Spliceosome malfunction causes neurodevelopmental disorders with overlapping features

Pre-mRNA splicing is a highly coordinated process. While its dysregulation has been linked to neurological deficits, our understanding of the underlying molecular and cellular mechanisms remains limited. We implicated pathogenic variants in U2AF2 and PRPF19, encoding spliceosome subunits in neurodevelopmental disorders (NDDs), by identifying 46 unrelated individuals with 23 de novo U2AF2 missense variants (including 7 recurrent variants in 30 individuals) and 6 individuals with de novo PRPF19 variants. Eight U2AF2 variants dysregulated splicing of a model substrate. Neuritogenesis was reduced in human neurons differentiated from human pluripotent stem cells carrying two U2AF2 hyper-recurrent variants. Neural loss of function (LoF) of the Drosophila orthologs U2af50 and Prp19 led to lethality, abnormal mushroom body (MB) patterning, and social deficits, which were differentially rescued by wild-type and mutant U2AF2 or PRPF19. Transcriptome profiling revealed splicing substrates or effectors (including Rbfox1, a third splicing factor), which rescued MB defects in U2af50deficient flies. Upon reanalysis of negative clinical exomes followed by data sharing, we further identified 6 patients with NDD who carried RBFOX1 missense variants which, by in vitro testing, showed LoF. Our study implicates 3 splicing factors as NDD-causative genes and establishes a genetic network with hierarchy underlying human brain development and function

Preservice teachers\u27 views of the nature of science during a postbaccalaureate science teaching program

The goals of this study were to determine preservice science teachers\u27 views of the nature of science and to describe the changes in those views that occur during a teacher education program. Fifteen students in a postbaccalaureate secondary science teaching program at a large university participated in this study. The participants\u27 views of science were ascertained by an investigator-developed survey and a follow-up interview administered before and after the university\u27s science teaching methods sequence. Before entering the teaching program, the participants had a contemporary (i.e., postpositivist) view of scientific theory, knowledge, and the role of a scientist and a traditional (i.e., empiricist or positivist) view of scientific method. Initially, there was an equal number of traditional, mixed, and contemporary views of the different aspects of science. After completing the methods sequence, the number of contemporary views doubled and the number of mixed views decreased by more than half. The number of participants with an overall contemporary view of science rose from 2 to 7. Since there was little direct instruction about the nature of science, it is possible to make positive changes in preservice teachers\u27 views of the nature of science in a teaching program in which contemporary teaching strategies such as conceptual change and cooperative learning are taught

Juan\u27s dilemma: A new twist on the old lemon battery

When life hands you lemons, make a battery! In this article, we describe an activity that we call Juan’s Dilemma, an extension of the familiar lemon-battery activity (Goodisman 2001). Juan’s Dilemma integrates oxidation and reduction chemistry with circuit theory in a fun, real-world exercise. We designed this activity for a ninth-grade physical science class, and our students have found it to be intriguing and challenging

A Single-chord Stellar Occultation by the Extreme Trans-Neptunian Object (541132) Leleākūhonua

A stellar occultation by the extreme large-perihelion trans-Neptunian object (541132) Leleākūhonua (also known by the provisional designation of 2015 TG387) was predicted by the Lucky Star project and observed with the Research and Education Collaborative Occultation Network on 2018 October 20 UT. A single detection and a nearby nondetection provide constraints for the size and albedo. When a circular profile is assumed, the radius is r = 110+14-10 km, corresponding to a geometric albedo Pv = 0.21+0.03-0.05, for an adopted absolute magnitude of HV = 5.6, typical of other objects in dynamically similar orbits. The occultation also provides a high-precision astrometric constraint

Discovery of <i>N</i>‑(4-Fluoro-3-methoxybenzyl)-6-(2-(((2<i>S</i>,5<i>R</i>)‑5-(hydroxymethyl)-1,4-dioxan-2-yl)methyl)‑2<i>H</i>‑tetrazol-5-yl)-2-methylpyrimidine-4-carboxamide. A Highly Selective and Orally Bioavailable Matrix Metalloproteinase-13 Inhibitor for the Potential Treatment of Osteoarthritis

Matrix metalloproteinase-13 (MMP-13) is a zinc-dependent protease responsible for the cleavage of type II collagen, the major structural protein of articular cartilage. Degradation of this cartilage matrix leads to the development of osteoarthritis. We previously have described highly potent and selective carboxylic acid containing MMP-13 inhibitors; however, nephrotoxicity in preclinical toxicology species precluded development. The accumulation of compound in the kidneys mediated by human organic anion transporter 3 (hOAT3) was hypothesized as a contributing factor for the finding. Herein we report our efforts to optimize the MMP-13 potency and pharmacokinetic properties of non-carboxylic acid leads resulting in the identification of compound <b>43a</b> lacking the previously observed preclinical toxicology at comparable exposures