Laquinimod Modulates Human Astrocyte Function and Dampens Astrocyte-Induced Neurotoxicity during Inflammation

Astrocytes greatly participate to inflammatory and neurotoxic reactions occurring in neurodegenerative diseases and are valuable pharmacological targets to support neuroprotection. Here we used human astrocytes generated from reprogrammed fibroblasts as a cellular model to study the effect of the compound Laquinimod and its active metabolite de-Laquinimod on astrocyte functions and the astrocyte–neuron interaction. We show that human iAstrocytes expressed the receptor for the inflammatory mediator IL1 and responded to it via nuclear translocation of NFκB, an event that did not occur if cells were treated with Laquinimod, indicating a direct anti-inflammatory activity of the drug on the human astrocyte. Similarly, while exposure to IL1 downregulated glial glutamate transporters GLAST and GLT1, treatment with Laquinimod supported maintenance of physiological levels of these proteins despite the inflammatory milieu. Laquinimod also induced nuclear translocation of the aryl hydrocarbon receptor (AHR), suggesting that drug action was mediated by activation of the AHR pathway. However, the drug was effective despite AHR inhibition via CH223191, indicating that AHR signaling in the astrocyte is dispensable for drug responses. Finally, in vitro experiments with rat spinal neurons showed that laquinimod did not exert neuroprotection directly on the neuron but dampened astrocyte-induced neurodegeneration. Our findings indicate that fibroblast-derived human astrocytes represent a suitable model to study astrocyte–neuron crosstalk and demonstrate indirect, partial neuroprotective efficacy for laquinimod.     

Electroclinic properties of chiral smectic a liquid crystalline polymers and block copolymers

The scope for the synthesis and investigation of chiral smectic A liquid crystalline (LC) polymers and block copolymers is discussed. LC block copolymers can combine the molecular order of liquid crystals and the supramolecular order typical of block copolymers, thus allowing to attain information on mesomorphic responses in restricted geometries. We present a general overview on several aspects of the syntheses and properties of LC block copolymers, specifically those obtained by starting from azomacroinitiators. These materials can exhibit an electroclinic effect, that is an electrically induced molecular tilt, which is characterized by a linear dependence on the applied field and a very fast response time in the paraelectric smectic A phase. The current progress in their potential application in electrooptics is outlined.     

Information Network Modeling for U.S. Banking Systemic Risk

In this work we investigate whether information theory measures like mutual information and transfer entropy, extracted from a bank network, Granger cause financial stress indexes like LIBOR-OIS (London Interbank Offered Rate-Overnight Index Swap) spread, STLFSI (St. Louis Fed Financial Stress Index) and USD/CHF (USA Dollar/Swiss Franc) exchange rate. The information theory measures are extracted from a Gaussian Graphical Model constructed from daily stock time series of the top 74 listed US banks. The graphical model is calculated with a recently developed algorithm (LoGo) which provides very fast inference model that allows us to update the graphical model each market day. We therefore can generate daily time series of mutual information and transfer entropy for each bank of the network. The Granger causality between the bank related measures and the financial stress indexes is investigated with both standard Granger-causality and Partial Granger-causality conditioned on control measures representative of the general economy conditions.     

Synthesis,spectroscopic characterization (IR, 1H, 13C and 119Sn NMR,electrospray mass spectrometry) and toxicity of new organotin(IV) complexes with N,N′,O‐ and N,N′,S‐scorpionate ligands

New organotin(IV) derivatives containing the anionic ligands bis(3,5‐dimethylpyrazol‐1‐yl)dithioacetate [LCS₂]⁻ and bis(3,5‐dimethylpyrazol‐1‐yl)acetate [LCO₂]⁻ have been synthesized from reaction between (CH₃)₂SnCl₂ and lithium salts of the ligands. Mononuclear complexes of the type {[LCX₂](CH₃)₂SnCl} (X = S or O) have been obtained and fully characterized by elemental analyses and FT‐IR in the solid state and by NMR (¹H, ¹³C and ¹¹⁹Sn) spectroscopy, conductivity measurements and electrospray ionization mass spectrometry in solution. The acute toxicity of new organotin(IV) derivatives on rat was studied, comparing their effect with those of dimethyltin chloride (CH₃)₂SnCl₂. The comparison of LD₅₀ of organotin(IV) complexes and (CH₃)₂SnCl₂ administered intraperitoneally, as a single dose, evaluated in vivo on rats, showed that toxicity decreases as follows: (CH₃)₂SnCl₂ > LCO₂ > LCS₂. The effect of these organotin(IV) complexes on DNA was evaluated in vitro and in vivo on rats treated with different doses of these compounds (1/20 LD₅₀ and 1/100 LD₅₀). The lymphocyte DNA status was assessed by the comet assay, a rapid and sensitive single‐cell electrophoresis technique, used to detect primary DNA damage in individual cells. After 36 h from the start of treatment the two new organotin(IV) derivatives induced a significant rise in comet assay parameters, indicating an increasing presence of damaged DNA. Copyright © 2005 John Wiley & Sons, Ltd.     

Hierarchical Analysis of Self‐Assembled PEGylated Hexaphenylalanine Photoluminescent Nanostructures

Despite the growing literature about diphenylalanine‐based peptide materials, it still remains a challenge to delineate the theoretical insight into peptide nanostructure formation and the structural features that could permit materials with enhanced properties to be engineered. Herein, we report the synthesis of a novel peptide building block composed of six phenylalanine residues and eight PEG units, PEG₈‐F6. This aromatic peptide self‐assembles in water in stable and well‐ordered nanostructures with optoelectronic properties. A variety of techniques, such as fluorescence, FTIR, CD, DLS, SEM, SAXS, and WAXS allowed us to correlate the photoluminescence properties of the self‐assembled nanostructures with the structural organization of the peptide building block at the micro‐ and nanoscale. Finally, a model of hexaphenylalanine in aqueous solution by molecular dynamics simulations is presented to suggest structural and energetic factors controlling the formation of nanostructures.     

A New Easy Access to Enantiomerically Pure 2,2'-Dihydroxy-1,1'-Binaphthyl

Optically pure binaphthyl structures make up the most important family of auxiliaries, ligands and catalysts used in enantioselective reactions. Syntheses of 2,2'-disubstituted-1,1'-binaphtyl derivatives were carried out one pot in water by oxidative coupling with FeCl₃ in the presence of - and -cyclodextrin (CD) derivatives. A new efficient and inexpensive preparation of trihydroxyethyl- and tri-2-hydroxypropyl- - and -CD afforded these powerful solubilizing agents. The resolution of racemic 2,2'-dihydroxy-1,1'-binaphthyl was easily achieved by semipreparative HPLC separating diastereomers obtained from the reaction with (-)menthyl chloroformate. Final basic hydrolysis afforded the enantiomerically pure product.     

Rapid quantitation of globotriaosylceramide in human plasma and urine: a potential application for monitoring enzyme replacement therapy in Anderson-Fabry disease

A method for measuring globotriaosylceramide (Gb3, or GL3) levels in plasma and urine of humans affected by Anderson-Fabry disease has been developed. The analyses are performed using flow injection analysis-electrospray ionization-tandem mass spectrometry (FIA-ESI-MS/MS). The method is rapid, sensitive and hence suitable for high-throughput analyses, requiring only a simple 50-fold dilution for the preparation of plasma and urine samples. The detection of the analytes of interest was achieved using a triple quadrupole instrument operating in the multiple reaction monitoring mode. The linearity of the calibration standard responses, the intra- and inter-assay precision, the accuracy and the detection limit of the method were evaluated. The proposed method allows a rapid and accurate assessment of globotriaosylceramide in biological samples. Data obtained from healthy volunteers and Anderson-Fabry affected subjects suggest a potential role for this technique in monitoring the effectiveness of Anderson-Fabry disease therapy. The results obtained in two actual cases treated with enzyme replacement therapy are reported and discussed.     

Determination of traces of iron in indium phosphide by electrothermal atomic absorption spectrometry combined with solvent extraction

An electrothermal atomic absorption (ETAAS) method for the determination of traces of iron (0.1-1.0 microgram g-1) in Fe-doped indium phosphide (InP) has been developed. In order to overcome the indium matrix-effect and to achieve a useful detection limit, a preliminary solvent-extraction of Fe(III) with acetylacetone (HAA) is necessary. After sample dissolution with hydrochloric acid (1 + 1) the digest is evaporated to dryness, Fe(II) is oxidized to Fe(III) with nitric acid, the residue is dissolved in 0.01 mol L-1 HCl and the iron is extracted at pH 2.0 with 0.5 mol L-1 HAA in toluene. The organic phase is injected into the graphite furnace and the iron is directly evaluated by external organic standard calibration. The limit of detection (3SB) resulting from further in-situ preconcentration is 0.03 microgram g-1. When the method was applied to the analysis of real samples containing 0.2-0.7 microgram g-1 Fe, the RSD was in the range 8-21%. Results were compared with those independently obtained on the decomposed sample solution with inductively coupled atomic emission spectrometry (ICP-AES). The detection limit of the ICP-AES method, that needs matrix-matched standards, is 0.20 microgram g-1.     

Baeyer-Villiger oxidation in compressed CO2

The aerobic Baeyer-Villiger oxidation of a wide range of ketones, both cyclic and acyclic to the corresponding esters or lactones can be efficiently carried out in compressed carbon dioxide in the presence of an aldehyde as co-reductant.