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Abstract Ibogaine and its main metabolite noribogaine provide important molecular prototypes for markedly different treatment of substance use disorders and co-morbid mental health illnesses. However, these compounds present a cardiac safety risk and a highly complex molecular mechanism. We introduce a class of iboga alkaloids – termed oxa-iboga – defined as benzofuran-containing iboga analogs and created via structural editing of the iboga skeleton. The oxa-iboga compounds lack the proarrhythmic adverse effects of ibogaine and noribogaine in primary human cardiomyocytes and show superior efficacy in animal models of opioid use disorder in male rats. They act as potent kappa opioid receptor agonists in vitro and in vivo, but exhibit atypical behavioral features compared to standard kappa opioid agonists. Oxa-noribogaine induces long-lasting suppression of morphine, heroin, and fentanyl intake after a single dose or a short treatment regimen, reversal of persistent opioid-induced hyperalgesia, and suppression of opioid drug seeking in rodent relapse models. As such, oxa-iboga compounds represent mechanistically distinct iboga analogs with therapeutic potential.

Science teacher leaders have been identified as an important lever for the implementation of science education reform. However, science reform implementation is locally controlled and not uniform across districts; therefore, the work of STLs within a reform context can vary. In this descriptive case study, we explore the work of 11 science teacher leaders who support science education reform in a variety of organizational contexts. Through the analysis of multiple data sources, we describe the roles that these science teacher leaders take up in their work and identified how variation in these roles related to localized contexts and priorities for science education. We identified seven roles that science teacher leaders enacted in their work: activist, ambassador, collaborator, innovator, networker, organizer, and translator. We found that each science teacher leader prioritized one or two of these roles in their work, with other roles supporting these primary roles. While most science teacher leaders named some aspect of collaborator, networker, and ambassador as part of their work, only the district-level science leaders named translator. Furthermore, there were important differences across the science teacher leaders in our sample, which related to their district and/or school contexts. We end with suggestions for leveraging the existing variation in the work of science teacher leaders for designing professional development including opportunities for science teacher leaders to surface the various roles they occupy in their work and to provide choice in professional learning based on those roles.

Determining the size of the addressable market is a key aspect of market intelligence and requires identifying and delineating projected budget data from potential customers. The market intelligence arena is characterized by a wide range of disparate sources, many of which are unstructured, ranging across competitive, market, financial, and technology sources, and typically necessitating significant manual work to analyze, reconcile, and integrate. The authors present an approach for classification of data from one of these sources, facilitating aggregation and analysis of intelligence information. We describe a concept proof using machine learning that extends a model for automatic mapping of publicly available budget data to segments and subsegments of a market segmentation taxonomy. This approach automates the tagging of market and market segment for each program and cost element by training classification models on the manually labeled historical data. We describe the evaluation and use of multiple natural language processing (NLP) and classification modeling methods. This work's contribution is demonstrating how NLP and machine learning techniques can provide useful data classification and automatic classification even when source data diverges from its specified taxonomic description.

T cell receptors (TCRs) enable T cells to specifically recognize mutations in cancer cells1-3. Here we developed a clinical-grade approach based on CRISPR-Cas9 non-viral precision genome-editing to simultaneously knockout the two endogenous TCR genes TRAC (which encodes TCRα) and TRBC (which encodes TCRβ). We also inserted into the TRAC locus two chains of a neoantigen-specific TCR (neoTCR) isolated from circulating T cells of patients. The neoTCRs were isolated using a personalized library of soluble predicted neoantigen-HLA capture reagents. Sixteen patients with different refractory solid cancers received up to three distinct neoTCR transgenic cell products. Each product expressed a patient-specific neoTCR and was administered in a cell-dose-escalation, first-in-human phase I clinical trial ( NCT03970382 ). One patient had grade 1 cytokine release syndrome and one patient had grade 3 encephalitis. All participants had the expected side effects from the lymphodepleting chemotherapy. Five patients had stable disease and the other eleven had disease progression as the best response on the therapy. neoTCR transgenic T cells were detected in tumour biopsy samples after infusion at frequencies higher than the native TCRs before infusion. This study demonstrates the feasibility of isolating and cloning multiple TCRs that recognize mutational neoantigens. Moreover, simultaneous knockout of the endogenous TCR and knock-in of neoTCRs using single-step, non-viral precision genome-editing are achieved. The manufacture of neoTCR engineered T cells at clinical grade, the safety of infusing up to three gene-edited neoTCR T cell products and the ability of the transgenic T cells to traffic to the tumours of patients are also demonstrated.

In the last few years, microplastics research has exploded, with the field exploring new procedures and techniques that focus on a variety of scientific and policy issues. As there are not standardized definitions for many terms in the field, including the term microplastic itself, researchers utilize the same labels to describe different aspects of microplastic pollution. Here we provide a visual tool, called a Hub for Interactive Literature (HIL), to assist researchers in identifying and targeting specific literature. Currently, there are four Hubs for Interactive Learning (HILs) corresponding to previously published reviews, including a scoping review of microplastics literature as well as three reviews examining the human exposure and health effects of microplastics, the unique liver carcinogenicity of polyvinyl chloride (PVC) microplastics, and micro and nanoplastics found in the air. The HILs incorporate all of the literature used to produce the corresponding reviews. A couple of advantages that HILs provide in their capacity as a supportive instrument are the filtering options and easily accessed original references. This tool can be leveraged by researchers to rapidly review microplastics research and isolate specific subtopics of interest to develop new conclusions and quickly identify data gaps. We give an in-depth look at the HIL corresponding to a scoping review of microplastics literature to exhibit the novel functionality and advantages of this exciting tool. We demonstrate a novel world map of the literature to show that microplastics are a global scientific and public health issue. The map offers the additional functionality of filtering the references by country. We also provide a brief description of the current HILs to show the flexibility and personalization available when using this method.

ANNE CARSON The glass essayist ELIZABETH SARAH COLES 344pp. Oxford University Press. 54 [pounds sterling] (US $83). WRONG NORMA ANNE CARSON 192pp. Cape. 14.99 [pounds sterling]. Anne Carson trained as [...]

Time management for educational leaders has remained highly relevant to scholars, policymakers and practitioners. We analyzed survey responses from 98 public high school principals to examine the congruency between average total hours they worked per week against the sum total of the average hours worked per week in each of five distinct categories of leadership tasks. The observed congruence was 0.32, while Cohen's kappa coefficient was 0.10. Female principals tended to underreport, and male principals tended to overreport, total work time. Principals with doctorate degrees exhibited higher congruence than those without, and overreporting was inversely related to highest degree. Principals in charge of large teaching staffs were more likely than their counterparts to be congruent and less likely to overreport total work time. Self-report appears to be an inaccurate method to measure time use among high school principals. If time use is a key component of the quality of principal leadership, more detailed and robust techniques for collecting time use data should be utilized in future studies.

Abstract Background Malnutrition and sickle cell anemia (SCA) result in high childhood mortality rates. Although maternal depression is an established risk factor for malnutrition in younger children, little is known about its impact on treatment response in children with malnutrition. We aimed to determine the relationship, if any, between maternal depression scores and malnutrition treatment outcomes in older children with SCA. Methods We conducted a planned ancillary study to our randomized controlled feasibility trial for managing severe acute malnutrition in children aged 5–12 with SCA in northern Nigeria (NCT03634488). Mothers of participants completed a depression screen using the Patient Health Questionnaire (PHQ-9).We used a multivariable linear regression model to describe the relationship between the baseline maternal PHQ-9 score and the trial participant’s final body mass index (BMI) z-score. Results Out of 108 mother-child dyads, 101 with maternal baseline PHQ-9 scores were eligible for inclusion in this analysis. At baseline, 25.7% of mothers (26 of 101) screened positive for at least mild depression (PHQ-9 score of 5 or above). The baseline maternal PHQ-9 score was negatively associated with the child’s BMI z-score after 12 weeks of malnutrition treatment (β=-0.045, p = 0.041). Conclusions Maternal depressive symptoms has an impact on malnutrition treatment outcomes. Treatment of malnutrition in older children with sickle cell anemia should include screening for maternal depression and, if indicated, appropriate maternal referral for depression evaluation and treatment. Trial Registration The trial was registered at clinicaltrials.gov (#NCT03634488) on January 30, 2018, https://clinicaltrials.gov/study/NCT03634488 .

ObjectiveTo investigate the genetic architecture of internalizing symptoms in childhood and adolescence.MethodIn 22 cohorts, multiple univariate genome-wide association studies (GWASs) were performed using repeated assessments of internalizing symptoms, in a total of 64,561 children and adolescents between 3 and 18 years of age. Results were aggregated in meta-analyses that accounted for sample overlap, first using all available data, and then using subsets of measurements grouped by rater, age, and instrument.ResultsThe meta-analysis of overall internalizing symptoms (INToverall) detected no genome-wide significant hits and showed low single nucleotide polymorphism (SNP) heritability (1.66%, 95% CI = 0.84-2.48%, neffective = 132,260). Stratified analyses indicated rater-based heterogeneity in genetic effects, with self-reported internalizing symptoms showing the highest heritability (5.63%, 95% CI = 3.08%-8.18%). The contribution of additive genetic effects on internalizing symptoms appeared to be stable over age, with overlapping estimates of SNP heritability from early childhood to adolescence. Genetic correlations were observed with adult anxiety, depression, and the well-being spectrum (|rg| > 0.70), as well as with insomnia, loneliness, attention-deficit/hyperactivity disorder, autism, and childhood aggression (range |rg| = 0.42-0.60), whereas there were no robust associations with schizophrenia, bipolar disorder, obsessive-compulsive disorder, or anorexia nervosa.ConclusionGenetic correlations indicate that childhood and adolescent internalizing symptoms share substantial genetic vulnerabilities with adult internalizing disorders and other childhood psychiatric traits, which could partially explain both the persistence of internalizing symptoms over time and the high comorbidity among childhood psychiatric traits. Reducing phenotypic heterogeneity in childhood samples will be key in paving the way to future GWAS success.

While endorsed as critical for promoting learning, students' interest in a topic has had minimal, if any, influence on curriculum development. Teachers thus are challenged to promote students' interest within an established curriculum. After students demonstrated misunderstandings after reading an article about bacteria, Sarah Stallings and Samuel Miller, a 4th-grade teacher and university researcher, decided to base their instruction on students' queries and concerns. This one lesson provided the impetus for a series of activities across the school year that allowed students to become more actively involved in choosing what they would learn and how they would learn it. What students viewed as important and interesting determined the nature and format of their daily studies.

The North Carolina Opportunity Scholarship Program is a private school voucher program that provides state-funded vouchers worth up to $4,200 to eligible students entering kindergarten through 12th grade. Because the public and private school sectors administer different assessments, we recruited approximately 700 students to take a common, nationally normed, standardized test. Matching on baseline achievement and rich demographic data, we use a quasi-experimental inverse propensity weighting approach to maximize comparability between the public and private school student samples. Our preferred specification examines first-year effects for new Opportunity Scholarship students, revealing positive estimates of 0.36 SD in math and 0.44 SD in language; there is no effect on reading scores. Results for renewal students are statistically significant in language scores only. In further analyses, we estimate separate effects for private schools that regularly administer another version of the assessment used in this study, the Iowa Test of Basic Skills. We conclude by discussing policy implications.

ABSTRACT Of the approximately 10 million cases of Mycobacterium tuberculosis (Mtb) infections each year, over 10% are resistant to the frontline antibiotic isoniazid (INH). INH resistance is predominantly caused by mutations that decrease the activity of the bacterial enzyme KatG, which mediates the conversion of the pro-drug INH to its active form INH-NAD. We previously discovered an inhibitor of Mtb respiration, C10, that enhances the bactericidal activity of INH, prevents the emergence of INH-resistant mutants, and re-sensitizes a collection of INH-resistant mutants to INH through an unknown mechanism. To investigate the mechanism of action of C10, we exploited the toxicity of high concentrations of C10 to select for resistant mutants. We discovered two mutations that confer resistance to the disruption of energy metabolism and allow for the growth of Mtb in high C10 concentrations, indicating that growth inhibition by C10 is associated with inhibition of respiration. Using these mutants as well as direct inhibitors of the Mtb electron transport chain, we provide evidence that inhibition of energy metabolism by C10 is neither sufficient nor necessary to potentiate killing by INH. Instead, we find that C10 acts downstream of INH-NAD synthesis, causing Mtb to become particularly sensitive to inhibition of the INH-NAD target, InhA, without changing the concentration of INH-NAD or the activity of InhA, the two predominant mechanisms of potentiating INH. Our studies revealed that there exists a vulnerability in Mtb that can be exploited to render Mtb sensitive to otherwise subinhibitory concentrations of InhA inhibitor.IMPORTANCEIsoniazid (INH) is a critical frontline antibiotic to treat Mycobacterium tuberculosis (Mtb) infections. INH efficacy is limited by its suboptimal penetration of the Mtb-containing lesion and by the prevalence of clinical INH resistance. We previously discovered a compound, C10, that enhances the bactericidal activity of INH, prevents the emergence of INH-resistant mutants, and re-sensitizes a set of INH-resistant mutants to INH. Resistance is typically mediated by katG mutations that decrease the activation of INH, which is required for INH to inhibit the essential enzyme InhA. Our current work demonstrates that C10 re-sensitizes INH-resistant katG-hypomorphs without enhancing the activation of INH. We furthermore show that C10 causes Mtb to become particularly vulnerable to InhA inhibition without compromising InhA activity on its own. Therefore, C10 represents a novel strategy to curtail the development of INH resistance and to sensitize Mtb to sub-lethal doses of INH, such as those achieved at the infection site.

We report the case of a 1-week-old male born full-term, who had two inconclusive severe combined immunodeficiency (SCID) newborn screens and developed scalp cellulitis and Escherichia coli bacteremia. He did not pass early confirmatory hearing screens. Initial blood counts and lymphocyte flow cytometry revealed profound neutropenia and lymphopenia with a T-/B-/NK- phenotype. Red blood cell adenosine deaminase 1 activity was within normal limits. A presumptive diagnosis of reticular dysgenesis was considered. Granulocyte colony-stimulating factor was started, but there was no improvement in neutrophil counts. Subsequent lymphocyte flow cytometry at around 4 weeks of age demonstrated an increase in T-, B- and NK-cell numbers, eliminating suspicion for SCID and raising concern for congenital neutropenia and bone marrow failure syndromes. Genetic testing revealed a novel variant in RAC2 [c.181C>A (p.Gln61Lys)] (Q61K). RAC2, a Ras-related GTPase, is the dominant RAC protein expressed in hematopoietic cells and is involved with various downstream immune-mediated responses. Pathogenic RAC2 variants show significant phenotypic heterogeneity (spanning from neutrophil defects to combined immunodeficiency) across dominant, constitutively activating, dominant activating, dominant negative, and autosomal recessive subtypes. Given the identification of a novel variant, functional testing was pursued to evaluate aberrant pathways described in other RAC2 pathogenic variants. In comparison to wild-type RAC2, the Q61K variant supported elevated superoxide production under both basal and PMA-stimulated conditions, increased PAK1 binding, and enhanced plasma membrane ruffling, consistent with other dominant, constitutively active mutations. This case highlights the diagnostic challenge associated with genetic variants identified via next-generation sequencing panels and the importance of functional assays to confirm variant pathogenicity.