Psychology Applied to the Improvement of Control of the Pitch of the Voice in Singing

The object of this research is to ascertain some of the elements in the acquisition of accuracy of pitch in singing. The study was divided into three divisions; (1) a preliminary series of five tests, in which no information was given the observer in regard to the accuracy of his singing; (2) a practice series of ten tests, during which the observer was informed of the error in pitch after each trial; and (3) a final series of five tests conducted in the same manner as the first. The object of the first test was to ascertain the accuracy of their singing without training; the second was the training series, the object of which was to correct the errors and to form new tonal concepts and voluntary control; and the object of the third series was to find out whether or not the observers had profited by the training in the second series and to what extent they carried it over into actual practice

A textual and critical study of poems by Edward Thomas, selected from manuscript sources

The Critical Introduction examines Thomas's 'way of seeing', approached through words, with their strengths and limitations as a means of communicating. Memory and the role of past experience in the present and future, sensuous perception with its limits as a means of understanding and content, humility and honesty in apprehending both folklore and the lore of child and creature, all are seen as integral to the poet's determination to understand himself and his relationships under the pressure of a war seen as part of a greater and continuing war of values. Notable, too, is the poet's treatment of his foreseen sacrifice and its relative insignificance. The Textual Introduction surveys B.M. Add. MS; . 44990 and, more fully, Bodleian Don. d. 28, establishing the different uses to which Thomas put them, the chronology of these drafts in relation to other data, and the relationship of printed editions to these sources. Bodleian Don. e.l0 - a commonplace book of 1901 - provides hitherto unmentioned evidence of Thomas's earlier interest in matters explored in the poems. The preparation of the early editions is covered, and a descriptive bibliography of early editions is included. The Text presents 32 poems from B.M. Add. Ms, . 44990, 1 from an early pamphlet, and 17 from Bodleian Don. d. 28, totalling 50' from some 130 consulted. (Drafts from Lockwood Memorial Library are examined in the Critical Introduction). The Notes cover alteration of these drafts in print, or as mentioned in letters to Farjeon. Critical commentary clarifies items of textual interest (e.g.Dand.28f.22 - "Roads") and amplifies the Critical Introduction. A .Bibliography, Index to the Poems, Appendices on Titles, Chronology of known imss. drafts, a Biographical Table 1914-17 and photographs of biographical interest are included, as are photocopies of textually significant readings from the Bodleian book and from early editions.(xiii, 290p, 16 plates

Disrupted glycosylation of lipids and proteins is a cause of neurodegeneration

Glycosyltransferases represent a large family of enzymes that catalyse the biosynthesis of oligosaccharides, polysaccharides, and glycoconjugates. A number of studies have implicated glycosyltransferases in the pathogenesis of neurodegenerative diseases but differentiating cause from effect has been difficult. We have recently discovered that mutations proximal to the substrate binding site of glycosyltransferase 8 domain containing 1 (GLT8D1) are associated with familial amyotrophic lateral sclerosis (ALS). We demonstrated that ALS-associated mutations reduce activity of the enzyme suggesting a loss-of-function mechanism that is an attractive therapeutic target. Our work is the first evidence that isolated dysfunction of a glycosyltransferase is sufficient to cause a neurodegenerative disease, but connection between neurodegeneration and genetic variation within glycosyltransferases is not new. Previous studies have identified associations between mutations in UGT8 and sporadic ALS, and between ST6GAL1 mutations and conversion of mild cognitive impairment into clinical Alzheimer’s disease. In this review we consider potential mechanisms connecting glycosyltransferase dysfunction to neurodegeneration. The most prominent candidates are ganglioside synthesis and impaired addition of O-linked β-N-acetylglucosamine (O-GlcNAc) groups to proteins important for axonal and synaptic function. Special consideration is given to examples where genetic mutations within glycosyltransferases are associated with neurodegeneration in recognition of the fact that these changes are likely to be upstream causes present from birth

Mutations in the Glycosyltransferase Domain of GLT8D1 Are Associated with Familial Amyotrophic Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a severe neurodegenerative disorder without effective neuroprotective therapy. Known genetic variants impair pathways, including RNA processing, axonal transport, and protein homeostasis. We report ALS-causing mutations within the gene encoding the glycosyltransferase GLT8D1. Exome sequencing in an autosomal-dominant ALS pedigree identified p.R92C mutations in GLT8D1, which co-segregate with disease. Sequencing of local and international cohorts demonstrated significant ALS association in the same exon, including additional rare deleterious mutations in conserved amino acids. Mutations are associated with the substrate binding site, and both R92C and G78W changes impair GLT8D1 enzyme activity. Mutated GLT8D1 exhibits in vitro cytotoxicity and induces motor deficits in zebrafish consistent with ALS. Relative toxicity of mutations in model systems mirrors clinical severity. In conclusion, we have linked ALS pathophysiology to inherited mutations that diminish the activity of a glycosyltransferase enzyme

Chapter Genetics of Familial Amyotrophic Lateral Sclerosis

Electronics engineerin

Genetics of Familial Amyotrophic Lateral Sclerosis

Electronics engineerin

Insights Arising from Gene Expression Profiling in Amyotrophic Lateral Sclerosis

Public health & preventive medicin

TDP43 proteinopathy is associated with aberrant DNA methylation in human amyotrophic lateral sclerosis

Background Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by motor neurone (MN) degeneration and death. ALS can be sporadic (sALS) or familial, with a number of associated gene mutations, including C9orf72 (C9ALS). DNA methylation is an epigenetic mechanism whereby a methyl group is attached to a cytosine (5mC), resulting in gene expression repression. 5mC can be further oxidized to 5‐hydroxymethylcytosine (5hmC). DNA methylation has been studied in other neurodegenerative diseases, but little work has been conducted in ALS. Aims To assess differences in DNA methylation in individuals with ALS and the relationship between DNA methylation and TDP43 pathology. Methods Post mortem tissue from controls, sALS cases and C9ALS cases were assessed by immunohistochemistry for 5mC and 5hmC in spinal cord, motor cortex and prefrontal cortex. LMNs were extracted from a subset of cases using laser capture microdissection. DNA from these underwent analysis using the MethylationEPIC array to determine which molecular processes were most affected. Results There were higher levels of 5mC and 5hmC in sALS and C9ALS in the residual lower motor neurones (LMNs) of the spinal cord. Importantly, in LMNs with TDP43 pathology there was less nuclear 5mC and 5hmC compared to the majority of residual LMNs that lacked TDP43 pathology. Enrichment analysis of the array data suggested RNA metabolism was particularly affected. Conclusions DNA methylation is a contributory factor in ALS LMN pathology. This is not so for glia or neocortical neurones