Accurate and precise spectrochemical analysis of Bi-Pb-Sr-Ca-Cu-O high-temperature superconductor materials

For quality tests of ceramic Bi-Pb-Sr-Ca-Cu-O superconductor materials (precursors and final products) accurate stoichiometric determinations of the metallic major components are necessary. Three methods were developed during the last decade in our group. Their properties and the results obtained are compared. The first classical analytical procedure requires to much manpower. The second combined chemical-spectrometric procedure is a routine method today, but also unsuitable for rapid tests. A new fully spectrometric procedure was recently developed using a simultaneously working Echelle spectrometer with CID detector, autosampler and a special self-made data evaluation software. The basis of this method are multiline measurements of each analyte element, a new method of spectral line selection for main component precision determinations, multi-component calibrations, and frequent external standardizations. For this method the sum of the confidence intervals of all element determinations was less than 1%, and no systematic error was detected.     

Feasibility of narrow-line cooling in optical dipole traps

We have investigated the influence of narrow-line laser cooling on the loading of Ca atoms into optical dipole traps. To describe the narrow-line cooling of alkaline-earth atoms in combination with optical dipole trapping, we have developed a model that takes into account the light shifts of the cooling transition in three dimensions. The model is compared with two experimental realizations of optical dipole traps for calcium at the wavelengths 514 nm and 10.6 μm.     

An improved criterion for absence of eigenvalues of one-dimensional Schrödinger operators

We study one-dimensional Schrödinger operators with complex measures as potentials and present an improved criterion for absence of eigenvalues which involves a weak local periodicity condition. As an application we consider quasiperiodic measures as potentials. (© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim)     

Experimental electron density of the complex carbides Sc3[Fe(C2)(2)] and Sc3[Co(C2)(2)

The nature of chemical bonding in the complex carbides Sc3[Fe(C2)2] (1) and Sc3[Co(C2)2] (2) has been explored by combined experimental and theoretical charge density studies. The structures of these organometallic carbides contain one-dimensional infinite TC4 (T = Fe, Co) ribbons embedded in a scandium matrix. Bonding in 1 and 2 was studied experimentally by multipolar refinements based on high-resolution X-ray data and compared to scalar-relativistic electronic structure calculations using the augmented spherical wave method. Besides substantial covalent T-C bonding within the TC4 ribbons, one also observes discrete Sc-C bonds of noticeable covalent character. Furthermore, our study highlights that even tiny differences in the electronic band structure of solids might be faithfully recovered in the properties of the Laplacian of the experimental electron density. In our case, the increase of the Fermi level in the organometallic Co(d9) carbide 2 relative to its isotypic Fe(d8) species 1 is reflected in the charge density picture by a significant change in the polarization pattern displayed by valence shell charge concentrations of the transition metal centers in the TC4 units. Hence, precise high-resolution X-ray diffraction data provide a reliable tool to discriminate and analyze the local electronic structures of isotypic solids, even in the presence of a severe coloring problem (Z(Fe)/Z(Co) = 26/27).     

Analysis of a high-throughput screening data set using potency-scaled molecular similarity algorithms

Molecular similarity methods for ligand-based virtual screening (VS) generally do not take compound potency as a variable or search parameter into account. We have incorporated a logarithmic potency scaling function into two conceptually distinct VS algorithms to account for relative compound potency during search calculations. A high-throughput screening (HTS) data set containing cathepsin B inhibitors was analyzed to evaluate the effects of potency scaling. Sets of template compounds were randomly selected from the HTS data and used to search for hits having varying potency levels in the presence or absence of potency scaling. Enrichment of potent compounds in small subsets of the HTS data set was observed as a consequence of potency scaling. In part, observed enrichments could be rationalized as a result of recentering chemical reference space on a subspace populated by potent compounds. Our findings suggest that VS calculations using multiple reference compounds can be directed toward the preferential detection of potent database hits by scaling compound contributions according to potency differences.     

Design, synthesis, and validation of a β-turn mimetic library targeting protein-protein and peptide-receptor interactions

The design and synthesis of a β-turn mimetic library as a key component of a small-molecule library targeting the major recognition motifs involved in protein-protein interactions is described. Analysis of a geometric characterization of 10,245 β-turns in the protein data bank (PDB) suggested that trans-pyrrolidine-3,4-dicarboxamide could serve as an effective and synthetically accessible library template. This was confirmed by initially screening select compounds against a series of peptide-activated GPCRs that recognize a β-turn structure in their endogenous ligands. This validation study was highlighted by identification of both nonbasic and basic small molecules with high affinities (K(i) = 390 and 23 nM, respectively) for the κ-opioid receptor (KOR). Consistent with the screening capabilities of collaborators and following the design validation, the complete library was assembled as 210 mixtures of 20 compounds, providing a total of 4200 compounds designed to mimic all possible permutations of 3 of the 4 residues in a naturally occurring β-turn. Unique to the design and because of the C(2) symmetry of the template, a typical 20 × 20 × 20-mix (8000 compounds prepared as 400 mixtures of 20 compounds) needed to represent 20 variations in the side chains of three amino acid residues reduces to a 210 × 20-mix, thereby simplifying the library synthesis and subsequent screening. The library was prepared using a solution-phase synthetic protocol with liquid-liquid or liquid-solid extractions for purification and conducted on a scale that insures its long-term availability for screening campaigns. Screening the library against the human opioid receptors (KOR, MOR, and DOR) identified not only the activity of library members expected to mimic the opioid receptor peptide ligands but also additional side-chain combinations that provided enhanced receptor binding selectivities (>100-fold) and affinities (as low as K(i) = 80 nM for KOR). A key insight to emerge from the studies is that the phenol of Tyr in endogenous ligands bearing the H-Tyr-Pro-Trp/Phe-Phe-NH(2) β-turn is important for MOR binding but may not be important for KOR (accommodated, but not preferred) and that the resulting selectivity for KOR observed with its removal can be increased by replacing the phenol OH with a chlorine substituent, further enhancing KOR affinity.     

Introduction of the conditional correlated Bernoulli model of similarity value distributions and its application to the prospective prediction of fingerprint search performance

A statistical approach named the conditional correlated Bernoulli model is introduced for modeling of similarity scores and predicting the potential of fingerprint search calculations to identify active compounds. Fingerprint features are rationalized as dependent Bernoulli variables and conditional distributions of Tanimoto similarity values of database compounds given a reference molecule are assessed. The conditional correlated Bernoulli model is utilized in the context of virtual screening to estimate the position of a compound obtaining a certain similarity value in a database ranking. Through the generation of receiver operating characteristic curves from cumulative distribution functions of conditional similarity values for known active and random database compounds, one can predict how successful a fingerprint search might be. The comparison of curves for different fingerprints makes it possible to identify fingerprints that are most likely to identify new active molecules in a database search given a set of known reference molecules.     

Monitoring cellular responses upon fatty acid exposure by Fourier transform infrared spectroscopy and Raman spectroscopy

We investigated the applicability of FTIR-spectroscopy as a high throughput screening method for detection of biochemical changes in intact liver cells in bulk upon fatty acid exposure. HepG2 cells adapted to serum free (HepG2-SF) growth were exposed to four different fatty acids, three octadecenoic acids, differing in cis/trans-configuration or double bond position (oleic acid, elaidic acid and vaccenic acid) as well as palmitic acid in three days. High throughput FTIR spectroscopic measurements on dried films of intact cells showed spectra with high signal-to-noise ratio and great reproducibility. When applying principal component analysis (PCA) a clear discrimination between fatty acid exposures was observed. Higher levels of triacylglycerides were accumulated in cells exposed to elaidic acid than when exposed to the other fatty acids; the least accumulation appeared to be in cells exposed to palmitic acid. An increased absorption at ~966 cm(-1) corresponding to trans-double bond was detected upon elaidic acid exposure but not upon vaccenic acid exposure. Instead, upon vaccenic acid exposure two new absorption bands were observed at 981 and 946 cm(-1) due to the presence of double bond conjugation. Raman spectroscopy on single cells, with and without treatment by vaccenic acid, confirmed the presence of conjugation. By fatty acid composition analysis, the conjugation was further specified to be conjugated linoleic acid (CLA) isomers. Thus, instead of being preserved as a monounsaturated fatty acid, vaccenic acid was converted into CLA in HepG2 cells. The results demonstrate the applicability of high-throughput FTIR spectroscopy as an explorative method in in vitro systems from which biologically relevant hypotheses can be generated and further investigated.     

Direct determination of the intracellular oxidation state of plutonium

Microprobe X-ray absorption near edge structure (μ-XANES) measurements were used to determine directly, for the first time, the oxidation state of intracellular plutonium in individual 0.1-μm(2) areas within single rat pheochromocytoma cells (PC12). The living cells were incubated in vitro for 3 h in the presence of Pu added to the media in different oxidation states (Pu(III), Pu(IV), and Pu(VI)) and in different chemical forms. Regardless of the initial oxidation state or chemical form of Pu presented to the cells, the XANES spectra of the intracellular Pu deposits were always consistent with tetravalent Pu even though the intracellular milieu is generally reducing.