Functional binding interaction identified between the axonal CAM L1 and members of the ERM family

Ayeast two-hybrid library was screened using the cytoplasmic domain of the axonal cell adhesion molecule L1 to identify binding partners that may be involved in the regulation of L1 function. The intracellular domain of L1 bound to ezrin, a member of the ezrin, radixin, and moesin (ERM) family of membrane–cytoskeleton linking proteins, at a site overlapping that for AP2, a clathrin adaptor. Binding of bacterial fusion proteins confirmed this interaction. To determine whether ERM proteins interact with L1 in vivo, extracellular antibodies to L1 were used to force cluster the protein on cultured hippocampal neurons and PC12 cells, which were then immunolabeled for ERM proteins. Confocal analysis revealed a precise pattern of codistribution between ERMs and L1 clusters in axons and PC12 neurites, whereas ERMs in dendrites and spectrin labeling remained evenly distributed. Transfection of hippocampal neurons grown on an L1 substrate with a dominant negative ERM construct resulted in extensive and abnormal elaboration of membrane protrusions and an increase in axon branching, highlighting the importance of the ERM–actin interaction in axon development. Together, our data indicate that L1 binds directly to members of the ERM family and suggest this association may coordinate aspects of axonal morphogenesis

Vgf is a novel biomarker associated with muscle weakness in amyotrophic lateral sclerosis (ALS), with a potential role in disease pathogenesis

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that affects nerve cells in the brain and the spinal cord. Previous proteomic evidence revealed that the content of certain peptide fragments including Vgf-derived peptide aa 398-411 (Vgf398-411) of the precursor Vgf protein in the cerebral spinal fluid (CSF) correctly identified patients with ALS from normal and disease controls. Using quantitative ELISA immunoassay we found that the CSF levels of Vgf decreases with muscle weakness in patients with ALS. In SOD1 G93A transgenic mice, loss of full-length Vgf content in CSF, serum and in SMI-32 immunopositive spinal cord motor neurons is noted in asymptomatic animals (approximately 75 days old) and continues to show a progressive decline as animals weaken. In vitro studies show that viral-mediated exogenous Vgf expression in primary mixed spinal cord neuron cultures attenuates excitotoxic injury. Thus, while Vgf may be a reliable biomarker of progression of muscle weakness in patients with ALS, restoration of Vgf expression in spinal cord motor neurons may therapeutically rescue spinal cord motorneurons against excitotoxic injury

Analysis of knockout mice suggests a role for VGF in the control of fat storage and energy expenditure

<p>Abstract</p> <p>Background</p> <p>Previous studies of mixed background mice have demonstrated that targeted deletion of <it>Vgf </it>produces a lean, hypermetabolic mouse that is resistant to diet-, lesion-, and genetically-induced obesity. To investigate potential mechanism(s) and site(s) of action of VGF, a neuronal and endocrine secreted protein and neuropeptide precursor, we further analyzed the metabolic phenotypes of two independent VGF knockout lines on C57Bl6 backgrounds.</p> <p>Results</p> <p>Unlike hyperactive VGF knockout mice on a mixed C57Bl6-129/SvJ background, homozygous mutant mice on a C57Bl6 background were hypermetabolic with similar locomotor activity levels to <it>Vgf+/Vgf+ </it>mice, during day and night cycles, indicating that mechanism(s) other than hyperactivity were responsible for their increased energy expenditure. In <it>Vgf-/Vgf- </it>knockout mice, morphological analysis of brown and white adipose tissues (BAT and WAT) indicated decreased fat storage in both tissues, and decreased adipocyte perimeter and area in WAT. Changes in gene expression measured by real-time RT-PCR were consistent with increased fatty acid oxidation and uptake in BAT, and increased lipolysis, decreased lipogenesis, and brown adipocyte differentiation in WAT, suggesting that increased sympathetic nervous system activity in <it>Vgf-/Vgf- </it>mice may be associated with or responsible for alterations in energy expenditure and fat storage. In addition, uncoupling protein 1 (UCP1) and UCP2 protein levels, mitochondrial number, and mitochondrial cristae density were upregulated in <it>Vgf-/Vgf- </it>BAT. Using immunohistochemical and histochemical techniques, we detected VGF in nerve fibers innervating BAT and <it>Vgf </it>promoter-driven reporter expression in cervical and thoracic spinal ganglia that project to and innervate the chest wall and tissues including BAT. Moreover, VGF peptide levels were quantified by radioimmunoassay in BAT, and were found to be down-regulated by a high fat diet. Lastly, despite being hypermetabolic, VGF knockout mice were cold intolerant.</p> <p>Conclusion</p> <p>We propose that VGF and/or VGF-derived peptides modulate sympathetic outflow pathways to regulate fat storage and energy expenditure.</p

Words, concepts, and the geometry of analogy

In Proceedings SLPCS 2016, arXiv:1608.01018In Proceedings SLPCS 2016, arXiv:1608.01018In Proceedings SLPCS 2016, arXiv:1608.01018© S. McGregor, M. Purver & G. Wiggins. This paper presents a geometric approach to the problem of modelling the relationship between words and concepts, focusing in particular on analogical phenomena in language and cognition. Grounded in recent theories regarding geometric conceptual spaces, we begin with an analysis of existing static distributional semantic models and move on to an exploration of a dynamic approach to using high dimensional spaces of word meaning to project subspaces where analogies can potentially be solved in an online, contextualised way. The crucial element of this analysis is the positioning of statistics in a geometric environment replete with opportunities for interpretation

Dual-specificity protein phosphatase 6 (DUSP6) overexpression reduces amyloid load and improves memory deficits in male 5xFAD mice

IntroductionDual specificity protein phosphatase 6 (DUSP6) was recently identified as a key hub gene in a causal VGF gene network that regulates late-onset Alzheimer’s disease (AD). Importantly, decreased DUSP6 levels are correlated with an increased clinical dementia rating (CDR) in human subjects, and DUSP6 levels are additionally decreased in the 5xFAD amyloidopathy mouse model.MethodsTo investigate the role of DUSP6 in AD, we stereotactically injected AAV5-DUSP6 or AAV5-GFP (control) into the dorsal hippocampus (dHc) of both female and male 5xFAD or wild type mice, to induce overexpression of DUSP6 or GFP.ResultsBarnes maze testing indicated that DUSP6 overexpression in the dHc of 5xFAD mice improved memory deficits and was associated with reduced amyloid plaque load, Aß1–40 and Aß1–42 levels, and amyloid precursor protein processing enzyme BACE1, in male but not in female mice. Microglial activation, which was increased in 5xFAD mice, was significantly reduced by dHc DUSP6 overexpression in both males and females, as was the number of “microglial clusters,” which correlated with reduced amyloid plaque size. Transcriptomic profiling of female 5xFAD hippocampus revealed upregulation of inflammatory and extracellular signal-regulated kinase pathways, while dHc DUSP6 overexpression in female 5xFAD mice downregulated a subset of genes in these pathways. Gene ontology analysis of DEGs (p &lt; 0.05) identified a greater number of synaptic pathways that were regulated by DUSP6 overexpression in male compared to female 5xFAD.DiscussionIn summary, DUSP6 overexpression in dHc reduced amyloid deposition and memory deficits in male but not female 5xFAD mice, whereas reduced neuroinflammation and microglial activation were observed in both males and females, suggesting that DUSP6-induced reduction of microglial activation did not contribute to sex-dependent improvement in memory deficits. The sex-dependent regulation of synaptic pathways by DUSP6 overexpression, however, correlated with the improvement of spatial memory deficits in male but not female 5xFAD

Searching for musical features using natural language queries: the C@merata evaluations at MediaEval

Musicological texts about classical music frequently include detailed technical discussions concerning the works being analysed. These references can be specific (e.g. C sharp in the treble clef) or general (fugal passage, Thor’s Hammer).Experts can usually identify the features in question in music scores but a means of performing this task automatically could be very useful for experts and beginnersalike. Following work on textual question answering over many years as co-or-ganisers of the QA tasks at the Cross Language Evaluation Forum, we decided in 2013 to propose a new type of task where the input would be a natural language phrase, together with a music score in MusicXML, and the required output would be one or more matching passages in the score. We report here on 3 years of theC@merata task at MediaEval. We describe the design of the task, the evaluation methods we devised for it, the approaches adopted by participant systems and the results obtained. Finally, we assess the progress which has been made in aligning natural language text with music and map out the main steps for the future. The novel aspects of this work are: (1) the task itself, linking musical references to actual music scores, (2) the evaluation methods we devised, based on modified versions of precision and recall, applied to demarcated musical passages, and (3) the progress which has been made in analysing and interpreting detailed technical references to music within texts