Search

UNLABELLED: Patients with H3K27M-mutant diffuse midline glioma (DMG) have no proven effective therapies. ONC201 has recently demonstrated efficacy in these patients, but the mechanism behind this finding remains unknown. We assessed clinical outcomes, tumor sequencing, and tissue/cerebrospinal fluid (CSF) correlate samples from patients treated in two completed multisite clinical studies. Patients treated with ONC201 following initial radiation but prior to recurrence demonstrated a median overall survival of 21.7 months, whereas those treated after recurrence had a median overall survival of 9.3 months. Radiographic response was associated with increased expression of key tricarboxylic acid cycle-related genes in baseline tumor sequencing. ONC201 treatment increased 2-hydroxyglutarate levels in cultured H3K27M-DMG cells and patient CSF samples. This corresponded with increases in repressive H3K27me3 in vitro and in human tumors accompanied by epigenetic downregulation of cell cycle regulation and neuroglial differentiation genes. Overall, ONC201 demonstrates efficacy in H3K27M-DMG by disrupting integrated metabolic and epigenetic pathways and reversing pathognomonic H3K27me3 reduction. SIGNIFICANCE: The clinical, radiographic, and molecular analyses included in this study demonstrate the efficacy of ONC201 in H3K27M-mutant DMG and support ONC201 as the first monotherapy to improve outcomes in H3K27M-mutant DMG beyond radiation. Mechanistically, ONC201 disrupts integrated metabolic and epigenetic pathways and reverses pathognomonic H3K27me3 reduction. This article is featured in Selected Articles from This Issue, p. 2293.

Language is an important element in the struggle for social change and decolonization within South African tertiary education. We explored the relationship between indigenous languages and cocurricular involvement to sense of belonging. Data were collected via a survey of 4210 students that included demographics, cocurricular involvement, and self-reported perceptions of sense of belonging. Culturally relevant frameworks by Jama et al. (South African Journal of Higher Education 22(5):992-1005, 2008) and Case (Higher Education 55(3):321-332, 2008) and previous work on student engagement in South Africa framed the exploratory model. Analyses revealed that indigenous languages and cocurricular involvement, among other variables, were significant predictors of sense of belonging.

This study utilized decennial United States census data from 1970 to 2010 to examine the effects of university anchor institution initiatives on gentrification in multiple cities across the country. Using a difference-in-differences approach, a gentrification composite variable for census tracts targeted by anchor initiatives is compared to the composite for similar tracts within the same city, providing plausibly causal estimates of the relationship between gentrification and the initiatives. There is evidence university anchor initiatives slow rates of gentrification, though the statistically negative effect is not large enough to override the larger trends in gentrification across time. Additionally, financial strategies tend to slow gentrification the most, while physical strategies may accelerate gentrification.

ONE OF THE MOST INFLUENTIAL political interventions made by a novelist in our time, Milan Kundera's essay on Central Europe appeared four decades ago. The fact that it was republished [...]

Abstract Introduction A transformation of food systems is urgently needed, given their contribution to three ongoing and interlinked global health pandemics: (1) undernutrition and food insecurity, (2) obesity and non-communicable diseases (NCDs), and (3) climate change and biodiversity loss. As policymakers make decisions that shape food systems, this study aimed to identify and prioritise policies with double- or triple-duty potential to achieve healthier and more environmentally sustainable food systems. Methods This study undertook a 4-step methodological approach, including (i) a compilation of international policy recommendations, (ii) an online survey, (iii) four regional workshops with international experts and (iv) a ranking for prioritisation. Policies were identified and prioritised based on their double- or triple-duty potential, synergies and trade-offs. Using participatory and transdisciplinary approaches, policies were identified to have double- or triple-duty potential if they were deemed effective in tackling two or three of the primary outcomes of interest: (1) undernutrition, (2) obesity/NCDs and (3) environmental degradation. Results The desk review identified 291 recommendations for governments, which were merged and classified into 46 initially proposed policies. Based on the results from the online survey, 61% of those policies were perceived to have double- or triple-duty potential. During the workshops, 4 potential synergies and 31 trade-offs of these policies were identified. The final list of 44 proposed policies for healthier and more environmentally sustainable food systems created was divided into two main policy domains: ‘food supply chains’ and ‘food environments’. The outcome with the most trade-offs identified was ‘undernutrition’, followed by ‘environmental sustainability’, and ‘obesity/NCDs’. Of the top five expert-ranked food supply chain policies, two were perceived to have triple-duty potential: (a) incentives for crop diversification; (b) support for start-ups, and small- and medium-sized enterprises. For food environments, three of the top five ranked policies had perceived triple-duty potential: (a) affordability of healthier and more sustainable diets; (b) subsidies for healthier and more sustainable foods; (c) restrictions on children's exposure to marketing through all media. Conclusion This study identified and prioritised a comprehensive list of double- and triple-duty government policies for creating healthier and more environmentally sustainable food systems. As some proposed policies may have trade-offs across outcomes, they should be carefully contextualised, designed, implemented and monitored.

ABSTRACTAdvertisements promoting energy-dense, nutrient-poor food and drinks influence children’s dietary choice and preference and are pervasive in children’s environments across Aotearoa, New Zealand. Using a combination of datasets from separate studies, this research seeks to describe the extent of children’s unhealthy food/drink advertising exposure in all primary and intermediate school food zones (n = 381) in Tāmaki Makaurau, Auckland, and assess whether this exposure correlates with indicators of neighbourhood deprivation. To achieve this, we developed a simple advertising exposure score using images of advertising collected from Google Street View, and investigated its spatial correlation with indicators of neighbourhood deprivation. Outdoor advertising was present in proximity to 61.9% of the sampled schools (n = 236); of which 83.1% of adverts promoted unhealthy food and/or drinks (n = 2669). Advertising exposure increased statistically significantly with neighbourhood deprivation (p

It is well known that it is harder to integrate conflicting insights across disparate disciplines than similar ones. In this article, I focus on the relation between economics, which is dominated by views that one could characterize as "pro-capitalist," and English, which is dominated by views that one could characterize as "anti-capitalist." It is crucial to examine this specific pair of disciplines because each has recently shown an apparent increased interest in the other, but without seriously challenging their own dominant views. I consider why current attempts at interdisciplinarity between economics and English have been inadequate. Whereas one might attribute this conflict mainly to the gap between economics' quantitative methods and English's traditionally qualitative ones, I find instead that differing assumptions are more important than differing methods in explaining conflicting insights between those in these two fields. Each discipline's interest in the other's concepts or methods remains superficial, falling short of deep engagement with the other in a way that truly challenges its own assumptions. To chart a possible way out of this impasse, I identify four key areas in which those in economics and English harbor conflicting assumptions about capitalism that undergird each discipline's internal consensus and suggest how to apply Allen F. Repko's and Rick Szostak's (2021) tools of integration to those assumptions. I find that different combinations of integrative techniques such as redefinition, transformation, organization, and extension are likely to work better at yielding common ground on some sets of assumptions than others. My goal is not to accomplish full integration, nor do I take it for granted that such integration is ultimately possible. Rather, I want to set an agenda and hone a toolset for integration without preconceptions about how this effort at integration will turn out. I conclude with a reflection on obstacles to integration and how researchers might try to overcome them.

Student engagement is a widely researched and utilized concept to enhance student experiences and outcomes. Most research on student engagement, however, focuses on curricular engagement with relatively little emphasis placed on the co-curriculum. This study utilizes Case's theory of relational engagement to analyse findings from three focus groups conducted at a university in South Africa to better understand how relational engagement is instantiated in the co-curriculum and how the co-curriculum differs from the standard academic curriculum in terms of engagement. In particular, we show relational engagement is just as important in the co-curriculum, highlighting student relations to broader university life, to fellow students, and to communities beyond the campus.

Interest in universities as anchor institutions within their communities and cities is growing as civic leaders search for ways to build local wealth. Systematic analysis of the effects of anchor institution initiatives remains difficult due to the disparate nature of anchor initiatives and a relative lack of a shared language describing the work. This article reviews the anchor literature to summarize current understandings of universities and economic development, then develops a typology of anchor institution initiatives based upon the literature. The typology is based upon the type of capital leveraged by initiatives: (a) financial, (b) physical, (c) intellectual, and (d) human. The author then uses the typology to categorize a number of initiatives found within the literature and through a rough sampling process. This typology offers a shared language for scholars to use to guide discussions around universities as anchor institutions, and, more importantly, the typology can frame analyses of the differential effects, costs, and benefits of different anchor strategies.

Lamkang (ISO 639-3 code: lmk) is a Tibeto-Burman language spoken in Manipur, India with under 10,000 speakers. As a part of revitalization and documentation efforts, members of the community have begun to record oral literature, personal histories, Bible translations, and the like in written form. The spelling conventions followed by these writers are mostly consistent with those used in current translations of the Bible. However, there continues to be variation across different writers. The different variants will need to be reconciled as the Lamkang move towards a single orthographic standard. In this paper, we present findings from samples of writing collected over the course of the first author’s 12 years of work with community writers and aim to characterize variations in the orthography in linguistic terms. We then compare these variations to orthographic variations in related South Central languages. Our goal is to provide an analysis of orthographic variation focusing on phonological and morphological structure. Existing literature on literacy shows that metalinguistic awareness can impact processing the written word, suggesting that this awareness, or lack thereof, could also impact orthographic choice. These linguistic factors, along with aesthetics and identity, may be used to explain and contribute to resolving orthographic variation in languages with similar structures.

BackgroundAmyotrophic lateral sclerosis (ALS) is a complex, late-onset, neurodegenerative disease with a genetic contribution to disease liability. Genome-wide association studies (GWAS) have identified ten risk loci to date, including the TNIP1/GPX3 locus on chromosome five. Given association analysis data alone cannot determine the most plausible risk gene for this locus, we undertook a comprehensive suite of in silico, in vivo and in vitro studies to address this.MethodsThe Functional Mapping and Annotation (FUMA) pipeline and five tools (conditional and joint analysis (GCTA-COJO), Stratified Linkage Disequilibrium Score Regression (S-LDSC), Polygenic Priority Scoring (PoPS), Summary-based Mendelian Randomisation (SMR-HEIDI) and transcriptome-wide association study (TWAS) analyses) were used to perform bioinformatic integration of GWAS data (Ncases = 20,806, Ncontrols = 59,804) with 'omics reference datasets including the blood (eQTLgen consortium N = 31,684) and brain (N = 2581). This was followed up by specific expression studies in ALS case-control cohorts (microarray Ntotal = 942, protein Ntotal = 300) and gene knockdown (KD) studies of human neuronal iPSC cells and zebrafish-morpholinos (MO).ResultsSMR analyses implicated both TNIP1 and GPX3 (p < 1.15 × 10-6), but there was no simple SNP/expression relationship. Integrating multiple datasets using PoPS supported GPX3 but not TNIP1. In vivo expression analyses from blood in ALS cases identified that lower GPX3 expression correlated with a more progressed disease (ALS functional rating score, p = 5.5 × 10-3, adjusted R2 = 0.042, Beffect = 27.4 ± 13.3 ng/ml/ALSFRS unit) with microarray and protein data suggesting lower expression with risk allele (recessive model p = 0.06, p = 0.02 respectively). Validation in vivo indicated gpx3 KD caused significant motor deficits in zebrafish-MO (mean difference vs. control ± 95% CI, vs. control, swim distance = 112 ± 28 mm, time = 1.29 ± 0.59 s, speed = 32.0 ± 2.53 mm/s, respectively, p for all

Parkinson's disease (PD) is associated with a reduction in 26/20S proteasome and mitochondrial function and depletion of dopamine. Activation of mitochondrial function with the NAD+ precursor nicotinamide riboside (NR) is a potential therapeutic for PD. However, despite recently started clinical trials, analysis of NR in mammalian animal PD models is lacking and data in simpler PD models is limited. We analyzed the effect of NR in C. elegans and in mouse 26/20S proteasome inhibition models of PD. In C. elegans, NR rescued α-synuclein overexpression induced phenotypes likely by activating the mitochondrial unfolded protein response. However, in a proteasome inhibitor-induced mouse model of PD, NR first partially rescued behavioural dysfunction, but later resulted in decrease in dopamine and its related gene expression in the substantia nigra. Our results suggest that reduction in 26/20S function with long term NR treatment may increase risk for developing reduced nigrostriatal DA function.

The growth of the number of persons pursuing education outside of their home country has created a relatively new population of transnationally mobile students who experience a pivotal developmental period crossing and across international borders. There are few suitable theoretical models to examine the developmental experiences of this growing population. In his last publication, Urie Bronfenbrenner acknowledged his ecological model was a developmental yet evolving model to be tested and amended by incorporating new evidence. This conceptual paper draws from existing empirical work to advance the ecological model and revise it to be more applicable to and explanatory of developmental experiences of international students in the United States. The resulting model, which we call the "Spanning Systems" model, can be used to identify spaces of potential contradictions or learning in a student's development.

This article draws on data from a British Council-funded project which aimed both to compare global early English language learning (EELL) pedagogic practices in 2020 with those in 2010 and to investigate current EELL teaching and learning in primary schools. The project had an explicit focus on classroom language practice, that is, the languages teachers (and learners) use to deliver and learn English content, a key pedagogic concern in the literature. This article first compares survey data on classroom language use in 2010 and 2020 before presenting a more in-depth consideration of the 2020 data from fourteen case studies to give an overview of current classroom language practices.

Traditional ecological models are promising for making sense of international student experiences, but the assumed monolithic nature of the structuring systems is inadequate for explaining development that occurs across multiple systems. We present and expand a model called the Spanning Systems Model that recognizes multiple ecologies. The model organizes ecologies in terms of home and host countries, arguing the systems are in some ways independent and in others intertwined. Student experiences are thus structured by both the systems in which the school is located as well as the systems from which the student is coming. Conceptualizing ecologies in this manner shifts the goal of a successful transition into higher education away from acculturation and towards a more complex, case-specific project of identifying areas of alignment and contradiction and tailoring experiences to each student's unique ecologies.

The use of L1 [learners' first language] in L2 [teaching of a new language] classes has long been debated in the field of TESOL [teaching English to speakers of other languages]. Although at least some use of the L1 is now widely advocated, questions remain about what might count as acceptable or effective use. While a number of studies have been carried out in secondary and tertiary settings to investigate these questions, research in primary school settings remains relatively rare. This article addresses the gap by investigating L1 use in primary classes in Turkey. Drawing on observational and interview data with five primary EFL teachers, we investigate how much, when, how, and why teachers use L1 in their English classrooms. The results showed that, despite some negative attitudes towards L1 use, the teachers used it to different degrees and for various purposes including giving instruction, providing feedback and asking questions. The teachers also identified a number of practical reasons for their decisions, namely, students' proficiency level, achieving target-curriculum, saving time and teaching specific language points. We conclude that L1 is an inseparable part of the L2 classroom, and each teacher has their own unique way of using it.

Interest in the Scholarship of Teaching and Learning (SoTL) is driven in part by the need to provide systematic academic development for faculty anchored in evidence-based practice such as the introduction of quality assurance frameworks. This article reports on a mixed-method evaluation of one institution's grassroots multidisciplinary faculty development program, called the Educational Research Series, to determine if it met the needs of its faculty, graduate student, and staff participants. Conducted at one mid-sized university in southern Ontario and framed, as was the program design and implementation, by both adult learning theory and constructivism, the evaluation collected data from session exit surveys, attendee interviews, and facilitator focus groups. The data analysis revealed that reasons for participating included increasing levels of understanding, receiving individual support, and learning about colleagues' research interests. The major strengths of the program included individual learning, resources, facilitator expertise, interactive sessions, and the multidisciplinary focus. The main challenges centered on depth versus breadth of the sessions, time, and educational language and theory. Participants recommended additional resources, communication among facilitators, institutional recognition, and increased depth of content. As a result of this evaluation, an Advanced Educational Research Series is being offered at the institution. This article will inform other institutions wishing to build SoTL as a field within their institutions.

This article concludes that the pertinent Malawi soil laws on land degradation neutrality (LDN) have weak Avoid, Reduce, and Reverse priorities. The article uses Roscoe Pound's theory of social engineering to underline ecological interdependence as an overriding interest in resolving the interests of people and nature. Using a doctrinal and comparative approach, the article identifies provisions in Uganda and Germany's soil-dedicated legal frameworks that incorporate the Avoid, Reduce, and Reverse priorities. The analysis leads to the finding that unlike in Germany and Uganda, there is a reticent consideration of soil conservation in Malawi's soil-related legislation to get soil users to Avoid, Reduce and Reverse. This is because Malawi's approach to soil conservation is human-centered; lacking an ecocentric and deep ecology approach to inform the legislation.

A sharp rise in autism spectrum disorder (ASD) prevalence estimates, beginning in the 1990s, suggested factors additional to genetics were at play. This stimulated increased research investment in nongenetic factors, including the study of environmental chemical exposures, diet, nutrition, lifestyle, social factors, and maternal medical conditions. Consequently, both peer- and non-peer-reviewed bodies of evidence investigating environmental contributors to ASD etiology have grown significantly. The heterogeneity in the design and conduct of this research results in an inconclusive and unwieldy ‘virtual stack’ of publications. We propose to develop a Web-based tool for Autism Research and the Environment (aWARE) to comprehensively aggregate and assess these highly variable and often conflicting data. The interactive aWARE tool will use an approach for the development of systematic evidence maps (SEMs) to identify and display all available relevant published evidence, enabling users to explore multiple research questions within the scope of the SEM. Throughout tool development, listening sessions and workshops will be used to seek perspectives from the broader autism community. New evidence will be indexed in the tool annually, which will serve as a living resource to investigate the association between environmental factors and ASD.

Childhood posterior fossa group A ependymomas (PFAs) have limited treatment options and bear dismal prognoses compared to group B ependymomas (PFBs). PFAs overexpress the oncohistone-like protein EZHIP (enhancer of Zeste homologs inhibitory protein), causing global reduction of repressive histone H3 lysine 27 trimethylation (H3K27me3), similar to the oncohistone H3K27M. Integrated metabolic analyses in patient-derived cells and tumors, single-cell RNA sequencing of tumors, and noninvasive metabolic imaging in patients demonstrated enhanced glycolysis and tricarboxylic acid (TCA) cycle metabolism in PFAs. Furthermore, high glycolytic gene expression in PFAs was associated with a poor outcome. PFAs demonstrated high EZHIP expression associated with poor prognosis and elevated activating mark histone H3 lysine 27 acetylation (H3K27ac). Genomic H3K27ac was enriched in PFAs at key glycolytic and TCA cycle–related genes including hexokinase-2 and pyruvate dehydrogenase. Similarly, mouse neuronal stem cells (NSCs) expressing wild-type EZHIP (EZHIP-WT) versus catalytically attenuated EZHIP-M406K demonstrated H3K27ac enrichment at hexokinase-2 and pyruvate dehydrogenase, accompanied by enhanced glycolysis and TCA cycle metabolism. AMPKα-2, a key component of the metabolic regulator AMP-activated protein kinase (AMPK), also showed H3K27ac enrichment in PFAs and EZHIP-WT NSCs. The AMPK activator metformin lowered EZHIP protein concentrations, increased H3K27me3, suppressed TCA cycle metabolism, and showed therapeutic efficacy in vitro and in vivo in patient-derived PFA xenografts in mice. Our data indicate that PFAs and EZHIP-WT–expressing NSCs are characterized by enhanced glycolysis and TCA cycle metabolism. Repurposing the antidiabetic drug metformin lowered pathogenic EZHIP, increased H3K27me3, and suppressed tumor growth, suggesting that targeting integrated metabolic/epigenetic pathways is a potential therapeutic strategy for treating childhood ependymomas.

Dr. Bryan L. Garton presented the 2018 AAAE Distinguished Lecture at the Annual Meeting of the American Association of Agricultural Education in Charleston, South Carolina in May 2018. The article is a philosophical work based upon the author's experiences in the agricultural education profession and in higher education.

Iron physiology is regulated by a complex interplay of extracellular transport systems, coordinated transcriptional responses, and iron efflux mechanisms. Dysregulation of iron metabolism can result in defects in myelination, neurotransmitter synthesis, and neuronal maturation. In neonates, germinal matrix-intraventricular hemorrhage (GMH-IVH) causes iron overload as a result of blood breakdown in the ventricles and brain parenchyma which can lead to post-hemorrhagic hydrocephalus (PHH). However, the precise mechanisms by which GMH-IVH results in PHH remain elusive. Understanding the molecular determinants of iron homeostasis in the developing brain may lead to improved therapies. This manuscript reviews the various roles iron has in brain development, characterizes our understanding of iron transport in the developing brain, and describes potential mechanisms by which iron overload may cause PHH and brain injury. We also review novel preclinical treatments for IVH that specifically target iron. Understanding iron handling within the brain and central nervous system may provide a basis for preventative, targeted treatments for iron-mediated pathogenesis of GMH-IVH and PHH.

Abstract Objective: To assess annual household purchases of sugar-sweetened beverages (SSBs), artificially sweetened beverages (AFSBs), and unsweetened beverages (USBs) by household composition and income, and over time. Design: Observational cohort study using beverage purchasing data linked to a supermarket database. ANOVA was used to compare total household purchase volumes (L) and the contribution of beverages purchased by category, household composition (size), household income (four categories from New Zealand (NZ) < $30 000 to > $90 000), and over time (trend from 2015 to 2019). Setting: Aotearoa NZ. Participants: ∼1800 households in the NielsenIQ Homescan® market research panel. Results: In 2019, the mean (sd) annual household purchase volume and relative contribution to total beverage volume of SSBs were 72·3 (93·0) L and 33 %, respectively. Corresponding values for AFSBs were 32·5 (79·3) L (15 %), and USBs were 112·5 (100·9) L (52 %). Larger households purchased more of all beverage types except AFSBs. Total purchases were similar by income, but households earning < $NZ 30 000 purchased fewer AFSBs and USBs (but not SSBs) than households earning > $NZ 90 000. Total and USB purchases were unchanged over time, but SSBs dropped by 5·9 L (P-trend = 0·04), and AFSBs increased by 5·3 L (P-trend = 0·00). Conclusions: USBs contributed the most to household beverage purchases. Total purchases were higher for larger households and similar by income, including for SSBs. The reduction over time was too small for health benefits. Findings support policies and interventions to reduce SSB consumption and highlight the importance of focusing on equitable outcomes.