Pharmacophore-driven identification of PPARγ agonists from natural sources

In a search for more effective and safe anti-diabetic compounds, we developed a pharmacophore model based on partial agonists of PPARγ. The model was used for the virtual screening of the Chinese Natural Product Database (CNPD), a library of plant-derived natural products primarily used in folk medicine. From the resulting hits, we selected methyl oleanonate, a compound found, among others, in Pistacia lentiscus var. Chia oleoresin (Chios mastic gum). The acid of methyl oleanonate, oleanonic acid, was identified as a PPARγ agonist through bioassay-guided chromatographic fractionations of Chios mastic gum fractions, whereas some other sub-fractions exhibited also biological activity towards PPARγ. The results from the present work are two-fold: on the one hand we demonstrate that the pharmacophore model we developed is able to select novel ligand scaffolds that act as PPARγ agonists; while at the same time it manifests that natural products are highly relevant for use in virtual screening-based drug discovery.     

Two-Dimensional Elastic Herglotz Functions and Their Applications in Inverse Scattering

In this work solutions of the spectral Navier equation that satisfy the Herglotz boundedness condition in two-dimensional linear elasticity are presented. Navier eigenvectors in polar coordinates are introduced and it is established that they form a linearly independent and complete set in the L ²-sense on every smooth curve. It is also proved that the classical solutions of the spectral Navier equation are expressed via Navier eigenvectors, and this expansion converges uniformly over compact subsets of R ². Two far-field patterns, the longitudinal and the transverse one corresponding to the displacement field are introduced, and the Herglotz norm is expressed as the sum of the L ²-norms of these patterns over the unit circle. It is also established that the space of elastic Herglotz functions is dense in the space of the classical solutions of the spectral Navier equation. Finally, connection to inverse elasticity scattering is established and reconstructions of rigid bodies are presented. This revised version was published online in June 2006 with corrections to the Cover Date.     

First-principles theory of van der Waals forces between macroscopic bodies

We present a first-principles method for the determination of the van der Waals interactions for a collection of finite-sized macroscopic bodies. The method is based on fluctuational electrodynamics and a rigorous multiple-scattering method for the electromagnetic field. As such, the method takes fully into account retardation, many-body, multipolar, and near-fields effects. By application of the method to the case of two metallic nanoparticles, we demonstrate the breakdown of the standard 1/r(2) distance law as the van der Waals force decays exponentially with distance when the nanoparticles are too close or too far apart.     

Cyclopenta[g]quinazolinone-based inhibitors of thymidylate synthase targeting α-folate receptor overexpressing tumours: synthetic approaches to 4-{N-[(6RS)-2-hydroxymethyl-4-oxo-3,4,7,8-tetrahydro-6H-cyclopenta[g]quinazolin-6-yl]-N-(prop-2-ynyl)amino}benzoic acid

An advanced intermediate for the synthesis of cyclopenta[g]quinazolinone-based antifolates such as (6RS)-CB300945 was prepared by a convergent methodology. The oxo-functionality required for the formation of the C-6-N-10 bond in 4 was introduced in the initial steps of the synthesis, then the tricyclic ring was constructed and finally the propargyl group was introduced using the (propargyl)Co₂(CO)₆⁺ complex without the need to protect the N-3-H or 2-hydroxymethyl functionalities.     

‘Horses for Courses’ in demand forecasting

Forecasting as a scientific discipline has progressed a lot in the last 40 years, with Nobel prizes being awarded for seminal work in the field, most notably to Engle, Granger and Kahneman. Despite these advances, even today we are unable to answer a very simple question, the one that is always the first tabled during discussions with practitioners: “what is the best method for my data?”. In essence, as there are horses for courses, there must also be forecasting methods that are more tailored to some types of data, and, therefore, enable practitioners to make informed method selection when facing new data. The current study attempts to shed light on this direction via identifying the main determinants of forecasting accuracy, through simulations and empirical investigations involving 14 popular forecasting methods (and combinations of them), seven time series features (seasonality, trend, cycle, randomness, number of observations, inter-demand interval and coefficient of variation) and one strategic decision (the forecasting horizon). Our main findings dictate that forecasting accuracy is influenced as follows: (a) for fast-moving data, cycle and randomness have the biggest (negative) effect and the longer the forecasting horizon, the more accuracy decreases; (b) for intermittent data, inter-demand interval has bigger (negative) impact than the coefficient of variation; and (c) for all types of data, increasing the length of a series has a small positive effect.     

Quantitative determination of alkannins and shikonins in endemic Mediterranean Alkanna species

The optical antipodes alkannin/shikonin (A/S) and their esters are potent pharmaceutical substances found in the roots of 150 Boraginaceous species. This study estimated and compared total and free A/S content and A/S enantiomeric ratio in roots of 11 Alkanna species (A. corcyrensis, A. tinctoria, A. pindicola, A. orientalis, A. methanaea, A. calliensis, A. graeca, A. primuliflora, A. stribrnyi, A. sieberi and A. noneiformis) growing wild in various Greek regions, to compare with cultivated species. It also re‐characterized the chirality of A/S commercial samples, since most of them were misnamed by the providers. Several Alkanna species were collected (groups 1 and 3) and botanically identified, whereas some Alkanna species were cultivated from collected seeds (group 2). Free A/S and derivatives were extracted from the dried roots of Alkanna species and analyzed by high performance liquid chromatography‐diode array detection (HPLC‐DAD). For total A/S content the hexane extracts of Alkanna roots were hydrolyzed and analyzed by HPLC‐DAD. Chirality determination and A/S enantiomeric ratio estimation was performed for several commercial samples by polarimetry,chiral LC‐DAD and circular dichroism studies. Quantitative analysis revealed that A/S content varied from one region to another even within the same species. Most of the cultivated samples contained greater amounts of free and total A/S compared with the wild ones, wheras no difference was observed in A/S enantiomeric ratio. All the Alkanna samples tested contain mainly alkannin derivatives. Some of the examined Alkanna species of the Greek flora that are endemic to the Mediterranean area could serve as alternative sources for medicinally valuable A/S derivatives. Most of the commercial A/S samples tested were misnamed in terms of chirality and re‐characterized. Copyright © 2013 John Wiley & Sons, Ltd.     

Evolutionary computation of a deterministic switching regressions estimator

Summary  A deterministic switching regressions estimator is evaluated using an evolutionary method based on genetic algorithms. Distinctive aspects of the method include (1) a combination of simple and random chromosomal crossover and (2) extension of the principle of natural selection to internal parameterization. The evolutionary computation duplicates, significantly faster, the results of an existing enumerative method in samples small enough to permit enumeration. It also provides the ability to calculate the estimator in much larger sample sizes than is possible with the enumerative approach. An example problem from the United States gasoline market is given. Funding support provided by the Gerondelis Foundation, Inc. is gratefully acknowledged.     

Cyclic voltammetry characterization of a La0.8Sr0.2Co0.2Fe0.8O3 − δ electrode interfaced to CGO/YSZ

The electrochemical characteristics of a La_0.8Sr_0.2Co_0.2Fe_0.8O_3 − δ cathode electrode interfaced to the CGO layer of a double layer CGO/YSZ electrolyte were studied using cyclic voltammetry, at temperatures of 600 to 850 °C and under oxygen partial pressures ranging from 0.07 to 21 kPa. The aim was to identify the electrochemical processes taking place under cathodic polarization on the basis of differences in the features of the cyclic voltammograms with changing conditions. Depending on temperature, sweep rate and oxygen partial pressure, current peaks appeared both in the forward and backward scans. Furthermore, reversed hysteresis was observed, i.e. higher currents in the backward scan than in the forward scan, with increasing oxygen partial pressure and decreasing temperature. The observed behavior was related to the electrochemical redox of B-sites and concomitant stoichiometry change as well as to the competing reaction of electrochemical oxygen redox, taking also into account the competitive action of chemical reactions occurring in the presence of gaseous oxygen.