RS-0406 arrests amyloid-B oligomer-induced behavioural deterioration in vivo

Clinically accessible compounds that arrest or reverse the effects of amyloid-ß (Aß) on progressively developing behavioural symptomatology and neuropathology in Alzheimer's disease (AD) have yet to become available. However, a viable strategy may be to target and neutralise soluble Aß oligomers, which have been shown to mediate synaptic dysfunction and to produce cognitive deficits in the intact organism. Inhibiting the aggregation of Aß is therapeutically attractive, as Aß aggregation is a pathological event and pharmacological interventions targeting this are likely to have a non-toxic profile. A behavioural assay, the alternating-lever cyclic-ratio schedule, was used to assess the effect of Aß oligomers and the non-peptide small molecule RS-0406 in male Sprague-Dawley rats. RS-0406 has been shown to inhibit Aß1-42 fibrillogenesis and protect against Aß1-42–induced cytotoxicity in primary hippocampal neurons. In the current study, RS-0406 ameliorated the adverse effects of secreted oligomers of human Aß on behaviour and dose dependently reduced the behavioural effects of Aß oligomers, with the highest dose, 10 µM, maintaining behaviour approximately at control levels. This effect appeared to be central; peripheral confounds having been extensively investigated. This is the first published report on the effects of RS-0406 in vivo and indicates that RS-0406 has potential as a pharmacotherapeutic intervention for behavioural deficits seen in the early stages of AD, and possibly as an intervention in the development of AD neuropathology. Indeed, an analogue of RS-0406 that could be administered peripherally might be a realistic candidate for the clinical treatment of AD.

Mid-infrared a-b plane response of YBa2Cu3O7-delta as a function of doping and temperature determined by attenuated total reflection

The mid-infrared optical response of c-axis thin films of YBa2Cu3O7-delta has been studied using Otto-configuration attenuated total reflectance. The measured reflectance-angle characteristics are dominated by a strong absorption feature due to the excitation of surface plasmons, and can be modeled to determine the a-b plane dielectric function. The results show that while epsilon(i,) and therefore sigma(r), are temperature independent, \epsilon(r)\ exhibits a moderate decrease with generalized Drude analysis shows that the plasma frequency is independent of temperature, but decreases with decreasing doping. The scattering rate increases with temperature, and also increases with decreasing doping, consistent with stronger coupling in the underdoped regime. The mass-enhancement is small but increases to 30-40% at delta = 0.6. Difficulties in reconciling the results with some current theories of high-T-c materials are discussed. Finally, the surface plasmon propagation lengths and penetration depths are shown to vary systematically with doping. (C) 2003 Elsevier B.V. All rights reserved.

The mid-infrared dielectric function of NBCO in the a-b plane from 85 K to 300 K

Results are reported on the a-b plane dielectric function (epsilon) of thin-film c-axis NdBa2Cu3O7-delta with close to optimal oxygen doping (T-c similar to 90 K) in the mid-infrared (wavelength 3.392 mum) over the temperature range 85 K to 300 K. An attenuated total reflectance technique based on the excitation of surface plasmon polaritons is used. The results show that \epsilon (r)\ decreases quasi-linearly with increasing temperature, while Ei is invariant with temperature to within experimental uncertainties. Representative values are epsilon = [epsilon (r) + i epsilon (i)] = (-12.9 +/- 0.6) + i(23.0 +/- 1.5) at T similar to 295 K and epsilon = (-15.7 +/- 0.7) + i(23.5 +/- 1.1) at T similar to 90 K. The raw data an interpreted in terms of the generalized Drude model which gives effective scattering rates (1/tau*) that increase with temperature from about 3800 cm(-1) at 90 K to about 4300 cm(-1) at 295 K. There are indications of a superlinear T-dependence in the scattering, 1/tau*: a fit to a function of the form 1/tau* = A + BTalpha gives alpha = 2.8 +/- 0.7. The effective plasma frequency, omega (p)*, with an average value of approximately 21 000 cm(-1) was independent of temperature.

Temperature dependence of the mid-infrared dielectric function of YBCO in the a-b plane: a re-evaluation

The a-b plane dielectric function (epsilon) of c-axis YBa2Cu3O7-delta thin films with T-c > 85 K was measured at lambda = 3.392 mum in the temperature range 85-300 It, using an attenuated total reflectance (ATR) technique based on the excitation of surface plasmons, The results show that \epsilon (r)\ decreases quasi-linearly with increasing temperature, while Ei is invariant to temperature within experimental uncertainties. Typical values are epsilon (ab) = -23 + 16.5i at similar to 295 R and epsilon (ab) = -27 + 15.5i at similar to 90 K. A generalised Drude analysis yields effective scattering rates (1/tau*) that increase with temperature from similar to 1500 to similar to 1900 cm(-1). The temperature dependent rates best fit an equation of the form 1/tau* = a + bT(alpha) with alpha = 1.46 +/- 0.40. The effective plasma frequencies of w(p)* similar to 18,500 cm(-1) are almost independent of temperature. The uniquely detailed temperature dependence of the results confirm and consolidate data obtained by other groups using normal reflectance methods, but contradict our previously published ATR measurements. Technical shortcomings in the earlier work are identified as the source of the discrepancy. (C) 2000 Elsevier Science B.V. All rights reserved.

A20 Regulation of NF-{kappa}B: Perspectives for Inflammatory Lung Disease.

Persistent activation of NF-B is central to the pathogenesis of many inflammatory lung disorders including Cystic Fibrosis, Asthma and Chronic Obstructive Pulmonary Disease. A20 is an endogenous negative regulator of NF-B signalling which has been widely described in autoimmune and inflammatory disorders including Diabetes and Crohn’s disease, but which has received little attention in terms of chronic lung disorders. This review examines the existing body of research on A20 regulation of NF-B signalling and details the mechanism and regulation of A20 action focusing, where possible, on pulmonary inflammation. A20 and its associated signalling molecules are highlighted as being of potential therapeutic interest for the treatment of inflammatory disorders and a proposed model of A20 activity in inflammatory lung disease is provided.

Ginkgolide B and bilobalide block the pore of the 5-HT3 receptor at a location that overlaps the picrotoxin binding site

Extracts from the Ginkgo biloba tree are widely used as herbal medicines, and include bilobalide (BB) and ginkgolides A and B (GA and GB). Here we examine their effects on human 5-HT(3)A and 5-HT(3)AB receptors, and compare these to the effects of the structurally related compounds picrotin (PTN) and picrotoxinin (PXN), the two components of picrotoxin (PTX), a known channel blocker of 5-HT3, nACh and GABA(A) receptors. The compounds inhibited 5-HT-induced responses of 5-HT3 receptors expressed in Xenopus oocytes, with IC50 values of 470 mu M (BB), 730 mu M (GB), 470 mu M (PTN), 11 mu M (PXN) and > 1 mM (GA) in 5-HT(3)A receptors, and 3.1 mM (BB), 3.9 mM (GB), 2.7 mM (PTN), 62 mu M (PXN) and > 1 mM (GA) in 5-HT(3)AB receptors. Radioligand binding on receptors expressed in HEK 293 cells showed none of the compounds displaced the specific 5-HT3 receptor antagonist [H-3]granisetron, confirming that they do not act at the agonist binding site. Inhibition by GB at 5-HT(3)A receptors is weakly use-dependent, and recovery is activity dependent, indicating channel block. To further probe their site of action at 5-HT(3)A receptors, BB and GB were applied alone or in combination with PXN, and the results fitted to a mathematical model; the data revealed partially overlapping sites of action. We conclude that BB and GB block the channel of the 5-HT(3)A receptor. Thus these compounds have comparable, although less potent, behaviour than at some other Cys-loop receptors, demonstrating their actions are conserved across the family. (C) 2010 Published by Elsevier Ltd.

Rotating massive main-sequence stars II. Simulating a population of LMC early B-type stars as a test of rotational mixing

Context. Rotational mixing in massive stars is a widely applied concept, with far-reaching consequences for stellar evolution, nucleosynthesis, and stellar explosions.

The association between complement component 2/complement factor B polymorphisms and age-related macular degeneration: A HuGE review and meta-analysis

The authors performed a systematic review of the association of complement component 2(C2)/complement factor B (CFB) gene polymorphisms with age-related macular degeneration (AMD). In total, data from 19 studies published between 2006 and 2011 were pooled for 4 polymorphisms: rs9332739 and rs547154 in the C2 gene and rs4151667 and rs641153 in the CFB gene. Data extraction and assessments for risk of bias were independently performed by 2 reviewers. Allele frequencies and allele and genotypic effects were pooled. Heterogeneity and publication bias were explored. Pooled minor allele frequencies for all 4 SNPs were between 4.7% and 9.6% for all polymorphisms, except for an Indian population in which the C allele at rs9332739 was the major allele. For the C2 polymorphisms, the minor C allele at rs9332739 and the minor T allele at rs547154 carried estimated relative risks (odds ratios) of 0.55 (95% confidence interval (CI): 0.46, 0.65) and 0.47 (95% CI: 0.39, 0.57), respectively. For the CFB polymorphisms, the minor A alleles at rs4151667 and rs614153 carried estimated risks of 0.54 (95% CI: 0.45, 0.64) and 0.41 (95% CI: 0.34, 0.51), respectively. These allele effects contributed to an absolute lowering of the risk of all AMD in Caucasian populations by 2.0%-6.0%. This meta-analysis provides a robust estimate of the protective association of C2/CFB with AMD.

Bacterial dioxygenase- and monooxygenase-catalysed sulfoxidation of benzo[b]thiophenes

Asymmetric heteroatom oxidation of benzo[b]thiophenes to yield the corresponding sulfoxides was catalysed by toluene dioxygenase (TDO), naphthalene dioxygenase (NDO) and styrene monooxygenase (SMO) enzymes present in P. putida mutant and E. coli recombinant whole cells. TDO-catalysed oxidation yielded the relatively unstable benzo[b] thiophene sulfoxide; its dimerization, followed by dehydrogenation, resulted in the isolation of stable tetracyclic sulfoxides as minor products with cis-dihydrodiols being the dominant metabolites. SMO mainly catalysed the formation of enantioenriched benzo[b] thiophene sulfoxide and 2-methyl benzo[b] thiophene sulfoxides which racemized at ambient temperature. The barriers to pyramidal sulfur inversion of 2- and 3-methyl benzo[b] thiophene sulfoxide metabolites, obtained using TDO and NDO as biocatalysts, were found to be ca.: 25-27 kcal mol(-1). The absolute configurations of the benzo[b] thiophene sulfoxides were determined by ECD spectroscopy, X-ray crystallography and stereochemical correlation. A site-directed mutant E. coli strain containing an engineered form of NDO, was found to change the regioselectivity toward preferential oxidation of the thiophene ring rather than the benzene ring.

Synthesis of protective Mo-Si-B coatings in molten salts and their oxidation behavior in an air-water mixture

The formation of various phases during boronizing of silicided molybdenum substrates (MoSi2/Mo) was investigated. Boronizing treatments were conducted in molten salts under an inert gas atmosphere in the 700-1000 degrees C temperature range for 3-7 h. Depending on the process type (non-current or electrochemical) and molten salt temperature, the formation of different boride phases (MoB, Mo2B5, MoB2, MoB4) was observed. At the same time, substantial oxidation of the bulk molybdenum disilicide phase (MoSi2) to the Mo5Si3 phase was observed in non-current boronizing. The oxidation resistance of the coatings was investigated by the weight change in an air-water (2.3 vol.%) mixture at a temperature of 500 degrees C for a period up to 700 h. Results indicated that a two-phase microstructure consisting of the MoSi2, matrix phase with 12-15 wt.% of the MoB4 phase greatly improved the oxidation resistance of the molybdenum substrates. The weight gain rate observed was 6.5 center dot 10(-4) mg/cm(2) h. (c) 2006 Elsevier B.V. All rights reserved.