Non-functional ubiquitin C-terminal hydrolase L1 drives podocyte injury through impairing proteasomes in autoimmune glomerulonephritis.

Little is known about the mechanistic significance of the ubiquitin proteasome system (UPS) in a kidney autoimmune environment. In membranous nephropathy (MN), autoantibodies target podocytes of the glomerular filter resulting in proteinuria. Converging biochemical, structural, mouse pathomechanistic, and clinical information we report that the deubiquitinase Ubiquitin C-terminal hydrolase L1 (UCH-L1) is induced by oxidative stress in podocytes and is directly involved in proteasome substrate accumulation. Mechanistically, this toxic gain-of-function is mediated by non-functional UCH-L1, which interacts with and thereby impairs proteasomes. In experimental MN, UCH-L1 becomes non-functional and MN patients with poor outcome exhibit autoantibodies with preferential reactivity to non-functional UCH-L1. Podocyte-specific deletion of UCH-L1 protects from experimental MN, whereas overexpression of non-functional UCH-L1 impairs podocyte proteostasis and drives injury in mice. In conclusion, the UPS is pathomechanistically linked to podocyte disease by aberrant proteasomal interactions of non-functional UCH-L1.

Social connectedness and dementia prevention: Pilot of the APPLE-Tree video-call intervention during the Covid-19 pandemic.

BACKGROUND AND OBJECTIVES: The Covid-19 pandemic reduced access to social activities and routine health care that are central to dementia prevention. We developed a group-based, video-call, cognitive well-being intervention; and investigated its acceptability and feasibility; exploring through participants' accounts how the intervention was experienced and used in the pandemic context. RESEARCH DESIGN AND METHOD: We recruited adults aged 60+ years with memory concerns (without dementia). Participants completed baseline assessments and qualitative interviews/focus groups before and after the 10-week intervention. Qualitative interview data and facilitator notes were integrated in a thematic analysis. RESULTS: 12/17 participants approached completed baseline assessments, attended 100/120 (83.3%) intervention sessions and met 140/170 (82.4%) of goals set. Most had not used video calling before. In the thematic analysis, our overarching theme was social connectedness. Three sub-themes were as follows: Retaining independence and social connectedness: social connectedness could not be at the expense of independence; Adapting social connectedness in the pandemic: participants strived to compensate for previous social connectedness as the pandemic reduced support networks; Managing social connections within and through the intervention: although there were tensions, for example, between sharing of achievements feeling supportive and competitive, participants engaged with various lifestyle changes; social connections supported group attendance and implementation of lifestyle changes. DISCUSSION AND IMPLICATIONS: Our intervention was acceptable and feasible to deliver by group video-call. We argue that dementia prevention is both an individual and societal concern. For more vulnerable populations, messages that lifestyle change can help memory should be communicated alongside supportive, relational approaches to enabling lifestyle changes.

Evaluating the effect of Brainfood groups for people with mild cognitive impairment and mild dementia: preliminary mixed-methodology study.

BACKGROUND: Brainfood is a 5-week group intervention for people with mild cognitive impairment and mild dementia, promoting cognitive health through a Mediterranean-style diet, exercise, mindfulness and health self-management. AIMS: To evaluate Brainfood acceptability and the feasibility of conducting a randomised controlled trial; in a single group study in two National Health Service (NHS) memory services. METHOD: Participants self-completed quantitative and semi-structured questionnaires. Recruitment, attendance and outcome completion were the primary outcomes. RESULTS: In total, 30 of 59 people invited to Brainfood attended; of the 26 (87%) who completed baseline measures: 25 (96%) completed post-intervention quantitative measures, 16 (67%) qualitative questions and 21 (81%) attended ≥3/5 sessions. Compared with baseline, participants reported significantly higher quality of life, Mediterranean diet adherence and exercising more, up to 2 months after the groups. Participants valued the groups and felt enabled to improve their well-being. CONCLUSIONS: Brainfood was acceptable and feasible to implement in an NHS setting. DECLARATION OF INTEREST: A.B. and C.C. developed Brainfood - they hold a creative commons license for the manual and make it available to use for free to all. The manual evolves iteratively, but the manual used in this research study is provided in an online supplement.