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I am an example of a transformed higher education administrator. In this essay, I describe how my journey to an education doctorate impacts my work as a scholar-practitioner in higher education. The CANDEL program challenged what I thought I understood about the status quo in higher education with respect to race, socioeconomic impacts, meritocracy, grit, and assumptions we make about students. The coursework and cohort model confronted my own biases and were foundational to my dissertation questions. Conducting my research on university leadership at my home institution gave me an opportunity to develop a shared equity leadership approach to solving complex problems. Equity-focused work in higher education is a long-game, ongoing, and essential to addressing the challenges facing our institutions. Without this, inequities experienced by faculty, staff and students will persist. The education doctorate and its scholar-practitioners are important drivers in shifting the American educational landscape.

The American Occupational Therapy Association's Fieldwork Performance Evaluation plays a vital role in occupational therapy education by guiding students and fieldwork educators in determining students' entry-level competence. This evaluation tool dates to 1953 and has undergone numerous revisions as the profession evolved and changes were made to the practice framework. Revisions have included changes to the stated purpose of the evaluation tool, items to be scored, scoring scale, and number of items on the tool. The purpose of this study was to survey Academic Fieldwork Coordinators (AFWCs) to examine their perceptions of the 2020 revision of the evaluation. We surveyed 68 AFWCs in occupational therapy and occupational therapy assistant programs. The majority had positive perceptions of the changes to the tool. The American Occupational Therapy Association, academic programs, and fieldwork sites should consider the findings of this study to help ensure effective and accurate evaluation of future students.

Videoconferencing was heavily utilized as an online learning tool at universities during the COVID-19 pandemic. Despite the high utilization, few studies have examined students' perspectives on their health, social interaction, and preferences in using specific videoconferencing features for online pedagogy and campus participation. This study surveyed 275 occupational therapy students from six class cohorts regarding the use of videoconferencing during the 2020-2021 academic year. Students reported physical changes in fatigue, eye, and back discomfort from the use of videoconferencing for extended periods, in addition to increased stress and anxiety during this period. Students reported lower class engagement during videoconferencing, as indicated by less frequency of asking/answering questions, paying attention, participating in breakout rooms with unfamiliar peers, and less motivation to attend classes. While students preferred in-person versus videoconferencing for overall classroom engagement and knowledge retention, preferences were equivocal for use of videoconferencing in meeting with professors, peer tutoring, group projects, and office hours. A benefit to videoconferencing availability was the ability to maintain social communication with friends and family, particularly for undergraduates. Comparisons among class cohorts are presented.

This article highlights how Tribal college leadership, faculty, and staff members define student success. Several major factors were described across the different levels of participants and are presented as the major themes: cultivating a familial environment, mission centered, cultural knowledge and wealth, community impact, and student goals achieved.

Since its first notable appearance in the "Second Handbook of Research on Mathematics Teaching and Learning," the phrase productive struggle has garnered support from a few, yet very influential, educational researchers. However, since the phrase was popularized by Hiroko Warshauer in 2011, examinations of the productive struggle have grown substantially within mathematics education. In this article, we present a systematic review of the literature on the productive struggle to quantify the breadth and depth of existing work in the area. Our analysis indicates that many studies: (1) provide a direct implementation of the productive struggle; (2) primarily involve teachers and not students; (3) present primarily qualitative or non-empirical research approaches; and (4) specify the NCTM content area focus less often across studies. Thus, we conclude that there are opportunities for rigorous research designs reporting on observable trends in the implementation of the productive struggle, explicitly targeting underexamined NCTM content and process standards, and focusing on how the productive struggle can support equity in mathematics. We believe that these opportunities should be investigated to provide a broader evidence base for developing meaningful experiences in mathematics for school-aged children that capitalize on the interconnectedness of attribution, meta-cognition, and controlled frustration in mathematics learning.

Foundational principles of formal math language in mathematics classrooms are necessary for students' ability to succeed academically. However, cultural dialects such as Black language are vilified within the scope of education, particularly in mathematics education, despite evidence that acknowledging students' cultural and linguistic backgrounds aids in their understanding of mathematical concepts. In a sociopolitical context that does not support the use of culture as it relates to race and gender, educators face even more challenges in pursuit of linguistic and cultural justice. We provide commentary on Black students' language use to facilitate critical conversations regarding mathematics teaching, learning, and culture and its implications for Black students. To this end, we provide recommendations for stakeholders in mathematics education that can provide a starting point to make mathematics education a more welcoming discipline.

Concurrent genital-anal human papillomavirus (HPV) infections may impose an increased anal cancer risk in women with HPV-related genital lesions. High viral load may facilitate genital-anal HPV concurrence. Genital and anal HPV is reduced by a bivalent HPV16/18 vaccine, yet the effect on concurrent genital-anal HPV remains unclear.This study analyzed viral load in concurrent genital-anal HPV infections, relative to genital-only and anal-only HPV infections and the impact of vaccination in young women. We included 1074 women, who provided both genital and anal swabs. HPV detection and genotyping was performed using the SPF10-DEIA-LiPA25. HPV copy numbers were measured with type-specific qPCRs and corrected for cellular content to obtain the viral load.Concurrent genital-anal HPV often had significantly higher genital viral load (0.09–371 c/cell) than genital-only HPV (3.17E-04-15.9 c/cell, p

While the disproportional application of school discipline has garnered notable attention, the relationship between trauma or adversity and school discipline is under examined. The purpose of the current scoping review was to map the state of the literature, empirical and theoretical, at the intersection of school discipline, and trauma or adversity. The findings identified a gap in our knowledge as only 14 of the 49 included articles detailed empirical studies focused on the relationship between adversity and school discipline, with very few from outside of the United States. However, this burgeoning body of knowledge points to a significant relationship between trauma/adversity and experiencing school discipline that warrants further study and contextualizes expanded adversities, including poverty and racism as adversity. We believe this is necessary to acknowledging the hidden and unaddressed trauma among students being disproportionally disciplined, leading to a greater understanding of student lives, and evidence-based, trauma-informed, and culturally attuned discipline.

The objective of this constructivist grounded theory study was to understand the experiences of students who have been disciplinarily excluded from school. Fifteen students (male, n = 11; Black, n = 10; having special education needs, n = 9) and 16 multidisciplinary staff in Ontario participated. Students experienced high rates of expanded adversities, including school and community violence, systemic racism and inequity. The importance of connection wove throughout the data; however, three themes were found to block connection: unacknowledged impact of adversity, a climate of fear, and the disproportionate impact of limited resources. Trauma-informed culturally attuned approaches that focus on the disproportionate impact of adversity and school discipline at the point of a disciplinary response, and throughout a student's educational experience, are essential.

Attention-deficit/hyperactivity disorder (ADHD) symptoms affect 40-60% of autistic children and have been linked to differences in adaptive behavior. It is unclear whether adaptive behavior in autistic youth is directly impacted by co-occurring ADHD symptoms or by another associated feature of both autism and ADHD, such as increased irritability. The current study examined relationships between irritability, ADHD symptoms, and adaptive behavior in 3- to 7-year-old autistic children. Results suggest that, after adjusting for co-occurring ADHD symptoms, higher levels of irritability are associated with differences in social adaptive behavior specifically. Understanding relationships between irritability, ADHD, and adaptive behavior in autistic children is critical because measures of adaptive behavior, such as the Vineland Scales of Adaptive Functioning, are often used as a proxy for global functioning, as well as for developing intervention plans and measuring outcomes as primary endpoints in clinical trials.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder (NDD) that affects approximately 4% of males and 1% of females in the United States. While causes of ASD are multi-factorial, single rare genetic variants contribute to around 20% of cases. Here, we report a case series of seven unrelated probands (6 males, 1 female) with ASD or another variable NDD phenotype attributed to de novo heterozygous loss of function or missense variants in the gene LARP1 (La ribonucleoprotein 1). LARP1 encodes an RNA-binding protein that post-transcriptionally regulates the stability and translation of thousands of mRNAs, including those regulating cellular metabolism and metabolic plasticity. Using lymphocytes collected and immortalized from an index proband who carries a truncating variant in one allele of LARP1, we demonstrated that lower cellular levels of LARP1 protein cause reduced rates of aerobic respiration and glycolysis. As expression of LARP1 increases during neurodevelopment, with higher levels in neurons and astrocytes, we propose that LARP1 haploinsufficiency contributes to ASD or related NDDs through attenuated metabolic activity in the developing fetal brain.

There is evidence that transcription factor (TF) encoding genes, which temporally control development in multiple cell types, can have tens of enhancers that regulate their expression. The NR2F1 TF developmentally promotes caudal and ventral cortical regional fates. Here, we epigenomically compared the activity of Nr2f1's enhancers during mouse cortical development with their activity in a transgenic assay. We identified at least six that are likely to be important in prenatal cortical development, with three harboring de novo mutants identified in ASD individuals. We chose to study the function of two of the most robust enhancers by deleting them singly or together. We found that they have distinct and overlapping functions in driving Nr2f1's regional and laminar expression in the developing cortex. Thus, these two enhancers, probably in combination with the others that we defined epigenetically, precisely tune Nr2f1's regional, cell type, and temporal expression during corticogenesis.

High-quality partnerships between families and schools can bring enormous benefits to the development, learning, and wellbeing of children. Decades of research has identified parenting self-efficacy as a key factor influencing parents' contributions toward effective home-school partnerships. However, the strength of this association has varied significantly across studies with the aggregated strength remaining unclear. This meta-analysis aimed to investigate the associations between parenting self-efficacy and various aspects of parents' contribution to the home-school partnership, namely home-based involvement, school-based involvement, home-school communication and relationships, as well as parental expectations and aspirations among parents of primary school students. Moderator effects were also examined. Through systematically searching six databases and screening papers, we included 50 independent studies involving 185 effect sizes (N = 20,043 children). Results showed a small to medium correlation between parenting self-efficacy and the multidimensional construct of home-school partnership outcomes (r = 0.189). The associations were stronger for education-focused parenting self-efficacy (r = 0.183) than general parenting self-efficacy (r = 0.114) and were stronger still for home-based participation (r = 0.248) and parental expectations and aspirations (r = 0.248) than school-based participation (r = 0.124) and parent-teacher communication/relationship (r = 0.090). We detected limited moderating effects of child gender, parent gender, ethnicity, sample type (general or targeted), and socio-economic status and publication bias. Overall, this meta-analysis provides evidence to support the positive relationship between parenting self-efficacy and parents' contributions to the strength of the home-school partnership. Implications and suggestions for future research are discussed.

Mobile health (mHealth) screening tools for autism are gaining in prevalence, and have benefits such as video content and direct resources linkage. However, it is unclear whether such tools will ameliorate autism inequities or will help only those already advantaged in autism care. To investigate this issue, we conducted semi-structured qualitative interviews with 18 primary care and Early Intervention/Early Childhood Special Education providers in six US states. Providers were given hypothetical scenarios in which a family presents to care with results from one of 9 mHealth autism screening tools. Providers discussed their clinical approach and assessed the tool's fit with their patient/client population. Each transcript was audio-recorded, transcribed, and coded; a phenomenological approach was used to develop key themes. 4 themes and 18 subthemes emerged. These included "Clinical and business factors" (e.g. scope of practice concerns and clinical efficiency), "Validity and trustworthiness" (e.g. familiarity, data privacy/security), "Family interaction quality" (e.g. supporting family advocacy, provision of information, affecting family anxiety, and emotional support), and "Accessibility" (e.g. English proficiency/language issues, cultural inclusivity, and literacy/educational level). Providers suggested modifications to enhance equity, such as portraying diverse families, reducing the reading level of text, and making tools shorter to better fit clinical context.

Hyper-realistic silicone masks provide a viable route to identity fraud. Over the last decade, more than 40 known criminal acts have been committed by perpetrators using this type of disguise. With the increasing availability and bespoke sophistication of these masks, research must now focus on ways to enhance their detection. In this study, we investigate whether super-recognisers (SRs), people who excel at identity recognition, are more likely to detect this type of fraud, in comparison to typical-recogniser controls. Across three tasks, we examined mask detection rates in the absence of a pre-task prompt (covert task), and again after making participants aware of their use in criminal settings (explicit task). Finally, participants were asked to indicate which aspects of the masks could support their detection (regions of interest task). The findings show an SR advantage for the detection of hyper-realistic masks across the covert and explicit mask detection tasks. In addition, the eye, mouth, and nose regions appear to be particularly indicative of the presence of a mask. The lack of natural skin texture, proportional features, expressiveness, and asymmetry are also salient cues. The theoretical and applied implications of these findings are discussed.

Black girls are the only group of girls across the United States disproportionally suspended from school. Studies have documented that disproportionality cannot be explained solely by greater misbehavior among students of color. Instead, discipline disparities are also informed by punitive/inequitable discipline policies and practices, less discussed has been the relationship between childhood adversity and school discipline outcomes at the intersection of race and gender. Examining this phenomenon is important and timely as schools are increasingly providing trauma-informed practices to support socioemotional learning. Yet doing so without data-driven practices rooted in an understanding of disproportionate adversity may render these practices insufficient for Black girls. Thus, this study asks, what types of childhood adversities do Black girls have the greatest risk of experiencing? Using 2016-2019 data from the National Survey of Children's Health (N = 63,674), risk ratios and Pearson's chi-square test of independence were performed to determine across-race and within-gender group differences by the type of childhood adversity. Analyses demonstrated that Black girls had a greater risk for six out of nine adversities compared with other girls of color and seven out of nine compared with White girls.

Background: Telehealth utilization exploded during the COVID-19 pandemic, including within school-based health programs. School-based tele-behavioral health can help programs overcome barriers of access to care, but the current state and effectiveness of such programs are unknown. Methods: A scoping literature review was conducted. Studies were included if they described in-school behavioral health services delivered via telehealth for children ages 5 to 18. From the included studies, population, location, setting, intervention, telehealth modality, clinician type, and outcomes assessed were extracted. Findings: Eighteen studies met inclusion criteria. All described psychotherapy or medication management delivered by psychologists (n = 7) and/or psychiatrists (n = 11). Treatment included psychotherapy (N = 8), psychiatric consultation (N = 7), medication management (N = 4), crisis stabilization (N = 1), and caregiver education (N = 1). Eight studies provide qualitative or quantitative outcomes, with 4 examining clinical effectiveness. Conclusions: Despite limited findings in the literature, school-based tele-behavioral health is feasible, effective, and acceptable for delivery of behavioral health care to children and adolescents.

The purpose of this research is to analyse the support that lecturers need to be able to implement a blended learning approach successfully. Blended learning is now seen as an approach that can create engaging learning environments, to enhance students' self-directed learning and improve the whole learning experience. The study investigated the perceptions of thirteen lecturers, at a particular higher education institution, regarding the advantages and challenges of blended learning in South Africa. A qualitative research design was chosen for this study because it enabled the authors to explore the theme in detail. Semi-structured open-ended interviews were conducted to collect the necessary data from the lecturers, who were chosen through the use of homogenous purposeful sampling. The data collected were coded, using the induction method. This helped to reveal relevant codes, which were categorised. A literature review was conducted, in which recent research on this topic was analysed and used to correlate the findings of the field research of this study. This study reports on the actual views and experiences of the participants. The research findings and relevance for teaching in higher education institutions are discussed. The conclusion is that, for such an approach to be successful, lecturers would require support from management, more training, improved professional development, as well as reliable technology and internet connections. In addition, lecturers would require additional time to implement such an approach.

An observational cross-sectional study was carriedy out to investigate antibiotic residues in Clarias gariepinus and Oreochromis niloticus from the intensive rearing system in Southern Benin. The targeted antibiotic families were tetracyclins, amphenicols, beta-lactams and macrolides. One hundred and forty-four (144) samples were used per antibiotic family for residue detection in the fish muscle, making 576 treated samples. The Charm II method based on radioimmunoassay was used. The results showed an overall residue prevalence of 11.1%, which is attributable to tetracyclines alone. There was no residue of the other antibiotic families in the treated fish muscles. The adult fish were the only contaminated age group with 22.2% residue prevalence compared to the fingerlings (p < 0.05). Likewise, the antibiotic residues were significantly (p< 0.05) more prevalent in Clarias gariepinus (16.7%) than in Oreochromis niloticus (5.6%). The adult fishes are generally fattier than the young ones, and that can lower the fish body antibiotic elimination capability. This first detection of tetracyclines residues in fish produced in Benin shows the need to rule and control antibiotic use in the developing fish industry to preserve consumers’ health. Keywords: Tilapia, African catfish, fish farm, antibiotic residue, Benin

Urbanization and climate change are contributing to severe flooding globally, damaging infrastructure, disrupting economies, and undermining human well-being. Approaches to make cities more resilient to floods are emerging, notably with the design of flood-resilient structures, but relatively little is known about the role of urban form and its complexity in the concentration of flooding. We leverage statistical mechanics to reduce the complexity of urban flooding and develop a mean-flow theory that relates flood hazards to urban form characterized by the ground slope, urban porosity, and the Mermin order parameter which measures symmetry in building arrangements. The mean-flow theory presents a dimensionless flood depth that scales linearly with the urban porosity and the order parameter, with different scaling for disordered square- and hexagon-like forms. A universal scaling is obtained by introducing an effective mean chord length representative of the unobstructed downslope travel distance for flood water, yielding an analytical model for neighborhood-scale flood hazards globally. The proposed mean-flow theory is applied to probe city-to-city variations in flood hazards, and shows promising results linking recorded flood losses to urban form and observed rainfall extremes.

Although widely acknowledged as an important social determinant of health, until recently researchers and policymakers have primarily approached housing insecurity as an urban issue, obscuring the visibility of its impacts in rural contexts, including the ways in which housing insecurity intersects with other health and structural inequities facing rural populations. Working to address this gap in the existing literature, this paper explores the experiences of housing insecurity in a rural context by reporting on an analysis of 210 in-depth interviews with 153 adults between the ages of 18-35, living in California's rural North State, a relatively overlooked far northern region of the state comprised of 12 north central and north eastern counties. Using in-depth qualitative interview data, we conducted an exploratory pattern-level analysis of participants' narratives structured by four dimensions of housing insecurity defined in the literature (housing affordability, housing stability, housing conditions, and neighborhood context). Drawing attention to the pervasiveness of rural housing insecurity within our sample, this analysis highlights the unique ways in which rurality creates distinct experiences not currently captured in the existing literature. Further research is needed across different types of rural communities to better understand the various ways that housing insecurity affects the everyday lives and health of rural residents. By grounding research within the experiences of rural residents, we are better able to respond to the crisis of rural housing insecurity and develop solutions that are tailored to rural residents' unique needs.

Probiotics are typically marketed as foods and dietary supplements, categories for products intended to maintain health in generally healthy populations and which, unlike drugs, cannot claim to treat or cure disease. This review addresses the existing evidence that probiotics are beneficial to healthy people. Our approach was to perform a descriptive review of efficacy evidence that probiotics can prevent urinary, vaginal, gastrointestinal, and respiratory infections, and improve risk factors associated with cardiovascular health or reduce antibiotic use. Other endpoints such as mental, dental, or immune health were not specifically addressed. We concluded that there is sufficient evidence of efficacy and safety for clinicians and consumers to consider using specific probiotics for some indications - such as the use of probiotics to support gut function during antibiotic use or to reduce the risk of respiratory tract infections - for certain people. However, we did not find a sufficiently high level of evidence to support unconditional, population-wide recommendations for other preventive endpoints we reviewed for healthy people. Although evidence for some indications is suggestive of the preventive benefits of probiotics, additional research is needed.

Introduction: Metallic luster dusts are decorative agents for cakes and other confections. While some powders are labeled “non-edible,” they are also marketed as “non-toxic.” We present a case of a child who developed acute metal pneumonitis after accidental aspiration of metallic luster dust. Case Report: A four-year-old presented to the emergency department (ED) in respiratorydistress after attempting to ingest gold decorative metallic luster dust. In the ED she was placed on supplemental oxygen. Her initial chest radiograph (CXR) was unremarkable. Her condition worsened despite high-flow nasal cannula oxygen, and she was intubated. A repeat CXR revealed patchy perihilar and peribronchial opacities. While receiving aggressive ventilatory support, her CXR worsened over the next 48 hours as bilateral interstitial and alveolar opacities progressed, likely representing acute metal pneumonitis with acute respiratory distress syndrome (ARDS). She remained intubated until hospital day (HD) 5, requiring supplemental oxygen until HD 9. She was discharged home on HD 10. A CXR obtained four months later demonstrated increased interstitial markings throughout both lungs with overinflation and subsegmental atelectasis. The patient had persistent dyspnea upon exertion, with pulmonology documenting that her symptoms were likely sequelae from inhalation of the cake luster dust. Conclusion: Non-edible metallic cake dusts are toxic. “Non-edible” labeling does not convey the health risks associated with handling by children, as evidenced by this case of metal pneumonitis with associated ARDS and chronic pulmonary disease. Accordingly, this descriptor should be abandoned for these products, and physicians should be aware of this potential complication.

The purpose of this study was to assess the efficacy, specificity, and predictive value of a newly discovered biomarker, Zinc finger-like1 protein (referred to as neuroendocrine marker, NEM) for the detection of prostate cancer (PCa). We retrospectively analyzed banked plasma samples from 508 men, with a median age of 67 years (range 48-97), to compare the performance of NEM and PSA in predicting subsequent histologic PCa. The cohort consisted of four groups of patients visiting a urology clinic: (1) patients not diagnosed with either benign prostatic disease or prostate cancer (PCa) were defined as normal; (2) patients diagnosed with benign hyperplasia (BPH) but not PCa; (3) patients with confirmed PCa; and (4) patients with cancer other than PCa. The normal men displayed a mean NEM plasma level of 0.948 ± 0.051 ng/mL, which increased to 1.813 ± 0.315 ng/mL in men with BPH, 86.49 ± 15.51 ng/mL in men with PCa, and 10.47 ± 1.029 ng/mL in men with other Ca. The corresponding concentrations of prostate-specific antigen (PSA) in these subjects were 1.787 ± 0.135, 5.405 ± 0.699, 35.77 ± 11.48 ng/mL, and 8.036 ± 0.518, respectively. Receiver operating characteristic (ROC) curve analysis was performed to compare NEM and PSA performance, and the Jouden Index for each biomarker was calculated to determine cut-off points for each biomarker. The area under the ROC curve to predict PCa was 0.99 for NEM and 0.81 for PSA (p < 0.0001). The cut-off for NEM was at 1.9 ng/mL, with sensitivity of 98% and specificity of 97%. The corresponding PSA values were 4.4 ng/mL, with sensitivity of 76% and specificity of 95%. The predictive value of each biomarker in a patient was matched with his pathologic data to determine the accuracy of each biomarker. NEM was more accurate than PSA in differentiating cancer from benign conditions, such as BPH or prostatitis. In conclusion, NEM was a better predictor of PCa than PSA in patients visiting urology clinics. NEM tests, either alone or in conjunction with other biomarkers, provide a reliable, non-invasive, and inexpensive test to remarkably reduce false positives and thereby reduce the number of diagnostic biopsies and associated painful procedures and the loss of quality of life.

BACKGROUND: Sex-differential biology may contribute to the consistently male-biased prevalence of autism spectrum disorder (ASD). Gene expression differences between males and females in the brain can indicate possible molecular and cellular mechanisms involved, although transcriptomic sex differences during human prenatal cortical development have been incompletely characterized, primarily due to small sample sizes. METHODS: We performed a meta-analysis of sex-differential expression and co-expression network analysis in 2 independent bulk RNA sequencing datasets generated from cortex of 273 prenatal donors without known neuropsychiatric disorders. To assess the intersection between neurotypical sex differences and neuropsychiatric disorder biology, we tested for enrichment of ASD-associated risk genes and expression changes, neuropsychiatric disorder risk genes, and cell type markers within identified sex-differentially expressed genes (sex-DEGs) and sex-differential co-expression modules. RESULTS: We identified 101 significant sex-DEGs, including Y-chromosome genes, genes impacted by X-chromosome inactivation, and autosomal genes. Known ASD risk genes, implicated by either common or rare variants, did not preferentially overlap with sex-DEGs. We identified 1 male-specific co-expression module enriched for immune signaling that is unique to 1 input dataset. CONCLUSIONS: Sex-differential gene expression is limited in prenatal human cortex tissue, although meta-analysis of large datasets allows for the identification of sex-DEGs, including autosomal genes that encode proteins involved in neural development. Lack of sex-DEG overlap with ASD risk genes in the prenatal cortex suggests that sex-differential modulation of ASD symptoms may occur in other brain regions, at other developmental stages, or in specific cell types, or may involve mechanisms that act downstream from mutation-carrying genes.

Heterozygous variants in SLC6A1, encoding the GAT-1 GABA transporter, are associated with seizures, developmental delay, and autism. The majority of affected individuals carry missense variants, many of which are recurrent germline de novo mutations, raising the possibility of gain-of-function or dominant-negative effects. To understand the functional consequences, we performed an in vitro GABA uptake assay for 213 unique variants, including 24 control variants. De novo variants consistently resulted in a decrease in GABA uptake, in keeping with haploinsufficiency underlying all neurodevelopmental phenotypes. Where present, ClinVar pathogenicity reports correlated well with GABA uptake data; the functional data can inform future reports for the remaining 72% of unscored variants. Surface localization was assessed for 86 variants; two-thirds of loss-of-function missense variants prevented GAT-1 from being present on the membrane while GAT-1 was on the surface but with reduced activity for the remaining third. Surprisingly, recurrent de novo missense variants showed moderate loss-of-function effects that reduced GABA uptake with no evidence for dominant-negative or gain-of-function effects. Using linear regression across multiple missense severity scores to extrapolate the functional data to all potential SLC6A1 missense variants, we observe an abundance of GAT-1 residues that are sensitive to substitution. The extent of this missense vulnerability accounts for the clinically observed missense enrichment; overlap with hypermutable CpG sites accounts for the recurrent missense variants. Strategies to increase the expression of the wild-type SLC6A1 allele are likely to be beneficial across neurodevelopmental disorders, though the developmental stage and extent of required rescue remain unknown.

PURPOSE: Rexinoids, agonists of nuclear retinoid X receptor (RXR), have been used for the treatment of cancers and are well tolerated in both animals and humans. However, the usefulness of rexinoids in treatment of breast cancer remains unknown. This study examines the efficacy of IRX4204, a highly specific rexinoid, in breast cancer cell lines and preclinical models to identify a biomarker for response and potential mechanism of action. EXPERIMENTAL DESIGN: IRX4204 effects on breast cancer cell growth and viability were determined using cell lines, syngeneic mouse models, and primary patient-derived xenograft (PDX) tumors. In vitro assays of cell cycle, apoptosis, senescence, and lipid metabolism were used to uncover a potential mechanism of action. Standard anti-HER2 therapies were screened in combination with IRX4204 on a panel of breast cancer cell lines to determine drug synergy. RESULTS: IRX4204 significantly inhibits the growth of HER2-positive breast cancer cell lines, including trastuzumab and lapatinib-resistant JIMT-1 and HCC1954. Treatment with IRX4204 reduced tumor growth rate in the MMTV-ErbB2 mouse and HER2-positive PDX model by 49% and 44%, respectively. Mechanistic studies revealed IRX4204 modulates lipid metabolism and induces senescence of HER2-positive cells. In addition, IRX4204 demonstrates additivity and synergy with HER2-targeted mAbs, tyrosine kinase inhibitors, and antibody-drug conjugates. CONCLUSIONS: These findings identify HER2 as a biomarker for IRX4204 treatment response and demonstrate a novel use of RXR agonists to synergize with current anti-HER2 therapies. Furthermore, our results suggest that RXR agonists can be useful for the treatment of anti-HER2 resistant and metastatic HER2-positive breast cancer.

Many autism spectrum disorder (ASD)-associated genes act as transcriptional regulators (TRs). Chromatin immunoprecipitation sequencing (ChIP-seq) was used to identify the regulatory targets of ARID1B, BCL11A, FOXP1, TBR1, and TCF7L2, ASD-associated TRs in the developing human and mouse cortex. These TRs shared substantial overlap in the binding sites, especially within open chromatin. The overlap within a promoter region, 1-2,000 bp upstream of the transcription start site, was highly predictive of brain-expressed genes. This signature was observed in 96 out of 102 ASD-associated genes. In vitro CRISPRi against ARID1B and TBR1 delineated downstream convergent biology in mouse cortical cultures. After 8 days, NeuN+ and CALB+ cells were decreased, GFAP+ cells were increased, and transcriptomic signatures correlated with the postmortem brain samples from individuals with ASD. We suggest that functional convergence across five ASD-associated TRs leads to shared neurodevelopmental outcomes of haploinsufficient disruption.

This paper provides insight into working-class parents' views of the structural and systemic injustices shaping post-school options and opportunities in contemporary Australia, drawing on interview data with a group of mothers living in growth corridor suburbs in the outer west of Melbourne. Illustrating aspects of Berlant's (2011) notion of "cruel optimism", the paper examines the concepts of diminished society and collective community afforded by success through education, an aspiration and achievement unequal among young Australians. As Reay (2017) argues, an ideological narrative that positions individuals as being responsible for their own achievement through education sets many up to fail. This paper gives voice to the lived experiences of this individual responsibilitisation. We draw on elements of Marxist analysis, a subset of critical theory, whereby economic circumstances are the basis upon which political and ideological realities are built, critiquing the ways in which neoliberal social and economic policy and ideology are normalised (Tyson, 2015).