A Novel Anti-Inflammatory d-Peptide Inhibits Disease Phenotype Progression in an ALS Mouse Model

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterised by selective neuronal death in the brain stem and spinal cord. The cause is unknown, but an increasing amount of evidence has firmly certified that neuroinflammation plays a key role in ALS pathogenesis. Neuroinflammation is a pathological hallmark of several neurodegenerative disorders and has been implicated as driver of disease progression. Here, we describe a treatment study demonstrating the therapeutic potential of a tandem version of the well-known all-d-peptide RD2 (RD2RD2) in a transgenic mouse model of ALS (SOD1*G93A). Mice were treated intraperitoneally for four weeks with RD2RD2 vs. placebo. SOD1*G93A mice were tested longitudinally during treatment in various behavioural and motor coordination tests. Brain and spinal cord samples were investigated immunohistochemically for gliosis and neurodegeneration. RD2RD2 treatment in SOD1*G93A mice resulted not only in a reduction of activated astrocytes and microglia in both the brain stem and lumbar spinal cord, but also in a rescue of neurons in the motor cortex. RD2RD2 treatment was able to slow progression of the disease phenotype, especially the motor deficits, to an extent that during the four weeks treatment duration, no significant progression was observed in any of the motor experiments. Based on the presented results, we conclude that RD2RD2 is a potential therapeutic candidate against ALS.     

Preparation of VPS and PVD coatings for metallographic and TEM investigations

The aim of the first part of the paper is to give some advice for the faultless metallographic preparation of vacuum plasma sprayed coatings. Several coating/substrate combinations using metals, alloys and ceramics were investigated to derive some general rules. The second part deals with a preparation technique for cross-sections- of physical vapour deposition coatings. This technique was optimized for TiN and Ti(C, N) coatings on hardmetals which were examined in an analytical transmission electron microscope.     

Formation,preservation, and cleavage of the disulfide bond by vanadium

Reaction of the disulfide [HpicanS](2) (HpicanS is the carboxamide based on picolinate (pic) and o-mercaptoaniline (anS); the [] brackets are used to denote disulfides) with [VOCl(2)(thf)(2)] leads to reductive scission of the disulfide bond and formation of the mixed-valence (V(IV)/V(V)) complex anion [(OVpicanS)(2)mu-O](-) (1), with the dianionic ligand coordinating through the pyridine-N atom, the deprotonated amide-N atom, and thiophenolate-S atom. Reductive cleavage of the SbondS bond is also observed as [VCl(2)(tmeda)(2)] (tmeda=tetramethylethylenediamine) is treated with the disulfides [HsalanS](2) or [HvananS](2) (HsalanS and HvananS are the Schiff bases formed between o-mercaptoaniline and salicylaldehyde (Hsal) or vanillin (Hvan), respectively), yielding the V(III) complexes [VCl(tmeda)(salanS)] (2 a), or [VCl(tmeda)(vananS)] (2 b). The disulfide bond remains intact in the aerial reaction between [HsalanS](2) and [VCl(3)(thf)(3)] to yield the V(V) complex [VOCl[salanS](2)] (3), where (salanS)(2-) coordinates through the two phenolate and one of the imine functions. The S-S bond is also preserved as [VO(van)(2)] or [VO(nap)(2)] (Hnap=2-hydroxynaphthalene-1-carbaldehyde) is treated with bis(2-aminophenyl)disulfide, [anS](2), a reaction which is accompanied by condensation of the aldehyde and the diamine, and complexation of the resulting bis(Schiff bases) [HvananS](2) or [HnapanS](2) to form the complexes [VO[vananS](2)] (4 a) or [VO[napanS](2)] (4 b). In 4 a and 4 b, the phenolate and imine functions, and presumably also one of the disulfide-S atoms, coordinate to V(IV). 2-Mercaptophenyl-2'-pyridinecarboxamide (H(2)picanS) retains its identity in the presence of V(III); reaction between [VCl(3)(thf)(3)] and H(2)picanS yields [V[picanS](2)](-) (5). The dithiophenolate 2,6-bis(mercaptophenylthio)dimethylpyridine (6 a) is oxidized, mediated by VO(2+), to the bis(disulfide) octathiadiaza-cyclo-hexaeicosane 6 b. The relevance of these reactions for the speciation of vanadium under physiological conditions is addressed. [HNEt(3)]-1.0.5 NEt(3,) 3.3 CH(2)Cl(2), [HsalanS](2), [HNEt(3)]-5, and 6 b.4 THF have been characterized by X-ray diffraction analysis.     

Organometallic chemistry of fluorinated allenes

Reaction of 1,1-difluoroallene and tetrafluoroallene with a series of transition metal complex fragments yields the mononuclear allene complexes [CpMn(CO)(2)(allene)] (1), [(CO)(4)Fe(allene)] (2), [(Ph(3)P)(2)Pt(C(3)H(2)F(2))] (4), [Ir(PPh(3))(2)(C(3)H(2)F(2))(2)Cl] (5), and the dinuclear complexes [mu-eta(1)-eta(3)-C(3)H(2)F(2))Fe(2)(CO)(7)] (3), [Ir(PPh(3))(C(3)H(2)F(2))(2)Cl](2) (6), and [mu-eta(2)-eta(2)-C(3)H(2)F(2))(CpMo(CO)(2))(2)] (9), respectively. In attempts to synthesize cationic complexes of fluorinated allenes [CpFe(CO)(2)(C(CF(3))=CH(2))] (7a), [CpFe(CO)(2)(C(CF(3))=CF(2))] (7b) and [mu-I-(CpFe(CO)(2))(2)][B(C(6)H(3)-3,5-(CF(3))(2))(4)] were isolated. The spectroscopic and structural data of these complexes revealed that the 1,1-difluoroallene ligand is coordinated exclusively with the double bond containing the hydrogen-substituted carbon atom. 1,1-Difluoroallene and tetrafluoroallene proved to be powerful pi acceptor ligands.     

A comparison of thermoreactive water-soluble poly-N,N-diethylacrylamide prepared by anionic and by group transfer polymerization

Several batches of poly-N,N-diethylacrylamide were synthesized by anionic and by group transfer polymerization (GTP). A radical poly-N,N-diethylacrylamide prepared from the same monomer was also included in the comparison. According to matrix-assisted laser desorption/ionization mass spectrometry (MALDI-MS) both types of living polymerization resulted in narrow molecular weight distributions with M_w/M_n values below 1.5. Average molecular weights (M_n) between 888 and 4678 g/mol were calculated in these cases. The radical polymer had an average molecular weight (M_n) of approximately 130,000 g/mol. The dry anionic and GTP polymers were investigated by differential scanning calorimetry (DSC) and x-ray diffraction spectrometry. Evidence for partial crystallinity in the solid state was found. The conformation of all polymers was examined by high resolution (600 MHz) NMR. According to these measurements, 75% of the ? CHR? groups of the anionic poly-N,N-diethylacrylamide were located in an isotactic triade. The remaining 25% had heterotactic structure, while no indication for the presence of syndiotactic protons was found. Poly-N,N-diethylacrylamide prepared by GTP, on the other hand, had mainly syndiotactic structure. The aqueous solutions of the polymers showed phase separation upon heating. Whereas the lower critical solution temperature (LCST) was approximately 30°C in the case of the poly-N,N-diethylacrylamide prepared by GTP and by radical polymerization, uncommonly high LCSTs of more than 40°C were observed for the anionic poly-N,N-diethylacrylamide. © 1994 John Wiley & Sons, Inc.     

Conjugate addition reactions of alpha-aminoalkylcuprates with alpha, beta-alkenyl-, alpha,beta-alkynyl-, alpha,beta-beta,gamma-allenyl-, and alpha,beta-gamma,delta-dienyl carboxylic acid derivatives, nitriles, and sulfoxides

alpha-Aminoalkylcuprates prepared from alpha-lithio carbamates and CuCN.2LiCl participate in 1,4-addition reactions with alpha, beta-unsaturated esters, thiol esters, imides, and nitriles in poor to excellent yields depending upon the electron-withdrawing substituent and the substitution pattern of the unsaturated substrate. These reagents also undergo conjugate addition reactions with alpha,beta-alkynyl esters, sulfoxides, and nitriles and with alpha,beta-beta,gamma-unsaturated allenyl esters. Excellent stereocontrol is achieved in the conjugate additions of alpha-aminoalkylcuprates to the allenyl esters, while poor stereoselectivity results in the conjugate additions to the alkynyl derivatives. Deprotection and cyclization of the alkynyl adducts affords pyrrolin-2-ones, while similar treatment of the allenyl adducts affords 4-alkylidine- pyrrolidin-2-ones and pyrrolizidinones.     

Synthese und Kristallstruktur von [(Me3Si)2BiCu(PMe3)3], dem ersten Komplex mit einer Bismut—Kupfer‐Bindung

Synthesis and Crystal Structure of [(Me₃Si)₂BiCu(PMe₃)₃] — the First Complex with a Bismuth—Copper Bond The reaction of CuO^t Bu with PMe₃ and Bi(SiMe₃)₃ in hexane yields the phosphine‐stabilized complex [(Me₃Si)₂Bi‐Cu( PMe₃)₃]. This synthesis gave rise to the first binuclear Bi—Cu compound to be structurally characterized by X‐ray crystallography.     

Reconstruction of the free energy in the metastable region using the path ensemble

By quenching into the metastable region of the three-dimensional Ising model, we investigate the paths that the magnetization (energy) takes as a function of time. We accumulate the magnetization (energy) paths into time-dependent distributions from which we reconstruct the free energy as a function of the magnetic field, temperature, and system size. From the reconstructed free energy, we obtain the free-energy barrier that is associated with the transition from a metastable state to the stable equilibrium state. Although mean-field theory predicts a sharp transition between the metastable and the unstable region where the free-energy barrier is zero, the results for the nearest-neighbor Ising model show that the free-energy barrier does not go to zero.