Pin1-Catalyzed Conformation Changes Regulate Protein Ubiquitination and Degradation.

The unique prolyl isomerase Pin1 binds to and catalyzes cis-trans conformational changes of specific Ser/Thr-Pro motifs after phosphorylation, thereby playing a pivotal role in regulating the structure and function of its protein substrates. In particular, Pin1 activity regulates the affinity of a substrate for E3 ubiquitin ligases, thereby modulating the turnover of a subset of proteins and coordinating their activities after phosphorylation in both physiological and disease states. In this review, we highlight recent advancements in Pin1-regulated ubiquitination in the context of cancer and neurodegenerative disease. Specifically, Pin1 promotes cancer progression by increasing the stabilities of numerous oncoproteins and decreasing the stabilities of many tumor suppressors. Meanwhile, Pin1 plays a critical role in different neurodegenerative disorders via the regulation of protein turnover. Finally, we propose a novel therapeutic approach wherein the ubiquitin-proteasome system can be leveraged for therapy by targeting pathogenic intracellular targets for TRIM21-dependent degradation using stereospecific antibodies.

Association of Brain Age, Lesion Volume, and Functional Outcome in Patients With Stroke.

BACKGROUND AND OBJECTIVES: Functional outcomes after stroke are strongly related to focal injury measures. However, the role of global brain health is less clear. In this study, we examined the impact of brain age, a measure of neurobiological aging derived from whole-brain structural neuroimaging, on poststroke outcomes, with a focus on sensorimotor performance. We hypothesized that more lesion damage would result in older brain age, which would in turn be associated with poorer outcomes. Related, we expected that brain age would mediate the relationship between lesion damage and outcomes. Finally, we hypothesized that structural brain resilience, which we define in the context of stroke as younger brain age given matched lesion damage, would differentiate people with good vs poor outcomes. METHODS: We conducted a cross-sectional observational study using a multisite dataset of 3-dimensional brain structural MRIs and clinical measures from the ENIGMA Stroke Recovery. Brain age was calculated from 77 neuroanatomical features using a ridge regression model trained and validated on 4,314 healthy controls. We performed a 3-step mediation analysis with robust mixed-effects linear regression models to examine relationships between brain age, lesion damage, and stroke outcomes. We used propensity score matching and logistic regression to examine whether brain resilience predicts good vs poor outcomes in patients with matched lesion damage. RESULTS: We examined 963 patients across 38 cohorts. Greater lesion damage was associated with older brain age (ß = 0.21; 95% CI 0.04-0.38, p = 0.015), which in turn was associated with poorer outcomes, both in the sensorimotor domain (ß = -0.28; 95% CI -0.41 to -0.15, p < 0.001) and across multiple domains of function (ß = -0.14; 95% CI -0.22 to -0.06, p < 0.001). Brain age mediated 15% of the impact of lesion damage on sensorimotor performance (95% CI 3%-58%, p = 0.01). Greater brain resilience explained why people have better outcomes, given matched lesion damage (odds ratio 1.04, 95% CI 1.01-1.08, p = 0.004). DISCUSSION: We provide evidence that younger brain age is associated with superior poststroke outcomes and modifies the impact of focal damage. The inclusion of imaging-based assessments of brain age and brain resilience may improve the prediction of poststroke outcomes compared with focal injury measures alone, opening new possibilities for potential therapeutic targets.

Acceptability of a Telerehabilitation Biofeedback System Among Stroke Survivors: A Qualitative Analysis.

Electromyography (EMG) biofeedback delivered via telerehabilitation can increase access to occupational therapy services for stroke survivors with severe impairment, but there is limited research on its acceptability. This study identified factors influencing the acceptability of a complex, muscle biofeedback system (Tele-REINVENT) for upper extremity sensorimotor stroke telerehabilitation among stroke survivors. We conducted interviews with stroke survivors (n = 4) who used Tele-REINVENT at home for 6 weeks and analyzed the data with reflexive thematic analysis. Biofeedback, customization, gamification, and predictability affected the acceptability of Tele-REINVENT among stroke survivors. Across themes, features and experiences that gave participants agency and control were more acceptable. Our findings contribute to the design and development of at-home EMG biofeedback interventions, which can improve access to advanced occupational therapy treatment options for those who need it most.

A large, curated, open-source stroke neuroimaging dataset to improve lesion segmentation algorithms.

Accurate lesion segmentation is critical in stroke rehabilitation research for the quantification of lesion burden and accurate image processing. Current automated lesion segmentation methods for T1-weighted (T1w) MRIs, commonly used in stroke research, lack accuracy and reliability. Manual segmentation remains the gold standard, but it is time-consuming, subjective, and requires neuroanatomical expertise. We previously released an open-source dataset of stroke T1w MRIs and manually-segmented lesion masks (ATLAS v1.2, N = 304) to encourage the development of better algorithms. However, many methods developed with ATLAS v1.2 report low accuracy, are not publicly accessible or are improperly validated, limiting their utility to the field. Here we present ATLAS v2.0 (N = 1271), a larger dataset of T1w MRIs and manually segmented lesion masks that includes training (n = 655), test (hidden masks, n = 300), and generalizability (hidden MRIs and masks, n = 316) datasets. Algorithm development using this larger sample should lead to more robust solutions; the hidden datasets allow for unbiased performance evaluation via segmentation challenges. We anticipate that ATLAS v2.0 will lead to improved algorithms, facilitating large-scale stroke research.

Engaging mothers with substance use issues and their children in early intervention: Understanding use of service and outcomes.

Mothers who use substances need integrated, multi-sectoral intervention services to support substance use discontinuation. We explored mothers' service use at Breaking the Cycle, an early intervention and prevention program for pregnant and parenting women and their young children in Toronto, Canada. We conducted retrospective analyses of families' service records and client charts (N = 160). Aims were to 1) describe women's use of service, 2) examine how early engagement of pregnant women related to postnatal service use, and 3) examine the circumstances in which women ended their service relationship with Breaking the Cycle. Specifically, we examined circumstances at service ending relating to women's service goals; custody status with children; and global substance-use, parent-child relationship, and child development outcomes. We found that these vulnerable women were actively engaged in many services and for a long duration, early engagement was associated with greater service use, and greater service use was associated with more positive circumstances upon ending service. Results provide support for a relational approach to service that promotes not only the relationship between mother and child, and mother and service provider, but also highlights relationships among staff, between staff and management, and between community partners as integral to effective service delivery. Integrating positive relationships at all levels is critical to support vulnerable families with complex needs.