Search

This article includes aspects of a larger study in which we critically examine how and what mainstream teacher candidates learn in preservice programs about supporting multilingual learners (MLs). Since 2015, the province of Ontario has required that all teacher candidates — not just future ESL specialists — be prepared to support MLs. Within this context, we provide a description and discussion of who multilingual learners are imagined to be in policy documents and by various actors in education, along with examples of teacher candidate learning from a mixed-methods case study of teacher-candidate learning in the Master of Teaching at the University of Toronto. Our article reveals the complexity of preparing teachers to support MLs and suggests possibilities for centring multilingual learners and countering racism in Canadian teacher education.

This study examines pre-service teacher candidates’ (TCs) stances and use of translanguaging and multimodality to support K-12 multilingual learners’ writing. Data were drawn from a course on supporting multilingual learners in a teacher education program in Ontario. Data sources were responses to the Pedagogical Content Knowledge for Language- Inclusive Teaching (PeCK–LIT) Test, and TCs’ unit plans and lesson plans. Analytical codes were derived from the literature on translanguaging: monolingual and translanguaging stance, translanguaging as a scaffold and resource, teacher-directed and student-directed, intentional and spontaneous translanguaging, and supporting monomodality and multimodality. Findings demonstrate the use of translanguaging strategies such as multilingual word walls and online translation tools. However, there were constraints to TCs’ stances, such as allowing translanguaging as a temporary scaffold towards English-only instruction and approaching writing as a discrete rather than multimodal skill. The paper recommends ways TCs can be supported in developing a holistic understanding of translanguaging and multimodality., Cette étude explore les postures des personnes enseignantes en formation initiale et leur utilisation du translanguaging et de la multimodalité pour soutenir l'écriture des apprenants multilingues de la maternelle à la 12e année. Les données, recueillies dans le cadre d'un cours portant sur les apprenants multilingues dans un programme de formation des enseignants en Ontario, proviennent de réponses au test Pedagogical Content Knowledge for Language-Inclusive Teaching (PeCK-LIT) et des plans de cours de ces personnes enseignantes en formation initiale. Les codes analytiques qui ont guidé l’analyses sont : posture monolingue et translanguaging, translanguaging comme soutien et ressource, translanguaging dirigé par l'enseignant et par l'élève, translanguaging intentionnel et spontané, et soutien à la mono- et à la multimodalité. Les résultats indiquent le recours à des stratégies de translanguaging. Cependant, ces stratégies sont parfois misent en oeuvre de façon restrictive, notamment, permettre le translanguaging comme soutien temporaire vers un enseignement exclusivement en anglais ou encore aborder la didactique de l'écriture comme une compétence isolée plutôt que multimodale. Les auteurs proposent des moyens afin de soutenir les personnes enseignantes en formation à développer une compréhension holistique du translanguaging et de la multimodalité.

Figure S5: Dual MoA of MEDI0562

Purpose:Immune checkpoint blockade has demonstrated clinical benefits across multiple solid tumor types; however, resistance and relapse often occur. New immunomodulatory targets, which are highly expressed in activated immune cells, are needed. MEDI0562, an agonistic humanized mAb, specifically binds to the costimulatory molecule OX40. This first-in-human study evaluated MEDI0562 in adults with advanced solid tumors.Patients and Methods:In this phase I, multicenter, open-label, single-arm, dose-escalation (3+3 design) study, patients received 0.03, 0.1, 0.3, 1.0, 3.0, or 10 mg/kg MEDI0562 through intravenous infusion every 2 weeks, until confirmed disease progression or unacceptable toxicity. The primary objective evaluated safety and tolerability. Secondary endpoints included antitumor activity, pharmacokinetics, immunogenicity, and pharmacodynamics.Results:In total, 55 patients received ≥1 dose of MEDI0562 and were included in the analysis. The most common tumor type was squamous cell carcinoma of the head and neck (47%). Median duration of treatment was 10 weeks (range, 2–48 weeks). Treatment-related adverse events (TRAEs) occurred in 67% of patients, most commonly fatigue (31%) and infusion-related reactions (14%). Grade 3 TRAEs occurred in 14% of patients with no apparent dose relationship; no TRAEs resulted in death. Two patients had immune-related partial responses per protocol and 44% had stable disease. MEDI0562 induced increased Ki67+ CD4+ and CD8+ memory T-cell proliferation in the periphery and decreased intratumoral OX40+ FOXP3+ cells.Conclusions:MEDI0562 was safely administered at doses up to 10 mg/kg in heavily pretreated patients. On-target pharmacodynamic effects were suggested in this setting. Further evaluation with immune checkpoint inhibitors is ongoing.

The SET domain containing 2, histone lysine methyltransferase encoded by SETD2 is a dual-function methyltransferase for histones and microtubules and plays an important role for transcriptional regulation, genomic stability, and cytoskeletal functions. Specifically, SETD2 is associated with trimethylation of histone H3 at lysine 36 (H3K36me3) and methylation of α-tubulin at lysine 40. Heterozygous loss of function and missense variants have previously been described with Luscan-Lumish syndrome (LLS), which is characterized by overgrowth, neurodevelopmental features, and absence of overt congenital anomalies. We have identified 15 individuals with de novo variants in codon 1740 of SETD2 whose features differ from those with LLS. Group 1 consists of 12 individuals with heterozygous variant c.5218C>T p.(Arg1740Trp) and Group 2 consists of 3 individuals with heterozygous variant c.5219G>A p.(Arg1740Gln). The phenotype of Group 1 includes microcephaly, profound intellectual disability, congenital anomalies affecting several organ systems, and similar facial features. Individuals in Group 2 had moderate to severe intellectual disability, low normal head circumference, and absence of additional major congenital anomalies. While LLS is likely due to loss of function of SETD2, the clinical features seen in individuals with variants affecting codon 1740 are more severe suggesting an alternative mechanism, such as gain of function, effects on epigenetic regulation, or posttranslational modification of the cytoskeleton. Our report is a prime example of different mutations in the same gene causing diverging phenotypes and the features observed in Group 1 suggest a new clinically recognizable syndrome uniquely associated with the heterozygous variant c.5218C>T p.(Arg1740Trp) in SETD2.

This article explores university English as a Second Language (ESL) instructors’ attitudes toward translanguaging in the classroom and possible reasons for instructors’ resistance in moving translanguaging ideology into English language teaching pedagogy. Many researchers have forwarded translanguaging as a theoretical and pedagogical approach to language education because of its potential cognitive, social, and affective benefits. A translanguaging pedagogy calls for instructors to affirm the dynamic and diverse language practices that multilingual students utilize as part of their unitary language repertoire. However, because English-only pedagogies, policies, and practices still permeate the ESL classroom, it is critical to understand how ESL instructors’ language ideologies and orientations play a role in shaping their pedagogical practices and classroom language policies. Using Ruíz’s orientations in language planning and translanguaging theory, this study examined the language orientations of five ESL instructors at a major Canadian university based on qualitative data gathered through semistructured interviews. The findings provide insights into instructors’ attitudes toward translanguaging, the relationship between instructors’ language learning experiences and their classroom language policy, and institutional opportunities and constraints. Le présent article explore les attitudes des professeurs d’anglais langue seconde (ESL) au niveau universitaire face au translangagisme en salle de classe ainsi que les raisons possibles de leur résistance à l’introduction de l’idéologie translangagière dans la pédagogie de l’enseignement de l’anglais. De nombreux travaux de recherche renvoient au translangagisme comme démarche théorique et pédagogique d’enseignement des langues en raison de ses avantages cognitifs, sociaux et affectifs. La pédagogie translangagière invite les professeurs à soutenir le dynamisme et la diversité des pratiques langagières que les étudiantes et étudiants multilingues utilisent déjà dans le cadre de leur répertoire linguistique unitaire. Toutefois, puisque l’enseignement de l’anglais langue seconde en classe reste imprégné de pédagogies, de politiques, et de pratiques exclusivement anglophones, il est essentiel de comprendre le rôle que jouent les idéologies et les orientations des professeurs d’anglais langue seconde dans la formation de leurs pratiques pédagogiques et de leurs politiques d’enseignement en classe. S’inspirant des orientations de Ruíz en matière de planification langagière et de théorie translangagière, la présente étude examine les orientations linguistiques de cinq professeures et professeurs d’anglais langue seconde dans une grande université canadienne à l’aide de données qualitatives recueillies dans le cadre d’entrevues semi-structurées. Les conclusions de l’enquête aident à mieux comprendre les attitudes des professeurs face au translangagisme, la relation entre les expériences d’apprentissage langagier des professeurs, et leur politique langagière en classe ainsi que les possibilités et les contraintes institutionnelles.

PURPOSE: To investigate the effect of PLXNA1 variants on the phenotype of patients with autosomal dominant and recessive inheritance patterns and to functionally characterize the zebrafish homologs plxna1a and plxna1b during development. METHODS: We assembled ten patients from seven families with biallelic or de novo PLXNA1 variants. We describe genotype-phenotype correlations, investigated the variants by structural modeling, and used Morpholino knockdown experiments in zebrafish to characterize the embryonic role of plxna1a and plxna1b. RESULTS: Shared phenotypic features among patients include global developmental delay (9/10), brain anomalies (6/10), and eye anomalies (7/10). Notably, seizures were predominantly reported in patients with monoallelic variants. Structural modeling of missense variants in PLXNA1 suggests distortion in the native protein. Our zebrafish studies enforce an embryonic role of plxna1a and plxna1b in the development of the central nervous system and the eye. CONCLUSION: We propose that different biallelic and monoallelic variants in PLXNA1 result in a novel neurodevelopmental syndrome mainly comprising developmental delay, brain, and eye anomalies. We hypothesize that biallelic variants in the extracellular Plexin-A1 domains lead to impaired dimerization or lack of receptor molecules, whereas monoallelic variants in the intracellular Plexin-A1 domains might impair downstream signaling through a dominant-negative effect.

Accumulation of unfolded proteins in the endoplasmic reticulum (ER) initiates a stress response mechanism to clear out the unfolded proteins by either facilitating their re-folding or inducing their degradation. When this fails, an apoptotic cascade is initiated so that the affected cell is eliminated. IRE1α is a critical sensor of the unfolded-protein response, essential for initiating the apoptotic signaling. Here, we report an infantile neurodegenerative disorder associated with enhanced activation of IRE1α and increased apoptosis. Three unrelated affected individuals with congenital microcephaly, infantile epileptic encephalopathy, and profound developmental delay were found to carry heterozygous variants (c.932T>C [p.Leu311Ser] or c.935T>C [p.Leu312Pro]) in RNF13, which codes for an IRE1α-interacting protein. Structural modeling predicted that the variants, located on the surface of the protein, would not alter overall protein folding. Accordingly, the abundance of RNF13 and IRE1α was not altered in affected individuals’ cells. However, both IRE1α-mediated stress signaling and stress-induced apoptosis were increased in affected individuals’ cells. These results indicate that the RNF13 variants confer gain of function to the encoded protein and thereby lead to altered signaling of the ER stress response associated with severe neurodegeneration in infancy.

Diagnostic exome sequencing (DES) has aided delineation of the phenotypic spectrum of rare genetic etiologies of intellectual disability (ID). A SET domain containing 5 gene (SETD5) phenotype of ID and dysmorphic features has been previously described in relation to patients with 3p25.3 deletions and in a few individuals with de novo sequence alterations. Herein, we present additional patients with pathogenic SETD5 sequence alterations. The majority of patients in this cohort and previously reported have developmental delay, behavioral/psychiatric issues, and variable hand and skeletal abnormalities. We also present an apparently unaffected carrier mother of an affected individual and a carrier mother with normal intelligence and affected twin sons. We suggest that the phenotype of SETD5 is more complex and variable than previously presented. Therefore, many features and presentations need to be considered when evaluating a patient for SETD5 alterations through DES.

Cornelia de Lange syndrome (CdLS) is a rare neurodevelopmental syndrome for which mutations in five causative genes that encode (SMC1A, SMC3, RAD21) or regulate (NIPBL, HDAC8) the cohesin complex, account for ~70% of cases. Herein we report on four female Subjects who were found to carry novel intragenic deletions in HDAC8. In one case, the deletion was found in mosaic state and it was determined to be present in ~38% of blood lymphocytes and in nearly all cells of a buccal sample. All deletions, for which parental blood samples were available, were shown to have arisen de novo. X-chromosome inactivation studies demonstrated marked skewing, suggesting strong selection against the mutated HDAC8 allele. Based on an investigation of the deletion breakpoints, we hypothesize that microhomology-mediated replicative mechanisms may be implicated in the formation of some of these rearrangements. This study broadens the mutational spectrum of HDAC8, provides the first description of a causative HDAC8 somatic mutation and increases the knowledge on possible mutational mechanisms underlying copy number variations in HDAC8. Moreover our findings highlight the clinical utility of considering copy number analysis in HDAC8 as well as the analysis on DNA from more than one tissue as an indispensable part of the routine molecular diagnosis of individuals with CdLS or CdLS-overlapping features.

CDC42BPB encodes MRCKβ (myotonic dystrophy-related Cdc42-binding kinase beta), a serine/threonine protein kinase, and a downstream effector of CDC42, which has recently been associated with Takenouchi-Kosaki syndrome, an autosomal dominant neurodevelopmental disorder. We identified 12 heterozygous predicted deleterious variants in CDC42BPB (9 missense, 2 frameshift, and 1 nonsense) in 14 unrelated individuals (confirmed de novo in 11/14) with neurodevelopmental disorders including developmental delay/intellectual disability, autism, hypotonia, and structural brain abnormalities including cerebellar vermis hypoplasia and agenesis/hypoplasia of the corpus callosum. The frameshift and nonsense variants in CDC42BPB are expected to be gene-disrupting and lead to haploinsufficiency via nonsense-mediated decay. All missense variants are located in highly conserved and functionally important protein domains/regions: 3 are found in the protein kinase domain, 2 are in the citron homology domain, and 4 in a 20-amino acid sequence between 2 coiled-coil regions, 2 of which are recurrent. Future studies will help to delineate the natural history and to elucidate the underlying biological mechanisms of the missense variants leading to the neurodevelopmental and behavioral phenotypes.

Purpose: Immune checkpoint blockade has demonstrated clinical benefits across multiple solid tumor types; however, resistance and relapse often occur. New immunomodulatory targets, which are highly expressed in activated immune cells, are needed. MEDI0562, an agonistic humanized mAb, specifically binds to the costimulatory molecule OX40. This first-in-human study evaluated MEDI0562 in adults with advanced solid tumors. Patients and Methods: In this phase I, multicenter, open-label, single-arm, dose-escalation (3+3 design) study, patients received 0.03, 0.1, 0.3, 1.0, 3.0, or 10 mg/kg MEDI0562 through intravenous infusion every 2 weeks, until confirmed disease progression or unacceptable toxicity. The primary objective evaluated safety and tolerability. Secondary endpoints included antitumor activity, pharmacokinetics, immunogenicity, and pharmacodynamics. Results: In total, 55 patients received ≥1 dose of MEDI0562 and were included in the analysis. The most common tumor type was squamous cell carcinoma of the head and neck (47%). Median duration of treatment was 10 weeks (range, 2–48 weeks). Treatment-related adverse events (TRAEs) occurred in 67% of patients, most commonly fatigue (31%) and infusion-related reactions (14%). Grade 3 TRAEs occurred in 14% of patients with no apparent dose relationship; no TRAEs resulted in death. Two patients had immune-related partial responses per protocol and 44% had stable disease. MEDI0562 induced increased Ki67+ CD4+ and CD8+ memory T-cell proliferation in the periphery and decreased intratumoral OX40+ FOXP3+ cells. Conclusions: MEDI0562 was safely administered at doses up to 10 mg/kg in heavily pretreated patients. On-target pharmacodynamic effects were suggested in this setting. Further evaluation with immune checkpoint inhibitors is ongoing.

Pathogenic de novo variants in the X-linked gene SLC35A2 encoding the major Golgi-localized UDP-galactose transporter required for proper protein and lipid glycosylation cause a rare type of congenital disorder of glycosylation known as SLC35A2-congenital disorders of glycosylation (CDG; formerly CDG-IIm). To date, 29 unique de novo variants from 32 unrelated individuals have been described in the literature. The majority of affected individuals are primarily characterized by varying degrees of neurological impairments with or without skeletal abnormalities. Surprisingly, most affected individuals do not show abnormalities in serum transferrin N-glycosylation, a common biomarker for most types of CDG. Here we present data characterizing 30 individuals and add 26 new variants, the single largest study involving SLC35A2-CDG. The great majority of these individuals had normal transferrin glycosylation. In addition, expanding the molecular and clinical spectrum of this rare disorder, we developed a robust and reliable biochemical assay to assess SLC35A2-dependent UDP-galactose transport activity in primary fibroblasts. Finally, we show that transport activity is directly correlated to the ratio of wild-type to mutant alleles in fibroblasts from affected individuals.

Grounded in poststructuralist understandings of language and identity and Davies and Harré’s (1990) positioning theory, this paper explores one South Korean student’s educational experiences in her English as a Second Language (ESL) classroom, specifically related to subject positions and identity construction pertaining to language. Using a researcher diary, semi-structured interviews, and dialogue journals with one Korean university student, this paper reports findings from a qualitative study. The findings suggest a critical awareness of the effects of positioning on language learning experiences. The results indicate that although a student may exercise agency to take up or resist subject positions, this positioning is part of a greater discourse, generally outside the control of the student that constructs identity through particular social experiences. The results of this study will be of interest to researchers in the areas of language identity, second language learning, and higher education in the 21st century. Keywords: power; positioning; subject positions; identity; English language; discourse; international students

Due to small numbers of reported patients with pathogenic variants in single genes, the phenotypic spectrum associated with genes causing neurodevelopmental disorders such as intellectual disability (ID) and autism spectrum disorder is expanding. Among these genes is KLF7 (Kruppel-like factor 7), which is located at 2q33.3 and has been implicated in several developmental processes. KLF7 has been proposed to be a candidate gene for the phenotype of autism features seen in patients with a 2q33.3q34 deletion. Herein, we report 4 unrelated individuals with de novo KLF7 missense variants who share similar clinical features of developmental delay/ID, hypotonia, feeding/swallowing issues, psychiatric features and neuromuscular symptoms, and add to the knowledge about the phenotypic spectrum associated with KLF7 haploinsufficiency.

A review of Language Learning, Gender and Desire—Japanese Women on the MoveTakahashi, K. (2013). Language Learning, Gender and Desire—Japanese Women on the Move. North York, ON: Multilingual Matters/Channel View Publications.

PROTOCOL SUMMARY Title: The DHA(docosahexaenoic acid) Oxford Learning and Behaviour (DOLAB) II Study. Type of Study: The study is a randomized, placebo controlled trial (RCT), double blind, fixed dose, parallel groups. Population: Four hundred children from academic year groups 3, 4 and 5 (who are generally aged 7 to 9 years) attending mainstream schools who are currently underperforming in reading (lowest quintile on nationally standardized achievement tests). Number of Sites: Up to two hundred schools from up to eight local authorities as required. Intervention: The active compound (DHA Omega-3), 600mg per day) and corn/soy placebo (matching in package, taste and appearance) will be administered in an oral supplement. Study Duration and process: The parents/guardians of children who are underperforming in reading (according to national tests or school records) will be invited to consent to their child participating in a short school-based session, involving brief assessments of reading and working memory, an optional pinprick blood sample, and behaviour ratings from their teachers and parents. Our previous study (DOLAB) indicated that we should anticipate that 1300 children will need to be screened at the Local Authority stage. Of those approximately half are likely to consent to participate in these brief assessments at school. Those children whose parents consent, and whose reading assessment scores place them in the lowest quintile (on a standardized reading test), will be invited to join the study provided they meet the other inclusion/exclusion criteria (n = 400). Baseline measures will be collected after which children will be randomly allocated to DHA Omega-3 or placebo conditions and followed up after 16 weeks. Recruitment will be carried out over two years. Research Questions: Primary: - Can supplementation with DHA Omega-3 improve child behaviour and learning in underperforming children in year groups 3, 4 and 5 (who are generally aged 7-9 years)? Outcomes assessed will include reading performance, working memory and ADHD-type symptoms (inattention, hyperactivity, impulsivity) as rated by parents. Secondary: - Can supplementation with DHA Omega-3 improve child ADHD-type symptoms (inattention, hyperactivity, impulsivity) as rated by teachers? - Do children’s levels of DHA Omega-3 or related fatty acids (assessed objectively via a pinprick blood sample) predict their learning or behaviour? - Are any observed changes in behaviour or cognitive performance associated with changes in blood fatty acid status?

HIV is frequently transmitted in the context of partners in a committed relationship, thus couples-focused HIV prevention interventions are a potentially promising modality for reducing infection. We conducted a systematic review of studies testing whether couples-focused behavioral prevention interventions reduce HIV transmission and risk behavior. We included studies using randomized controlled trial designs, quasi-randomized controlled trials, and nonrandomized controlled studies. We searched five electronic databases and screened 7,628 records. Six studies enrolling 1,084 index couples met inclusion criteria and were included in this review. Results across studies consistently indicated that couples-focused programs reduced unprotected sexual intercourse and increased condom use compared with control groups. However, studies were heterogeneous in population, type of intervention, comparison groups, and outcomes measures, and so meta-analysis to calculate pooled effects was inappropriate. Although couples-focused approaches to HIV prevention appear initially promising, additional research is necessary to build a stronger theoretical and methodological basis for couples-focused HIV prevention, and future interventions must pay closer attention to same-sex couples, adolescents, and young people in relationships.