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

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

Structure of the gene encoding VGF, a nervous system-specific mRNA that is rapidly and selectively induced by nerve growth factor in PC12 cells

Nerve growth factor (NGF) plays a critical role in the development and survival of neurons in the peripheral nervous system. Following treatment with NGF but not epidermal growth factor, rat pheochromocytoma (PC12) cells undergo neural differentiation. We have cloned a nervous system-specific mRNA, NGF33.1, that is rapidly and relatively selectively induced by treatment of PC12 cells with NGF and basic fibroblast growth factor in comparison with epidermal growth factor. Analysis of the nucleic acid and predicted amino acid sequences of the NGF33.1 cDNA clone suggested that this clone corresponded to the NGF-inducible mRN

Intranasal Peptide Therapeutics: A Promising Avenue for Overcoming the Challenges of Traditional CNS Drug Development

The central nervous system (CNS) has, among all organ systems in the human body, the highest failure rate of traditional small-molecule drug development, ranging from 80–100% depending on the area of disease research. This has led to widespread abandonment by the pharmaceutical industry of research and development for CNS disorders, despite increased diagnoses of neurodegenerative disorders and the continued lack of adequate treatment options for brain injuries, stroke, neurodevelopmental disorders, and neuropsychiatric illness. However, new approaches, concurrent with the development of sophisticated bioinformatic and genomic tools, are being used to explore peptide-based therapeutics to manipulate endogenous pathways and targets, including “undruggable” intracellular protein-protein interactions (PPIs). The development of peptide-based therapeutics was previously rejected due to systemic off-target effects and poor bioavailability arising from traditional oral and systemic delivery methods. However, targeted nose-to-brain, or intranasal (IN), approaches have begun to emerge that allow CNS-specific delivery of therapeutics via the trigeminal and olfactory nerve pathways, laying the foundation for improved alternatives to systemic drug delivery. Here we review a dozen promising IN peptide therapeutics in preclinical and clinical development for neurodegenerative (Alzheimer’s, Parkinson’s), neuropsychiatric (depression, PTSD, schizophrenia), and neurodevelopmental disorders (autism), with insulin, NAP (davunetide), IGF-1, PACAP, NPY, oxytocin, and GLP-1 agonists prominent among them

The Prohormone VGF Regulates β Cell Function via Insulin Secretory Granule Biogenesis

The prohormone VGF is expressed in neuroendocrine and endocrine tissues and regulates nutrient and energy status both centrally and peripherally. We and others have shown that VGF-derived peptides have direct action on the islet β cell as secretagogues and cytoprotective agents; however, the endogenous function of VGF in the β cell has not been described. Here, we demonstrate that VGF regulates secretory granule formation. VGF loss-of-function studies in both isolated islets and conditional knockout mice reveal a profound decrease in stimulus-coupled insulin secretion. Moreover, VGF is necessary to facilitate efficient exit of granule cargo from the trans-Golgi network and proinsulin processing. It also functions to replenish insulin granule stores following nutrient stimulation. Our data support a model in which VGF operates at a critical node of granule biogenesis in the islet β cell to coordinate insulin biosynthesis with β cell secretory capacity