Longitudinal investigation of neuroinflammation and metabolite profiles in the APPswe×PS1Δe9 transgenic mouse model of Alzheimer's disease

There is increasing evidence linking neuroinflammation to many neurological disorders including Alzheimer's disease (AD); however, its exact contribution to disease manifestation and/or progression is poorly understood. Therefore, there is a need to investigate neuroinflammation in both health and disease. Here, we investigate cognitive decline, neuroinflammatory and other pathophysiological changes in the APP_swe×PS1_Δe9 transgenic mouse model of AD. Transgenic (TG) mice were compared to C57BL/6 wild type (WT) mice at 6, 12 and 18 months of age. Neuroinflammation was investigated by [¹⁸F]DPA‐714 positron emission tomography and myo‐inositol levels using ¹H magnetic resonance spectroscopy (MRS) in vivo. Neuronal and cellular dysfunction was investigated by looking at N‐acetylaspartate (NAA), choline‐containing compounds, taurine and glutamate also using MRS. Cognitive decline was first observed at 12 m of age in the TG mice as assessed by working memory tests . A significant increase in [¹⁸F]DPA‐714 uptake was seen in the hippocampus and cortex of 18 m‐old TG mice when compared to age‐matched WT mice and 6 m‐old TG mice. No overall effect of gene was seen on metabolite levels; however, a significant reduction in NAA was observed in 18 m‐old TG mice when compared to WT. In addition, age resulted in a decrease in glutamate and an increase in choline levels. Therefore, we can conclude that increased neuroinflammation and cognitive decline are observed in TG animals, whereas NAA alterations occurring with age are exacerbated in the TG mice. These results support the role of neuroinflammation and metabolite alteration in AD and in ageing.

     

Interlinking hare and lynx dynamics using a century’s worth of annual data

The classic fur trade records on Canadian lynx (Lynx canadensis) have rarely been analysed in direct conjunction with data on its principal prey, the snowshoe hare (Lepus americanus). Comparable long-term data for hare exist only for a region south of Hudson Bay. We fitted a bivariate log-linear time-series model to this hare and lynx data to disentangle the within- and between-population interactions of these species. To reduce problems with fur returns being non-normal and non-linearly related to abundance, we transformed the fur returns to a normal distribution based on sample quantiles. The estimated effect on next year’s lynx abundance of a 1% increase in current hare abundance was a 0.23% (SE = 0.05) increase in lynx. Conversely, a 1% increase in current lynx abundance corresponded to a 0.46% (SE = 0.12) decrease in next year’s hare abundance. This contrasts with some earlier studies. However, these studies mixed hare data from south of Hudson Bay with lynx totals for all of Canada. Despite this asymmetry of interaction strengths, coefficients of determination were similar for hare versus lynx and lynx versus hare, because hare abundance varies more than lynx. Both species showed clear intraspecific density-dependence of about equal strength. A 1% increase in current abundance increased next year’s abundance by about 0.75%. Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

A generic approach for the purification of signaling complexes that specifically interact with the carboxyl-terminal domain of G protein-coupled receptors

G protein-coupled receptors (GPCRs) constitute the largest family of membrane receptors and are major drug targets. Recent progress has shown that GPCRs are part of large protein complexes that regulate their activity. We present here a generic approach for identification of these complexes that is based on the use of receptor subdomains and that overcomes the limitations of currently used genetics and proteomics approaches. Our approach consists of a carefully balanced combination of chemically synthesized His6-tagged baits, immobilized metal affinity chromatography, one- and two-dimensional gel electrophoresis separation and mass spectrometric identification. The carboxyl-terminal tails (C-tails) of the human MT1 and MT2 melatonin receptors, two class A GPCRs, were used as models to purify protein complexes from mouse brain lysates. We identified 32 proteins that interacted with the C-tail of MT1, 14 proteins that interacted with the C-tail of MT2, and eight proteins that interacted with both C-tails. Several randomly selected proteins were validated by Western blotting, and the functional relevance of our data was further confirmed by showing the interaction between the full-length MT1 and the regulator of G protein signaling Z1 in transfected HEK 293 cells and native tissue. Taken together, we have established an integrated and generic purification strategy for the identification of high quality and functionally relevant GPCR-associated protein complexes that significantly widens the repertoire of available techniques.     

Assessing the contribution of inflammation in models of Alzheimer's disease

Inflammation has long been proposed as having a role in AD (Alzheimer's disease), although it remains unclear whether inflammation represents a cause or consequence of AD. Evidence from the clinical setting in support of a role for inflammation in AD includes increased expression of inflammatory mediators and microglial activation in the post-mortem AD brain. Also, epidemiological studies on AD patients under long-term treatment with non-steroidal anti-inflammatory drugs suggest some benefits, although recent prospective trials showed no effect. Furthermore, in AD patients, infection and other systemic inflammatory events worsen symptoms. Finally, several inflammatory genes are associated with increased risk of AD. Therefore, to elucidate the underlying mechanisms of AD and the role of inflammation, researchers have turned to experimental models and here we present a short overview of some key findings from these studies. Activation of microglia is seen in various transgenic models of AD, with both a protective role and a detrimental role being ascribed to it. Early microglial activation is probably beneficial in AD, through phagocytosis of amyloid β-peptide. At later stages however, pro-inflammatory cytokine release from microglia could contribute to neuronal demise. A better understanding of microglial phenotype at the various stages of AD is therefore still required. Although most studies suggest a detrimental role for pro-inflammatory cytokines such as interleukin-1 and tumour necrosis factor in AD, contradictory findings do exist. Age-related and differential cellular expression of these inflammatory mediators is probably a key determinant of their exact contribution to AD. In conclusion, there is no doubt that inflammatory processes are part of the pathophysiology of AD, but a better understanding of the exact contribution at different stages of the disease process is still required before appropriate treatment strategies can be devised.     

Design and synthesis of 3-phenyl tetrahydronaphthalenic derivatives as new selective MT2 melatoninergic ligands

Tetrahydronaphthalenic analogues of melatonin have been synthesized and evaluated as melatonin receptor ligands. Introduction of a phenyl substituent in the 3-position of the tetraline ring allows to obtain MT(2) selective ligands. Activity and MT(2) selectivity can be modulated with suitable modifications of the N-acyl substituent. The (+)-(RR)-cis enantiomer of the N-[2-(7-methoxy-3-phenyl-1,2,3,4-tetrahydro-naphthalen-1-yl)ethyl]cyclobutyl carboxamide (14) is one of the most MT(2) selective ligands described until now and behaves as an antagonist.     

Molecular simulation of zeolite flexibility

We present a transferable force field able to model the structure of zeolites when different cation types are considered. Based on simple functional forms and interactions, it can be easily implemented in most common molecular simulation codes. The optimised force field is validated on structural properties (lattice parameters and Si–O–Al angles) for a large variety of zeolites, including faujasites of different Si/Al ratio and different extra-framework cation types (Li⁺, Na⁺, K⁺, Mg²⁺, Ca²⁺ and Co²⁺). The transferability of the force field was successfully tested on zeolites of different topologies such as FAU, LTA, MFI, FER and TON. The predictive capabilities of the potential were tested on structural deformations of alkaline earth Na, Co-X faujasites with different ion-exchange ratios.     

Low Incidence of Chest Wall Pain with a Risk-Adapted Lung Stereotactic Body Radiation Therapy Approach Using Three or Five Fractions Based on Chest Wall Dosimetry

Purpose

To examine the frequency and potential of dose-volume predictors for chest wall (CW) toxicity (pain and/or rib fracture) for patients receiving lung stereotactic body radiotherapy (SBRT) using treatment planning methods to minimize CW dose and a risk-adapted fractionation scheme.

Methods

We reviewed data from 72 treatment plans, from 69 lung SBRT patients with at least one year of follow-up or CW toxicity, who were treated at our center between 2010 and 2013. Treatment plans were optimized to reduce CW dose and patients received a risk-adapted fractionation of 18 Gy×3 fractions (54 Gy total) if the CW V30 was less than 30 mL or 10–12 Gy×5 fractions (50–60 Gy total) otherwise. The association between CW toxicity and patient characteristics, treatment parameters and dose metrics, including biologically equivalent dose, were analyzed using logistic regression.

Results

With a median follow-up of 20 months, 6 (8.3%) patients developed CW pain including three (4.2%) grade 1, two (2.8%) grade 2 and one (1.4%) grade 3. Five (6.9%) patients developed rib fractures, one of which was symptomatic. No significant associations between CW toxicity and patient and dosimetric variables were identified on univariate nor multivariate analysis.

Conclusions

Optimization of treatment plans to reduce CW dose and a risk-adapted fractionation strategy of three or five fractions based on the CW V30 resulted in a low incidence of CW toxicity. Under these conditions, none of the patient characteristics or dose metrics we examined appeared to be predictive of CW pain.     

Anticipatory parental care: acquiring resources for offspring prior to conception.

Many organisms acquire and defend resources outside the breeding season and this is thought to be for immediate survival and reproductive benefits. Female red squirrels (Tamiasciurus hudsonicus) acquire traditional food cache sites up to four months prior to the presence of any physiological or behavioural cues associated with mating or offspring dependency. They subsequently relinquish these resources to one of their offspring at independence (ten months later). We experimentally show that acquisition of these cache sites cannot be explained by conventional arguments such as enhanced survival of the parent or increased reproductive output. Instead this behaviour functions as a form of parental care.