UBB+1 reduces amyloid-beta cytotoxicity by activation of autophagy in yeast

UBB+1 is a mutated version of ubiquitin B peptide caused by a transcriptional frameshift due to the RNA polymerase II "slippage". The accumulation of UBB+1 has been linked to ubiquitin-proteasome system (UPS) dysfunction and neurodegeneration. Alzheimer\u27s disease (AD) is defined as a progressive neurodegeneration and aggregation of amyloid-beta peptides (A beta) is a prominent neuropathological feature of AD. In our previous study, we found that yeast cells expressing UBB+1 at lower level display an increased resistance to cellular stresses under conditions of chronological aging. In order to examine the molecular mechanisms behind, here we performed genome-wide transcriptional analyses and molecular/cellular biology assays. We found that low UBB+1 expression activated the autophagy pathway, increased vacuolar activity, and promoted transport of autophagic marker ATG8p into vacuole. Furthermore, we introduced low UBB+1 expression to our humanized yeast AD models, that constitutively express A beta 42 and A beta 40 peptide, respectively. The co-expression of UBB+1 with A beta 42 or A beta 40 peptide led to reduced intracellular A beta levels, ameliorated viability, and increased chronological life span. In an autophagy deficient background strain (atg1 Delta), intracellular A beta levels were not affected by UBB+1 expression. Our findings offer insights for reducing intracellular A beta toxicity via autophagydependent cellular pathways under low level of UBB+1 expression

Development of a method for heat shock stress assessment in yeast based on transcription of specific genes

All living cells, including yeast cells, are challenged by different types of stresses in their environments and must cope with challenges such as heat, chemical stress, or oxidative damage. By reversibly adjusting the physiology while maintaining structural and genetic integrity, cells can achieve a competitive advantage and adapt environmental fluctuations. The yeast Saccharomyces cerevisiae has been extensively used as a model for study of stress responses due to the strong conservation of many essential cellular processes between yeast and human cells. We focused here on developing a tool to detect and quantify early responses using specific transcriptional responses. We analyzed the published transcriptional data on S.\ua0cerevisiae DBY strain responses to 10 different stresses in different time points. The principal component analysis (PCA) and the Pearson analysis were used to assess the stress response genes that are highly expressed in each individual stress condition. Except for these stress response genes, we also identified the reference genes in each stress condition, which would not be induced under stress condition and show stable transcriptional expression over time. We then tested our candidates experimentally in the CEN.PK strain. After data analysis, we identified two stress response genes (UBI4 and RRP) and two reference genes (MEX67 and SSY1) under heat shock (HS) condition. These genes were further verified by real-time PCR at mild (42\ub0C), severe (46\ub0C), to lethal temperature (50\ub0C), respectively

Individual Characteristics and the Probability of Telecourse Enrollment: An Examination of Student Choice

This study presents an empirical examination of the factors influencing undergraduate students to choose enrollment in an economics course via a distance education delivery format - specifically, a telecourse. The results indicate that age, work status, living distance to campus, and previous telecourse enrollment significantly influence a student's decision

Individual Characteristics and the Probability of Telecourse Enrollment: An Examination of Student Choice

This study presents an empirical examination of the factors influencing undergraduate students to choose enrollment in an economics course via a distance education delivery format - specifically, a telecourse. The results indicate that age, work status, living distance to campus, and previous telecourse enrollment significantly influence a student's decision

Implementation evaluation of multiple complex early years interventions: : an evaluation framework and study protocol

Introduction: Implementation evaluations are integral to understanding whether, how and why interventions work. However, unpicking the mechanisms of complex interventions is often challenging in usual service settings where multiple services are delivered concurrently. Furthermore, many locally developed and/or adapted interventions have not undergone any evaluation, thus limiting the evidence base available. Born in Bradford’s Better Start cohort is evaluating the impact of multiple early life interventions being delivered as part of the Big Lottery Fund’s ‘A Better Start’ programme to improve the health and well-being of children living in one of the most socially and ethnically diverse areas of the UK. In this paper, we outline our evaluation framework and protocol for embedding pragmatic implementation evaluation across multiple early years interventions and services. Methods and analysis: The evaluation framework is based on a modified version of The Conceptual Framework for Implementation Fidelity. Using qualitative and quantitative methods, our evaluation framework incorporates semistructured interviews, focus groups, routinely collected data and questionnaires. We will explore factors related to content, delivery and reach of interventions at both individual and wider community levels. Potential moderating factors impacting intervention success such as participants’ satisfaction, strategies to facilitate implementation, quality of delivery and context will also be examined. Interview and focus guides will be based on the Theoretical Domains Framework to further explore the barriers and facilitators of implementation. Descriptive statistics will be employed to analyse the routinely collected quantitative data and thematic analysis will be used to analyse qualitative data. Ethics and dissemination: The Health Research Authority (HRA) has confirmed our implementation evaluations do not require review by an NHS Research Ethics Committee (HRA decision 60/88/81). Findings will be shared widely to aid commissioning decisions and will also be disseminated through peer-reviewed journals, summary reports, conferences and community newsletters

Different expression levels of human mutant ubiquitin B+1 (UBB+1) can modify chronological lifespan or stress resistance of saccharomyces cerevisiae

The ubiquitin-proteasome system (UPS) is the main pathway responsible for the degradation of misfolded proteins, and its dysregulation has been implicated in several neurodegenerative diseases, including Alzheimer’s disease (AD). UBB+1, a mutant variant of ubiquitin B, was found to accumulate in neurons of AD patients and it has been linked to UPS dysfunction and neuronal death. Using the yeast Saccharomyces cerevisiae as a model system, we constitutively expressed UBB+1to evaluate its effects on proteasome function and cell death, particularly under conditions of chronological aging. We showed that the expression of UBB+1caused inhibition of the three proteasomal proteolytic activities (caspase-like (β1), trypsin-like (β2) and chymotrypsin-like (β5) activities) in yeast. Interestingly, this inhibition did not alter cell viability of growing cells. Moreover, we showed that cells expressing UBB+1at lower level displayed an increased capacity to degrade induced misfolded proteins. When we evaluated cells during chronological aging, UBB+1expression at lower level, prevented cells to accumulate reactive oxygen species (ROS) and avert apoptosis, dramatically increasing yeast life span. Since proteasome inhibition by UBB+1has previously been shown to induce chaperone expression and thus protect against stress, we evaluated our UBB+1model under heat shock and oxidative stress. Higher expression of UBB+1caused thermotolerance in yeast due to induction of chaperones, which occurred to a lesser extent at lower expression level of UBB+1(where we observed the phenotype of extended life span). Altering UPS capacity by differential expression of UBB+1protects cells against several stresses during chronological aging. This system can be valuable to study the effects of UBB+1on misfolded proteins involved in neurodegeneration and aging

Effective Electromagnetic Lagrangian at Finite Temperature and Density in the Electroweak Model

Using the exact propagators in a constant magnetic field, the effective electromagnetic Lagrangian at finite temperature and density is calculated to all orders in the field strength B within the framework of the complete electroweak model, in the weak coupling limit. The partition function and free energy are obtained explicitly and the finite temperature effective coupling is derived in closed form. Some implications of this result, potentially interesting to astrophysics and cosmology, are discussed.Comment: 14 pages, Revtex

Outcome measurement in functional neurological disorder: a systematic review and recommendations.

OBJECTIVES: We aimed to identify existing outcome measures for functional neurological disorder (FND), to inform the development of recommendations and to guide future research on FND outcomes. METHODS: A systematic review was conducted to identify existing FND-specific outcome measures and the most common measurement domains and measures in previous treatment studies. Searches of Embase, MEDLINE and PsycINFO were conducted between January 1965 and June 2019. The findings were discussed during two international meetings of the FND-Core Outcome Measures group. RESULTS: Five FND-specific measures were identified-three clinician-rated and two patient-rated-but their measurement properties have not been rigorously evaluated. No single measure was identified for use across the range of FND symptoms in adults. Across randomised controlled trials (k=40) and observational treatment studies (k=40), outcome measures most often assessed core FND symptom change. Other domains measured commonly were additional physical and psychological symptoms, life impact (ie, quality of life, disability and general functioning) and health economics/cost-utility (eg, healthcare resource use and quality-adjusted life years). CONCLUSIONS: There are few well-validated FND-specific outcome measures. Thus, at present, we recommend that existing outcome measures, known to be reliable, valid and responsive in FND or closely related populations, are used to capture key outcome domains. Increased consistency in outcome measurement will facilitate comparison of treatment effects across FND symptom types and treatment modalities. Future work needs to more rigorously validate outcome measures used in this population