POU3F3, also referred to as Brain-1, is a well-known transcription factor involved in the development of the central nervous system, but it has not previously been associated with a neurodevelopmental disorder. Here, we report the identification of 19 individuals with heterozygous POU3F3 disruptions, most of which are de novo variants. All individuals had developmental delays and/or intellectual disability and impairments in speech and language skills. Thirteen individuals had characteristic low-set, prominent, and/or cupped ears. Brain abnormalities were observed in seven of eleven MRI reports. POU3F3 is an intronless gene, insensitive to nonsense-mediated decay, and 13 individuals carried protein-truncating variants. All truncating variants that we tested in cellular models led to aberrant subcellular localization of the encoded protein. Luciferase assays demonstrated negative effects of these alleles on transcriptional activation of a reporter with a FOXP2-derived binding motif. In addition to the loss-of-function variants, five individuals had missense variants that clustered at specific positions within the functional domains, and one small in-frame deletion was identified. Two missense variants showed reduced transactivation capacity in our assays, whereas one variant displayed gain-of-function effects, suggesting a distinct pathophysiological mechanism. In bioluminescence resonance energy transfer (BRET) interaction assays, all the truncated POU3F3 versions that we tested had significantly impaired dimerization capacities, whereas all missense variants showed unaffected dimerization with wild-type POU3F3. Taken together, our identification and functional cell-based analyses of pathogenic variants in POU3F3, coupled with a clinical characterization, implicate disruptions of this gene in a characteristic neurodevelopmental disorder.
Mathematics is not a race-neutral subject. Access and opportunity in mathematics for students of color in the United States continue to be limited. While a great deal of attention has been given to increasing the number of underrepresented minority students in the mathematics pipeline, there is little consideration of who they are as learners or the context in which their mathematics learning takes place. We argue that culturally relevant instruction coupled with teaching for social justice can motivate marginalized students to learn mathematics. Throughout this conceptual article, we (a) explore the theoretical frameworks underlying culturally relevant pedagogy (CRP) and social justice pedagogy (SJP), (b) present illustrative cases of mathematics teaching that reveal the possibilities and challenges associated with these pedagogical approaches, and (c) offer to the field of teacher education recommendations related to the successful use of CRP and SJP within today's classrooms.
Dormancy is a common strategy adopted by bacterial cells as a means of surviving adverse environmental conditions. For Streptomyces bacteria, this involves developing chains of dormant exospores that extend away from the colony surface. Both spore formation and subsequent spore germination are tightly controlled processes, and while significant progress has been made in understanding the underlying regulatory and enzymatic bases for these, there are still significant gaps in our understanding. One class of proteins with a potential role in spore-associated processes are the so-called resuscitation-promoting factors, or Rpfs, which in other actinobacteria are needed to restore active growth to dormant cell populations. The model species Streptomyces coelicolor encodes five Rpf proteins (RpfA to RfpE), and here we show that these proteins have overlapping functions during growth. Collectively, the S. coelicolor Rpfs promote spore germination and are critical for growth under nutrient-limiting conditions. Previous studies have revealed structural similarities between the Rpf domain and lysozyme, and our in vitro biochemical assays revealed various levels of peptidoglycan cleavage capabilities for each of these five Streptomyces enzymes. Peptidoglycan remodeling by enzymes such as these must be stringently governed so as to retain the structural integrity of the cell wall. Our results suggest that one of the Rpfs, RpfB, is subject to a unique mode of enzymatic autoregulation, mediated by a domain of previously unknown function (DUF348) located within the N terminus of the protein; removal of this domain led to significantly enhanced peptidoglycan cleavage. Streptomyces species are Gram-positive bacteria that abound in soil environments. They are renowned for their secondary metabolic capabilities; they produce a multitude of compounds that have found utility in both medicine and agriculture, including a vast array of antibiotics, chemotherapeutics, immunosuppressants, and antiparasitic agents (1). They are also well known for their complex, multicellular developmental cycle (2). The Streptomyces life cycle can be broadly divided into two stages: vegetative growth and reproductive development. Unlike most bacteria, Streptomyces organisms are filamentous, and during the vegetative phase of their life cycle, they grow by hyphal tip extension and branching, ultimately forming an interwoven network of cells known as the vegetative mycelium (3). Under certain as yet poorly defined stress conditions, vegetative growth ceases, and reproductive growth ensues. Here, unbranched filamentous cells, termed aerial hyphae, grow away from the vegetative mycelium and extend into the air. These cells then undergo a synchronous round of chromosome segregation, cell division, and cell wall modification to yield chains of dormant exospores (4). These spores are resistant to a wide variety of environmental insults and can be widely dispersed.A dormant cell state is not unique to the streptomycetes, and indeed many well-studied bacteria (e...
The purpose of this study was to examine the relationship between mathematics content knowledge and teacher efficacy during an elementary mathematics methods course. A positive moderate relationship between content knowledge and personal teaching efficacy was found, and this relationship was stable during the course. No relationship was found between content knowledge and outcome expectancy. Written artifacts were used to understand and elaborate on these findings. Those data suggest that prior learning experiences may help explain this relationship. Additionally, they suggest that preservice teachers with different levels of content knowledge may attend to different sources of information when making efficacy judgments about teaching.
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