Confirmatory factor analysis of Clinical Outcomes in Routine Evaluation (CORE-OM) used as a measure of emotional distress in people with tinnitus

BACKGROUND: People with troublesome tinnitus often experience emotional distress. Therefore a psychometrically sound instrument which can evaluate levels of distress and change over time is necessary to understand this experience. Clinical Outcomes in Routine Evaluation (CORE-OM) is a measure of emotional distress which has been widely used in mental health research. Although originally designed as a 4-factor questionnaire, factor analyses have not supported this structure and a number of alternative factor structures have been proposed in different samples. The aims of this study were to test the factor structure of the CORE-OM using a large representative tinnitus sample and to use it to investigate levels of emotional distress amongst people with a range of tinnitus experience. METHODS: The CORE-OM was completed by 342 people experiencing tinnitus who self-rated their tinnitus on a 5-point scale from ‘not a problem’ to ‘a very big problem’. Confirmatory factor analysis was used to test all ten factor models which have been previously derived across a range of population samples. Model fit was assessed using fit criterion and theoretical considerations. Mean scores on the full questionnaire and its subscales were compared between tinnitus problem categories using one-way ANOVA. RESULTS: The best fitting model included 33 of the 34 original items and was divided into three factors: negatively worded items, positively worded items and risk. The full questionnaire and each factor were found to have good internal consistency and factor loadings were high. There was a statistically significant difference in total CORE-OM scores across the five tinnitus problem categories. However there was no significant difference between those who rated their tinnitus ‘not a problem’, and ‘a small problem’ or ‘a moderate problem.’ CONCLUSION: This study found a 3-factor structure for the CORE-OM to be a good fit for a tinnitus population. It also found evidence of a relationship between emotional distress as measured by CORE-OM and perception of tinnitus as a problem. Its use in tinnitus clinics is to be recommended, particularly when emotional distress is a target of therapy. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12955-016-0524-5) contains supplementary material, which is available to authorized users

Chaperones in Neurodegeneration

Cellular protein homeostasis (proteostasis) maintains the integrity of the proteome and includes protein synthesis, folding, oligomerization, and turnover; chaperone proteins assist with all of these processes. Neurons appear to be especially susceptible to failures in proteostasis, and this is now increasingly recognized as a major origin of neurodegenerative disease. This review, based on a mini-symposium presented at the 2015 Society for Neuroscience meeting, describes new work in the area of neuronal proteostasis, with a specific focus on the roles and therapeutic uses of protein chaperones. We first present a brief review of protein misfolding and aggregation in neurodegenerative disease. We then discuss different aspects of chaperone control of neuronal proteostasis on topics ranging from chaperone engineering, to chaperone-mediated blockade of protein oligomerization and cytotoxicity, to the potential rescue of neurodegenerative processes using modified chaperone proteins. SIGNIFICANCE STATEMENT Aberrant protein homeostasis within neurons results in protein misfolding and aggregation. In this review, we discuss specific roles for protein chaperones in the oligomerization, assembly, and disaggregation of proteins known to be abnormally folded in neurodegenerative disease. Collectively, our goal is to identify therapeutic mechanisms to reduce the cellular toxicity of abnormal aggregates

Fission Yeast Does Not Age under Favorable Conditions, but Does So after Stress

SummaryBackgroundMany unicellular organisms age: as time passes, they divide more slowly and ultimately die. In budding yeast, asymmetric segregation of cellular damage results in aging mother cells and rejuvenated daughters. We hypothesize that the organisms in which this asymmetry is lacking, or can be modulated, may not undergo aging.ResultsWe performed a complete pedigree analysis of microcolonies of the fission yeast Schizosaccharomyces pombe growing from a single cell. When cells were grown under favorable conditions, none of the lineages exhibited aging, which is defined as a consecutive increase in division time and increased death probability. Under favorable conditions, few cells died, and their death was random and sudden rather than following a gradual increase in division time. Cell death correlated with the inheritance of Hsp104-associated protein aggregates. After stress, the cells that inherited large aggregates aged, showing a consecutive increase in division time and an increased death probability. Their sisters, who inherited little or no aggregates, did not age.ConclusionsWe conclude that S. pombe does not age under favorable growth conditions, but does so under stress. This transition appears to be passive rather than active and results from the formation of a single large aggregate, which segregates asymmetrically at the subsequent cell division. We argue that this damage-induced asymmetric segregation has evolved to sacrifice some cells so that others may survive unscathed after severe environmental stresses

Mining Disaggregase Sequence Space to Safely Counter TDP-43, FUS, and α-Synuclein Proteotoxicity.

Hsp104 is an AAA+ protein disaggregase, which can be potentiated via diverse mutations in its autoregulatory middle domain (MD) to mitigate toxic misfolding of TDP-43, FUS, and α-synuclein implicated in fatal neurodegenerative disorders. Problematically, potentiated MD variants can exhibit off-target toxicity. Here, we mine disaggregase sequence space to safely enhance Hsp104 activity via single mutations in nucleotide-binding domain 1 (NBD1) or NBD2. Like MD variants, NBD variants counter TDP-43, FUS, and α-synuclein toxicity and exhibit elevated ATPase and disaggregase activity. Unlike MD variants, non-toxic NBD1 and NBD2 variants emerge that rescue TDP-43, FUS, and α-synuclein toxicity. Potentiating substitutions alter NBD1 residues that contact ATP, ATP-binding residues, or the MD. Mutating the NBD2 protomer interface can also safely ameliorate Hsp104. Thus, we disambiguate allosteric regulation of Hsp104 by several tunable structural contacts, which can be engineered to spawn enhanced therapeutic disaggregases with minimal off-target toxicity

Small Heat Shock Proteins Potentiate Amyloid Dissolution by Protein Disaggregases from Yeast and Humans

The authors define how small heat-shock proteins synergize to regulate the assembly and disassembly of a beneficial prion, and then they exploit this knowledge to identify the human amyloid depolymerase

The Parkinson\u27s Disease Protein α-Synuclein Disrupts Cellular Rab Homeostasis

α-Synuclein (α-syn), a protein of unknown function, is the most abundant protein in Lewy bodies, the histological hallmark of Parkinson\u27s disease (PD). In yeast α-syn inhibits endoplasmic reticulum (ER)-to-Golgi (ER→Golgi) vesicle trafficking, which is rescued by overexpression of a Rab GTPase that regulates ER→Golgi trafficking. The homologous Rab1 rescues α-syn toxicity in dopaminergic neuronal models of PD. Here we investigate this conserved feature of α-syn pathobiology. In a cell-free system with purified transport factors α-syn inhibited ER→Golgi trafficking in an α-syn dose-dependent manner. Vesicles budded efficiently from the ER, but their docking or fusion to Golgi membranes was inhibited. Thus, the in vivo trafficking problem is due to a direct effect of α-syn on the transport machinery. By ultrastructural analysis the earliest in vivo defect was an accumulation of morphologically undocked vesicles, starting near the plasma membrane and growing into massive intracellular vesicular clusters in a dose-dependent manner. By immunofluorescence/immunoelectron microscopy, these clusters were associated both with α-syn and with diverse vesicle markers, suggesting that α-syn can impair multiple trafficking steps. Other Rabs did not ameliorate α-syn toxicity in yeast, but RAB3A, which is highly expressed in neurons and localized to presynaptic termini, and RAB8A, which is localized to post-Golgi vesicles, suppressed toxicity in neuronal models of PD. Thus, α-syn causes general defects in vesicle trafficking, to which dopaminergic neurons are especially sensitive

Method and key observations from constructing a mine water heat subsurface observatory in Glasgow UK

The UK Geoenergy Observatories project (UKGEOS) is developing a subsurface Observatory in Glasgow for research and innovation in mine water heat and heat storage. This report provides an overview of the timing and tasks adopted in borehole construction and initial testing. It has been subdivided into three stages: planning/feasibility, exploration and appraisal. The fourth delivery or development stage, which is to construct the above ground infrastructure for mine water circulation and thermal perturbation, is ongoing in 2021 and is not covered in this report. Land availability, prior land use and environmental protection were key constraints in establishment of the Observatory, as well as subsurface geological factors. These are likely common to many mine water heat projects. Observations made during construction of the Glasgow Observatory are summarised to help to de-risk future mine water projects. These include difficulties associated with completing boreholes through sands and gravels in superficial deposits, and the challenge of identifying the type and size of mine workings during drilling. A key learning was the value of using a downhole optical or acoustic camera to better understand the nature of mine workings prior to screen installation