👤 Luke A Wiley

The process model of emotion regulation highlights affect's ebb and flow in daily life in response to external events or internal processes, such as stress. Collectively daily stress and affect can shape daily experiences and influence long-term health. Understanding the dynamics of the stress-affect relationship requires examining intensity (average level), inertia (autoregression), and variability (residual variances), yet few studies simultaneously consider both arousal (high vs low, denoted as H vs L) and valence (positive vs negative, denoted as PA vs NA) dimensions of affect. Participants (N = 424; 72.4 % women, M Show less

24 h behaviours (sleep, time awake in bed, moderate-to-vigorous physical activity [MVPA], light physical activity [LPA], and sedentary behaviour [SB]) may influence long-term mental health through their associations with affective experiences in everyday life. Here, we investigated the daily, prospective associations between 24 h behaviours and affect. Actigraphy-measured 24 h behaviours and self-reported affect data were collected across 7-15 consecutive days in healthy, community-dwelling adults (N = 354, M Associations between 24 h behaviours and next-day affect emerged at the within-person, not between-person level. Relative to the remaining behaviours, more LPA predicted 0.14 [95 % CI 0.03, 0.26] higher high arousal positive affect, whereas less SB predicted lower high and low arousal positive affect (-0.14 [-0.25, -0.02] and -0.12 [-0.24, -0.01], respectively) higher high arousal negative affect (0.13 [0.03, 0.23]). Further, within-person 30-min reallocation to LPA from SB, sleep, and time awake in bed also predicted ≥0.03 [0.00, 0.06] higher high arousal positive affect. 30-minute reallocation of time to LPA and MVPA from SB predicted 0.04 [0.01, 0.06] higher high arousal positive affect and -0.02 [-0.04, -0.00] lower low arousal negative affect. Findings provide stepping stone evidence for identifying optimal daily compositions of 24 h behaviours for affective enhancements in healthy individuals. Replacing time in SB with LPA and MVPA for improving affect should be experimentally tested in daily settings and clinical populations, to inform diagnostic and intervention strategies for better daily affect and mental health. Show less

Juvenile neuronal ceroid lipofuscinosis (JNCL) is a childhood neurodegenerative disease with early-onset, severe central vision loss. Affected children develop seizures and CNS degeneration accompanied by severe motor and cognitive deficits. There is no cure for JNCL, and patients usually die during the second or third decade of life. In this study, independent lines of induced pluripotent stem cells (iPSCs) were generated from two patients with molecularly confirmed mutations in CLN3, the gene mutated in JNCL. Clinical-grade adeno-associated adenovirus serotype 2 (AAV2) carrying the full-length coding sequence of human CLN3 was generated in a U.S. Food and Drug Administration-registered cGMP facility. AAV2-CLN3 was efficacious in restoring full-length CLN3 transcript and protein in patient-specific fibroblasts and iPSC-derived retinal neurons. When injected into the subretinal space of wild-type mice, purified AAV2-CLN3 did not show any evidence of retinal toxicity. This study provides proof-of-principle for initiation of a clinical trial using AAV-mediated gene augmentation for the treatment of children with CLN3-associated retinal degeneration. Show less

Neurotrophins, essential regulators of many aspects of neuronal differentiation and function, signal via four receptors, p75, TrkA, TrkB and TrkC. The three Trk paralogs are members of the LIG superfamily of membrane proteins, which share extracellular domains consisting of leucine-rich repeat and C2 Ig domains. Another LIG protein, LINGO-1 has been reported to bind and influence signaling of p75 as well as TrkA, TrkB and TrkC. Here we examine the manner in which LINGO-1 influences the function of TrkA, TrkB and TrkC. We report that Trk activation promotes Trk association with LINGO-1, and that this association promotes Trk degradation by a lysosomal mechanism. This mechanism resembles the mechanism by which another LIG protein, LRIG1, promotes lysosomal degradation of receptor tyrosine kinases such as the EGF receptor. We present evidence indicating that the Trk/LINGO-1 interaction occurs, in part, within recycling endosomes. We show that a mutant form of LINGO-1, with much of the extracellular domain deleted, has the capacity to enhance TrkA signaling in PC12 cells, possibly by acting as an inhibitor of Trk down-regulation by full length LINGO-1. We propose that LINGO-1 functions as a negative feedback regulator of signaling by cognate receptor tyrosine kinases including TrkA, TrkB and TrkC. Show less

Sequential proteolytic cleavages of amyloid-β protein precursor (AβPP) by β-secretase and γ-secretase generate amyloid β (Aβ) peptides, which are thought to contribute to Alzheimer's disease (AD). Much of this processing occurs in endosomes following endocytosis of AβPP from the plasma membrane. However, this pathogenic mode of processing AβPP may occur in competition with lysosomal degradation of AβPP, a common fate of membrane proteins trafficking through the endosomal system. Following up on published reports that LINGO-1 binds and promotes the amyloidogenic processing of AβPP we have examined the consequences of LINGO-1/AβPP interactions. We report that LINGO-1 and its paralogs, LINGO-2 and LINGO-3, decrease processing of AβPP in the amyloidogenic pathway by promoting lysosomal degradation of AβPP. We also report that LINGO-1 levels are reduced in AD brain, representing a possible pathogenic mechanism stimulating the generation of Aβ peptides in AD. Show less

Axon outgrowth inhibition in response to trauma is thought to be mediated via the binding of myelin-associated inhibitory factors (e.g. Nogo-66, myelin-associated glycoprotein, oligodendrocyte myelin glycoprotein, and myelin basic protein) to a putative tripartite LINGO-1·p75(NTR)·Nogo-66 receptor (NgR) complex at the cell surface. We found that endogenous LINGO-1 expression in neurons in the cortex and cerebellum is intracellular. Mutation or truncation of the highly conserved LINGO-1 C terminus altered this intracellular localization, causing poor intracellular retention and increased plasma membrane expression. p75(NTR) associated predominantly with natively expressed LINGO-1 containing immature N-glycans, characteristic of protein that has not completed trans-Golgi-mediated processing, whereas mutant forms of LINGO-1 with enhanced plasma membrane expression did not associate with p75(NTR). Co-immunoprecipitation experiments demonstrated that LINGO-1 and NgR competed for binding to p75(NTR) in a manner that is difficult to reconcile with the existence of a LINGO-1·p75(NTR)·NgR ternary complex. These findings contradict models postulating functional LINGO-1·p75(NTR)·NgR complexes in the plasma membrane. Show less