A Hot‐Segment‐Based Approach for the Design of Cross‐Amyloid Interaction Surface Mimics as Inhibitors of Amyloid Self‐Assembly

The design of inhibitors of protein–protein interactions mediating amyloid self‐assembly is a major challenge mainly due to the dynamic nature of the involved structures and interfaces. Interactions of amyloidogenic polypeptides with other proteins are important modulators of self‐assembly. Here we present a hot‐segment‐linking approach to design a series of mimics of the IAPP cross‐amyloid interaction surface with Aβ (ISMs) as nanomolar inhibitors of amyloidogenesis and cytotoxicity of Aβ, IAPP, or both polypeptides. The nature of the linker determines ISM structure and inhibitory function including both potency and target selectivity. Importantly, ISMs effectively suppress both self‐ and cross‐seeded IAPP self‐assembly. Our results provide a novel class of highly potent peptide leads for targeting protein aggregation in Alzheimer’s disease, type 2 diabetes, or both diseases and a chemical approach to inhibit amyloid self‐assembly and pathogenic interactions of other proteins as well.     

The existence of a positive solution for nonlinear fractional differential equations with integral boundary value conditions

In this paper, first, we consider the existence of a positive solution for the nonlinear fractional differential equation boundary value problem where 0≤λ < 1,^CD^α is the Caputo's differential operator of order α, and f:[0,1] × [0,∞)→[0,∞) is a continuous function. Using some cone theoretic techniques, we deduce a general existence theorem for this problem. Then, we consider two following more general problems for arbitrary α, 1≤n < α≤n + 1: Problem 1: where , 0≤λ < k + 1; Problem 2: where 0≤λ≤α and D^α is the Riemann–Liouville fractional derivative of order α. For these problems, we give existence results, which improve recent results in the literature. Copyright © 2016 John Wiley & Sons, Ltd.     

Liquid-phase epitaxy of multicomponent layer-based porous coordination polymer thin films of [M(L)(P)0.5] type: importance of deposition sequence on the oriented growth

The progressive liquid-phase layer-by-layer (LbL) growth of anisotropic multicomponent layer-based porous coordination polymers (PCPs) of the general formula [M(L)(P)(0.5)] (M: Cu(2+), Zn(2+); L: dicarboxylate linker; P: dinitrogen pillar ligand) was investigated by using either pyridyl- or carboxyl-terminated self-assembled monolayers (SAMs) on gold substrates as templates. It was found that the deposition of smooth, highly crystalline, and oriented multilayer films of these PCPs depends on the conditions at the early growth cycles. In the case of a two-step process with an equimolar mixture of L and P, growth along the [001] direction is strongly preferred. However, employing a three-step scheme with full separation of all components allows deposition along the [100] direction on carboxyl-terminated SAMs. Interestingly, the growth of additional layers on top of previously grown oriented seeding layers proved to be insensitive to the particular growth scheme and full retention of the initial orientation, either along the [001] or [100] direction, was observed. This homo- and heteroepitaxial LbL growth allows full control over the orientation and the layer sequence, including introduction of functionalized linkers and pillars.     

Further results on the least eigenvalue of connected graphs

In this paper, we identify within connected graphs of order n and size n+k (with and ) the graphs whose least eigenvalue is minimal. It is also observed that the same graphs have the largest spectral spread if n is large enough.     

Hydrolysis of serine-containing peptides at neutral pH promoted by [MoO4]2- oxyanion

Hydrolysis of the dipeptides glycylserine (GlySer), leucylserine (LeuSer), histidylserine (HisSer), glycylalanine (GlyAla), and serylglycine (SerGly) was examined in oxomolybdate solutions by means of (1)H, (13)C, and (95)Mo NMR spectroscopy. In the presence of a mixture of oxomolybdates, the hydrolysis of the peptide bond in GlySer proceeded under neutral pD conditions (pD = 7.0, 60 °C) with a rate constant of k(obs) = 5.9 × 10(-6) s(-1). NMR spectra did not show evidence of the formation of paramagnetic species, excluding the possibility of Mo(VI) reduction to Mo(V), indicating that the cleavage of the peptide bond is purely hydrolytic. The pD dependence of k(obs) exhibits a bell-shaped profile, with the fastest cleavage observed at pD 7.0. Comparison of the rate profile with the concentration profile of oxomolybdate species implicated monomolybdate MoO(4)(2-) as the kinetically active complex. Kinetics experiments at pD 7.0 using a fixed amount of GlySer and increasing amounts of MoO(4)(2-) allowed for calculation of the catalytic rate constant (k(2) = 9.25 × 10(-6) s(-1)) and the formation constant for the GlySer-MoO(4)(2-) complex (K(f) = 15.25 M(-1)). The origin of the hydrolytic activity of molybdate is most likely a combination of the polarization of amide oxygen in GlySer due to the binding to molybdate, followed by the intramolecular attack of the Ser hydroxyl group.     

Polyoxomolybdate promoted hydrolysis of a DNA-model phosphoester studied by NMR and EXAFS spectroscopy

Hydrolysis of (p-nitrophenyl)phosphate (NPP), a commonly used phosphatase model substrate, was examined in molybdate solutions by means of (1)H, (31)P, and (95)Mo NMR spectroscopy and Mo K-edge Extended X-ray Absorption Fine Structure (EXAFS) spectroscopy. At 50 °C and pD 5.1 the cleavage of the phosphoester bond in NPP proceeds with a rate constant of 2.73 × 10(-5) s(-1) representing an acceleration of nearly 3 orders of magnitude as compared to the hydrolysis measured in the absence of molybdate. The pD dependence of k(obs) exhibits a bell-shaped profile, with the fastest cleavage observed in solutions where [Mo(7)O(24)](6-) is the major species in solution. Mixing of NPP and [Mo(7)O(24)](6-) resulted in formation of these two intermediate complexes that were detected by (31)P NMR spectroscopy. Complex A was characterized by a (31)P NMR resonance at -4.27 ppm and complex B was characterized by a (31)P NMR resonance at -7.42 ppm. On the basis of the previous results from diffusion ordered NMR spectroscopy, performed with the hydrolytically inactive substrate phenylphosphonate (PhP), the structure of these two complexes was deduced to be (NPP)(2)Mo(5)O(21)(4-) (complex A) and (NPP)(2)Mo(12)O(36)(H(2)O)(6)(4-) (complex B). The pH studies point out that both complexes are hydrolytically active and lead to the hydrolysis of phosphoester bond in NPP. The NMR spectra did not show evidence of any paramagnetic species, excluding the possibility of Mo(VI) reduction to Mo(V), and indicating that the cleavage of the phosphomonoester bond is purely hydrolytic. The Mo K-edge XANES region also did not show any sign of Mo(VI) to Mo(V) reduction during the hydrolytic reaction. (95)Mo NMR and Mo K-edge EXAFS spectra measured during different stages of the hydrolytic reaction showed a gradual disappearance of [Mo(7)O(24)](6-) during the hydrolytic reaction and appearance of [P(2)Mo(5)O(23)](6-), which was the final complex observed at the end of hydrolytic reaction.     

Composite hydrogels with temperature sensitive heterogeneities: influence of gel matrix on the volume phase transition of embedded poly-(N-isopropylacrylamide) microgels

The thermo-responsive behaviour of poly-(N-isopropylacrylamide) (PNiPAM) microgels embedded in covalently cross-linked non-temperature-sensitive polyacrylamide (PAam) hydrogel matrixes with different compositions was investigated by using small angle neutron scattering (SANS). The composition of the composite hydrogel was varied by (a) increasing the cross-linker and acrylamide concentration leading to strong hydrogel matrixes and (b) by increasing the microgel concentration to obtain composite gels with an internal structure. Additionally we synthesized composite hydrogels by using γ-irradiation as initiation for the polymerisation. This leads to the formation of chemical bonds between the PNiPAM microgels and the surrounding polyacrylamide matrix. Thus it is possible to synthesize hydrogels without an additional cross-linker, as well as pure particle networks. Some samples were prepared at two different temperatures, below and above the volume phase transition temperature of PNiPAM, resulting in highly swollen or totally collapsed microgels during the incorporation step. The volume phase transition of microgels is not influenced by a hydrogel matrix with high acrylamide concentration independent of the preparation temperature. However, an increased cross-linker concentration leads to a corset like constraint on microgel swelling. Microgels, which are embedded in the collapsed state (at 50 °C), are not able to swell upon cooling, whereas microgels embedded in the swollen state can collapse upon heating. For samples with an increased microgel concentration, the close microgel packing was disturbed by the formation of the polyacrylamide matrix. The hydrogel matrix squeezes the microgels together and leads to partial aggregation. The experiments demonstrate how composite hydrogels with stimuli-sensitive heterogeneities can be prepared such that the full responsiveness of the embedded microgels is retained while the macroscopic dimensions of the gel are not affected by the volume phase transition of the microgels.     

Chemical composition and antimicrobial activity of Satureja kitaibelii essential oil against pathogenic microbial strains

Plant species Satureja kitaibelii Wierzb. ex Heuff. is used as a spice and as a natural preservative for food and herbal tea, owing to its characteristic scent and flavor as well as high antimicrobial activity. In the present study, the antimicrobial activity of isolated essential oil of S. kitaibelii was tested against a panel of 30 pathogenic microorganisms (foodborne microbes, selected multiresistant bacterial isolates from the patient wounds and dermatophyte isolates). Limonene (15.54%), p-cymene (9.99%), and borneol (8.91%) appeared as the main components in 44 identified compounds representing 98.44% of the oil. Essential oil of S. kitaibelii showed significant activity against a wide spectrum of foodborne microbes (MIC=0.18-25.5 microg mL(-1)) and multiresistant bacterial isolates (MIC=6.25-50.0 microg mL(-1)), as well as against dermatophyte strains (MIC=12.5-50.0 microg mL(-1)). These results demonstrate that S. kitaibelii essential oil could be used as a natural potential antimicrobial agent against pathogenic strains in the treatment of foodborne disease, wound and skin infections.     

Crystallographic report: 1‐[4‐(2‐Thienyl)phenyl]germatrane

In the title compound, germanium is penta‐coordinated and adopts a trigonal bipyramidal geometry. The (2‐thienyl)phenyl group and the nitrogen atom each occupy an apical position with a transannular N→Ge bond distances of 2.247(4) and 2.219(4) Å for the two independent molecules. Copyright © 2005 John Wiley & Sons, Ltd.