Cerebellar Predominant Increase in mRNA Expression Levels of Sirt1 and Sirt3 Isoforms in a Transgenic Mouse Model of Huntington’s Disease

Neurochemical Research - The potential role of Sirt1 and Sirt2 subtypes of Sirtuins (class III NAD+-dependent deacetylases) in the pathogenesis of Huntington’s disease (HD) has been...     

Synthesis of xylal- and arabinal-based crown ethers and their application as asymmetric phase transfer catalysts

New xylal- and arabinal-based monoaza-15-crown-5 ethers were synthesized starting from l - and d -xylose, and l - and d -arabinose, respectively. These monosaccharide-based chiral macrocycles were tested as phase transfer catalysts in a few asymmetric reactions. The xylal-based crown compounds proved to be efficient catalysts in a few liquid-liquid phase reactions. The epoxidation of trans-chalcone and the Darzens condensation of α-chloroacetophenone with benzaldehyde took place with complete diastereoselectivity and up to 77% ee and 58% ee, respectively. It was found that the substituents in the aromatic ring of the chalcone and the α-chloroacetophenone had an influence on the enantioselectivity. The highest ee values were obtained in the epoxidation of 4-chlorochalcone (81% ee) and in the reaction of a 2-naphthyl analogue (96% ee), while in the Darzens condensation of 4-phenyl-α-chloroacetophenone with benzaldehyde, a maximum ee of 91% was detected. The configuration of the monosaccharide unit in the crown ring influenced the absolute configuration of the epoxyketones synthesized.     

Identification and characterization of plastid trnF(GAA) pseudogenes in four species of Solanum (Solanaceae)

Non-functional trnF pseudogenes that rarely occur in embryophytes have been found in Solanaceae. We have sequenced the trnL-F intergenic spacer of four species of Solanum, and found duplicated regions of the original trnF gene. These repeats were 94–260 bp long causing large length variation in the trnL-F intergenic spacer resulting from differences in pseudogene copy number (2–4). The duplicated trnF regions are comprised of several highly structured motifs, which were partial residues, or entire parts of the Anticodon, T- and D-domains of the original gene, but all lacked the acceptor stems at the 5′- or 3′-end. Pseudogenes included several transitions and transversions in their sequences compared to the original trnF gene. Among pseudogene copies, T-domains were more frequent and fragmented than D-domain elements. Our results demonstrate that although chloroplast evolution is uniform such structural duplications in the sequences used for phylogenetic reconstructions should be treated with great caution.     

Doxycycline could aggravate the absence-like epileptic seizures of WAG/Rij rats via matrix metalloproteinase inhibition

Matrix metalloproteinases (MMPs) are known to be activated in the brain by epileptic seizures and elevated MMP-9 activity has been found in a genetic model of generalized absence epilepsy (Wistar Albino Glaxo Rijswijk/WAG/Rij rats). In this study we posed the question, whether MMP inhibitory dose of doxycycline (20 mg/kg) could affect the spike-wave-discharges (SWDs) of the WAG/Rij rat. We found that intraperitoneal (i.p.) administration of 20 mg/kg doxycycline significantly increased the incidence and duration of SWDs for 4 h. As doxycycline has both MMP inhibitory and anti-inflammatory effects we also tested a lower dose of doxycycline (10 mg/kg, i.p.) and a selective broad-spectrum MMP inhibitor GM6001 (N-[2(R)-2-(hydroxamido carbonylmethyl)-4-methylpentanoyl]-l-tryptophane methylamide) intracerebroventricularly (i.c.v., 10 ng/rat). While 10 mg/kg doxycycline significantly increased the SWD number for 1 h, GM6001 significantly increased the SWD number during the whole 4-h recording period. Our results could indicate that the induction of MMPs in the epileptic brain, besides contributing to structural remodeling, would also be associated with such functions as homeostatic synaptic plasticity which might counteract epileptic seizures.     

Exposure to an inhomogeneous static magnetic field increases thermal pain threshold in healthy human volunteers

In the present experiment, the effect of a single 30 min inhomogeneous static magnetic field (SMF) exposure on thermal pain threshold (TPT) was examined in 15 young healthy human volunteers. The SMF had a maximum peak‐to‐peak amplitude of 330 mT with a maximum gradient of 13.2 T/m. In either of two experimental sessions (SMF or SHAM), four blocks of 12 TPT trials were carried out under SMF or SHAM exposure on all fingertips of the dominant hand, excluding the thumb. TPT and visual analog scale (VAS) data were recorded at 0, 15, and 30 min exposure time, and 30 min following exposure. SMF treatment resulted in a statistically significant increase in TPT during the entire exposure duration and diminished within‐block thermal habituation, leaving pain perception unchanged. These results indicate that SMF‐induced peripheral neuronal or circulatory mechanisms may be involved in the observed TPT increase by setting the pain fibre adaptation potential to higher levels. Bioelectromagnetics 32:131–139, 2011. © 2010 Wiley‐Liss, Inc.     

Exact epidemic models on graphs using graph-automorphism driven lumping

The dynamics of disease transmission strongly depends on the properties of the population contact network. Pair-approximation models and individual-based network simulation have been used extensively to model contact networks with non-trivial properties. In this paper, using a continuous time Markov chain, we start from the exact formulation of a simple epidemic model on an arbitrary contact network and rigorously derive and prove some known results that were previously mainly justified based on some biological hypotheses. The main result of the paper is the illustration of the link between graph automorphisms and the process of lumping whereby the number of equations in a system of linear differential equations can be significantly reduced. The main advantage of lumping is that the simplified lumped system is not an approximation of the original system but rather an exact version of this. For a special class of graphs, we show how the lumped system can be obtained by using graph automorphisms. Finally, we discuss the advantages and possible applications of exact epidemic models and lumping.     

β1-Integrin is up-regulated via Rac1-dependent reactive oxygen species as part of the hypertrophic cardiomyocyte response

β₁-Integrin mediates cardiomyocyte growth and survival and its proper regulation is essential for the structural and functional integrity of the heart. β₁-Integrin expression is enhanced in hypertrophy, but the mechanism and significance of its up-regulation are unknown. Because reactive oxygen species (ROS) are important mediators of myocardial remodeling we examined their role in regulated β₁-integrin expression. Hypertrophy was induced in neonatal cardiomyocytes by endothelin-1 (ET-1), which activated the regulatory NADPH oxidase subunit Rac1, evoked ROS, and enhanced fetal gene expression and cardiomyocyte size. ET-1 also enhanced cell adhesion and FAK phosphorylation and inhibited oxidative stress-induced cardiomyocyte apoptosis. Further, ET-1 increased β₁-integrin mRNA and protein expression via Rac1-ROS-dependent MEK/ERK and EGF receptor-PI3K/Akt activation as shown by adenoviral dominant-negative Rac1 or overexpression of copper/zinc-superoxide dismutase. The relevance of regulated β₁-integrin expression was examined in cardiomyocytes, in which targeting siRNA impeded the ET-1-induced β₁-integrin up-regulation. In these cells, ET-1-induced cell adhesion, FAK phosphorylation, and hypertrophic response were significantly blunted, whereas its antiapoptotic effect was predominantly unchanged, suggesting at least partial dissociation of prohypertrophic and prosurvival signaling elicited by ET-1. In conclusion, β₁-integrin up-regulation in response to ET-1 is mediated via Rac1-ROS-dependent activation of prohypertrophic pathways and is mandatory for ET-1-induced FAK activation, cell adhesion, and hypertrophic response.     

Model for the exceptional reactivity of peroxiredoxins 2 and 3 with hydrogen peroxide: a kinetic and computational study

Peroxiredoxins (Prx) are thiol peroxidases that exhibit exceptionally high reactivity toward peroxides, but the chemical basis for this is not well understood. We present strong experimental evidence that two highly conserved arginine residues play a vital role in this activity of human Prx2 and Prx3. Point mutation of either ArgI or ArgII (in Prx3 Arg-123 and Arg-146, which are ∼3–4 Å or ∼6–7 Å away from the active site peroxidative cysteine (C_p), respectively) in each case resulted in a 5 orders of magnitude loss in reactivity. A further 2 orders of magnitude decrease in the second-order rate constant was observed for the double arginine mutants of both isoforms, suggesting a cooperative function for these residues. Detailed ab initio theoretical calculations carried out with the high level G4 procedure suggest strong catalytic effects of H-bond-donating functional groups to the C_p sulfur and the reactive and leaving oxygens of the peroxide in a cooperative manner. Using a guanidinium cation in the calculations to mimic the functional group of arginine, we were able to locate two transition structures that indicate rate enhancements consistent with our experimentally observed rate constants. Our results provide strong evidence for a vital role of ArgI in activating the peroxide that also involves H-bonding to ArgII. This mechanism could explain the exceptional reactivity of peroxiredoxins toward H₂O₂ and may have wider implications for protein thiol reactivity toward peroxides.