Thioredoxins function as deglutathionylase enzymes in the yeast Saccharomyces cerevisiae

<p>Abstract</p> <p>Background</p> <p>Protein-SH groups are amongst the most easily oxidized residues in proteins, but irreversible oxidation can be prevented by protein glutathionylation, in which protein-SH groups form mixed disulphides with glutathione. Glutaredoxins and thioredoxins are key oxidoreductases which have been implicated in regulating glutathionylation/deglutathionylation in diverse organisms. Glutaredoxins have been proposed to be the predominant deglutathionylase enzymes in many plant and mammalian species, whereas, thioredoxins have generally been thought to be relatively inefficient in deglutathionylation.</p> <p>Results</p> <p>We show here that the levels of glutathionylated proteins in yeast are regulated in parallel with the growth cycle, and are maximal during stationary phase growth. This increase in glutathionylation is not a response to increased reactive oxygen species generated from the shift to respiratory metabolism, but appears to be a general response to starvation conditions. Our data indicate that glutathionylation levels are constitutively high in all growth phases in thioredoxin mutants and are unaffected in glutaredoxin mutants. We have confirmed that thioredoxins, but not glutaredoxins, catalyse deglutathionylation of model glutathionylated substrates using purified thioredoxin and glutaredoxin proteins. Furthermore, we show that the deglutathionylase activity of thioredoxins is required to reduce the high levels of glutathionylation in stationary phase cells, which occurs as cells exit stationary phase and resume vegetative growth.</p> <p>Conclusions</p> <p>There is increasing evidence that the thioredoxin and glutathione redox systems have overlapping functions and these present data indicate that the thioredoxin system plays a key role in regulating the modification of proteins by the glutathione system.</p

A psychosocial goal-setting and manualised support intervention for independence in dementia (NIDUS-Family) versus goal setting and routine care: a single-masked, phase 3, superiority, randomised controlled trial

Summary Background Although national guidelines recommend that everyone with dementia receives personalised post-diagnostic support, few do. Unlike previous interventions that improved personalised outcomes in people with dementia, the NIDUS-Family intervention is fully manualised and deliverable by trained and supervised, non-clinical facilitators. We aimed to investigate the effectiveness of home-based goal setting plus NIDUS-Family in supporting the attainment of personalised goals set by people with dementia and their carers. Methods We did a two-arm, single-masked, multi-site, randomised, clinical trial recruiting patient–carer dyads from community settings. We randomly assigned dyads to either home-based goal setting plus NIDUS-Family or goal setting and routine care (control). Randomisation was blocked and stratified by site (2:1; intervention to control), with allocations assigned via a remote web-based system. NIDUS-Family is tailored to goals set by dyads by selecting modules involving behavioural interventions, carer support, psychoeducation, communication and coping skills, enablement, and environmental adaptations. The intervention involved six to eight video-call or telephone sessions (or in person when COVID-19-related restrictions allowed) over 6 months, then telephone follow-ups every 2–3 months for 6 months. The primary outcome was carer-rated goal attainment scaling (GAS) score at 12 months. Analyses were done by intention to treat. This trial is registered with the ISRCTN registry, ISRCTN11425138. Findings Between April 30, 2020, and May 9, 2021, we assessed 1083 potential dyads for eligibility, 781 (72·1%) of whom were excluded. Of 302 eligible dyads, we randomly assigned 98 (32·4%) to the control group and 204 (67·5%) to the intervention group. The mean age of participants with dementia was 79·9 years (SD 8·2), 169 (56%) were women, and 133 (44%) were men. 247 (82%) dyads completed the primary outcome, which favoured the intervention (mean GAS score at 12 months 58·7 [SD 13·0; n=163] vs 49·0 [14·1; n=84]; adjusted difference in means 10·23 [95% CI 5·75–14·71]; p<0·001). 31 (15·2%) participants in the intervention group and 14 (14·3%) in the control group experienced serious adverse events. Interpretation To our knowledge, NIDUS-Family is the first readily scalable intervention for people with dementia and their family carers that improves attainment of personalised goals. We therefore recommend that it be implemented in health and care services

Remote versus face-to-face delivery of early intervention programs for children with autism spectrum disorders: Perceptions of rural families and service providers

To date, research investigating the use of remote technologies to extend face-to-face early intervention services for children with autism spectrum disorder (ASD) is limited. This study explored the perceived advantages and disadvantages of a follow-up early intervention service delivered via remote technology, as compared to previous face-to-face services. The remote technology service focused on parent coaching rather than direct intervention with the child. A generic method of qualitative enquiry involving semi-structured interviews was used to explore the experiences of four rurally-based parents of children with ASD, eight rurally-based service providers, and a metropolitan-based ASD-specialist in regards to their participation in remote technology and face-to-face services. Qualitative content analysis revealed that the parents, service providers and the ASD-specialist perceived remote technologies to be beneficial in: (a) upskilling of parents and local service provider; (b) reducing cost, time and travel; (c) flexible, regular, ongoing support; (d) enabling families to access support from home, and (e) enhancing connections between team members. However, the participants were often frustrated by technical difficulties, and all agreed that remote technology should augment rather than replace face-to-face contact. This study provides preliminary support for the use of remote technologies to extend early intervention services for children with ASD

The yeast Tsa1 peroxiredoxin is a ribosome-associated antioxidant

International audienceThe yeast Tsa1 peroxiredoxin, like other 2-Cys peroxiredoxins, has dual activities as a peroxidase and as a molecular chaperone. Its peroxidase function predominates in lower MW forms, whereas, a super-chaperone form predominates in high MW complexes. Loss of TSA1 results in aggregation of ribosomal proteins indicating that Tsa1 functions to maintain the integrity of the translation apparatus. We report here that Tsa1 functions as an antioxidant on actively translating ribosomes. Its peroxidase activity is required for ribosomal function since mutation of the peroxidatic cysteine residue, which inactivates peroxidase but not chaperone activity, results in sensitivity to translation inhibitors. The peroxidatic Cys residue is also required for a shift from ribosomes to its HMW form in response to peroxide stress. Thus, Tsa1 appears to function predominantly as an antioxidant in protecting both the cytosol and actively translating ribosomes against endogenous ROS, but shifts towards its chaperone function in response to oxidative stress conditions. Analysis of the distribution of Tsa1 in thioredoxin system mutants revealed that the ribosome-associated form of Tsa1 is increased in mutants lacking thioredoxin reductase (trr1) and thioredoxins (trx1 trx2) in parallel with the general increase in total Tsa1 levels which is observed in these mutants. We show that de-regulation of Tsa1 in the trr1 mutant specifically promotes translation defects including hypersensitivity to translation inhibitors, increased translational error-rates and ribosomal protein aggregation. These data have important implications for the role of peroxiredoxins in stress and growth control since peroxiredoxins are likely to be deregulated in a similar manner during many different disease states

Improving transfer of learning: an innovative comentoring program to enhance workplace implementation after an occupational therapy course on autism spectrum disorders

Introduction: Research suggests that learning gained through training is infrequently implemented in the workplace. A shortterm postcourse comentoring program was developed with the aim of facilitating workplace implementation of learning after a 3-day course for occupational therapists. The program was evaluated for usefulness, successes, challenges, recommended improvements, and associations with changes in self-rated knowledge and confidence. Method: Two months after the course, 42 participants completed an evaluation of the comentoring program with closed-and open-ended questions addressing usefulness, successes, challenges, pairing preferences, and recommendations. They also completed a record on whether or not they had worked on goals nominated in their comentoring contract. Before and 2 months after the course, they completed a self-rated questionnaire on knowledge and confidence. Results: The comentoring program was recommended by 80% of participants. Benefits included opportunities for information and resource sharing, debriefing, problem solving, reassurance, and implementation of ideas. Ninety-five percent of participants worked on some or all their comentoring goals. Although there were significant improvements in knowledge (P < 0.001) and confidence (P < 0.001), the total comentoring evaluation score was not significantly associated with these changes. It is therefore possible that these improvements related to the course itself rather than the comentoring program. Challenges related to time, scheduling, distance, and pairing of comentors. Conclusion: Reported benefits of the program included enhanced psychosocial support and prompting to trial newly learned strategies. Effectiveness may be improved by setting aside time for comentoring in the workplace and better matching of comentors

Development of a decision-support framework to support professionals and promote comfort among older hospital inpatients living with dementia

Background: Acute hospital wards can be difficult places for many people living with dementia. Promoting comfort and wellbeing can be challenging in this environment. There is little evidence-based support for professionals working on acute care wards on how to respond to distress and maximise comfort and wellbeing among patients living with dementia. Objectives: Our overall aim was to codesign an evidence-based easy-to-use heuristic decision-support framework, which was acceptable and practical but acknowledges the complex and acute nature of caring for patients with dementia in the hospital. This paper presents the development process and resulting framework. Methods: A codesign study was informed by data from (1) a literature review of the care and management of people living with dementia in acute hospitals; (2) a cohort study of comfort and discomfort in people with dementia in acute hospitals; and (3) interviews with family carers and health care professionals. We synthesised evidence from these data sources and presented to key stakeholders through codesign meetings and workshops to produce our decision-support framework. Results: The framework consists of a series of flowcharts and operates using a three-stage process of: (1) assess comfort/discomfort; (2) consider causes of discomfort; and (3) address patient needs to manage the discomfort. Conclusion: Working with key stakeholders, synthesising diverse quantitative and qualitative evidence to build a clinical framework is a feasible approach to help address the needs of patients living with dementia in an acute hospital setting. The result is a framework which is now ready for evaluation and implementation. Patient and Public Contribution: We worked closely with people living with dementia and family carers throughout this study, including the development of the study protocol with input on study development and design, through to inclusion in stakeholder workshops and codesign of the decision support framework.</p