Correlations of Behavioral Deficits with Brain Pathology Assessed through Longitudinal MRI and Histopathology in the R6/2 Mouse Model of HD

Huntington's disease (HD) is caused by the expansion of a CAG repeat in the huntingtin (HTT) gene. The R6/2 mouse model of HD expresses a mutant version of exon 1 HTT and develops motor and cognitive impairments, a widespread huntingtin (HTT) aggregate pathology and brain atrophy. Despite the vast number of studies that have been performed on this model, the association between the molecular and cellular neuropathology with brain atrophy, and with the development of behavioral phenotypes remains poorly understood. In an attempt to link these factors, we have performed longitudinal assessments of behavior (rotarod, open field, passive avoidance) and of regional brain abnormalities determined through magnetic resonance imaging (MRI) (whole brain, striatum, cortex, hippocampus, corpus callosum), as well as an end-stage histological assessment. Detailed correlative analyses of these three measures were then performed. We found a gender-dependent emergence of motor impairments that was associated with an age-related loss of regional brain volumes. MRI measurements further indicated that there was no striatal atrophy, but rather a lack of striatal growth beyond 8 weeks of age. T2 relaxivity further indicated tissue-level changes within brain regions. Despite these dramatic motor and neuroanatomical abnormalities, R6/2 mice did not exhibit neuronal loss in the striatum or motor cortex, although there was a significant increase in neuronal density due to tissue atrophy. The deposition of the mutant HTT (mHTT) protein, the hallmark of HD molecular pathology, was widely distributed throughout the brain. End-stage histopathological assessments were not found to be as robustly correlated with the longitudinal measures of brain atrophy or motor impairments. In conclusion, modeling pre-manifest and early progression of the disease in more slowly progressing animal models will be key to establishing which changes are causally related. © 2013 Rattray et al

Statistical Analysis of the Processes Controlling Choline and Ethanolamine Glycerophospholipid Molecular Species Composition

The regulation and maintenance of the cellular lipidome through biosynthetic, remodeling, and catabolic mechanisms are critical for biological homeostasis during development, health and disease. These complex mechanisms control the architectures of lipid molecular species, which have diverse yet highly regulated fatty acid chains at both the sn1 and sn2 positions. Phosphatidylcholine (PC) and phosphatidylethanolamine (PE) serve as the predominant biophysical scaffolds in membranes, acting as reservoirs for potent lipid signals and regulating numerous enzymatic processes. Here we report the first rigorous computational dissection of the mechanisms influencing PC and PE molecular architectures from high-throughput shotgun lipidomic data. Using novel statistical approaches, we have analyzed multidimensional mass spectrometry-based shotgun lipidomic data from developmental mouse heart and mature mouse heart, lung, brain, and liver tissues. We show that in PC and PE, sn1 and sn2 positions are largely independent, though for low abundance species regulatory processes may interact with both the sn1 and sn2 chain simultaneously, leading to cooperative effects. Chains with similar biochemical properties appear to be remodeled similarly. We also see that sn2 positions are more regulated than sn1, and that PC exhibits stronger cooperative effects than PE. A key aspect of our work is a novel statistically rigorous approach to determine cooperativity based on a modified Fisher's exact test using Markov Chain Monte Carlo sampling. This computational approach provides a novel tool for developing mechanistic insight into lipidomic regulation

Deciphering the universe of RNA structures and trans RNA-RNA interactions of transcriptomes in vivo: from experimental protocols to computational analyses

The last few years have seen an explosion of experimental and computational methods for investigating RNA structures of entire transcriptomes in vivo. Very recent experimental protocols now also allow trans RNA–RNA interactions to be probed in a transcriptome-wide manner. All of the experimental strategies require comprehensive computational pipelines for analysing the raw data and converting it back into actual RNA structure features or trans RNA–RNA interactions. The overall performance of these methods thus strongly depends on the experimental and the computational protocols employed. In order to get the best out of both worlds, both aspects need to be optimised simultaneously. This review introduced the methods and proposes ideas how they could be further improved

The Effect of Ethanol Extract of Aerial Parts of the Mentha piperita in the Acquisition, Tolerance Expression and Dependence to Morphine in Adult Male Mice

Background & aim: Morphine dependence is a compulsive pattern of drug taking, resulting from the positive reinforcement of the rewarding effects of drug taking and the negative reinforcement of withdrawal syndrome that accompanies the cessation of drug taking. The objective of this study was to investigate the effect of ethanol extract of aerial parts of the Mentha piperita in the acquisition, tolerance expression and dependence to morphine in adult male mice Methods: In the present study, 75 NMRI mice were divided into fifiteen groups. The Hot-plate test was used to survey the morphine activity. Morphine was injected (2.5, 5, 10, 20, 40 mg/kg, i.p.) twice daily for seven days, except in 8th day in which morphine was administrated at a single dose (50 mg/kg). The extract (50, 75, 100 mg/kg) was injected for eight days. The control animals were intact, and sham animals only received morphine. Naloxone was injected (10 mg/kg) five hours after the final dose of morphine and the withdrawal signs were recorded during a 30 minute period. The data were expressed as mean values ± SEM and tested, using analysis of one-way ANOVA test. Results: Peppermint extract at doses of 75 and 100 kg significantly improved the tolerance expression and dependence to morphine in animals and significantly reduced the symptoms of withdrawal. Conclusion: Peppermint extract was commuted morphine tolerance and dependence in mice.The plant contained component(s) that alleviate morphine withdrawal syndrome. The extract possibly be effective in improving tolerance to morphine

Packet Error Rate(PER)-based Cross-layer Optimization of CDMA Networks

In CDMA systems, outer loop power control (OLPC) determines the target value of SNR at the receiver, mostly by using look-up tables to map bit error rates (BERs) to SNR-targets. In this contribution, transmission delay and packet loss rate constraints in the data link layer (DLL) are invoked in order to determine the optimum outer loop SNR-target setpoint analytically, according to the number of active users in cell. Optimality is, in this sense, the maximization of system throughput. Using the optimum SNR-target, the optimal spreading factor is determined. Subsequently, the joint optimization of outer loop SNR-target and variable spreading factor (VSF), at the physical(PHY)-layer, with truncated automatic repeat request (ARQ) error control mechanism at the data link layer are proposed. Our scheme is compared with 'constant SNR-target' and 'PHY-layer based variable SNR-target' cases under continuous power and rate variation to show (analytically and by simulations) the achievable gain through the coupling of physical and data link layers parameters

The fruit essential oil of Cuminum cyminum L. reduced the acquisition but not expression of ineffective dose of morphine-induced conditioned place preference in morphine- sensitized mice

Background: Cuminum cyminum fruit essential oil (FEO) dose-dependently can attenuate the expression of morphine tolerance and dependence in morphine-dependent mice. Objective: In this study, the effects of Cuminum cyminum FEO on acquisition and expression of morphine-induced conditioned place preference (CPP) in morphine-sensitized mice were studied. Methods: Repeated subcutaneous (s.c.) administration of morphine (5 mg/kg), once daily for three and 5 days free of the opioid (sensitization period), increased conditioning response induced by ineffective doses of morphine (0.25, 0.5 and 0.75 mg/kg). Results: The results showed that intra-peritoneal (i.p.) injection of Cumin FEO (0.001, 0.01, 0.1, 0.5, 1 and 2% 5 ml/kg) or Tween-80 (0.5% 5 ml/kg), 60 min before administration of morphine or saline during sensitization period (acquisition), decreased the conditioning response induced by ineffective dose of morphine (0.5 mg/kg s.c.) at the doses of 1% (P<0.05) and 2% (P<0.001) while Cumin FEO (0.001-2% i.p.), just 60 min before the test on post-conditioning phase (expression experiments), did not alter the conditioning scores in morphine- and non-sensitized mice. Conclusion: Our findings showed that the Cuminum cyminum fruit essential oil reduces the acquisition but not expression of morphine-induced conditioned place preference in morphine-sensitized mice