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Adenosine deaminase acting on RNA1 (ADAR1) preserves genomic integrity by preventing retroviral integration and retrotransposition during stress responses. However, inflammatory-microenvironment-induced ADAR1p110 to p150 splice isoform switching drives cancer stem cell (CSC) generation and therapeutic resistance in 20 malignancies. Previously, predicting and preventing ADAR1p150-mediated malignant RNA editing represented a significant challenge. Thus, we developed lentiviral ADAR1 and splicing reporters for non-invasive detection of splicing-mediated ADAR1 adenosine-to-inosine (A-to-I) RNA editing activation; a quantitative ADAR1p150 intracellular flow cytometric assay; a selective small-molecule inhibitor of splicing-mediated ADAR1 activation, Rebecsinib, which inhibits leukemia stem cell (LSC) self-renewal and prolongs humanized LSC mouse model survival at doses that spare normal hematopoietic stem and progenitor cells (HSPCs); and pre-IND studies showing favorable Rebecsinib toxicokinetic and pharmacodynamic (TK/PD) properties. Together, these results lay the foundation for developing Rebecsinib as a clinical ADAR1p150 antagonist aimed at obviating malignant microenvironment-driven LSC generation.

Pediatric acute myeloid leukemia (pAML) is typified by high relapse rates and a relative paucity of somatic DNA mutations. Although seminal studies show that splicing factor mutations and mis-splicing fuel therapy-resistant leukemia stem cell (LSC) generation in adults, splicing deregulation has not been extensively studied in pAML. Herein, we describe single-cell proteogenomics analyses, transcriptome-wide analyses of FACS-purified hematopoietic stem and progenitor cells followed by differential splicing analyses, dual-fluorescence lentiviral splicing reporter assays, and the potential of a selective splicing modulator, Rebecsinib, in pAML. Using these methods, we discover transcriptomic splicing deregulation typified by differential exon usage. In addition, we discover downregulation of splicing regulator RBFOX2 and CD47 splice isoform upregulation. Importantly, splicing deregulation in pAML induces a therapeutic vulnerability to Rebecsinib in survival, self-renewal, and lentiviral splicing reporter assays. Taken together, the detection and targeting of splicing deregulation represent a potentially clinically tractable strategy for pAML therapy.

Replication studies in special education are necessary to strengthen the foundation upon which instruction and intervention for students with disabilities are built. J. Jenkins et al. (2017) found intermittent reading fluency progress monitoring schedules did not delay decision-making and were similar in decision-making accuracy to the traditional weekly progress monitoring schedule. Results of the current pilot study, although underpowered, conceptually replicated the original claims and extended their work by investigating their questions in the area of mathematics computation. Implications for research and practice are shared.

Intervention dosage is an often-overlooked aspect of implementation fidelity. Tracking intervention dosage is critical for ensuring students with disabilities were present for and received the intervention for as many minutes as intended. Used in tandem with student performance data, intervention dosage can provide a clearer picture of intervention success. This article presents strategies for how teachers can plan for, collect, and use intervention dosage data to inform instructional data-based decision making.

Background/Context: Most students with disabilities receive the majority of their instruction in general education classrooms. Yet, general education teachers persistently describe feeling unprepared to academically support students with disabilities in those spaces. Because disabled students are typically excluded from mathematics education research, and because special education researchers typically describe mathematics teaching and learning in ways that are incongruent with ambitious mathematics instruction, there is arguably a lack of guidance for these teachers. In the absence of clear guidance, teachers may turn to the well-established mathematical ability hierarchy, which positions disabled students (among others) as less capable. Purpose/Objective/Research Question/Focus of Study: The purpose of this study was to uncover teachers' talk about the mathematical capabilities of students with (and without) disabilities. Existing coding schemes (perhaps inadvertently) treat teachers' views as uniform across students despite evidence that teachers hold different views of different students, in part because of the multiple and varied identities that students bring to the classroom. By using an adapted interview protocol, which yielded more (and more nuanced) analytic categories, I foregrounded students' disability status as a factor that could relate to differences in teachers' conceptions of who they view as mathematically capable. Research Design: I interviewed general education mathematics teachers (N = 20) about their students (n = 407) using an adapted version of Jackson et al.'s (2017) semi-structured protocol that focused on uncovering teachers' usages of diagnostic and prognostic frames. I used open and concept coding to develop an expanded version of Jackson et al.'s coding scheme and then applied the new coding framework to the entire data set. I used student demographic data to compare within-group percentages, noticing to what degree students with disabilities were represented within particular qualitative categories in relation to their representation within the entire data set. I also used transformed data to estimate two multinomial logistic regressions: one that used diagnostic frames as the outcome variable, and one that used prognostic frames as the outcome variable. Both models used students' disability status and teacher dummy codes as predictor variables. Conclusions/Recommendations: The majority of teachers in this sample explained mathematical struggle in "unproductive" terms and said they would aim instructional adjustment at "unproductive" outcomes for students with and without disabilities. However, students with disabilities were overrepresented in unproductive categories and underrepresented in productive categories in relation to both diagnostic and prognostic frames. Regression analyses indicated that a student was statistically less likely to get a productive diagnostic or prognostic frame if they had a disability label. Findings from this study highlight the necessity of including teachers' views of their students' mathematical capabilities in instructional improvement efforts. Second, they indicate that student-level factors, such as disability status, relate to qualitatively and quantitatively meaningful differences in teachers' views of their students, suggesting the importance of attending to broader narratives around constructs that may be associated with teachers' views, and the subsequent enactment of those views, in mathematics instruction.

We present BVRI and unfiltered (Clear) light curves of 70 stripped-envelope supernovae (SESNe), observed between 2003 and 2020, from the Lick Observatory Supernova Search follow-up program. Our SESN sample consists of 19 spectroscopically normal SNe Ib, 2 peculiar SNe Ib, six SNe Ibn, 14 normal SNe Ic, 1 peculiar SN Ic, 10 SNe Ic-BL, 15 SNe IIb, 1 ambiguous SN IIb/Ib/c, and 2 superluminous SNe. Our follow-up photometry has (on a per-SN basis) a mean coverage of 81 photometric points (median of 58 points) and a mean cadence of 3.6 d (median of 1.2 d). From our full sample, a subset of 38 SNe have pre-maximum coverage in at least one passband, allowing for the peak brightness of each SN in this subset to be quantitatively determined. We describe our data collection and processing techniques, with emphasis toward our automated photometry pipeline, from which we derive publicly available data products to enable and encourage further study by the community. Using these data products, we derive host-galaxy extinction values through the empirical colour evolution relationship and, for the first time, produce accurate rise-time measurements for a large sample of SESNe in both optical and infrared passbands. By modelling multiband light curves, we find that SNe Ic tend to have lower ejecta masses and lower ejecta velocities than SNe Ib and IIb, but higher 56Ni masses.

Many students who experience difficulty with mathematics may also require behavioral support. We suggest educators create an appropriate scope and sequence for mathematics intervention by focusing on the critical mathematics content. Educators can then design the intervention with a common session structure. Finally, educators can embed and intensify supports for a student by increasing the dosage, focusing on the alignment of the intervention, and attending to transfer.

General education preservice teachers' (PSTs') views about inclusion have been well documented, yet PSTs' views about the nature of disability, which are less understood, could reveal limitations of an inclusion-only focus. We investigated general education PSTs' (N = 59) views of disability and inclusion at the beginning and end of a one-semester introductory course about special education. Using multiple modes of measurement, quantitative and qualitative data revealed that despite changing their definitions of disability and increasing their pro-inclusion stance, PSTs retained the use of deficit language, which complicates our interpretation of their views. Implications for teacher preparation include a necessary attention to both inclusion and disability.

In this systematic review, we explored mathematics interventions for middle school (Grades 6, 7, and 8) implemented with students who experienced difficulty in the area of mathematics, including students with an identified learning disability in mathematics. A total of 72 single-subject and group comparison studies met inclusion criteria, with 59 studies demonstrating positive effects on student-level mathematics outcomes. The majority of mathematics interventions focused on foundational, prealgebraic skills (e.g., operations and problem solving) related to algebraic reasoning. To understand the landscape of effective mathematics interventions and inform instruction within mathematics intervention, we identified six instructional components used with regularity within the effective studies. These components included explicit instruction, multiple representations, problem-solving instruction, mathematical language, mnemonics, and graphic organizers.

We present BVRI and unfiltered light curves of 93 Type Ia supernovae (SNe Ia) from the Lick Observatory Supernova Search (LOSS) follow-up program conducted between 2005 and 2018. Our sample consists of 78 spectroscopically normal SNe Ia, with the remainder divided between distinct subclasses (3 SN 1991bg-like, 3 SN 1991T-like, 4 SNe Iax, 2 peculiar, and 3 super-Chandrasekhar events), and has a median redshift of 0.0192. The SNe in our sample have a median coverage of 16 photometric epochs at a cadence of 5.4 d, and the median first observed epoch is ∼4.6 d before maximum B-band light. We describe how the SNe in our sample are discovered, observed, and processed, and we compare the results from our newly developed automated photometry pipeline to those from the previous processing pipeline used by LOSS. After investigating potential biases, we derive a final systematic uncertainty of 0.03 mag in BVRI for our data set. We perform an analysis of our light curves with particular focus on using template fitting to measure the parameters that are useful in standardizing SNe Ia as distance indicators. All of the data are available to the community, and we encourage future studies to incorporate our light curves in their analyses.

The University of Wyoming recently implemented a Learning Assistant (LA) program with the goal of supporting undergraduate students in traditionally lecture-based STEM courses. The authors performed a multi-method qualitative study utilizing a focus group and individual interviews in order to investigate the impact of the program's pilot year on the LAs. They found that the LAs report a greater understanding of and appreciation for content, the learning process, and instructors who implement an active learning curriculum. The authors provide recommendations for improving the support provided to the LAs.

This article is about a school-district-initiated partnership with university faculty and their effort to implement a mathematics multi-tiered system of support (MTSS). In addition to reporting research about MTSS implementation, we describe how this district translated research into practice. We also share the perceptions of key stakeholders about implementing mathematics MTSS in their district. We found that stakeholders identified time and human capacity as barriers to implementation, while the primary facilitator to implementation was identified as the acquisition of concrete strategies and tools supporting instruction. These stakeholder perceptions have implications for other districts with limited resources attempting to implement mathematics MTSS in their buildings through professional development and coaching.

This replication study examined the alternate form reliability, criterion validity, and predictive utility of two curriculum-based measurement (CBM) tools in science, Vocabulary-Matching (VM) and Statement Verification for Science (SV-S), for the purpose of screening. In all, 205 seventh-grade students from four middle schools were given alternate forms of each science CBM tool. Scores from the Idaho Standards Achievement Test (ISAT) science assessment were obtained. Stronger evidence of reliability and validity with the ISAT was found for VM compared with SV-S. With regard to predictive utility, VM more accurately classified students' at-risk status compared with SV-S for identifying proficiency on the ISAT. Practical implications and directions for future research are also discussed.

Post-transcriptional adenosine-to-inosine RNA editing mediated by adenosine deaminase acting on RNA1 (ADAR1) promotes cancer progression and therapeutic resistance. However, ADAR1 editase-dependent mechanisms governing leukemia stem cell (LSC) generation have not been elucidated. In blast crisis chronic myeloid leukemia (BC CML), we show that increased JAK2 signaling and BCR-ABL1 amplification activate ADAR1. In a humanized BC CML mouse model, combined JAK2 and BCR-ABL1 inhibition prevents LSC self-renewal commensurate with ADAR1 downregulation. Lentiviral ADAR1 wild-type, but not an editing-defective ADAR1(E912A) mutant, induces self-renewal gene expression and impairs biogenesis of stem cell regulatory let-7 microRNAs. Combined RNA sequencing, qRT-PCR, CLIP-ADAR1, and pri-let-7 mutagenesis data suggest that ADAR1 promotes LSC generation via let-7 pri-microRNA editing and LIN28B upregulation. A small-molecule tool compound antagonizes ADAR1's effect on LSC self-renewal in stromal co-cultures and restores let-7 biogenesis. Thus, ADAR1 activation represents a unique therapeutic vulnerability in LSCs with active JAK2 signaling.

Formative research suggests that a human embryonic stem cell-specific alternative splicing gene regulatory network, which is repressed by Muscleblind-like (MBNL) RNA binding proteins, is involved in cell reprogramming. In this study, RNA sequencing, splice isoform-specific quantitative RT-PCR, lentiviral transduction, and in vivo humanized mouse model studies demonstrated that malignant reprogramming of progenitors into self-renewing blast crisis chronic myeloid leukemia stem cells (BC LSCs) was partially driven by decreased MBNL3. Lentiviral knockdown of MBNL3 resulted in reversion to an embryonic alternative splice isoform program typified by overexpression of CD44 transcript variant 3, containing variant exons 8-10, and BC LSC proliferation. Although isoform-specific lentiviral CD44v3 overexpression enhanced chronic phase chronic myeloid leukemia (CML) progenitor replating capacity, lentiviral shRNA knockdown abrogated these effects. Combined treatment with a humanized pan-CD44 monoclonal antibody and a breakpoint cluster region - ABL proto-oncogene 1, nonreceptor tyrosine kinase (BCR-ABL1) antagonist inhibited LSC maintenance in a niche-dependent manner. In summary, MBNL3 down-regulation-related reversion to an embryonic alternative splicing program, typified by CD44v3 overexpression, represents a previously unidentified mechanism governing malignant progenitor reprogramming in malignant microenvironments and provides a pivotal opportunity for selective BC LSC detection and therapeutic elimination.

Background: Posterior nasal fricatives are a learned compensatory articulation error and commonly substituted for oral fricatives. Treatment of such articulation errors requires the modification or teaching of skilled movements. A motor-based approach is designed to teach the complex motor skill movement sequences required in the production of sounds. Although motor learning research is well established, little has been done to determine how the approach changes the underlying physiology of articulatory movements. While the underlying anatomical configuration of the posterior nasal fricative has been described, no studies have quantified anatomic and physiological changes pre- and post-treatment. Aims: To use magnetic resonance imaging (MRI) to visualize and quantify the results of motor-based speech-intervention approach on articulatory placement for the treatment of the posterior nasal fricative. Methods & Procedures: A 6-year-old male with a history of ear infections and posterior nasal fricative substitution for /s/ underwent six 1-h sessions of a motor-based treatment approach over the course of 2 weeks. Pre- and post-treatment evaluation included perceptual and instrumental assessment of speech and resonance. Perceptual resonance was rated by two speech-language therapists and articulation was assessed at the single-word level. Instrumental assessment included the See-Scape, Nasometer II and MRI during the sustained phonation of /s/. Amira v5.6 Visualization and Volume modelling software used the midsagittal and oblique coronal plane to measure dimensions of the articulatory anatomy. Outcomes & Results: Interrater reliability was assessed using a Pearson product moment correlation (a = 0.05) and ranged from r = 0.91 to 0.95. Intra-rater reliability was assessed using the intra-class correlation coefficient (0.976) demonstrating a high degree of reliability with a 95% confidence interval. Articulation improved from 0% accuracy for /s/ in isolation at baseline to 100% for /s/ at the word level and 95% accuracy during conversational speech by session 6. Post-treatment results from this study revealed a greater shortening of the levator veli palatini (levator) muscle length during articulatory movements, more pronounced velar knee and dimple, decreased velar thickness, increased velar length and altered tongue position. Conclusions & Implications: This study demonstrated the use of pre- and post-treatment imaging methodology to quantify articulatory changes following an intensive motor-based treatment approach. MRI demonstrated quantifiable changes in articulatory placement. Individuals who exhibit non-developmental and phoneme-specific articulation errors, such as the posterior nasal fricative, may be excellent candidates for short-term, intensive and frequent speech therapy sessions to remediate the production of the posterior nasal fricative.

Background: Many pathways are implicated in pathogenesis of Alzheimer's disease (AD). Stem cells are a promising strategy to simultaneously correct multiple pathways; however, therapeutic mechanisms of stem cells are not well described. Here, we used spatial transcriptomics to quantitate gene expression following intracranial transplantation of human neural stem cells (hNSCs) in a mouse model of AD. Method: The 5XFAD mouse model was utilized. An hNSC cell line (HK532‐IGF1, Palisade Bio) was transplanted into fimbria fornix of the hippocampus (6 total injections, 180,000‐600,000 total cells). Spatial memory was assessed by Morris water maze. Amyloid plaques were assessed by immunofluorescence and ELISA. Hemibrains were submitted for spatial transcriptomics (Visium 10X, 10X Genomics) and significant differentially expressed genes (DEGs) were identified (p < 0.05). Pathway enrichment was performed using the Kyoto Encyclopedia of Genes and Genomes (KEGG), and CellChat network analysis examined communication between cell populations. Result: hNSC transplantation restored learning curves of 5XFAD mice in Morris water maze, mimicking wild‐type performance (Fig 1A). However, there were no changes in amyloid‐beta burden (Fig 1B‐C). Spatial transcriptomics elucidated non‐amyloid hNSC therapeutic mechanisms. In hippocampal subregions, we discovered 1061 normalized DEGs. KEGG pathway analysis revealed significant impact on protein processing ("ubiquitin mediated proteolysis", "protein export", and "proteosome"), "long‐term potentiation," and "metabolic pathways" (Fig 2). Plaque induced genes were normalized upon hNSC transplantation, particularly in microglia (Fig 3A). A reduction in stage 1 and stage 2 disease associated microglia (DAM) was seen, without affecting homeostatic microglia (Fig 3B). CellChat analysis showed hNSCs interacted with stage 1 and stage 2 DAM along many pathways (Fig 3C). Pathologic signaling between hippocampus and DAM upregulated in the 5XFAD model was again normalized upon hNSC transplantation. Conclusion: Transplantation of hNSCs rescued memory in 5XFAD mice. No change in amyloid plaque burden was noted, but spatial transcriptomics revealed many genes dysregulated in 5XFAD that were normalized with hNSC transplantation. hNSCs interacted with and normalized populations of stage 1 and stage 2 DAM. Our results suggest that hNSCs exert beneficial effects in part by modulating microglia‐mediated neuroinflammation in AD. [ABSTRACT FROM AUTHOR]

The article presents the clinical trial of resin bonded retainers. It is stated that there have been many improvements in resin bonded retainers since they were developed. As stated, the clinical and radiographic study requires careful examination and needs a framework design which must include abutment coverage which may help creating a correct path for insertion. It was observed that resin bonded retainers are a conservative form of prosthesis and cause no harm to the periodontal apparatus. The success or failure of this technique depends on the dentist's manual dexterity and experience.