Development and validation of automated SPE-HPLC-MS/MS methods for the quantification of asenapine, a new antipsychotic agent, and its two major metabolites in human urine

To support the evaluation of the pharmacokinetic parameters of asenapine (ASE) in urine, we developed and validated online solid‐phase extraction high‐performance liquid chromatography methods with tandem mass spectrometry detection (SPE‐LC‐MS/MS) for the quantification of ASE and two of its major metabolites, N‐desmethylasenapine (DMA) and asenapine‐N⁺‐glucuronide (ASG). The linearity in human urine was found acceptable for quantification in a concentration range of 0.500–100 ng/mL for ASE and DMA and 10.0–3000 ng/mL for ASG, respectively. Copyright © 2012 John Wiley & Sons, Ltd.     

Simultaneous analysis of plasma and CSF by NMR and hierarchical models fusion

Because cerebrospinal fluid (CSF) is the biofluid which interacts most closely with the central nervous system, it holds promise as a reporter of neurological disease, for example multiple sclerosis (MScl). To characterize the metabolomics profile of neuroinflammatory aspects of this disease we studied an animal model of MScl-experimental autoimmune/allergic encephalomyelitis (EAE). Because CSF also exchanges metabolites with blood via the blood-brain barrier, malfunctions occurring in the CNS may be reflected in the biochemical composition of blood plasma. The combination of blood plasma and CSF provides more complete information about the disease. Both biofluids can be studied by use of NMR spectroscopy. It is then necessary to perform combined analysis of the two different datasets. Mid-level data fusion was therefore applied to blood plasma and CSF datasets. First, relevant information was extracted from each biofluid dataset by use of linear support vector machine recursive feature elimination. The selected variables from each dataset were concatenated for joint analysis by partial least squares discriminant analysis (PLS-DA). The combined metabolomics information from plasma and CSF enables more efficient and reliable discrimination of the onset of EAE. Second, we introduced hierarchical models fusion, in which previously developed PLS-DA models are hierarchically combined. We show that this approach enables neuroinflamed rats (even on the day of onset) to be distinguished from either healthy or peripherally inflamed rats. Moreover, progression of EAE can be investigated because the model separates the onset and peak of the disease.     

A simple method to fabricate electrochemical sensor systems with predictable high-redox cycling amplification

In this paper an easy to fabricate SU8/glass-based microfluidic sensor is described with two closely spaced parallel electrodes for highly selective measurements using the redox cycling effect. By varying the length of the microfluidic entrance channel, a diffusion barrier is created for non-cycling species effectively increasing selectivity for redox cycling species. Using this sensor, a redox cycling amplification of ～6500× is measured using the ferrocyanide redox couple. Moreover, a simple, but accurate analytical expression is derived that predicts the amplification factor based on the sensor geometry.     

Volume of submanifolds

We propose a geometric definition of the volume of submanifolds using tubular neighborhoods.     

The Fundamental Pro-groupoid of an Affine 2-scheme

A natural question in the theory of Tannakian categories is: What if you don’t remember Forget? Working over an arbitrary commutative ring R, we prove that an answer to this question is given by the functor represented by the étale fundamental groupoid π ₁(spec(R)), i.e. the separable absolute Galois group of R when it is a field. This gives a new definition for étale π ₁(spec(R)) in terms of the category of R-modules rather than the category of étale covers. More generally, we introduce a new notion of “commutative 2-ring” that includes both Grothendieck topoi and symmetric monoidal categories of modules, and define a notion of π ₁ for the corresponding “affine 2-schemes.” These results help to simplify and clarify some of the peculiarities of the étale fundamental group. For example, étale fundamental groups are not “true” groups but only profinite groups, and one cannot hope to recover more: the “Tannakian” functor represented by the étale fundamental group of a scheme preserves finite products but not all products.     

On the extraction of weights from pairwise comparison matrices

We study properties of weight extraction methods for pairwise comparison matrices that minimize suitable measures of inconsistency, ‘average error gravity’ measures, including one that leads to the geometric row means. The measures share essential global properties with the AHP inconsistency measure. By embedding the geometric mean in a larger class of methods we shed light on the choice between it and its traditional AHP competitor, the principal right eigenvector. We also suggest how to assess the extent of inconsistency by developing an alternative to the Random Consistency Index, which is not based on random comparison matrices, but based on judgemental error distributions. We define and discuss natural invariance requirements and show that the minimizers of average error gravity generally satisfy them, except a requirement regarding the order in which matrices and weights are synthesized. Only the geometric row mean satisfies this requirement also. For weight extraction we recommend the geometric mean.     

Prism-based multicolor fluorescence correlation spectrometer

We report the design and application of a prism-based detection system for fluorescence (cross) correlation spectroscopy. The system utilizes a single laser wavelength for the simultaneous excitation of several dyes of different emission spectra. Fluorescence light is spectrally separated with a prismatic setup, and wavelengths are selected by scanning a fiber-coupled avalanche photodiode across the image spots. Multicolor autocorrelations are demonstrated with standard and tandem dyes, and fluorescence cross-correlation measurements of biotinylated nanocontainers and streptavidin are presented. This spectrometer offers high optical stability and no focal volume mismatch for the multicolor detection of molecular dynamics and interactions, with single-molecule sensitivity.     

Molecular orbital studies of gas-phase interactions between complex molecules

Describing interactions among large molecules theoretically is a challenging task. As an example, we investigated gas-phase interactions between a linear nonionic oligomer and various model compounds (cofactors), which have been reported to associate experimentally, using PM3 semiempirical molecular orbital theory. As oligomer, we studied the hexamer of poly(ethylene oxide) (PEO), and as cofactors, we studied corilagin and related compounds containing phenolic groups (R-OH). These systems are of interest because they are models for PEO/cofactor flocculation systems, used in industrial applications. The PM3 delocalized molecular orbitals (DLMO) describe the bonding between (PEO)6 and cofactors, and some of them cover the complete complex. The DLMOs which cover the traditionally considered hydrogen bonds R-OH...O or R-CH...O show a distinct "pinch", a decrease of the electron density, between the H...O atoms. Calculations of Gibbs free energy, entropy, and enthalpy show that the PEO/cofactor complexes do not form at room temperature, because the loss of entropy exceeds the increase in enthalpy. The change in enthalpy is linearly related to the change in entropy for the different complexes. Even though bond lengths, bond angles, DLMOs, and electron densities for the PEO/cofactor complexes are consistent with the definition of hydrogen bonds, the number of intermolecular R-OH...O and R-CH...O bonds does not correlate with the enthalpy of association, indicating that the bonding mechanism for these systems is the sum of many small contributions of many delocalized orbitals.     

Mid-infrared and infrared emission spectroscopy of Cu-exchanged montmorillonite

Middle Infrared Spectroscopy (Mid-IR) and Infrared Emission Spectroscopy (IES) were employed to characterise Cu-exchanged montmorillonites, which were derived from two different types of montmorillonite clays, Ca-exchanged montmorillonite (Cheto clay) and Na-exchanged montmorillonite (Miles clay). Copper was exchanged under both acidic and basic conditions at different Cu/clay ratios. All Cu-exchanged montmorillonites experienced a shift in most of non-lattice bands, with hydroxyl bands playing a major role in the characterisation of the clays. Furthermore, a relationship between the ratio of bands at 3630 and 3500 cm(-1) and the Cu concentration of the starting solutions was indicated and used to compare the degree of cation exchange between two preparation methods. Two dehydration stages were observed in the IES experiments. Additional bands were observed in all Cu-exchanged montmorillonites prepared with the 'basic conditions method,' and these bands were assigned to ammonia molecules trapped within the clay structure or absorbed on the surface of the clay.