Inceptor as a regulator of brain insulin sensitivity.

While historically viewed as an insulin insensitive organ, it is now accepted that insulin has a role in brain physiology. Changes in brain insulin and IGF1 signaling have been associated with neurological diseases, however the molecular factors regulating brain insulin sensitivity remain uncertain. In this study, we proposed that a recently described protein, termed Inceptor, may play a role in brain insulin and IGF1 resistance. We studied Inceptor in healthy and diseased nervous tissue to understand the distribution of the protein and examine how it may change in states of insulin resistance. We found that Inceptor is in fact present in cerebellum, hippocampus, hypothalamus, and cortex of the brain in neurons, with higher levels in cortex of female compared to male mice. We also confirmed that Inceptor colocalized with IR and IGF1R in brain. We saw little difference in insulin receptor signaling following Inceptor knockdown in neuron cultures, or in Inceptor levels with high-fat diet in mouse or Alzheimer's disease in mouse or human tissue. These results all provide significant advancements to our understanding of Inceptor in the brain. PROTOCOL REGISTRATION: The Stage 1 registered report manuscript was accepted-in-principle on 9 August 2022. This manuscript was registered through Open Science Forum (OSF) on 24 August 2022 and is available here: https://osf.io/9q8sw .

Implementation, Feasibility, and Perception of Facilitated Process Groups in Surgical Residency.

OBJECTIVE: Recent studies have demonstrated burnout in surgeons, with trainees affected at alarming levels. However, few studies have focused on specific wellbeing initiatives in surgical residency. We implemented facilitated process groups at our residency program and aimed to understand the feasibility and perception of this program. DESIGN: We recruited a psychologist to conduct weekly process groups. Each postgraduate year (PGY) class was scheduled for a rotating 1-hour session every 6 weeks during protected didactic time. A presurvey was conducted shortly following program commencement for PGY1-5 residents (11/2020-1/2021) and a postsurvey conducted after 9 to 10 months of implementation for PGY2-5 residents. Surveys included demographics, a 2-item Maslach Burnout Inventory, and questions about stress, lifestyle, and perception of the process groups, including qualitative feedback. SETTING: The study took place at within the General Surgery Residency at Massachusetts General Hospital, a tertiary-care institution in Boston, Massachusetts. PARTICIPANTS: Participants in process groups were all General Surgery residents during the timeframe of the study. Participation in the presurvey and postsurvey was voluntary for residents. RESULTS: A total of 32 and 35 residents completed the presurveys and postsurveys, respectively. Groups were similar with regards to gender and race. A total of 97% and 57% of postsurvey respondents attended ≥1 and ≥3 process groups, respectively, with 95% citing clinical/other obligations as the cause of missing sessions. Perception of process groups was highly positive and persisted across both surveys. There were no significant differences in perception or burnout questions, except for a slight decrease in "I think process groups might help me process personal challenges" on postsurvey. Of 15 qualitative postsurvey responses, 73% were positive and the remainder were neutral. CONCLUSIONS: Based on current measures, it is feasible to implement facilitated process groups for surgical residents. Resident perception of these groups was persistently positive.

SOD1 mediates lysosome-to-mitochondria communication and its dysregulation by amyloid-ß oligomers.

Altered mitochondrial DNA (mtDNA) occurs in neurodegenerative disorders like Alzheimer's disease (AD); how mtDNA synthesis is linked to neurodegeneration is poorly understood. We previously discovered Nutrient-induced Mitochondrial Activity (NiMA), an inter-organelle signaling pathway where nutrient-stimulated lysosomal mTORC1 activity regulates mtDNA replication in neurons by a mechanism sensitive to amyloid-ß oligomers (AßOs), a primary factor in AD pathogenesis (Norambuena et al., 2018). Using 5-ethynyl-2'-deoxyuridine (EdU) incorporation into mtDNA of cultured neurons, along with photoacoustic and mitochondrial metabolic imaging of cultured neurons and mouse brains, we show these effects being mediated by mTORC1-catalyzed T40 phosphorylation of superoxide dismutase 1 (SOD1). Mechanistically, tau, another key factor in AD pathogenesis and other tauopathies, reduced the lysosomal content of the tuberous sclerosis complex (TSC), thereby increasing NiMA and suppressing SOD1 activity and mtDNA synthesis. AßOs inhibited these actions. Dysregulation of mtDNA synthesis was observed in fibroblasts derived from tuberous sclerosis (TS) patients, who lack functional TSC and elevated SOD1 activity was also observed in human AD brain. Together, these findings imply that tau and SOD1 couple nutrient availability to mtDNA replication, linking mitochondrial dysfunction to AD.

Exercise restrictions trigger psychological difficulty in active and athletic adults with hypertrophic cardiomyopathy.

OBJECTIVE: We examined the extent and nature of the psychological difficulty experienced by athletic adults with hypertrophic cardiomyopathy (HCM), correlates of that difficulty and coping mechanisms. METHODS: A survey assessed athletic history and psychological impact of exercise restrictions. LASSO penalised linear regression identified factors associated with psychological difficulty. Semistructured interviews provided deeper insight into the nature and origins of psychological difficulty. RESULTS: 54 individuals (33% female, mean age 55.9) completed the survey. The majority were recreational athletes at the time of restriction (67%). There was a drop in athleticism after diagnosis, including time spent exercising (p=0.04) and identification as an athlete (p=0.0005). Most respondents (54%) found it stressful and/or difficult to adjust to exercise restrictions. Greater psychological morbidity was associated with history of elite or competitive athletics, athletic identity and decrease in time spent exercising. 16 individuals (44% female, mean age 52.4) were interviewed. Long-term effects included weight gain and uncertainty about exercising safely. The role of exercise in interviewees' lives contracted significantly after restriction, from multiple functions (eg, social, stress relief, fitness) to solely health maintenance. Interviewees reported a unique form of social support: having family and friends participate with them in lower intensity exercise. Lack of understanding from family or friends and avoiding exercise completely were detrimental to coping. CONCLUSIONS: Athletic adults with HCM experience multifaceted, lasting difficulty adjusting to exercise recommendations. These data can guide clinicians in identifying patients at highest risk for distress and in helping to bolster coping and adaptation.

Investigation of the anti-inflammatory, antinociceptive effect of ellagic acid as measured by digital paw pressure via the Randall-Selitto meter in male Sprague-Dawley rats.

Ellagic acid (EA), a dietary supplement, is purported to have anti-inflammatory, antinociceptive properties via cyclooxygenase (COX) inhibition. We measured the antinociceptive efficacy of EA alone and in combination with a nonselective COX inhibitor and a selective COX-2 inhibitor. We assigned 54 male Sprague-Dawley rats to 1 of 6 groups to be given the following compounds: (1) vehicle, (2) ketorolac (nonselective COX inhibitor), (3) meloxicam (selective COX-2 inhibitor), (4) EA, (5) EA plus ketorolac, and (6) EA plus meloxicam. Inflammatory pain was induced in the right hind paw by injecting carrageenan. Rats were given study compounds via intraperitoneal injection 30 minutes after paw injections. Pain tolerance was assessed using the Randall-Selitto instrument at 30 minutes and 4, 8, 12, and 24 hours. The highest pressure tolerated was recorded in grams. The analysis of variance suggested a significant difference (F = 2.44; P = .048). The least significant difference post hoc analysis suggested that at 8 hours, EA plus ketorolac provided greater antinociception than all other compounds (P = .04). Furthermore the combination of EA plus ketorolac provided longer antinociception than all other compounds (P = .03) such that EA plus ketorolac was effective at 24 hours.