Chronic BACE-1 Inhibitor Administration in TASTPM Mice (APP KM670/671NL and PSEN1 M146V Mutation): An EEG Study

Objective. In this exploratory study, we tested whether electroencephalographic (EEG) rhythms may reflect the effects of a chronic administration (4 weeks) of an anti-amyloid β-site amyloid precursor protein (APP) cleaving enzyme 1 inhibitor (BACE-1; ER-901356; Eisai Co., Ltd., Tokyo, Japan) in TASTPM (double mutation in APP KM670/671NL and PSEN1 M146V) producing Alzheimer’s disease (AD) amyloid neuropathology as compared to wild type (WT) mice. Methods. Ongoing EEG rhythms were recorded from a bipolar frontoparietal and two monopolar frontomedial (prelimbic) and hippocampal channels in 11 WT Vehicle, 10 WT BACE-1, 10 TASTPM Vehicle, and 11 TASTPM BACE-1 mice (males; aged 8/9 months old at the beginning of treatment). Normalized EEG power (density) was compared between the first day (Day 0) and after 4 weeks (Week 4) of the BACE-1 inhibitor (10 mg/Kg) or vehicle administration in the 4 mouse groups. Frequency and magnitude of individual EEG delta and theta frequency peaks (IDF and ITF) were considered during animal conditions of behaviorally passive and active wakefulness. Cognitive status was not tested. Results. Compared with the WT group, the TASTPM group generally showed a significantly lower reactivity in frontoparietal ITF power during the active over the passive condition (p < 0.05). Notably, there was no other statistically significant effect (e.g., additional electrodes, recording time, and BACE-1 inhibitor). Conclusions. The above EEG biomarkers reflected differences between the WT and TASTPM groups, but no BACE-1 inhibitor effect. The results suggest an enhanced experimental design with the use of younger mice, longer drug administrations, an effective control drug, and neuropathological amyloid markers.     

Operating Problems, Analysis, and Improvements of the Dynamic Performance of a Kraft Mill Power System

A new mill is supplied by a weak power system subject to numerous faults. The faults cause supply-voltage dips which result in production interruptions. The major problems that were experienced, the studies that were conducted, and the alterations made to improve the dynamic performance of the utility and mill power systems are described.     

Enrichment of polyunsaturated fatty acids from sardine cannery effluents by enzymatic selective esterification

The sardine canning industry produces vast quantities of effluents that need expensive reprocessing. Their oily component contains valuable n−3 polyunsaturated fatty acids, namely EPA (5,8,11,14,17-eicosapentaenoic acid) and DHA (7,10,13, 16,19-docosahexaenoic acid), up to 10% each. Our aim was to develop a process allowing the recovery of these fatty acids. After removing solid particles, proteins, and peptides from the crude effluent, the obtained oil was hydrolyzed. EPA and DHA were enriched from the recovered free fatty acid fraction by selective enzymatic esterification. Lipases were used as biocatalysts: Lipozyme^TM allowed up to 80% DHA enrichment but gave no EPA enrichment. By immobilizing Candida rugosa lipase on Amberlite IRC50 cation-exchange resin, a 30% EPA enrichment was obtained.     

Kinetic properties of Penicillium cyclopium lipases studied with vinyl esters

Penicillium cyclopium produces two lipases with different substrate specificities. Lipase I is predominantly active on triacylglycerols whereas lipase II hydrolyzes mono- and diacylglycerols but not triacylglycerols. In this study, we compared the kinetic properties of P. cyclopium lipases and human pancreatic lipase, a classical triacylglycerol lipase, by using vinyl esters as substrates. Results indicate that P. cyclopium lipases I and II and human pancreatic lipase hydrolyze solutions of vinyl propionate or vinyl butyrate at high relative rates compared with emulsions of the same esters, although, in all cases, maximal activity is reached in the presence of emulsified particles, at substrate concentrations above the solubility limit. It appears that partially water-soluble short-chain vinyl esters are suitable substrates for comparing the activity of lipolytic enzymes of different origin and specificity toward esters in solution and in emulsion.     

Oxidative DNA Damage and Cisplatin Neurotoxicity Is Exacerbated by Inhibition of OGG1 Glycosylase Activity and APE1 Endonuclease Activity in Sensory Neurons

Cisplatin can induce peripheral neuropathy, which is a common complication of anti-cancer treatment and negatively impacts cancer survivors during and after completion of treatment; therefore, the mechanisms by which cisplatin alters sensory neuronal function to elicit neuropathy are the subject of much investigation. Our previous work suggests that the DNA repair activity of APE1/Ref-1, the rate-limiting enzyme of the base excision repair (BER) pathway, is critical for neuroprotection against cisplatin. A specific role for 8-oxoguanine DNA glycosylase-1 (OGG1), the glycosylase that removes the most common oxidative DNA lesion, and putative coordination of OGG1 with APE1/Ref-1 in sensory neurons, has not been investigated. We investigated whether inhibiting OGG1 glycosylase activity with the small molecule inhibitor, TH5487, and/or APE1/Ref-1 endonuclease activity with APE Repair Inhibitor III would alter the neurotoxic effects of cisplatin in sensory neuronal cultures. Sensory neuron function was assessed by calcitonin gene-related peptide (CGRP) release, as a marker of sensitivity and by neurite outgrowth. Cisplatin altered neuropeptide release in an inverse U-shaped fashion, with low concentrations enhancing and higher concentrations diminishing CGRP release. Pretreatment with BER inhibitors exacerbated the functional effects of cisplatin and enhanced 8oxo-dG and adduct lesions in the presence of cisplatin. Our studies demonstrate that inhibition of OGG1 and APE1 endonuclease activity enhances oxidative DNA damage and exacerbates neurotoxicity, thus limiting oxidative DNA damage in sensory neurons that might alleviate cisplatin-induced neuropathy.