BDNF signaling in epilepsy: TRKB-induced JAK/STAT pathway and phosphorylation of LSF in neurons

Epilepsy is a neurological disorder that causes recurrent and unprovoked seizures due to imbalances in synaptic transmission in distinct regions of the brain. In both human patients and animal models of epilepsy, there is a marked increase in brain-derived neurotrophic factor (BDNF), a critical signaling molecule in the brain that contributes to two divergent pathways important to disease pathology: 1) the regulation of type A receptors for the major inhibitory neurotransmitter GABA (GABAARs), and 2) aberrant neurogenesis with ectopic expression of new neurons from progenitor cells that disrupt neural network activity in the hippocampus. The first part of my thesis addresses how neurons regulate levels of α1-containing GABAARs through BDNF signaling at its receptors, tropomyosin receptor kinase B (TrkB) and p75 neurotrophin receptor (p75NTR). I hypothesized and showed that BDNF, working at TrkB, rapidly activates the Janus kinase and signal transducers and activators of transcription (JAK/STAT) pathway in neurons and identified a novel intracellular receptor signaling complex composed of p75NTR and JAK2 that is present in neuronal processes, cell body, and nucleus. Based on this finding, we suggest that an intracellular p75NTR/JAK2 signalsome recruits STAT3, a transcriptional activator of the gene coding for the cAMP inducible early repressor (ICER) that blocks synthesis of α1 subunits reducing synaptic GABAARs in response to status epilepticus. This model is consistent with our collaborative studies that show a JAK2 inhibitor, WP1066, inhibits development of spontaneous seizures in an epilepsy model and my observation that WP1066 degrades JAK2 protein in primary neurons. The second part of my thesis addresses BDNF regulation of the Late SV40 Factor (LSF), a ubiquitous transcription factor that regulates cell cycle progression and survival. I show that BDNF through the mitogen-activated protein kinase pathway selectively phosphorylates LSF at serine 291 (p291LSF) and that p291LSF is present throughout neurogenesis, increases with status epilepticus in the hippocampus, and is highest in structures associated with neurogenesis (such as olfactory bulb and hippocampus when compared to cortex). Taken together, these results suggest LSF may play an important role in neuronal development and potentially in epilepsy, providing an additional target for future therapeutic intervention.2016-12-15T00:00:00

Organic Agriculture in Bhutan: Barriers Going to 100%

This study seeks to provide an overview of organic agriculture in Bhutan. In an effort to promote sustainability and achieve the goals set by a Gross National Happiness inspired government, Bhutan has pledged to go 100% organic by 2020. This pledge is at odds with the country’s goal to increase self sufficiency and food security. I look at the barriers to going organic, the programs and initiatives in place to overcome or mitigate those barriers, and the path of least resistance in the future. I asked farmers, scholars, researchers, and members of the government for their opinions on the prospects of a 100% organic Bhutan. Through their answers, I hope to have identified what prevents Bhutan from becoming organic, what is pushing the movement forward now, and what is most important for the movement in the future

Perceptions of preparedness regarding administrative responsibilities: a comparative analysis of preservice and in-service secondary music educators.

This study investigated perceptions of knowledge and preparation regarding administrative responsibilities among in-service and preservice music teachers. Samples were selected randomly through NAfME and NASM databases. Data collection and analysis answered research questions asking how knowledgeable these groups felt about administrative topics, how they felt their undergraduate coursework prepared them for administrative responsibilities, and if there were any significant differences in preparedness among different subject areas taught by in-service directors. The findings report in-service teachers felt more knowledgeable of all administrative topics. Among in-service and preservice teachers, one significant difference was found; regarding preparedness pertaining to laws of communication via social media. Among subject areas, band directors reported significantly higher preparedness regarding creation of instrument inventories than choir and orchestra directors. Overall low ratings of preparedness in administrative areas and concerns reported in qualitative data suggest needed adjustments in curricula to better serve the practical needs of future music teachers

The Partnership Paradigm Is A Unified Field Theory For Human Betterment: How It Works in the Minnesota Climate Crisis Movement

“Intersectionality” is a byword of activists today. While we continue to ply our special causes and organize our various turfs, we are no longer content or even able to isolate ourselves within them as if they were solitary silos. These days most of us realize our causes and constituencies intersect. We attend each others' hearings, workshops and marches, trade ideas across the spectrum, form coalitions, and share hearts and minds on a digital scale that collapses time. We connect dots innumerable as the pixels in a picture, while the clouds grow darker and the lightning strikes nearer

Introduction: self-translating, from minorisation to empowerment

This introductory chapter discusses the implications of self-translation in multilingual contexts in Europe, aiming at mapping out innovative perspectives to the study of power and, by so doing, empowering self-translation. We start by critically engaging with the ‘cultural’ and ‘power turns’ in translation studies, as a way of delineating what the particularities of self-translation are when practised by author-translators in multilingual spaces. Focusing on the European milieu, defined broadly in terms of its geographies, we then discuss multilingualism, cultural awareness and ethnic diversity as staple terms in both academic and political ideologies across Europe, emphasising that one of the aspects of multilingualism is precisely the power differentials between languages and cultures. We explore these unequal power relations and centre–periphery dichotomies of Europe’s ‘minorised’ languages, literatures and cultures, suggesting the usage of ‘minorised’ in preference to the others discussed, inasmuch as it highlights both hegemonic power hierarchies and also the continual resistance to them. This is followed by a brief overview of the emerging debates in the subdiscipline of self-translation in recent times. It is within them that we situate our contribution, arguing that the self-translators’ double affiliation as authors and translators turns them into powerful cultural and ideological mediators and places them in a privileged position to challenge (or submit to) power. Here another term, ‘self-censorship,’ is suggested as invaluable to self-translation studies where self-editing often occurs before translation is begun. Finally, the introduction presents the organisation of the book and the main ideas discussed by the 11 authors in their individual chapters

The N-Terminal residues 43 to 60 form the interface for dopamine mediated α-synuclein dimerisation

α-synuclein (α-syn) is a major component of the intracellular inclusions called Lewy bodies, which are a key pathological feature in the brains of Parkinson's disease patients. The neurotransmitter dopamine (DA) inhibits the fibrillisation of α-syn into amyloid, and promotes α-syn aggregation into SDS-stable soluble oligomers. While this inhibition of amyloid formation requires the oxidation of both DA and the methionines in α-syn, the molecular basis for these processes is still unclear. This study sought to define the protein sequences required for the generation of oligomers. We tested N- (α-syn residues 43-140) and C-terminally (1-95) truncated α-syn, and found that similar to full-length protein both truncated species formed soluble DA: α-syn oligomers, albeit 1-95 had a different profile. Using nuclear magnetic resonance (NMR), and the N-terminally truncated α-syn 43-140 protein, we analysed the structural characteristics of the DA:α-syn 43-140 dimer and α-syn 43-140 monomer and found the dimerisation interface encompassed residues 43 to 60. Narrowing the interface to this small region will help define the mechanism by which DA mediates the formation of SDS-stable soluble DA:α-syn oligomers

Redox control of protein degradation

Intracellular proteolysis is critical to maintain timely degradation of altered proteins including oxidized proteins. This review attempts to summarize the most relevant findings about oxidant protein modification, as well as the impact of reactive oxygen species on the proteolytic systems that regulate cell response to an oxidant environment: the ubiquitin-proteasome system (UPS), autophagy and the unfolded protein response (UPR). In the presence of an oxidant environment, these systems are critical to ensure proteostasis and cell survival. An example of altered degradation of oxidized proteins in pathology is provided for neurodegenerative diseases. Future work will determine if protein oxidation is a valid target to combat proteinopathies

Post translational changes to α-synuclein control iron and dopamine trafficking : a concept for neuron vulnerability in Parkinson's disease

Parkinson's disease is a multifactorial neurodegenerative disorder, the aetiology of which remains elusive. The primary clinical feature of progressively impaired motor control is caused by a loss of midbrain substantia nigra dopamine neurons that have a high α-synuclein (α-syn) and iron content. α-Syn is a neuronal protein that is highly modified post-translationally and central to the Lewy body neuropathology of the disease. This review provides an overview of findings on the role post translational modifications to α-syn have in membrane binding and intracellular vesicle trafficking. Furthermore, we propose a concept in which acetylation and phosphorylation of α-syn modulate endocytic import of iron and vesicle transport of dopamine during normal physiology. Disregulated phosphorylation and oxidation of α-syn mediate iron and dopamine dependent oxidative stress through impaired cellular location and increase propensity for α-syn aggregation. The proposition highlights a connection between α-syn, iron and dopamine, three pathological components associated with disease progression in sporadic Parkinson's disease