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Disruption of Minor Intron Splicing by Disease-associated Mutations in U12 snRNA
Get PDFIn eukaryotic gene expression, the removal of introns from pre-mRNA is an essential function carried out by spliceosomes. Human cells have two distinct spliceosomes: U2-dependent and U12-dependent. U2- dependent spliceosomes, or major spliceosomes, remove over 99% of introns, whereas U-12 dependent spliceosomes remove less than 0.5% of introns. Mutations in spliceosome machinery are a notable cause of human disease. In particular, mutations to components unique to the minor spliceosome demonstrate that it plays a vital role in human development. Mutations in the gene encoding the minor spliceosomal small nuclear RNA (snRNA) U12, RNU12, are associated with two rare developmental disorders: 1) CDAGS syndrome (craniosynostosis and clavicular hypoplasia; delayed closure of the fontanelles, cranial defects, and, in some patients, deafness; anal anomalies; genitourinary malformations; and skin eruption) and 2) early onset cerebellar ataxia. Recent work identified rare biallelic variants in RNU12 as the likely cause of CDAGS syndrome, while a single homozygous mutation was identified as the likely cause of early onset cerebellar ataxia. Mutations associated with these diseases are clustered in or near the stem- loop III of U12 snRNA, with three of the mutations located in the Sm protein binding site. Further investigation of the mutation associated with early onset cerebellar ataxia suggests that mutations in RNU12 disrupt U12 snRNA function through the destabilization of the 3’ stem-loop, which precedes overall destabilization of the U12 snRNA. Using our in vivo orthogonal splicing assay, we quantified the effects of pathogenic RNU12 mutations on U12-dependent splicing. Splicing activity varies depending on the location of the mutation. Splicing was significantly reduced among three U12 variants located in the Sm protein binding site. Sm proteins are responsible for proper assembly of snRNPs (small nuclear ribonucleoproteins) prior to pre-mRNA splicing. Similarly, splicing activity was substantially impaired in the mutation located three nucleotides downstream of the U12 snRNA sequence. While the impact of this variant on the minor spliceosome complex is unclear, one possibility is that this mutation could affect 3’ end processing of U12 snRNA. The effects of the two variants within stem-loop III of U12 snRNA differ. Whereas splicing activity was considerably diminished with the 86G\u3eA mutation, activity in cells with the 84C\u3eT mutation was near wild-type levels. It is presumed that these mutations affect the secondary structure of the snRNA due to the fact that they are located at the base of stem-loop III, farther away from the U12-65K protein binding site. Further work remains to fully define the mechanisms of splicing impairment that are the result of disease-associated mutations in U12 snRNA.https://collected.jcu.edu/celebration_2023/1000/thumbnail.jp
Determined Mechanism for the Formation of 2-bromo-3-methylbutane
Get PDFCarbocation rearrangements are particularly interesting mechanistic steps in organic reactions. Carbocations form when a carbon atom within a molecule is electron deficient, giving it a positive charge. A rearrangement occurs when either a hydrogen atom or methyl group from an adjacent carbon atom in the molecule moves to the carbocation, thus moving the carbocation to the adjacent carbon. This rearrangement only occurs if the newly formed carbocation is more stable than the previous carbocation. These concepts are typically taught in organic chemistry courses. Researchers from Villanova University, the University of Wisconsin-River Falls, and Bethel University designed an experiment to help students understand these concepts in experimental reactions with the use of spectroscopy.(1) However, in their experiment, they were unable to propose a mechanism for the formation of 2-bromo-3-methylbutane from neopentyl alcohol. This research proposes and confirms a mechanism for the formation of that product
Inflating value with other people’s money
Get PDFA one country case study using a historical-institutional balance sheet approach provides a unique vantage point on financialization. By clarifying conceptual distinctions between assets and liabilities in households and banks and representing historical financial data in disaggregated forms, Kurt Mettenheim and Olivier Butzbach offer a significant critical genealogy of the production of money and value in the US
Catholic Higher Education and Catholic Social Thought
No full textResponding to the signs of the time, this book brings the lens of Catholic social thought (CST) to the enterprise of Catholic higher education in the United States. This book throws light on what Catholic colleges and universities might and must do in order both to preserve their mission and renew it for the future
Matter, nature, cosmos: The scientific art of the early modern English stage
Get PDFHow does our understanding of early modern performance, culture and identity change when we decentre Shakespeare? And how might a more inclusive approach to early modern drama help enable students to discuss a range of issues, including race and gender, in more productive ways?Underpinned by these questions, this collection offers a wide-ranging, authoritative guide to research on drama in Shakespeare\u27s England, mapping the variety of approaches to the context and work of Shakespeare and his contemporaries. By paying attention to repertory, performance in and beyond playhouses, modes of performance, and lost and less-studied plays, the handbook reshapes our critical narratives about early modern drama