Mechanism for the initiation of spliceosome disassembly.

Pre-mRNA splicing requires the assembly, remodeling, and disassembly of the multi-megadalton ribonucleoprotein complex called the spliceosome1. Recent studies have shed light on spliceosome assembly and remodeling for catalysis2-6, but the mechanism of disassembly remains unclear. Here, we report 2.6 to 3.2 Å resolution cryo-electron microscopy structures of nematode and human terminal intron-lariat spliceosomes along with biochemical and genetic data. Our results uncover how four disassembly factors and the conserved RNA helicase DHX15 initiate spliceosome disassembly. The disassembly factors probe large inner and outer spliceosome surfaces to detect the release of ligated mRNA. Two of these factors, TFIP11 and C19L1, and three general spliceosome subunits, SYF1, SYF2 and SDE2, then dock and activate DHX15 on the catalytic U6 snRNA to initiate disassembly. U6 thus controls both the start5 and end of pre-mRNA splicing. Taken together, our results explain the molecular basis of canonical spliceosome disassembly and provide a framework to understand general spliceosomal RNA helicase control and the discard of aberrant spliceosomes.

Publisher Correction: Guided self-organization and cortical plate formation in human brain organoids.

This corrects the article DOI: 10.1038/nbt.3906.

Guided self-organization and cortical plate formation in human brain organoids.

Three-dimensional cell culture models have either relied on the self-organizing properties of mammalian cells or used bioengineered constructs to arrange cells in an organ-like configuration. While self-organizing organoids excel at recapitulating early developmental events, bioengineered constructs reproducibly generate desired tissue architectures. Here, we combine these two approaches to reproducibly generate human forebrain tissue while maintaining its self-organizing capacity. We use poly(lactide-co-glycolide) copolymer (PLGA) fiber microfilaments as a floating scaffold to generate elongated embryoid bodies. Microfilament-engineered cerebral organoids (enCORs) display enhanced neuroectoderm formation and improved cortical development. Furthermore, reconstitution of the basement membrane leads to characteristic cortical tissue architecture, including formation of a polarized cortical plate and radial units. Thus, enCORs model the distinctive radial organization of the cerebral cortex and allow for the study of neuronal migration. Our data demonstrate that combining 3D cell culture with bioengineering can increase reproducibility and improve tissue architecture.

Student Views on the Use of 2 Styles of Video-Enhanced Feedback Compared to Standard Lecture Feedback During Clinical Skills Training.

BACKGROUND: Feedback plays an important role in the learning process. However, often this may be delivered in an unstructured fashion that can detract from its potential benefit. Further, students may have different preferences in how feedback should be delivered, which may be influenced by which method they feel will lead to the most effective learning. The aim of this study was to evaluate student views on 3 different modes of feedback particularly in relation to the benefit each conferred. METHODS: Undergraduate medical students participating in a surgical suturing study were asked to give feedback using a semi-structured questionnaire. Discrete questions using a Likert scale and open responses were solicited. Students received either standard lecture feedback (SLF), individualized video feedback (IVF), or enhanced unsupervised video feedback (UVF). RESULTS: Students had a strong preference for IVF over UVF or SLF. These responses correlated with their perception of how much each type of feedback improved their performance. However, there was no statistical difference in suturing skill improvement between IVF and UVF, which were both significantly better than SLF. CONCLUSION: Students have a strong preference for IVF. This relates to a perception that this will lead to the greatest level of skill improvement. However, an equal effect in improvement can be achieved by using less resource-demanding UVF.