Chromophoric Barbituric Acid Derivatives with Adjustable Hydrogen-Bonding Patterns as Component for Supramolecular Structures

Summary: The barbituric acid moiety of the presented dyes shows multifunctional properties like acidochromism, solvatochromism, and adjustable hydrogen-bonding pattern for molecular recognition. Hydrogen-bonding ability, acidity and solvatochromic effects are studied for a series of N-alkyl substituted 5-(4-nitrophenyl)-barbiturates. Solvatochromism and metal ion complexation are also investigated using chromophoric thiobarbituric acid derivatives.     

Evaluation of 3- and 4-Phenoxybenzamides as Selective Inhibitors of the Mono-ADP-Ribosyltransferase PARP10

Intracellular ADP-ribosyltransferases catalyze mono- and poly-ADP-ribosylation and affect a broad range of biological processes. The mono-ADP-ribosyltransferase PARP10 is involved in signaling and DNA repair. Previous studies identified OUL35 as a selective, cell permeable inhibitor of PARP10. We have further explored the chemical space of OUL35 by synthesizing and investigating structurally related analogs. Key synthetic steps were metal-catalyzed cross-couplings and functional group modifications. We identified 4-(4-cyanophenoxy)benzamide and 3-(4-carbamoylphenoxy)benzamide as PARP10 inhibitors with distinct selectivities. Both compounds were cell permeable and interfered with PARP10 toxicity. Moreover, both revealed some inhibition of PARP2 but not PARP1, unlike clinically used PARP inhibitors, which typically inhibit both enzymes. Using crystallography and molecular modeling the binding of the compounds to different ADP-ribosyltransferases was explored regarding selectivity. Together, these studies define additional compounds that interfere with PARP10 function and thus expand our repertoire of inhibitors to further optimize selectivity and potency.     

Determination of phenylalanine and tyrosine by liquid chromatography/mass spectrometry

Phenylketonuria is a common metabolic disorder disease. Those affected appear normal at birth, but without treatment they develop severe psychomotor retardation. Throughout life, they must control their blood levels of phenylalanine (Phe) and consume a diet containing adequate amounts of Phe and tyrosine (Tyr). We have developed a liquid chromatographic/mass spectrometric (LC/MS) method for the quantitative evaluation of Phe and Tyr in food samples. This method takes advantage of the good separation of LC and the selective and reliable quantification provided by MS in the electrospray ionization mode. The LC/MS method is very suitable for the determination of selected amino acids in various matrixes. It is sensitive to levels as low as about 0.30 ppm for Tyr and 0.70 ppm for Phe and robust. Nearly 100 nondietary food samples were analyzed by the developed method.     

An improved flow analysis-ion chromatography method for determination of cationic and anionic species at trace levels in Antarctic ice cores

A method was developed for the quantitative determination of cations and anions in Antarctic ice cores at μg L⁻¹ and sub-μg L⁻¹ levels by ion chromatography (IC), after ultra-clean decontamination procedures. Strict manipulation and decontamination procedures were used in sub-sampling, in order to minimise sample contamination. Na⁺, NH₄⁺, K⁺, Mg²⁺ and Ca²⁺ were determined by 12-min isocratic elution (H₂SO₄ eluent). Contemporaneously, in a parallel device, F⁻, MSA (methanesulfonic acid), Cl⁻, NO₃⁻ and SO₄²⁻ were analysed in a single 12-min run with multiple-step elution using Na₂CO₃/NaHCO₃ as eluent. Melted ice samples were pumped from their still-closed containers (polystyrene accuvettes with polyethylene caps), shared between the two ion chromatographic systems, online filtered (0.45 μm Teflon membrane) and pre-concentrated (anions and cations pre-concentration columns) using a flow analysis system, thus avoiding uptake of contaminants from the laboratory atmosphere. Sensitivity, linear range, reproducibility and detection limit were evaluated for each chemical species. Anion or cation detection limits ranged from 0.01 to 0.15 μg L⁻¹ by using a relatively small sample volume (1.5 mL). Such values are significantly lower than those reported in literature for almost all the components. These methods were successfully applied to the analysis of cations and anions at trace levels in the Dome C ice core. The composition of the atmospheric aerosol for the last 850 kyr was reconstructed by high-resolution continuous chemical stratigraphies. Concentration trends in the last nine glacial-interglacial climatic cycles were shown and briefly discussed.     

Quantum Logics with Given Centers and Variable State Spaces

We ask which logics with a given center allowfor enlargements with an arbitrary state space. We showthat these are precisely those logics the center ofwhich possesses a two-valued state and the state space of which is nonempty. This extends theresults of Binder as well as our previous results andsupplements the results of Foulis and Ptak and ofNavara, Ptak, and Rogalewicz. We also comment on some related questions.     

A priori error estimates for upwind finite volume schemes for two-dimensional linear convection diffusion problems

It is still an open problem to prove a priori error estimates for finite volume schemes of higher order MUSCL type, including limiters, on unstructured meshes, which show some improvement compared to first order schemes. In this paper we use these higher order schemes for the discretization of convection dominated elliptic problems in a convex bounded domain Ω in R² and we can prove such kind of an a priori error estimate. In the part of the estimate, which refers to the discretization of the convective term, we gain h^1/2. Although the original problem is linear, the numerical problem becomes nonlinear, due to MUSCL type reconstruction/limiter technique.     

Structural and dynamical characterization of fibrils from a disease-associated alanine expansion domain using proteolysis and solid-state NMR spectroscopy

The nuclear poly(A) binding protein PABPN1 possesses a natural 10 alanine stretch that can be extended to 17 Ala by codon expansion. The expansions are associated with the disease oculopharyngeal muscular dystrophy (OPMD), which is characterized histopathologically by intranuclear fibrillar deposits. Here, we have studied the Ala extended fibrillar N-terminal fragment of PABPN1, (N-(+7)Ala), comprising 152 amino acids. At natural abundance, cross-polarized 13C MAS NMR spectra are dominated by the three Ala signals with characteristic beta-sheet chemical shifts. In contrast, directly polarized 13C MAS spectra show a multitude of narrow lines, suggesting a large portion of highly mobile sites. Proteolytic cleavage of the protein combined with MALDI-TOF mass spectrometry revealed a protease-resistant peptide encompassing residues 13/14 to 50-52 with the poly-Ala stretch in the center. Measurements of the 1H-13Calpha dipolar couplings of 13C/15N-labeled N-(+7)Ala revealed high order parameters of 0.77 for the poly-Ala stretch of the fibril, while the majority of the residues of N-(+7)Ala exhibited very low order parameters between 0.06 and 0.15. Only some Gly residues that are flanking the Ala-rich region had significant order parameters of 0.47. Thus, site-specific dynamic mapping represents a useful tool to identify the topology of fibrillar proteins.