The role of ligand and receptor dimerisation in control of CD28 and CTLA4 function

The CD28-CTLA4 system is central to the regulation of T cell responses, with dysregulation associated with autoimmune disease and cancer progression. CD28 and CTLA4 are homodimeric T cell receptors providing co-stimulatory and inhibitory functions, respectively, through their shared ligands, CD80 and CD86. Whilst CD86 exists as a monomer, CD80 can form non-covalent dimers in the cell membrane and is therefore able to form higher-order lattice structures with CTLA4, providing an avidity advantage and a unique membrane organization compared to CD86. CD80 also interacts in cis with PDL1 at the CD80 dimer interface, although the function of this interaction is unknown. Functionally, CTLA4 removes CD80 and CD86 from opposing cells, targeting ligand for destruction via transendocytosis. However, why two ligands are required for this regulation, and how the properties of ligand:CTLA4 interactions contribute to this mechanism are poorly understood. We removed the avidity influence on receptor-ligand interactions by creating mutants unable to form functional dimers. We demonstrate that following transendocytosis, CD80 remains bound to CTLA4, resulting in ubiquitination and reduced CTLA4 availability. We show this is due to CD80:CTLA4 lattice formation, as dimer disruption by mutation or presence of PDL1 averts CTLA4 ubiquitination. We show loss of avid CD80:CTLA4 paradoxically enhances sensitivity to CTLA4 mediated transendocytosis, as the ability of CD80 to dissociate from CTLA4 following transendocytosis is augmented, permitting CTLA4 recycling and further transendocytosis - a feature normally seen with CD86. Finally, we detected signs of altered CD28 engagement resulting from mutant CD80 co-stimulation indicating monomeric ligands may have improved CD28 signalling. Our results provide further detail on CTLA4 transendocytosis, where dimerisation and avidity of ligand interactions, (including those regulated by PDL1), are significant in altering the fate of CTLA4, and influencing CD28 mediated co-stimulation

What Does Written Reflection Reveal About Novice Teachers’ Knowledge, Beliefs, and Skills Related to Literacy Assessment?

Assessment of literacy learning has been a long-standing focus for future teachers in elementary education. Teacher educators use ongoing written reflection to promote learning before, during, and after coursework and field experiences. In this study, the researchers examined the effects of ongoing written reflection on two groups of novice teachers’ knowledge, beliefs, and skills about literacy assessment in a semester-long graduate-level literacy assessment course with embedded fieldwork. First, the researchers conducted qualitative and descriptive analyses to examine what novice teachers reflected about in their ongoing written reflections. Second, they conducted comparative analyses to examine the extent to which the two groups differed in what they reflected about. Qualitative and descriptive analysis of written reflections revealed four prominent categories in which novice teachers reflected: (a) content knowledge related to literacy assessment, (b) beliefs about literacy assessment, (c) empathy and perspective-taking in the literacy assessment and instruction process, and (d) instructional planning and decision making. Comparative analyses revealed significant differences between the two groups of novice teachers in all four categories

Three Years In--Changing Plan Features in the U.S. Health Insurance Marketplace

Background: A central objective of recent U.S. healthcare policy reform, most notably the Affordable Care Act\u27s (ACA) Health Insurance Marketplace, has been to increase access to stable, affordable health insurance. However, changing market dynamics (rising premiums, changes in issuer participation and plan availability) raise significant concerns about the marketplaces\u27 ability to provide a stable source of healthcare for Americans that rely on them. By looking at the effect of instability on changes in the consumer choice set, we can analyze potential incentives to switch plans among price-sensitive enrollees, which can then be used to inform policy going forward. Methods: Data on health plan features for non-tobacco users in 2512 counties in 34 states participating in federally-facilitated exchanges from 2014 to 2016 was obtained from the Centers for Medicaid & Medicare Services. We examined how changes in individual plan features, including premiums, deductibles, issuers, and plan types, impact consumers who had purchased the lowest-cost silver or bronze plan in their county the previous year. We calculated the cost of staying in the same plan versus switching to another plan the following year, and analyzed how costs vary across geographic regions. Results: In most counties in 2015 and 2016 (53.7 and 68.2%, respectively), the lowest-cost silver plan from the previous year was still available, but was no longer the cheapest plan. In these counties, consumers who switched to the new lowest-cost plan would pay less in monthly premiums on average, by $51.48 and$55.01, respectively, compared to staying in the same plan. Despite potential premium savings from switching, however, the majority would still pay higher average premiums compared to the previous year, and most would face higher deductibles and an increased probability of having to change provider networks. Conclusion: While the ACA has shown promise in expanding healthcare access, continued changes in the availability and affordability of health plans are likely to result in churning and switching among enrollees, which may have negative ramifications for their health going forward. Future healthcare policy reform should aim to stabilize marketplace dynamics in order to encourage greater care continuity and limit churning

Three years in – changing plan features in the U.S. health insurance marketplace

Abstract Background A central objective of recent U.S. healthcare policy reform, most notably the Affordable Care Act’s (ACA) Health Insurance Marketplace, has been to increase access to stable, affordable health insurance. However, changing market dynamics (rising premiums, changes in issuer participation and plan availability) raise significant concerns about the marketplaces’ ability to provide a stable source of healthcare for Americans that rely on them. By looking at the effect of instability on changes in the consumer choice set, we can analyze potential incentives to switch plans among price-sensitive enrollees, which can then be used to inform policy going forward. Methods Data on health plan features for non-tobacco users in 2512 counties in 34 states participating in federally-facilitated exchanges from 2014 to 2016 was obtained from the Centers for Medicaid & Medicare Services. We examined how changes in individual plan features, including premiums, deductibles, issuers, and plan types, impact consumers who had purchased the lowest-cost silver or bronze plan in their county the previous year. We calculated the cost of staying in the same plan versus switching to another plan the following year, and analyzed how costs vary across geographic regions. Results In most counties in 2015 and 2016 (53.7 and 68.2%, respectively), the lowest-cost silver plan from the previous year was still available, but was no longer the cheapest plan. In these counties, consumers who switched to the new lowest-cost plan would pay less in monthly premiums on average, by $51.48 and$55.01, respectively, compared to staying in the same plan. Despite potential premium savings from switching, however, the majority would still pay higher average premiums compared to the previous year, and most would face higher deductibles and an increased probability of having to change provider networks. Conclusion While the ACA has shown promise in expanding healthcare access, continued changes in the availability and affordability of health plans are likely to result in churning and switching among enrollees, which may have negative ramifications for their health going forward. Future healthcare policy reform should aim to stabilize marketplace dynamics in order to encourage greater care continuity and limit churning.https://deepblue.lib.umich.edu/bitstream/2027.42/144501/1/12913_2018_Article_3198.pd

The CTLA-4 immune checkpoint protein regulates PD-L1:PD-1 interaction via transendocytosis of its ligand CD80

CTLA-4 and PD-1 are key immune checkpoint receptors that are targeted in the treatment of cancer. A recently identified physical interaction between the respective ligands, CD80 and PD-L1, has been shown to block PD-L1/PD-1 binding and to prevent PD-L1 inhibitory functions. Since CTLA-4 is known to capture and degrade its ligands via transendocytosis, we investigated the interplay between CD80 transendocytosis and CD80/PD-L1 interaction. We find that transendocytosis of CD80 results in a time-dependent recovery of PD-L1 availability that correlates with CD80 removal. Moreover, CD80 transendocytosis is highly specific in that only CD80 is internalised, while its heterodimeric PD-L1 partner remains on the plasma membrane of the antigen-presenting cell (APC). CTLA-4 interactions with CD80 do not appear to be inhibited by PD-L1, but efficient removal of CD80 requires an intact CTLA-4 cytoplasmic domain, distinguishing this process from more general trogocytosis and simple CTLA-4 binding to CD80/PD-L1 complexes. These data are consistent with CTLA-4 acting as modulator of PD-L1:PD-1 interactions via control of CD80

Three year results of the Friendly Schools whole-of-school intervention on children\u27s bullying behaviour

A group randomized controlled trial tested the efficacy of the Friendly Schools program to reduce student bullying behaviour. This socio-ecological intervention targeted the whole school, classroom, family, and individual students to reduce bullying behaviour. Self-report data were collected in 29 schools over three years from a cohort of 1968 eight to nine-year-olds. Surveys measured frequency of being bullied, bullying others, telling if bullied and observing bullying. Results indicate that intervention students were significantly less likely to observe bullying at 12, 24 and 36 months and be bullied after 12 and 36 months, and significantly more likely to tell if bullied after 12 months than comparison students. No differences were found for self-reported perpetration of bullying. The findings suggest whole-of-school programs that engage students in their different social contexts appear to reduce their experiences of being bullied and increase their likelihood of telling someone if they are bullied

Financial Burden and Mental Health Among LGBTQIA+ Adolescent and Young Adult Cancer Survivors During the COVID-19 Pandemic

Background In the United States, the cost of cancer treatment can lead to severe financial burden for cancer survivors. The economic impacts of the COVID-19 pandemic compound cancer survivors’ financial challenges. Financial burden may be particularly challenging for lesbian, gay, bisexual, transgender, queer, intersex, asexual and other sexual and gender minority (LGBTQIA+) survivors. LGBTQIA+ survivors who are adolescent and young adults (AYA) may face elevated financial burden due to multiple, intersecting identities. Methods An explanatory sequential mixed methods design was applied, beginning with a survey of AYA cancer survivors in the Mountain West region of the United States. Survey measures included demographics, COVID-19 impacts, the COmprehensive Score for financial Toxicity (COST), Perceived Stress Scale-4 (PSS-4), and PROMIS anxiety and depression scales. Two-way t-tests were used to analyze differences in outcomes between LGBTQIA+ and non-LGBTQIA+ AYAs. All LGBTQIA+ survey participants were invited to complete an interview, and those who agreed participated in descriptive interviews about financial burden due to cancer, COVID-19, and LGBTQIA+ identity. Interviews were audio recorded, transcribed, and analyzed using Dedoose. Results Survey participants (N=325) were LGBTQIA+ (n=29, 8.9%), primarily female (n= 197, 60.6%), non-Hispanic White (n= 267, 82.2%), and received treatment during COVID-19 (n= 174, 54.0%). LGBTQIA+ interview participants (n=9, 100%) identified as a sexual minority and (n=2, 22.2%) identified as a gender minority. Most were non-Hispanic White (n=6, 66.7%) and had received treatment during COVID-19 (n=7, 77.8%). Statistical analyses revealed that LGBTQIA+ AYAs reported significantly worse COST scores than non-LGBTQIA+ AYAs (p=0.002). LGBTQIA+ AYAs also reported significantly higher PSS-4 (p=0.001), PROMIS anxiety (p=0.002) and depression scores (p<0.001) than non-LGBTQIA+ AYAs, reflecting worse mental health outcomes. High costs of cancer treatment and employment disruptions due to COVID-19 contributed to substantial financial stress, which exacerbated existing mental health challenges and introduced new ones. Conclusions LGBTQIA+ AYA survivors reported substantial financial burden and psychological distress exacerbated by cancer, the COVID-19 pandemic, and LGBTQIA+ stigma. Given their multiple intersecting identities and potential for marginalization, LGBTQIA+ AYA survivors deserve prioritization in research to reduce financial burden and poor mental health