Inhibiting and Reversing Amyloid‐β Peptide (1–40) Fibril Formation with Gramicidin S and Engineered Analogues

In Alzheimer’s disease, amyloid‐β (Aβ) peptides aggregate into extracellular fibrillar deposits. Although these deposits may not be the prime cause of the neurodegeneration that characterizes this disease, inhibition or dissolution of amyloid fibril formation by Aβ peptides is likely to affect its development. ThT fluorescence measurements and AFM images showed that the natural antibiotic gramicidin S significantly inhibited Aβ amyloid formation in vitro and could dissolve amyloids that had formed in the absence of the antibiotic. In silico docking suggested that gramicidin S, a cyclic decapeptide that adopts a β‐sheet conformation, binds to the Aβ peptide hairpin‐stacked fibril through β‐sheet interactions. This may explain why gramicidin S reduces fibril formation. Analogues of gramicidin S were also tested. An analogue with a potency that was four‐times higher than that of the natural product was identified.     

A Space–Time Integral Estimate For A Large Data Semi-linear Wave Equation on the Schwarzschild Manifold

We consider the wave equation with in . The wave equation on a spherically symmetric manifold with a single closed geodesic surface or on the exterior of the Schwarzschild manifold can be reduced to this form. Using a smoothed Morawetz estimate which does not require a spherical harmonic decomposition, we show that there is decay in for initial data in the energy class, even if the initial data is large. This requires certain conditions on the potentials V, V _L and f. We show that a key condition on the weight in the smoothed Morawetz estimate can be reduced to an ODE condition, which is verified numerically.      

Incorporation of nonmethyl branches by isoprenoid-like logic: multiple beta-alkylation events in the biosynthesis of myxovirescin A1

Several polyketide secondary metabolites are predicted to undergo isoprenoid-like beta-alkylations during biosynthesis. One such secondary metabolite is myxovirescin A1, produced by Myxococcus xanthus. Myxovirescin is of special interest in that it appears to undergo two distinct beta-alkylations. Additionally, the myxovirescin biosynthetic gene cluster lacks tandem thiolation domains required in the synthesis of other beta-branched secondary metabolites. To probe the origins of the beta-branches in myxovirescin, we heterologously overexpressed the proteins predicted to be responsible for myxovirescin beta-alkylation and reconstituted their activities in vitro on model substrates. Our results confirm that myxovirescin undergoes two isoprenoid-like beta-alkylations during its biosynthesis, including an unprecedented beta-ethylation. The study of its biosynthesis should shed light on the scope and requirements for isoprenoid-like biosynthetic logic in a polyketide context.     

Yb valence states in YbC2: a HERFD-XANES spectroscopic investigation

The valence state of Yb in YbC(2) was analyzed using high-energy-resolution fluorescence detection (HERFD) X-ray absorption near-edge structure (XANES) spectroscopy and time-of-flight neutron powder diffraction to clarify a controversy in the literature. The unit cell volume of YbC(2) suggests a mixed Yb valence, which was formerly determined to be 2.8 by magnetization measurements and paramagnetic neutron scattering techniques. However, the nature of the intermediate valence was not clearly established. Both homogeneous and heterogeneous mixed valences were assumed in different publications. The temperature-dependent behavior of the valence state was only predicted, albeit not explicitly studied. In this work, the valence state of Yb in YbC(2) is, therefore, investigated thoroughly by HERFD-XANES spectroscopy at low and high temperatures. Our measurements result in an average Yb valence of 2.81 that is temperature-independent from 15 to 1123 K. These findings are confirmed by neutron powder diffraction experiments, which reveal a constant C-C distance of 128.7(9) pm in a temperature range from 5 to 100 K. A significant temperature dependence of the Yb valence state in YbC(2) can, therefore, be excluded by our experimental results.     

Improving the robustness in railway station areas

In order to improve the robustness of a railway system in station areas, this paper introduces an iterative approach to successively optimize the train routing through station areas and to enhance this solution by applying some changes to the timetable in a tabu search environment. We present our vision on robustness and describe how this vision can be used in practice. By introducing the spread of the trains in the objective function for the route choice and timetabling module, we improve the robustness of a railway system. Using a discrete event simulation model, the performance of our algorithms is evaluated based on a case study for the Brussels’ area. The computational results indicate an average improvement in robustness of 6.2% together with a decrease in delay propagation of about 25%. Furthermore, the effect of some measures like changing the train offer to further increase the robustness is evaluated and compared.     

Nonperturbative Quantum Field Evolution

We introduce a nonperturbative, first-principles approach to time-dependent problems in quantum field theory. In this approach, the time-evolution of quantum field configurations is calculated in real time and at the amplitude level. This method is particularly suitable for treating systems interacting with a time-dependent background field. As a test problem, we apply this approach to QED and study electron acceleration and the associated photon emission in a time- and space-dependent electromagnetic background field.     

Synthesis of sugar nucleotides by application of phosphoramidites

A new method for the construction of pyrophosphates is reported based on the coupling of a sugar phosphate and a nucleoside phosphoramidite. The in situ formed phosphate-phosphite intermediate was subsequently oxidized with tBuOOH. Three UDP-N-acetylglucosamine derivatives were prepared using this one-pot procedure in good yields.