<em>MAPT </em>expression and splicing is differentially regulated by brain region: relation to genotype and implication for tauopathies

The MAPT (microtubule-associated protein tau) locus is one of the most remarkable in neurogenetics due not only to its involvement in multiple neurodegenerative disorders, including progressive supranuclear palsy, corticobasal degeneration, Parksinson's disease and possibly Alzheimer's disease, but also due its genetic evolution and complex alternative splicing features which are, to some extent, linked and so all the more intriguing. Therefore, obtaining robust information regarding the expression, splicing and genetic regulation of this gene within the human brain is of immense importance. In this study, we used 2011 brain samples originating from 439 individuals to provide the most reliable and coherent information on the regional expression, splicing and regulation of MAPT available to date. We found significant regional variation in mRNA expression and splicing of MAPT within the human brain. Furthermore, at the gene level, the regional distribution of mRNA expression and total tau protein expression levels were largely in agreement, appearing to be highly correlated. Finally and most importantly, we show that while the reported H1/H2 association with gene level expression is likely to be due to a technical artefact, this polymorphism is associated with the expression of exon 3-containing isoforms in human brain. These findings would suggest that contrary to the prevailing view, genetic risk factors for neurodegenerative diseases at the MAPT locus are likely to operate by changing mRNA splicing in different brain regions, as opposed to the overall expression of the MAPT gene

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

Designing futures through student engagement: A policy futures perspective

Futures research is gaining increased prominence in educational research and development (Tesar, 2021), and particularly now as we emerge from the global COVID-19 pandemic, which has provided a lever for change and an opportunity for innovation in learning, teaching and assessment (Hall et al., 2022; Jandri¿ et al., 2022). Designing Futures (DF) is an initiative that aims to transform the student learning experience at university, including through promoting student entrepreneurship and enhanced interaction with enterprise, industry and the innovation sector, supported by a national employability policy agenda, and concomitant, significant government funding. Ireland¿s Higher Education Authority has invested ¿7.57m in the DF programme at University of Galway for a period of five years, 2020-2025. However, introducing such a programme as DF within higher education raises problematic tensions around the purpose of higher education today, as set amidst the current policy futures perspective. Specifically, how do we balance policy imperatives to work more closely with enterprise and industry, while at the same time protecting the essential role of higher education, which must be to provide a formative context for all students to reach their fullest potential as active citizens? This paper helps to position the concept of student engagement, taking DF as an exemplar initiative, and examining the concept as it is construed and deployed in an innovative, futures-oriented educational programme. This review is critical for DF, to ensure we remain fundamentally focused on education, and not just for the world of work, which is of course important, but beyond enterprise and industry: to ensure students¿ readiness for the complex and challenging world of today, and tomorrow. Furthermore, this constitutes an important contribution to the literature, at a time when the identity of the university and purpose of higher education are the focus of an educationally problematic neo-liberal agenda (Mintz, 2021).The Designing Futures Project is funded by the The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: Higher Education Authority's Human Capital Initiative.peer-reviewe

Contributing factors for drought in United States forest ecosystems under projected future climates and their uncertainty

Observations of increasing global forest die-off related to drought are leading to more questions about potential increases in drought occurrence, severity, and ecological consequence in the future. Dry soils and warm temperatures interact to affect trees during drought; so understanding shifting risks requires some understanding of changes in both temperature and precipitation. Unfortunately, strong precipitation uncertainties in climate models yield substantial uncertainty in projections of drought occurrence. We argue that disambiguation of drought effects into temperature and precipitation-mediated processes can alleviate some of the implied uncertainty. In particular, the disambiguation can clarify geographic diversity in forest sensitivity to multifarious drivers of drought and mortality, making more specific use of geographically diverse climate projections. Such a framework may provide forest managers with an easier heuristic in discerning geographically diverse adaptation options. Warming temperatures in the future mean three things with respect to drought in forests: (1) droughts, typically already unusually hot periods, will become hotter, (2) the drying capacity of the air, measured as the vapor pressure deficit (VPD) will become greater, and (3) a smaller fraction of precipitation will fall as snow. More hot-temperature extremes will be more stressful in a direct way to living tissue, and greater VPD will increase pressure gradients within trees, exacerbating the risk of hydraulic failure. Reduced storage in snowpacks reduces summer water availability in some places. Warmer temperatures do not directly cause drier soils, however. In a hydrologic sense, warmer temperatures do little to cause ‘‘drought” as defined by water balances. Instead, much of the future additional longwave energy flux is expected to cause warming rather than evaporating water. Precipitation variations, in contrast, affect water balances and moisture availability directly; so uncertainties in future precipitation generate uncertainty in drought occurrence and severity projections. Although specific projections in annual and seasonal precipitation are uncertain, changes in inter-storm spacing and precipitation type (snow vs. rain) have greater certainty and may have utility in improving spatial projections of drought as perceived by vegetation, a value not currently captured by simple temperature-driven evaporation projections. This review ties different types of future climate shifts to expected consequences for drought and potential influences on physiology, and then explains sources of uncertainty for consideration in future mortality projections. One intention is to provide guidance on partitioning of uncertainty in projections of forest stresses

Conceptualising Student Engagement as a Theoretical Framework for Innovative Higher Education Practices : A Literature Review

Funded by the Irish Government (2020-2025), Designing Futures (DF) is a flagship university programme which provides a range of campus-based initiatives with the aim of supporting students to design their own personalised learning journey, equipping them for both their future lives and careers.&nbsp; It is being implemented and evaluated using an iterative process according to the principles of Educational Design Research (McKenney and Reeves, 2018) and Developmental Evaluation (Patton, 2011).&nbsp; This paper reports on a systematic review undertaken to scope out relevant theoretical frameworks for the project, in particular those that promote student engagement for all and enhance their belonging on campus.&nbsp; Informed by a realist approach, the research team worked from an initial set of 2031 articles and to a final set of 53 texts.&nbsp;&nbsp; The review outcomes are described according to three research questions, the goodness of fit of “student engagement” as a theoretical framework in this context; practices that foster effective student engagement; and research methodologies commonly deployed to promote student engagement.&nbsp; Finally, a working theoretical model for the Designing Futures project is proposed based on the literature reviewed.&nbsp; This utility of this model will be tested and refined as data is collected over the life cycle of the project

EPIC in action, measuring entrepreneurial competencies in higher education

Increasingly university programmes are introducing a range of experiential learning based programmes to support students to develop their entrepreneurial competencies during their time at university. This paper describes how the University of Galway is utilising the Entrepreneurial Potential and Innovation Competences Tool (EPIC) to track the changes in student self-reported competencies having participated in one of its flagship student entrepreneurial programmes. Based in Ideaslab, the university’s Human Centre Design Studio, the approach used is experiential, design centric and informed by D.School, Stanford. Initial findings from the EPIC surveys completed by 23 students are reported. These data are part of a university wide initiative and further data will be collected over the next three semesters. In so doing, we hope to add to the body of knowledge concerning the utility of this approach to measuring the changes in entrepreneurial competencies following participating in a university based entrepreneurial learning activity.Designing Futures (DF) is a flagship programme which received €7.57m funding through Human Capital Initiative, Pillar 3 by Ireland’s Higher Education Authority (HEA, 2020).peer-reviewe