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"Stuart, Catherine"
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Functional characterization of human recessive DIS3 variants in premature ovarian insufficiency
Premature ovarian insufficiency (POI) is characterized by the loss or complete absence of ovarian activity in women under the age of 40. Clinical presentation of POI varies with phenotypic severity ranging from premature loss of menses to complete gonadal dysgenesis. POI is genetically heterogeneous with >100 causative gene variants identified thus far. The etiology of POI varies from syndromic, idiopathic, monogenic to autoimmune causes the condition. Genetic diagnoses are beneficial to those impacted by POI as it allows for improved clinical management and fertility preservation. Identifying novel variants in candidate POI genes, however, is insufficient to make clinical diagnoses. The impact of missense variants can be predicted using bioinformatic algorithms but computational approaches have limitations and can generate false positive and false negative predictions. Functional characterization of missense variants, is therefore imperative, particularly for genes lacking a well-established genotype:phenotype correlation. Here we used whole-exome sequencing (WES) to identify the first case of a homozygous missense variant in DIS3 (c.2320C > T; p.His774Tyr) a critical component of the RNA exosome in a POI patient. This adds to the previously described compound heterozygous patient. We perform the first functional characterization of a human POI-associated DIS3 variant. A slight defect in mitotic growth was caused by the variant in a Saccharomyces cerevisiae model. Transgenic rescue of Dis3 knockdown in Drosophila melanogaster with human DIS3 carrying the patient variant led to aberrant ovarian development and egg chamber degeneration. This supports a potential deleterious impact of the human c.2320C > T; p.His774Tyr variant. Summary Sentence DIS3 variant identified in a patient with premature ovarian insufficiency has reduced capacity to rescue Drosophila ovarian Dis3 knockdown compared to wildtype, suggesting the variant is hypomorphic and the RNA exosome is critical for ovarian function. Graphical Abstract
Journal Article
Hornblendite delineates zones of mass transfer through the lower crust
Geochemical signatures throughout the layered Earth require significant mass transfer through the lower crust, yet geological pathways are under-recognized. Elongate bodies of basic to ultrabasic rocks are ubiquitous in exposures of the lower crust. Ultrabasic hornblendite bodies hosted within granulite facies gabbroic gneiss of the Pembroke Valley, Fiordland, New Zealand, are typical occurrences usually reported as igneous cumulate hornblendite. Their igneous features contrast with the metamorphic character of their host gabbroic gneiss. Both rock types have a common parent; field relationships are consistent with modification of host gabbroic gneiss into hornblendite. This precludes any interpretation involving cumulate processes in forming the hornblendite; these bodies are imposter cumulates. Instead, replacement of the host gabbroic gneiss formed hornblendite as a result of channeled high melt flux through the lower crust. High melt/rock ratios and disequilibrium between the migrating magma (granodiorite) and its host gabbroic gneiss induced dissolution (grain-scale magmatic assimilation) of gneiss and crystallization of mainly hornblende from the migrating magma. The extent of this reaction-replacement mechanism indicates that such hornblendite bodies delineate significant melt conduits. Accordingly, many of the ubiquitous basic to ultrabasic elongate bodies of the lower crust likely map the ‘missing’ mass transfer zones.
Journal Article
Mapping of in vivo cleavage sites uncovers a major role for yeast RNase III in regulating protein-coding genes
A large fraction of newly transcribed RNA is degraded in the nucleus, but nuclear mRNA degradation pathways remain largely understudied. The yeast nuclear endoribonuclease Rnt1 has a well-characterized role in the maturation of many ncRNA precursors. However, the scope and consequence of its function in mRNA degradation pathways are much less defined. Here, we take a whole-transcriptome approach to identify Rnt1 cleavage sites throughout the yeast transcriptome in vivo, at single-nucleotide resolution. We discover previously unknown Rnt1 cleavage sites in many protein-coding regions and find that the sequences and structures necessary for cleavage mirror those required for the cleavage of known targets. We show that the nuclear localization of Rnt1 functions as an additional layer of target selection control, and that cleaved mRNAs are likely exported to the cytoplasm to be degraded by Xrn1. Further, we find that several cleavage products are much more abundant in our degradome sequencing libraries than decapping products, and strikingly, mutations in one Rnt1 target, YDR514C , suppress the growth defect of an RNT1 deletion. Overexpression of YDR514C results in slow growth, further suggesting that Rnt1 may limit the expression of YDR514C to maintain proper cell growth. This study uncovers a broader target range and function for the well-known RNase III enzyme.
Journal Article
Mapping of in vivo cleavage sites uncovers a major role for yeast RNase III in regulating protein-coding genes
A large fraction of newly transcribed RNA is degraded in the nucleus, but nuclear mRNA degradation pathways remain largely understudied. The yeast nuclear endoribonuclease Rnt1 has a well-characterized role in the maturation of many ncRNA precursors. However, the scope and consequence of its function in mRNA degradation pathways are much less defined. Here, we take a whole-transcriptome approach to identify Rnt1 cleavage sites throughout the yeast transcriptome in vivo, at single-nucleotide resolution. We discover previously unknown Rnt1 cleavage sites in many protein-coding regions and find that the sequences and structures necessary for cleavage mirror those required for the cleavage of known targets. We show that the nuclear localization of Rnt1 functions as an additional layer of target selection control, and that cleaved mRNAs are likely exported to the cytoplasm to be degraded by Xrn1. Further, we find that several cleavage products are much more abundant in our degradome sequencing libraries than decapping products, and strikingly, mutations in one Rnt1 target, YDR514C , suppress the growth defect of an RNT1 deletion. Overexpression of YDR514C results in slow growth, further suggesting that Rnt1 may limit the expression of YDR514C to maintain proper cell growth. This study uncovers a broader target range and function for the well-known RNase III enzyme.
Journal Article
A protocol for the preparation of patients for theatre and recovery
This article explores the creation of a specific protocol to prepare children and young people with learning disabilities effectively for theatre and to ensure appropriate support during recovery. The TEACH approach (time, environment, attitude, communication and help) was adopted to provide a framework for reasonably adjusted care. The theatre and recovery protocol was developed following complaints by parents of children with learning disabilities about unsatisfactory care, and after cancelled operations. The young person is offered a pre-admission visit and a hospital passport, which explores their likes and dislikes and enables staff to prepare for their specific needs and requirements. In recovery, a quieter and larger area has been created. The protocol has enabled staff to feel more confident and to individually address the young person’s needs. This protocol could easily be adopted for many other people regardless of age or disability who need to have care altered to meet their needs.
Journal Article
Mapping of in vivo cleavage sites uncovers a major role for yeast RNase III in regulating protein-coding genes
A large fraction of newly transcribed RNA is degraded in the nucleus, but nuclear mRNA degradation pathways remain largely understudied. The yeast nuclear endoribonuclease Rnt1 has a well-characterized role in the maturation of many ncRNA precursors. However, the scope and consequence of its function in mRNA degradation pathways is much less defined. Here, we take a whole-transcriptome approach to identify Rnt1 cleavage sites throughout the yeast transcriptome in vivo, at single-nucleotide resolution. We discover previously unknown Rnt1 cleavage sites in many protein-coding regions and find that the sequences and structures necessary for cleavage mirror those required for the cleavage of known targets. We show that the nuclear localization of Rnt1 functions as an additional layer of target selection control and that cleaved mRNAs are likely exported to the cytoplasm to be degraded by Xrn1. Further, we find that several cleavage products are much more abundant in our degradome sequencing libraries than decapping products, and strikingly, mutations in one Rnt1 target,
, suppress the growth defect of a
deletion. Overexpression of
results in slow growth, further suggesting that Rnt1 may limit the expression of
to maintain proper cell growth. This study uncovers a broader target range and function for the well-known RNase III enzyme.
Journal Article
Layers Upon Layers
A nyone with an eating disorder assuredly has had problematic relationships within the family of origin, both during the course of his or her development and in current family interactions. Whether one is a parent dealing with an eating-disordered child or a therapist working with this child and his or her family, relationships will inevitably be fraught with issues of control, questions regarding intervention, and anxieties that permeate the very physical being of each person involved. These often overwhelming anxieties, struggles for intra- and interpersonal control, awareness-and disavowal-of one's presence vis-a-vis the other shift seamlessly back and forth in any relationship. There are few arenas in which these kinds of issues are more urgent than in relationships where concerns about anorexia, bulimia, or compulsive binge eating prevail.
Book Chapter
Defect passivation on cast-mono crystalline screen-printed cells
Cast-mono crystalline silicon wafers contain crystallographic defects, which can severely impact the electrical performance of solar cells. This paper demon- strates that applying hydrogenation processes at moderate temperatures to finished screen print cells can passivate dislocation clusters within the cast-mono crystalline silicon wafers far better than the hydrogenation received during standard commercial firing conditions. Efficiency enhancements of up to 2% absolute are demonstrated on wafers with high dislocation densities. The impact of illumination to manipulate the charge state of hydrogen during annealing is investigated and found to not be significant on the wafers used in this study. This finding is contrary to a previous study on similar wafers that concluded increased H or H0 from laser illumination was responsible for the further passivation of positively charged dangling bonds within the dislocation clusters.
Journal Article