DBA/2J Genetic Background Exacerbates Spontaneous Lethal Seizures but Lessens Amyloid Deposition in a Mouse Model of Alzheimer’s Disease

Alzheimer’s disease (AD) is a leading cause of dementia in the elderly and is characterized by amyloid plaques, neurofibrillary tangles (NFTs) and neuronal dysfunction. Early onset AD (EOAD) is commonly caused by mutations in amyloid precursor protein (APP) or genes involved in the processing of APP including the presenilins (e.g. PSEN1 or PSEN2). In general, mouse models relevant to EOAD recapitulate amyloidosis, show only limited amounts of NFTs and neuronal cell dysfunction and low but significant levels of seizure susceptibility. To investigate the effect of genetic background on these phenotypes, we generated APP^swe and PSEN1^de9 transgenic mice on the seizure prone inbred strain background, DBA/2J. Previous studies show that the DBA/2J genetic background modifies plaque deposition in the presence of mutant APP but the impact of PSEN1^de9 has not been tested. Our study shows that DBA/2J.APP^swePSEN1^de9 mice are significantly more prone to premature lethality, likely to due to lethal seizures, compared to B6.APP^swePSEN1^de9 mice—70% of DBA/2J.APP^swePSEN1^de9 mice die between 2-3 months of age. Of the DBA/2J.APP^swePSEN1^de9 mice that survived to 6 months of age, plaque deposition was greatly reduced compared to age-matched B6.APP^swePSEN1^de9 mice. The reduction in plaque deposition appears to be independent of microglia numbers, reactive astrocytosis and complement C5 activity.     

7-Azaindole-3-acetic acid derivatives: Potent and selective CRTh2 receptor antagonists

High throughput screening identified a 7-azaindole-3-acetic acid scaffold as a novel CRTh2 receptor antagonist chemotype, which could be optimised to furnish a highly selective compound with good functional potency for inhibition of human eosinophil shape change in whole blood and oral bioavailability in the rat.     

High-Throughput Metabolic Fingerprinting of Legume Silage Fermentations via Fourier Transform Infrared Spectroscopy and Chemometrics

Silage quality is typically assessed by the measurement of several individual parameters, including pH, lactic acid, acetic acid, bacterial numbers, and protein content. The objective of this study was to use a holistic metabolic fingerprinting approach, combining a high-throughput microtiter plate-based fermentation system with Fourier transform infrared (FT-IR) spectroscopy, to obtain a snapshot of the sample metabolome (typically low-molecular-weight compounds) at a given time. The aim was to study the dynamics of red clover or grass silage fermentations in response to various inoculants incorporating lactic acid bacteria (LAB). The hyperspectral multivariate datasets generated by FT-IR spectroscopy are difficult to interpret visually, so chemometrics methods were used to deconvolute the data. Two-phase principal component-discriminant function analysis allowed discrimination between herbage types and different LAB inoculants and modeling of fermentation dynamics over time. Further analysis of FT-IR spectra by the use of genetic algorithms to identify the underlying biochemical differences between treatments revealed that the amide I and amide II regions (wavenumbers of 1,550 to 1,750 cm⁻¹) of the spectra were most frequently selected (reflecting changes in proteins and free amino acids) in comparisons between control and inoculant-treated fermentations. This corresponds to the known importance of rapid fermentation for the efficient conservation of forage proteins.     

Alteration of the Pathogenicity of Pasteurella pneumotropica for the Murine Lung Caused by Changes in Pulmonary Antibacterial Activity

Pasteurella pneumotropica is a potential pulmonary pathogen in mice. In healthy animals, this organism was killed rapidly by the normal function of the intrapulmonary phagocytic defense mechanisms. Impairment of this bactericidal activity by the acute renal failure of nephrectomy resulted in multiplication of the Pasteurella in the lung, both when the animals were nephrectomized first and then infected, and when the animals were infected first and nephrectomized several hours after the infection. The study demonstrates that the pathogenicity of the Pasteurella organisms is governed by the functional state of these pulmonary antibacterial mechanisms.     

EPR spectroscopic detection of free radical outflow from an isolated muscle bed in exercising humans.

There is no direct evidence to support the contention that contracting skeletal muscle and/or associated vasculature generates free radicals in exercising humans. The unique combination of isolated quadriceps exercise and the measurement of femoral arterial and venous free radical concentrations with the use of electron paramagnetic resonance (EPR) spectroscopy enabled this assumption to be tested in seven healthy men. Application of ex vivo spin trapping using alpha-phenyl-tert-butylnitrone (PBN) resulted in the detection of oxygen- or carbon-centered free radicals (a(N) = 1.38 +/- 0.01 mT and a(beta)(H) = 0.17 +/-0.01 mT, where a(N) and a(beta)(H) are the nitrogen and beta-hydrogen coupling constants, respectively) with consistently higher EPR signal intensities of the PBN spin adduct observed in the venous compared with the arterial circulation (P < 0.05). Incremental exercise further increased the venoarterial intensity difference [85 +/- 58 arbitrary units (AU) at 24 +/- 6% maximal work rate (WR(max)) vs. 387 +/- 214 AU at 69 +/- 7% WR(max); P < 0.05]. When combined with measured changes in femoral venous blood flow (Q), this resulted in a net adduct outflow of 130 +/- 118 and 1,146 +/- 582 AU/min (P < 0.05), which was positively associated with leg oxygen uptake (r(2) = 0.47, P < 0.05) and Q (r(2) = 0.47, P < 0.05). These results provide the first evidence for oxygen- or carbon-centered free radical outflow from an active muscle bed in humans.