isolation, may play a key role in the longevity and stability of cratons.This work was supported by the Spanish research projects 01-LECEMA22F- EUROMARGINS-ESF, CTM2005-08071-C03-03/ MAR, and Consolider TopoIberia CSD2006-00041 (J.C.A. and M.F.), NSERC (Natural Sciences and Engineering Research Council of Canada) grants (G.R.), and ARC and Macquarie University grants (W.L.G.).Peer reviewe