Analysis of the effects of depression associated polymorphisms on the activity of the BICC1 promoter in amygdala neurones

ACKNOWLEDGMENTS This work was funded by The BBSRC (BB/D004659/1) the Wellcome Trust (080980/Z/06/Z) and the Medical Research Council (G0701003).Peer reviewedPublisher PD

f(R) theories

Over the past decade, f(R) theories have been extensively studied as one of the simplest modifications to General Relativity. In this article we review various applications of f(R) theories to cosmology and gravity - such as inflation, dark energy, local gravity constraints, cosmological perturbations, and spherically symmetric solutions in weak and strong gravitational backgrounds. We present a number of ways to distinguish those theories from General Relativity observationally and experimentally. We also discuss the extension to other modified gravity theories such as Brans-Dicke theory and Gauss-Bonnet gravity, and address models that can satisfy both cosmological and local gravity constraints.Comment: 156 pages, 14 figures, Invited review article in Living Reviews in Relativity, Published version, Comments are welcom

Directional genetic selection by pulp mill effluent on multiple natural populations of three-spined stickleback (Gasterosteus aculeatus)

Contamination can cause a rapid environmental change which may require populations to respond with evolutionary changes. To evaluate the effects of pulp mill effluents on population genetics, we sampled three-spined sticklebacks (Gasterosteus aculeatus) near four pulp mills and four adjacent reference sites and analyzed Amplified Fragment Length Polymorphism (AFLP) to compare genetic variability. A fine scale genetic structure was detected and samples from polluted sites separated from reference sites in multidimensional scaling plots (P < 0.005, 1000 permutations) and locus-by-locus Analysis of Molecular Variance (AMOVA) further confirmed that habitats are significantly separated (FST = 0.021, P < 0.01, 1023 permutations). The amount of genetic variation between populations did not differ between habitats, and populations from both habitats had similar levels of heterozygosity (polluted sites Nei’s Hs = 0.11, reference sites Nei’s Hs = 0.11). Still, pairwise FST: s between three, out of four, pairs of polluted-reference sites were significant. A FST-outlier analysis showed that 21 (8.4%) loci were statistically different from a neutral distribution at the P < 0.05 level and therefore indicated to be under divergent selection. When removing 13 FST-outlier loci, significant at the P < 0.01 level, differentiation between habitats disappeared in a multidimensional scaling plot. In conclusion, pulp mill effluence has acted as a selective agent on natural populations of G. aculeatus, causing a convergence in genotype composition change at multiple sites in an open environment

Resolving the Evolutionary History of Campanula (Campanulaceae) in Western North America

Recent phylogenetic works have begun to address long-standing questions regarding the systematics of Campanula (Campanulaceae). Yet, aspects of the evolutionary history, particularly in northwestern North America, remain unresolved. Thus, our primary goal in this study was to infer the phylogenetic positions of northwestern Campanula species within the greater Campanuloideae tree. We combined new sequence data from 5 markers (atpB, rbcL, matK, and trnL-F regions of the chloroplast and the nuclear ITS) representing 12 species of Campanula with previously published datasets for worldwide campanuloids, allowing us to include approximately 75% of North American Campanuleae in a phylogenetic analysis of the Campanuloideae. Because all but one of North American Campanula species are nested within a single campanuloid subclade (the Rapunculus clade), we conducted a separate set of analyses focused specifically on this group. Our findings show that i) the campanuloids have colonized North America at least 6 times, 4 of which led to radiations, ii) all but one North American campanuloid are nested within the Rapunculus clade, iii) in northwestern North America, a C. piperi – C. lasiocarpa ancestor gave rise to a monophyletic Cordilleran clade that is sister to a clade containing C. rotundifolia, iv) within the Cordilleran clade, C. parryi var. parryi and C. parryi var. idahoensis exhibit a deep, species-level genetic divergence, and v) C. rotundifolia is genetically diverse across its range and polyphyletic. Potential causes of diversification and endemism in northwestern North America are discussed

Inhibition of Src kinase activity attenuates amyloid associated microgliosis in a murine model of Alzheimer’s disease

<p>Abstract</p> <p>Background</p> <p>Microglial activation is an important histologic characteristic of the pathology of Alzheimer’s disease (AD). One hypothesis is that amyloid beta (Aβ) peptide serves as a specific stimulus for tyrosine kinase-based microglial activation leading to pro-inflammatory changes that contribute to disease. Therefore, inhibiting Aβ stimulation of microglia may prove to be an important therapeutic strategy for AD.</p> <p>Methods</p> <p>Primary murine microglia cultures and the murine microglia cell line, BV2, were used for stimulation with fibrillar Aβ1-42. The non-receptor tyrosine kinase inhibitor, dasatinib, was used to treat the cells to determine whether Src family kinase activity was required for the Aβ stimulated signaling response and subsequent increase in TNFα secretion using Western blot analysis and enzyme-linked immunosorbent assay (ELISA), respectively. A histologic longitudinal analysis was performed using an AD transgenic mouse model, APP/PS1, to determine an age at which microglial protein tyrosine kinase levels increased in order to administer dasatinib via mini osmotic pump diffusion. Effects of dasatinib administration on microglial and astroglial activation, protein phosphotyrosine levels, active Src kinase levels, Aβ plaque deposition, and spatial working memory were assessed via immunohistochemistry, Western blot, and T maze analysis.</p> <p>Results</p> <p>Aβ fibrils stimulated primary murine microglia via a tyrosine kinase pathway involving Src kinase that was attenuated by dasatinib. Dasatinib administration to APP/PS1 mice decreased protein phosphotyrosine, active Src, reactive microglia, and TNFα levels in the hippocampus and temporal cortex. The drug had no effect on GFAP levels, Aβ plaque load, or the related tyrosine kinase, Lyn. These anti-inflammatory changes correlated with improved performance on the T maze test in dasatinib infused animals compared to control animals.</p> <p>Conclusions</p> <p>These data suggest that amyloid dependent microgliosis may be Src kinase dependent <it>in vitro</it> and <it>in vivo.</it> This study defines a role for Src kinase in the microgliosis characteristic of diseased brains and suggests that particular tyrosine kinase inhibition may be a valid anti-inflammatory approach to disease. Dasatinib is an FDA-approved drug for treating chronic myeloid leukemia cancer with a reported ability to cross the blood-brain barrier. Therefore, this suggests a novel use for this drug as well as similar acting molecules.</p

Use of an innovative model to evaluate mobility in seniors with lower-limb amputations of vascular origin: a pilot study

<p>Abstract</p> <p>Background</p> <p>The mobility of older individuals has often been only partially assessed, without considering all important aspects such as potential (available) versus effective (used) mobilities and the physical and psychosocial factors that modulate them. This study proposes a new model for evaluating mobility that considers all important aspects, applied here to lower-limb amputees with vascular origin. This model integrates the concepts of potential mobility (e.g. balance, speed of movement), effective mobility (e.g. life habits, movements in living areas) and factors that modulate these two types of mobility (e.g. strength, sensitivity, social support, depression). The main objective was to characterize potential and effective mobility as well as mobility modulators in a small sample of people with lower-limb amputations of vascular origin with different characteristics. The second objective of this pilot study was to assess the feasibility of measuring all variables in the model in a residential context.</p> <p>Methods</p> <p>An observational and transversal design was used with a heterogeneous sample of 10 participants with a lower-limb amputation of vascular origin, aged 51 to 83, assessed between eight and 18 months after discharge from an acute care hospital. A questionnaire of participant characteristics and 16 reliable and valid measurements were used.</p> <p>Results</p> <p>The results show that the potential mobility indicators do not accurately predict effective mobility, i.e., participants who perform well on traditional measures done in the laboratory or clinic are not always those who perform well in the real world. The model generated 4 different profiles (categories) of participants ranging from reduced to excellent potential mobility and low to excellent effective mobility, and characterized the modulating factors. The evaluations were acceptable in terms of the time taken (three hours) and the overall measurements, with a few exceptions, which were modified to optimize the data collected and the classification of the participants. For the population assessed, the results showed that some of the negative modulators (particularly living alone, no rehabilitation, pain, limited social support, poor muscle strength) played an important role in reducing effective mobility.</p> <p>Conclusion</p> <p>The first use of the model revealed interesting data that add to our understanding of important aspects linked to potential and effective mobility as well as modulators. The feasibility of measuring all variables in the model in a residential context was demonstrated. A study with a large number of participants is now warranted to rigorously characterize mobility levels of lower-limb amputees with vascular origin.</p

Visual attention and action: How cueing, direct mapping, and social interactions drive orienting

Despite considerable interest in both action perception and social attention over the last 2 decades, there has been surprisingly little investigation concerning how the manual actions of other humans orient visual attention. The present review draws together studies that have measured the orienting of attention, following observation of another’s goal-directed action. Our review proposes that, in line with the literature on eye gaze, action is a particularly strong orienting cue for the visual system. However, we additionally suggest that action may orient visual attention using mechanisms, which gaze direction does not (i.e., neural direct mapping and corepresentation). Finally, we review the implications of these gaze-independent mechanisms for the study of attention to action. We suggest that our understanding of attention to action may benefit from being studied in the context of joint action paradigms, where the role of higher level action goals and social factors can be investigated