Syntheses of C-5-spirocyclic C-glycoside SGLT2 inhibitors

Several syntheses of C-5-spirocycle-containing C-glycosides are discussed. A multigram-scale synthesis capitalizing on a one-pot aldol-Cannizzaro sequence is described. Spiro oxetane formation using an unprotected penta-ol C-glycoside as substrate is also exemplified. Functional assessment of these compounds for potency and selectivity was evaluated at human SGLT2 and SGLT1.     

Speciation Analyses by Differential Atomization Using a Platinum Loop-Carbon Bed Dual Stage Atomizer

It has become increasingly evident in recent years that the toxicity of a metal is dependent not only on its concentration but also on its particular chemical form. The chemical form of an element determines metabolic effects and therefore its toxicity. Speciation of heavy metals may also influence the synergistic effects of groups of elements in the biospheres¹.     

Optimal adaptive replacement in a renewal process

In this paper we present an exact method for computing the Weibull renewal function and its derivative for application in maintenance optimization. The computational method provides a solid extension to previous work by which an approximation to the renewal function was used in a Bayesian approach to determine optimal replacement times. In the maintenance scenario, under the assumption an item is replaced by a new one upon failure, the underlying process between planned replacement times is a renewal process. The Bayesian approach takes into account failure and survival information at each planned replacement stage to update the optimal time until the next planned replacement. To provide a simple approach to carry out in practice, we limit the decision process to a one‐step optimization problem in the sequential decision problem. We make the Weibull assumption for the lifetime distribution of an item and calculate accurately the renewal function and its derivative. A method for finding zeros of a function is adapted to the maintenance optimization problem, making use of the availability of the derivative of the renewal function. Furthermore, we develop the maximum likelihood estimate version of the Bayesian approach and illustrate it with simulated examples. The maintenance algorithm retains the adaptive concept of the Bayesian methodology but reduces the computational need. Copyright © 2014 John Wiley & Sons, Ltd.     

Indecomposability in inverse limits with set-valued functions

In this paper, we develop a sufficient condition for the inverse limit of upper semi-continuous functions to be an indecomposable continuum. This condition generalizes and extends those of Ingram and Varagona. Additionally, we demonstrate a method of constructing upper semi-continuous functions whose inverse limit has the full projection property.     

Topologically weakly mixing homeomorphisms of the Klein bottle that are uniformly rigid

In this paper we prove that there is a large family of topologically weakly mixing homeomorphisms of the Klein bottle that are uniformly rigid. We do this by viewing the Klein bottle as the quotient of the two-torus by an appropriate group action and producing topologically weakly mixing homeomorphisms of the two-torus that are uniformly rigid and equivariant with respect to the action.     

Maximal number of distinct H-eigenpairs for a two-dimensional real tensor

Based on the generalized characteristic polynomial introduced by J. Canny in Generalized characteristic polynomials [J. Symbolic Comput., 1990, 9(3): 241–250], it is immediate that for any m-order n-dimensional real tensor, the number of distinct H-eigenvalues is less than or equal to n(m?1) ^n?1. However, there is no known bounds on the maximal number of distinct Heigenvectors in general. We prove that for any m ? 2, an m-order 2-dimensional tensor A exists such that A has 2(m ? 1) distinct H-eigenpairs. We give examples of 4-order 2-dimensional tensors with six distinct H-eigenvalues as well as six distinct H-eigenvectors. We demonstrate the structure of eigenpairs for a higher order tensor is far more complicated than that of a matrix. Furthermore, we introduce a new class of weakly symmetric tensors, called p-symmetric tensors, and show under certain conditions, p-symmetry will effectively reduce the maximal number of distinct H-eigenvectors for a given two-dimensional tensor. Lastly, we provide a complete classification of the H-eigenvectors of a given 4-order 2-dimensional nonnegative p-symmetric tensor. Additionally, we give sufficient conditions which prevent a given 4-order 2-dimensional nonnegative irreducible weakly symmetric tensor from possessing six pairwise distinct H-eigenvectors.     

Optimization of two methods for the analysis of hydrogen peroxide: high performance liquid chromatography with fluorescence detection and high performance liquid chromatography with electrochemical detection in direct current mode

Two complementary methods were optimized for the separation and detection of trace levels of hydrogen peroxide. The first method utilized reversed-phase high-performance liquid chromatography with fluorescence detection (HPLC-FD). With this approach, hydrogen peroxide was detected based upon its participation in the hemin-catalyzed oxidation of p-hydroxyphenylacetic acid to yield the fluorescent dimer. The second method utilized high performance liquid chromatography with electrochemical detection (HPLC-ED). With this approach, hydrogen peroxide was detected based upon its oxidation at a gold working electrode at an applied potential of 400 mV vs. hydrogen reference electrode (Pd/H(2)). Both methods were linear across the range of 15-300 μM, and the electrochemical method was linear across a wider range of 7.4-15,000 μM. The limit of detection for hydrogen peroxide was 6 μM by HPLC/FD, and 0.6 μM by HPLC/ED. A series of organic peroxides and inorganic ions were evaluated for their potential to interfere with the detection of hydrogen peroxide. Studies investigating the recovery of hydrogen peroxide with three different extraction protocols were also performed. Post-blast debris from the detonation of a mixture of concentrated hydrogen peroxide with nitromethane was analyzed on both systems. Hydrogen peroxide residues were successfully detected on this post-blast debris.     

Does chemical cross-linking with NHS esters reflect the chemical equilibrium of protein-protein noncovalent interactions in solution?

Chemical cross-linking in combination with mass spectrometry has emerged as a powerful tool to study noncovalent protein complexes. Nevertheless, there are still many questions to answer. Does the amount of detected cross-linked complex correlate with the amount of protein complex in solution? In which concentration and affinity range is specific cross-linking possible? To answer these questions, we performed systematic cross-linking studies with two complexes, using the N-hydroxysuccinimidyl ester disuccinimidyl suberate (DSS): (1) NCoA-1 and mutants of the interacting peptide STAT6Y, covering a K_D range of 30 nM to >25 μM, and (2) α-thrombin and basic pancreatic trypsin inhibitor (BPTI), a system that shows a buffer-dependent K_D value between 100 and 320 μM. Samples were analyzed by matrix-assisted laser desorption/ionization mass spectrometry (MALDI-MS). For NCoA-1· STAT6Y, a good correlation between the amount of cross-linked species and the calculated fraction of complex present in solution was observed. Thus, chemical cross-linking in combination with MALDI-MS can be used to rank binding affinities. For the mid-affinity range up to about K_D ≈ 25 μM, experiments with a nonbinding peptide and studies of the concentration dependence showed that only specific complexes undergo cross-linking with DSS. To study in which affinity range specific cross-linking can be applied, the weak α-thrombin · BPTI complex was investigated. We found that the detected complex is a nonspecifically cross-linked species. Consequently, based on the experimental approach used in this study, chemical cross-linking is not suitable for studying low-affinity complexes with K_D ? 25 μM.