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Morton, Sarah

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Morton

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Morton, Sarah
Author's Publications: search.filters.isAuthorOfPublication.13a6f5eb-aa72-4cc6-a50f-3bb31cf3557d

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    AIFM1 mutation presenting with fatal encephalomyopathy and mitochondrial disease in an infant
    (Cold Spring Harbor Laboratory Press, 2017) Morton, Sarah; Prabhu, Sanjay; Lidov, Hart; Shi, Jiahai; Anselm, Irina; Brownstein, Catherine; Bainbridge, Matthew N.; Beggs, Alan; Vargas, Sara; Agrawal, Pankaj
    Apoptosis-inducing factor mitochondrion-associated 1 (AIFM1), encoded by the gene AIFM1, has roles in electron transport, apoptosis, ferredoxin metabolism, reactive oxygen species generation, and immune system regulation. Here we describe a patient with a novel AIFM1 variant presenting unusually early in life with mitochondrial disease, rapid deterioration, and death. Autopsy, at the age of 4 mo, revealed features of mitochondrial encephalopathy, myopathy, and involvement of peripheral nerves with axonal degeneration. In addition, there was microvesicular steatosis in the liver, thymic noninvolution, follicular bronchiolitis, and pulmonary arterial medial hypertrophy. This report adds to the clinical and pathological spectrum of disease related to AIFM1 mutations and provides insights into the role of AIFM1 in cellular function.
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    Skeletal Muscle MicroRNA and Messenger RNA Profiling in Cofilin-2 Deficient Mice Reveals Cell Cycle Dysregulation Hindering Muscle Regeneration
    (Public Library of Science, 2015) Morton, Sarah; Joshi, Mugdha; Savic, Talia; Beggs, Alan; Agrawal, Pankaj
    Congenital myopathies are rare skeletal muscle diseases presenting in early age with hypotonia and weakness often linked to a genetic defect. Mutations in the gene for cofilin-2 (CFL2) have been identified in several families as a cause of congenital myopathy with nemaline bodies and cores. Here we explore the global messenger and microRNA expression patterns in quadriceps muscle samples from cofillin-2-null mice and compare them with sibling-matched wild-type mice to determine the molecular pathways and mechanisms involved. Cell cycle processes are markedly dysregulated, with altered expression of genes involved in mitotic spindle formation, and evidence of loss of cell cycle checkpoint regulation. Importantly, alterations in cell cycle, apoptosis and proliferation pathways are present in both mRNA and miRNA expression patterns. Specifically, p21 transcript levels were increased, and the expression of p21 targets, such as cyclin D and cyclin E, was decreased. We therefore hypothesize that deficiency of cofilin-2 is associated with interruption of the cell cycle at several checkpoints, hindering muscle regeneration. Identification of these pathways is an important step towards developing appropriate therapies against various congenital myopathies.
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    Separating Putative Pathogens from Background Contamination with Principal Orthogonal Decomposition: Evidence for Leptospira in the Ugandan Neonatal Septisome
    (Frontiers Media S.A., 2016) Schiff, Steven J.; Kiwanuka, Julius; Riggio, Gina; Nguyen, Lan; Mu, Kevin; Sproul, Emily; Bazira, Joel; Mwanga-Amumpaire, Juliet; Tumusiime, Dickson; Nyesigire, Eunice; Lwanga, Nkangi; Bogale, Kaleb T.; Kapur, Vivek; Broach, James R.; Morton, Sarah; Warf, Benjamin; Poss, Mary
    Neonatal sepsis (NS) is responsible for over 1 million yearly deaths worldwide. In the developing world, NS is often treated without an identified microbial pathogen. Amplicon sequencing of the bacterial 16S rRNA gene can be used to identify organisms that are difficult to detect by routine microbiological methods. However, contaminating bacteria are ubiquitous in both hospital settings and research reagents and must be accounted for to make effective use of these data. In this study, we sequenced the bacterial 16S rRNA gene obtained from blood and cerebrospinal fluid (CSF) of 80 neonates presenting with NS to the Mbarara Regional Hospital in Uganda. Assuming that patterns of background contamination would be independent of pathogenic microorganism DNA, we applied a novel quantitative approach using principal orthogonal decomposition to separate background contamination from potential pathogens in sequencing data. We designed our quantitative approach contrasting blood, CSF, and control specimens and employed a variety of statistical random matrix bootstrap hypotheses to estimate statistical significance. These analyses demonstrate that Leptospira appears present in some infants presenting within 48 h of birth, indicative of infection in utero, and up to 28 days of age, suggesting environmental exposure. This organism cannot be cultured in routine bacteriological settings and is enzootic in the cattle that often live in close proximity to the rural peoples of western Uganda. Our findings demonstrate that statistical approaches to remove background organisms common in 16S sequence data can reveal putative pathogens in small volume biological samples from newborns. This computational analysis thus reveals an important medical finding that has the potential to alter therapy and prevention efforts in a critically ill population.