How Does Music Connect the Artist and Fans?

This paper discusses the connection that subcultures and fan-bases of certain musical acts feel with their favorite artists on an emotional and psychological level. Analyzing the lyrical content of rock artists Kurt Cobain, Layne Staley, Chris Cornell, and Chester Bennington, all of which suffered from depression and/or addiction and eventually committed suicide, this paper aims to look at how the lyrics of their songs connect their experiences in real life to their fans who may be suffering the same illnesses, and how they could be seen as a cry for help

The Republic of Fabulachia: Queer Visions for a Post-Coal Appalachian Future

This thesis explores the ways in which four young white queer Central Appalachian organizers navigate tradition and change in their efforts to envision a just and sustainable post-coal Appalachian future. Based on oral history interviews conducted during the summer of 2016 with Ada Smith, Kenny Bilbrey, Sam Gleaves, and Ivy Brashier, this thesis examines their engagement with and challenges to narrow constructions of Appalachian and mainstream queer constructions of the traditional. It additionally considers their collective vision for an Appalachian Transition in which local communities reclaim decision making power about the fate of their future, and the potential to use this moment of deep economic, environmental, and political uncertainty to boldly demand a future in which LGBTQ+ people, people of color and all mountain people are able to survive and thrive in the places that we love.Master of Art

The Relationship Between Antecedent Variables and Collective Organizational Engagement in U.S. Manufacturers

Manufacturing leaders face challenges that influence organizational outcomes such as, collective organizational engagement. Because of the complexities in the U.S. manufacturing industry, manufacturing leaders must identify resources and strategies that influence collective organizational engagement levels. Grounded in employee engagement theory and resource management theory, the purpose of this quantitative correlational study was to examine the relationship between motivating work design, human resource management practices, strategic implementation, and collective organizational engagement. The sample included 123 participants from large manufacturing organizations within the U.S. Mid-Atlantic region who held non-executive titles. The results of the multiple linear regression were significant, F(3, 122) = 28.603, p \u3c 0.05, R^2 = 0.419. In the final model, human resource management practice (p \u3c 0.05; B = .255) and strategic implementation (p \u3c 0.05; B = .298), provided a significant contribution to the model; motivating work design did not demonstrate statistical significance. A key recommendation for business leaders is to leverage human resource management practices such as job rewards, job security, and job performance feedback to enhance or improve collective organizational engagement levels. Implications for positive social change include the potential to promote individual self-worth and positive well-being

Modulation of Ampa Receptor Desensitization by Nootropic Drugs and Endogenous Proteins

AMPA receptors play a central role in basal excitatory synaptic transmission as well as synaptic maturation and plasticity. An important characteristic of AMPA receptors (AMPARs) is the rapid and profound desensitization that occurs within milliseconds of glutamate binding; however, the mechanisms controlling desensitization of native AMPARs are incompletely understood. We have applied patch-clamp recording techniques in cultured neurons and heterologous cells to (1) test a model of AMPAR desensitization based on the crystal structure of the extracellular domains and (2) determine whether proteins associated with synaptic AMPARs affect desensitization and/or other channel properties. A key finding from crystallization of the extracellular domains of the receptor is that the benzothiadiazine positive modulator cyclothiazide, which blocks AMPAR desensitization, binds at and stabilizes the dimer interface formed by adjacent subunits. This and other data suggested a model in which desensitization involves a conformational change disrupting the dimer interface. Our data from intact hippocampal AMPAR indicate the benzothiadiazines prevent the conformational change to the desensitized state, and, conversely, cannot bind desensitized AMPARs.The transmembrane AMPAR regulatory protein (TARP) stargazin (γ2) serves multiple roles in trafficking and stabilizing synaptic AMPARs and may be incorporated as an auxiliary subunit. Transfection of hippocampal neurons with stargazin produced two distinct effects on AMPAR functional properties without affecting surface receptor density: reduced glutamate-evoked desensitization and increased efficacy of the partial agonist kainate. Kinetic and dose-response analyses suggest that stargazin affects glutamate desensitization through an allosteric interaction that destabilizes the desensitized state of the receptor, and that potentiation of kainate responses reflects increased efficacy rather than altered affinity. Stargazin's effects were also observed in HEK 293 cells transfected with various heteromeric and homomeric AMPARs, with subunit-dependent effects on glutamate desensitization, kainate efficacy, and trafficking. We show that two regions of stargazin mediate its functional effects: the C-terminal intracellular domain appears more important for effects on glutamate-evoked desensitization and receptor trafficking, while the first extracellular domain makes a larger contribution to altered kainate efficacy. These data indicate that TARPs directly modulate channel function and, as auxiliary subunits of AMPARs, contribute to functional heterogeneity of the desensitization properties of neuronal AMPARs.Department of Biochemistry and Molecular Biolog

Amyloid and intracellular accumulation of BRI2

Familial British dementia (FBD) and familial Danish dementia (FDD) are caused by mutations in the BRI2 gene. These diseases are characterized clinically by progressive dementia and ataxia and neuropathologically by amyloid deposits and neurofibrillary tangles. Herein, we investigate BRI2 protein accumulation in FBD, FDD, Alzheimer disease and Gerstmann-Sträussler-Scheinker disease. In FBD and FDD, we observed reduced processing of the mutant BRI2 pro-protein, which was found accumulating intracellularly in the Golgi of neurons and glial cells. In addition, we observed an accumulation of a mature form of BRI2 protein in dystrophic neurites, surrounding amyloid cores. Accumulation of BRI2 was also observed in dystrophic neurites of Alzheimer disease and Gerstmann-Sträussler-Scheinker disease cases. Although it remains to be determined whether intracellular accumulation of BRI2 may lead to cell damage in these degenerative diseases, our study provides new insights into the role of mutant BRI2 in the pathogenesis of FBD and FDD and implicates BRI2 as a potential indicator of neuritic damage in diseases characterized by cerebral amyloid deposition

Novel tau filament fold in chronic traumatic encephalopathy encloses hydrophobic molecules

Chronic traumatic encephalopathy (CTE) is a neurodegenerative tauopathy that is associated with repetitive head impacts or exposure to blast waves. First described as punch-drunk syndrome and dementia pugilistica in retired boxers1-3, CTE has since been identified in former participants of other contact sports, ex-military personnel and after physical abuse4-7. No disease-modifying therapies currently exist, and diagnosis requires an autopsy. CTE is defined by an abundance of hyperphosphorylated tau protein in neurons, astrocytes and cell processes around blood vessels8,9. This, together with the accumulation of tau inclusions in cortical layers II and III, distinguishes CTE from Alzheimer's disease and other tauopathies10,11. However, the morphologies of tau filaments in CTE and the mechanisms by which brain trauma can lead to their formation are unknown. Here we determine the structures of tau filaments from the brains of three individuals with CTE at resolutions down to 2.3 Å, using cryo-electron microscopy. We show that filament structures are identical in the three cases but are distinct from those of Alzheimer's and Pick's diseases, and from those formed in vitro12-15. Similar to Alzheimer's disease12,14,16-18, all six brain tau isoforms assemble into filaments in CTE, and residues K274-R379 of three-repeat tau and S305-R379 of four-repeat tau form the ordered core of two identical C-shaped protofilaments. However, a different conformation of the β-helix region creates a hydrophobic cavity that is absent in tau filaments from the brains of patients with Alzheimer's disease. This cavity encloses an additional density that is not connected to tau, which suggests that the incorporation of cofactors may have a role in tau aggregation in CTE. Moreover, filaments in CTE have distinct protofilament interfaces to those of Alzheimer's disease. Our structures provide a unifying neuropathological criterion for CTE, and support the hypothesis that the formation and propagation of distinct conformers of assembled tau underlie different neurodegenerative diseases

A novel ferritin light chain mutation in neuroferritinopathy with an atypical presentation

Neuroferritinopathy or hereditary ferritinopathy is an inherited neurodegenerative disease caused by mutations in ferritin light chain (FTL) gene. The clinical features of the disease are highly variable, and include a movement disorder, behavioral abnormalities, and cognitive impairment. Neuropathologically, the disease is characterized by abnormal iron and ferritin deposition in the central nervous system. We report a family in which neuroferritinopathy begins with chronic headaches, later developing progressive orolingual and arm dystonia, dysarthria, cerebellar ataxia, pyramidal tract signs, and psychiatric symptoms. In the absence of classic clinical symptoms, the initial diagnosis of the disease was based on magnetic resonance imaging studies. Biochemical studies on the proband showed normal serum ferritin levels, but remarkably low cerebrospinal fluid (CSF) ferritin levels. A novel FTL mutation was identified in the proband. Our findings expand the genetic and clinical diversity of neuroferritinopathy and suggest CSF ferritin levels as a novel potential biochemical marker for the diagnosis of neuroferritinopathy

Tau filaments from multiple cases of sporadic and inherited Alzheimer's disease adopt a common fold.

The ordered assembly of tau protein into abnormal filaments is a defining characteristic of Alzheimer's disease (AD) and other neurodegenerative disorders. It is not known if the structures of tau filaments vary within, or between, the brains of individuals with AD. We used a combination of electron cryo-microscopy (cryo-EM) and immuno-gold negative-stain electron microscopy (immuno-EM) to determine the structures of paired helical filaments (PHFs) and straight filaments (SFs) from the frontal cortex of 17 cases of AD (15 sporadic and 2 inherited) and 2 cases of atypical AD (posterior cortical atrophy). The high-resolution structures of PHFs and SFs from the frontal cortex of 3 cases of AD, 2 sporadic and 1 inherited, were determined by cryo-EM. We also used immuno-EM to study the PHFs and SFs from a number of cortical and subcortical brain regions. PHFs outnumbered SFs in all AD cases. By cryo-EM, PHFs and SFs were made of two C-shaped protofilaments with a combined cross-β/β-helix structure, as described previously for one case of AD. The higher resolution structures obtained here showed two additional amino acids at each end of the protofilament. The immuno-EM findings, which indicated the presence of repeats 3 and 4, but not of the N-terminal regions of repeats 1 and 2, of tau in the filament cores of all AD cases, were consistent with the cryo-EM results. These findings show that there is no significant variation in tau filament structures between individuals with AD. This knowledge will be crucial for understanding the mechanisms that underlie tau filament formation and for developing novel diagnostics and therapies

Modeling familial British and Danish dementia

Familial British dementia (FBD) and familial Danish dementia (FDD) are two autosomal dominant neurodegenerative diseases caused by mutations in the BRI ( 2 ) gene. FBD and FDD are characterized by widespread cerebral amyloid angiopathy (CAA), parenchymal amyloid deposition, and neurofibrillary tangles. Transgenic mice expressing wild-type and mutant forms of the BRI(2) protein, Bri ( 2 ) knock-in mutant mice, and Bri ( 2 ) gene knock-out mice have been developed. Transgenic mice expressing a human FDD-mutated form of the BRI ( 2 ) gene have partially reproduced the neuropathological lesions observed in FDD. These mice develop extensive CAA, parenchymal amyloid deposition, and neuroinflammation in the central nervous system. These animal models allow the study of the molecular mechanism(s) underlying the neuronal dysfunction in these diseases and allow the development of potential therapeutic approaches for these and related neurodegenerative conditions. In this review, a comprehensive account of the advances in the development of animal models for FBD and FDD and of their relevance to the study of Alzheimer disease is presented