Fragmentation of decorin, biglycan, lumican and keratocan is elevated in degenerate human meniscus, knee and hip articular cartilages compared with age-matched macroscopically normal and control tissues

Introduction: The small leucine-rich proteoglycans (SLRPs) modulate tissue organization, cellular proliferation, matrix adhesion, growth factor and cytokine responses, and sterically protect the surface of collagen type I and II fibrils from proteolysis. Catabolism of SLRPs has important consequences for the integrity of articular cartilage and meniscus by interfering with their tissue homeostatic functions. Methods: SLRPs were dissociatively extracted from articular cartilage from total knee and hip replacements, menisci from total knee replacements, macroscopically normal and fibrillated knee articular cartilage from mature age-matched donors, and normal young articular cartilage. The tissue extracts were digested with chondroitinase ABC and keratanase-I before identification of SLRP core protein species by Western blotting using antibodies to the carboxyl-termini of the SLRPs. Results: Multiple core-protein species were detected for all of the SLRPs (except fibromodulin) in the degenerate osteoarthritic articular cartilage and menisci. Fibromodulin had markedly less fragments detected with the carboxyl-terminal antibody compared with other SLRPs. There were fewer SLRP catabolites in osteoarthritic hip than in knee articular cartilage. Fragmentation of all SLRPs in normal age-matched, nonfibrillated knee articular cartilage was less than in fibrillated articular cartilage from the same knee joint or total knee replacement articular cartilage specimens of similar age. There was little fragmentation of SLRPs in normal control knee articular cartilage. Only decorin exhibited a consistent increase in fragmentation in menisci in association with osteoarthritis. There were no fragments of decorin, biglycan, lumican, or keratocan that were unique to any tissue. A single fibromodulin fragment was detected in osteoarthritic articular cartilage but not meniscus. All SLRPs showed a modest age-related increase in fragmentation in knee articular and meniscal cartilage but not in other tissues. Conclusion: Enhanced fragmentation of SLRPs is evident in degenerate articular cartilage and meniscus. Specific decorin and fibromodulin core protein fragments in degenerate meniscus and/or human articular cartilage may be of value as biomarkers of disease. Once the enzymes responsible for their generation have been identified, further research may identify them as therapeutic targets

CommunityRx, a social care assistance intervention for family and friend caregivers delivered at the point of care: Two concurrent blinded randomized controlled trials

Background: CommunityRx is an evidence-based social care intervention delivered to family and friend caregivers (“caregivers”) at the point of healthcare to address health-related social risks (HRSRs). Two CommunityRx randomized controlled trials (RCTs) are being fielded concurrently on Chicago’s South Side, a predominantly African American/Black community. CommunityRx-Hunger is a double-blind RCT enrolling caregivers of hospitalized children. CommunityRx-Dementia is a single-blind RCT enrolling caregivers of community-residing people with dementia. RCTs with caregivers face recruitment barriers, including caregiver burden and lack of systematic strategies to identify caregivers in clinical settings. COVID-19 pandemic-related visitor restrictions exacerbated these barriers and prompted the need for iteration of the protocols from in-person to remote operations. This study describes these protocols and methods used for successful iteration to overcome barriers. Methods and findings: CommunityRx uses individual-level data to generate personalized, local community resource referrals for basic, health and caregiving needs. In early 2020, two in-person RCT protocols were pre-tested. In March 2020, when pandemic conditions prohibited face-to-face clinical enrollment, both protocols were iterated to efficient, caregiver-centered remote operations. Iterations were enabled in part by the Automated Randomized Controlled Trial Information-Communication System (ARCTICS), a trial management system innovation engineered to integrate the data collection database (REDCap) with community resource referral (NowPow) and SMS texting (Mosio) platforms. Enabled by engaged Community Advisory Boards and ARCTICS, both RCTs quickly adapted to remote operations. To accommodate these adaptations, launch was delayed until November (CommunityRx-Hunger) and December (CommunityRx-Dementia) 2020. Despite the delay, 65% of all planned participants (CommunityRx-Hunger n = 417/640; CommunityRx-Dementia n = 222/344) were enrolled by December 2021, halfway through our projected enrollment timeline. Both trials enrolled 13% more participants in the first 12 months than originally projected for in-person enrollment. Discussion: Our asset-based, community-engaged approach combined with widely accessible institutional and commercial information technologies facilitated rapid migration of in-person trials to remote operations. Remote or hybrid RCT designs for social care interventions may be a viable, scalable alternative to in-person recruitment and intervention delivery protocols, particularly for caregivers and other groups that are under-represented in traditional health services research. Trial registration: ClinicalTrials.gov: CommunityRx-Hunger (NCT04171999, 11/21/2019); CommunityRx for Caregivers (NCT04146545, 10/31/2019).</p

Microplastic ingestion ubiquitous in marine turtles

Despite concerns regarding the environmental impacts of microplastics, knowledge of the incidence and levels of synthetic particles in large marine vertebrates is lacking. Here, we utilize an optimized enzymatic digestion methodology, previously developed for zooplankton, to explore whether synthetic particles could be isolated from marine turtle ingesta. We report the presence of synthetic particles in every turtle subjected to investigation (n = 102) which included individuals from all seven species of marine turtle, sampled from three ocean basins (Atlantic [ATL]: n = 30, four species; Mediterranean (MED): n = 56, two species; Pacific (PAC): n = 16, five species). Most particles (n = 811) were fibres (ATL: 77.1% MED: 85.3% PAC: 64.8%) with blue and black being the dominant colours. In lesser quantities were fragments (ATL: 22.9%: MED: 14.7% PAC: 20.2%) and microbeads (4.8%; PAC only; to our knowledge the first isolation of microbeads from marine megavertebrates). Fourier transform infrared spectroscopy (FT‐IR) of a subsample of particles (n = 169) showed a range of synthetic materials such as elastomers (MED: 61.2%; PAC: 3.4%), thermoplastics (ATL: 36.8%: MED: 20.7% PAC: 27.7%) and synthetic regenerated cellulosic fibres (SRCF; ATL: 63.2%: MED: 5.8% PAC: 68.9%). Synthetic particles being isolated from species occupying different trophic levels suggest the possibility of multiple ingestion pathways. These include exposure from polluted seawater and sediments and/or additional trophic transfer from contaminated prey/forage items. We assess the likelihood that microplastic ingestion presents a significant conservation problem at current levels compared to other anthropogenic threats

Who Invited You? The Complex Story Of Aquatic Invasive Species

Invasive species represent a global threat to ecosystems, human health, and the economy. A basic knowledge of invasive species biology is crucial to understand current and future impacts and implications. The purpose of this book is to provide a broad background on invasive species, and also details on specific examples through case studies. The students in the course Aquatic Invasive Species (MAR 442) at the University of New England in Biddeford, Maine, have researched and reviewed scientific literature to educate readers about these issues. The class, comprised of fifteen junior and senior Marine Science, Marine Affairs, Animal Behavior, and Environmental Sciences students, selected the different topics, presented the material, wrote the chapters, and assembled the final versions into this book. This book cannot be all inclusive, but we think this book will provide an excellent broad overview of the most important aspects of Invasive Species Biology and might stimulate the reader to dive deeper into the material.https://dune.une.edu/marinesci_studproj/1003/thumbnail.jp

Using chatbot technology to improve Brazilian adolescents' body image and mental health at scale: Randomized controlled trial

Accessible, cost-effective, and scalable mental health interventions are limited, particularly in low- and middle-income countries, where disparities between mental health needs and services are greatest. Microinterventions (ie, brief, stand-alone, or digital approaches) aim to provide immediate reprieve and enhancements in mental health states and offer a novel and scalable framework for embedding evidence-based mental health promotion techniques into digital environments. Body image is a global public health issue that increases young peoples' risk of developing more severe mental and physical health issues. Embedding body image microinterventions into digital environments is one avenue for providing young people with immediate and short-term reprieve and protection from the negative exposure effects associated with social media. This 2-armed, fully remote, and preregistered randomized controlled trial assessed the impact of a body image chatbot containing microinterventions on Brazilian adolescents' state and trait body image and associated well-being outcomes. Geographically diverse Brazilian adolescents aged 13-18 years (901/1715, 52.54% girls) were randomized into the chatbot or an assessment-only control condition and completed web-based self-assessments at baseline, immediately after the intervention time frame, and at 1-week and 1-month follow-ups. The primary outcomes were mean change in state (at chatbot entry and at the completion of a microintervention technique) and trait body image (before and after the intervention), with the secondary outcomes being mean change in affect (state and trait) and body image self-efficacy between the assessment time points. Most participants who entered the chatbot (258/327, 78.9%) completed ≥1 microintervention technique, with participants completing an average of 5 techniques over the 72-hour intervention period. Chatbot users experienced small significant improvements in primary (state: P<.001, Cohen d=0.30, 95% CI 0.25-0.34; and trait body image: P=.02, Cohen d range=0.10, 95% CI 0.01-0.18, to 0.26, 95% CI 0.13-0.32) and secondary outcomes across various time points (state: P<.001, Cohen d=0.28, 95% CI 0.22-0.33; trait positive affect: P=.02, Cohen d range=0.15, 95% CI 0.03-0.27, to 0.23, 95% CI 0.08-0.37; negative affect: P=.03, Cohen d range=-0.16, 95% CI -0.30 to -0.02, to -0.18, 95% CI -0.33 to -0.03; and self-efficacy: P=.02, Cohen d range=0.14, 95% CI 0.03-0.25, to 0.19, 95% CI 0.08-0.32) relative to the control condition. Intervention benefits were moderated by baseline levels of concerns but not by gender. This is the first large-scale randomized controlled trial assessing a body image chatbot among Brazilian adolescents. Intervention attrition was high (531/858, 61.9%) and reflected the broader digital intervention literature; barriers to engagement were discussed. Meanwhile, the findings support the emerging literature that indicates microinterventions and chatbot technology are acceptable and effective web-based service provisions. This study also offers a blueprint for accessible, cost-effective, and scalable digital approaches that address disparities between health care needs and provisions in low- and middle-income countries. Clinicaltrials.gov NCT04825184; http://clinicaltrials.gov/ct2/show/NCT04825184. RR2-10.1186/s12889-021-12129-1. [Abstract copyright: ©Emily L Matheson, Harriet G Smith, Ana C S Amaral, Juliana F F Meireles, Mireille C Almeida, Jake Linardon, Matthew Fuller-Tyszkiewicz, Phillippa C Diedrichs. Originally published in JMIR mHealth and uHealth (https://mhealth.jmir.org), 19.06.2023.

Targeted degradation of zDHHC-PATs decreases substrate S -palmitoylation

Reversible S-palmitoylation of protein cysteines, catalysed by a family of integral membrane zDHHC-motif containing palmitoyl acyl transferases (zDHHC-PATs), controls the localisation, activity, and interactions of numerous integral and peripheral membrane proteins. There are compelling reasons to want to inhibit the activity of individual zDHHC-PATs in both the laboratory and the clinic, but the specificity of existing tools is poor. Given the extensive conservation of the zDHHC-PAT active site, development of isoform-specific competitive inhibitors is highly challenging. We therefore hypothesised that proteolysis-targeting chimaeras (PROTACs) may offer greater specificity to target this class of enzymes. In proof-of-principle experiments we engineered cell lines expressing tetracycline-inducible Halo-tagged zDHHC5 or zDHHC20, and evaluated the impact of Halo-PROTACs on zDHHC-PAT expression and substrate palmitoylation. In HEK-derived FT-293 cells, Halo-zDHHC5 degradation significantly decreased palmitoylation of its substrate phospholemman, and Halo-zDHHC20 degradation significantly diminished palmitoylation of its substrate IFITM3, but not of the SARS-CoV-2 spike protein. In contrast, in a second kidney derived cell line, Vero E6, Halo-zDHHC20 degradation did not alter palmitoylation of either IFITM3 or SARS-CoV-2 spike. We conclude from these experiments that PROTAC-mediated targeting of zDHHC-PATs to decrease substrate palmitoylation is feasible. However, given the well-established degeneracy in the zDHHC-PAT family, in some settings the activity of non-targeted zDHHC-PATs may substitute and preserve substrate palmitoylation

Cross-National Differences in Victimization : Disentangling the Impact of Composition and Context

Varying rates of criminal victimization across countries are assumed to be the outcome of countrylevel structural constraints that determine the supply ofmotivated o¡enders, as well as the differential composition within countries of suitable targets and capable guardianship. However, previous empirical tests of these ‘compositional’ and ‘contextual’ explanations of cross-national di¡erences have been performed upon macro-level crime data due to the unavailability of comparable individual-level data across countries. This limitation has had two important consequences for cross-national crime research. First, micro-/meso-level mechanisms underlying cross-national differences cannot be truly inferred from macro-level data. Secondly, the e¡ects of contextual measures (e.g. income inequality) on crime are uncontrolled for compositional heterogeneity. In this paper, these limitations are overcome by analysing individual-level victimization data across 18 countries from the International CrimeVictims Survey. Results from multi-level analyses on theft and violent victimization indicate that the national level of income inequality is positively related to risk, independent of compositional (i.e. micro- and meso-level) di¡erences. Furthermore, crossnational variation in victimization rates is not only shaped by di¡erences in national context, but also by varying composition. More speci¢cally, countries had higher crime rates the more they consisted of urban residents and regions with lowaverage social cohesion.

2019 Scholars at Work Conference Program

Program for the 2019 Scholars at Work Conference at Minnesota State University, Mankato on March 29, 2019

Cholinergic Modulation of Narcoleptic Attacks in Double Orexin Receptor Knockout Mice

To investigate how cholinergic systems regulate aspects of the sleep disorder narcolepsy, we video-monitored mice lacking both orexin (hypocretin) receptors (double knockout; DKO mice) while pharmacologically altering cholinergic transmission. Spontaneous behavioral arrests in DKO mice were highly similar to those reported in orexin-deficient mice and were never observed in wild-type (WT) mice. A survival analysis revealed that arrest lifetimes were exponentially distributed indicating that random, Markovian processes determine arrest lifetime. Low doses (0.01, 0.03 mg/kg, IP), but not a high dose (0.08 mg/kg, IP) of the cholinesterase inhibitor physostigmine increased the number of arrests but did not alter arrest lifetimes. The muscarinic antagonist atropine (0.5 mg/kg, IP) decreased the number of arrests, also without altering arrest lifetimes. To determine if muscarinic transmission in pontine areas linked to REM sleep control also influences behavioral arrests, we microinjected neostigmine (50 nl, 62.5 µM) or neostigmine + atropine (62.5 µM and 111 µM respectively) into the nucleus pontis oralis and caudalis. Neostigmine increased the number of arrests in DKO mice without altering arrest lifetimes but did not provoke arrests in WT mice. Co-injection of atropine abolished this effect. Collectively, our findings establish that behavioral arrests in DKO mice are similar to those in orexin deficient mice and that arrests have exponentially distributed lifetimes. We also show, for the first time in a rodent narcolepsy model, that cholinergic systems can regulate arrest dynamics. Since perturbations of muscarinic transmission altered arrest frequency but not lifetime, our findings suggest cholinergic systems influence arrest initiation without influencing circuits that determine arrest duration