Palmitoylation of the Parkinson's disease-associated protein synaptotagmin-11 links its turnover to α-synuclein homeostasis.

Synaptotagmin-11 (Syt11) is a vesicle-trafficking protein that is linked genetically to Parkinson's disease (PD). Likewise, the protein α-synuclein regulates vesicle trafficking, and its abnormal aggregation in neurons is the defining cytopathology of PD. Because of their functional similarities in the same disease context, we investigated whether the two proteins were connected. We found that Syt11 was palmitoylated in mouse and human brain tissue and in cultured cortical neurons and that this modification to Syt11 disrupted α-synuclein homeostasis in neurons. Palmitoylation of two cysteines adjacent to the transmembrane domain, Cys39 and Cys40, localized Syt11 to digitonin-insoluble portions of intracellular membranes and protected it from degradation by the endolysosomal system. In neurons, palmitoylation of Syt11 increased its abundance and enhanced the binding of α-synuclein to intracellular membranes. As a result, the abundance of the physiologic tetrameric form of α-synuclein was decreased, and that of its aggregation-prone monomeric form was increased. These effects were replicated by overexpression of wild-type Syt11 but not a palmitoylation-deficient mutant. These findings suggest that palmitoylation-mediated increases in Syt11 amounts may promote pathological α-synuclein aggregation in PD.

In Utero Exposure to Caffeine and Acetaminophen, the Gut Microbiome, and Neurodevelopmental Outcomes: A Prospective Birth Cohort Study.

Pregnant individuals are exposed to acetaminophen and caffeine, but it is unknown how these exposures interact with the developing gut microbiome. We aimed to determine whether acetaminophen and/or caffeine relate to the childhood gut microbiome and whether features of the gut microbiome alter the relationship between acetaminophen/caffeine and neurodevelopment. Forty-nine and 85 participants provided meconium and stool samples at 6-7, respectively, for exposure and microbiome assessment. Fecal acetaminophen and caffeine concentrations were quantified, and fecal DNA underwent metagenomic sequencing. Caregivers and study staff assessed the participants' motor and cognitive development using standardized scales. Prenatal exposures had stronger associations with the childhood microbiome than concurrent exposures. Prenatal acetaminophen exposure was associated with a trend of lower gut bacterial diversity in childhood [ß = -0.17 Shannon Index, 95% CI: (-0.31, -0.04)] and was marginally associated with differences in the relative abundances of features of the gut microbiome at the phylum (Firmicutes, Actinobacteria) and gene pathway levels. Among the participants with a higher relative abundance of Proteobacteria, prenatal exposure to acetaminophen and caffeine was associated with lower scores on WISC-IV subscales. Acetaminophen during bacterial colonization of the naïve gut is associated with lasting alterations in childhood microbiome composition. Future studies may inform our understanding of downstream health effects.

Content analysis of the impact of COVID-19 on weight and shape control behaviors and social media content of U.S. adolescents and young adults.

OBJECTIVE: The current study examines impacts of the COVID-19 pandemic on weight/shape control behaviors among adolescents and young adults in the U.S., and perceived changes to related social media content. METHOD: A sample of youth (14-24 years) from MyVoice, a national text-message-based cohort, provided open-ended responses to questions on changes in eating and exercise habits due to concern about weight/shape, and social media content related to weight/shape, during the pandemic. Responses were collected using a secure online platform and analyzed using content analysis. RESULTS: Among respondents (n = 939/1153, response rate = 81%), 40.0% adopted behaviors for the purpose of weight/shape control during the pandemic. Nearly half (49.2%) reported seeing posts about weight/shape on social media during the pandemic. DISCUSSION: Findings from this study indicate that weight/shape concerns among adolescents and young adults in the U.S. may have increased due to the COVID-19 pandemic, with social media content as a potentially contributing factor.

Comparing Dermabond PRINEO versus Dermabond or staples for wound closure: a randomized control trial following total shoulder arthroplasty.

BACKGROUND: The method of surgical incision closure after total shoulder arthroplasty is an important factor to consider, as it affects operating room time, procedure cost, cosmetic outcomes, and patient satisfaction. The optimal method of wound management is unknown, but should be cost-effective, reproducible, and provide a reliable clinical result. This study aimed to compare the following wound closure methods after total shoulder arthroplasty: staples, Dermabond, and Dermabond PRINEO. We hypothesized that wound closure time for Dermabond PRINEO would be faster than Dermabond and comparable to that of staples, and Dermabond PRINEO would be more cost-effective than Dermabond and staples, and provide equal or superior closure outcomes to Dermabond and staples. METHODS: A randomized, prospective clinical trial comparing wound closure time and cost for 2 surgeons' traditional technique with that of Dermabond PRINEO was conducted. This study included at least 18 subjects in each group. Surgeon 1's patients were randomized to traditional Dermabond or Dermabond PRINEO, whereas surgeon 2's patients were randomized to staples or Dermabond PRINEO. Cosmetic outcomes and satisfaction scores were collected at 6 weeks and 3 months, postoperatively. Incisions were photographed, at both the 6-week and 3-month visits, and subsequently evaluated by a plastic surgeon blinded to the treatment method. RESULTS: The wound closure time for surgeon 1 was significantly faster for Dermabond PRINEO vs. Dermabond, and surgeon 2 closed significantly faster with staples vs. Dermabond PRINEO. The mean cost of closure was significantly less with Dermabond PRINEO compared with Dermabond, whereas the mean cost of staples was significantly less than Dermabond PRINEO. For both surgeons 1 and 2, there were no significant differences in patient satisfaction at 6 weeks or 3 months. In addition, the wound closure methods did not produce differing cosmetic outcomes. CONCLUSIONS: Although significant, the closing time for each method did not differ by a clinically relevant amount. Staples were the most cost-effective closing method, followed by Dermabond PRINEO. As neither method was superior over the other in terms of patient satisfaction, adverse events, and cosmetic outcomes, cost-effectiveness may be the greatest differentiator between the 3 methods.

Upregulation of Cellular Palmitoylation Mitigates α-Synuclein Accumulation and Neurotoxicity.

BACKGROUND: Synucleinopathies, including Parkinson's disease (PD), are characterized by α-synuclein (αS) cytoplasmic inclusions. αS-dependent vesicle-trafficking defects are important in PD pathogenesis, but their mechanisms are not well understood. Protein palmitoylation, post-translational addition of the fatty acid palmitate to cysteines, promotes trafficking by anchoring specific proteins to the vesicle membrane. αS itself cannot be palmitoylated as it lacks cysteines, but it binds to membranes, where palmitoylation occurs, via an amphipathic helix. We hypothesized that abnormal αS membrane-binding impairs trafficking by disrupting palmitoylation. Accordingly, we investigated the therapeutic potential of increasing cellular palmitoylation. OBJECTIVES: We asked whether upregulating palmitoylation by inhibiting the depalmitoylase acyl-protein-thioesterase-1 (APT1) ameliorates pathologic αS-mediated cellular phenotypes and sought to identify the mechanism. METHODS: Using human neuroblastoma cells, rat neurons, and iPSC-derived PD patient neurons, we examined the effects of pharmacologic and genetic downregulation of APT1 on αS-associated phenotypes. RESULTS: APT1 inhibition or knockdown decreased αS cytoplasmic inclusions, reduced αS serine-129 phosphorylation (a PD neuropathological marker), and protected against αS-dependent neurotoxicity. We identified the APT1 substrate microtubule-associated-protein-6 (MAP6), which binds to vesicles in a palmitoylation-dependent manner, as a key mediator of these effects. Mechanistically, we found that pathologic αS accelerated palmitate turnover on MAP6, suggesting that APT1 inhibition corrects a pathological αS-dependent palmitoylation deficit. We confirmed the disease relevance of this mechanism by demonstrating decreased MAP6 palmitoylation in neurons from αS gene triplication patients. CONCLUSIONS: Our findings demonstrate a novel link between the fundamental process of palmitoylation and αS pathophysiology. Upregulating palmitoylation represents an unexplored therapeutic strategy for synucleinopathies. © 2020 International Parkinson and Movement Disorder Society.

Variations in Gambling Disorder Symptomatology Across Sexual Identity Among College Student-Athletes.

Gambling disorder has serious negative consequences for individual health and wellbeing, while being more prevalent among college student-athletes compared to the general college population. While previous research reports that sexual minority (i.e., gay, lesbian and bisexual) populations have higher rates of addictive behaviors such as alcohol and drug abuse, no previous research has explored risk for gambling disorder symptomatology by sexual identity status. The aim of the current study is to identify differences in the severity of gambling disorder symptomatology between sexual minority and heterosexual student-athletes. A stratified random sample of 19,299 National Collegiate Athletic Association college student-athletes participated in an anonymous survey assessing gambling disorder symptomatology. Student-athletes completed measures assessing their past 12-month problem gambling as measured by the DSM-5 diagnostic criteria for gambling disorder and provided information on their sexual identity. Gay and bisexual men had disordered gambling scores 3.42 times higher than heterosexual men (p < .01), when adjusting for race/ethnicity, and years in college. Gay/lesbian and bisexual women reported disordered gambling scores 2.57 higher than heterosexual women (p < .01) when adjusting for race/ethnicity and years in college. This is the first study to compare the prevalence of gambling disorder symptomatology across sexual identity status. The higher number of gambling disorder symptoms observed among sexual minorities in the current study underlines the need for more research on this topic, and supports the exploration of intervention efforts designed to better address problem gambling among sexual minority communities.