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      Neurodevelopmental protein Musashi 1 interacts with the Zika genome and promotes viral replication

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          Abstract

          A recent outbreak of Zika virus in Brazil has led to a simultaneous increase in reports of neonatal microcephaly. Zika targets cerebral neural precursors, a cell population essential for cortical development, but the cause of this neurotropism remains obscure. Here we report that the neural RNA-binding protein Musashi-1 (MSI1) interacts with the Zika genome and enables viral replication. Zika infection disrupts the binding of MSI1 to its endogenous targets, thereby deregulating expression of factors implicated in neural stem cell function. We further show that MSI1 is highly expressed in neural progenitors of the human embryonic brain, and is mutated in individuals with autosomal recessive primary microcephaly. Selective MSI1 expression in neural precursors could therefore explain the exceptional vulnerability of these cells to Zika infection.

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          Most cited references33

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          DNA sequencing of a cytogenetically normal acute myeloid leukemia genome

          Lay Summary Acute myeloid leukemia is a highly malignant hematopoietic tumor that affects about 13,000 adults yearly in the United States. The treatment of this disease has changed little in the past two decades, since most of the genetic events that initiate the disease remain undiscovered. Whole genome sequencing is now possible at a reasonable cost and timeframe to utilize this approach for unbiased discovery of tumor-specific somatic mutations that alter the protein-coding genes. Here we show the results obtained by sequencing a typical acute myeloid leukemia genome and its matched normal counterpart, obtained from the patient’s skin. We discovered 10 genes with acquired mutations; two were previously described mutations thought to contribute to tumor progression, and 8 were novel mutations present in virtually all tumor cells at presentation and relapse, whose function is not yet known. Our study establishes whole genome sequencing as an unbiased method for discovering initiating mutations in cancer genomes, and for identifying novel genes that may respond to targeted therapies. We used massively parallel sequencing technology to sequence the genomic DNA of tumor and normal skin cells obtained from a patient with a typical presentation of FAB M1 Acute Myeloid Leukemia (AML) with normal cytogenetics. 32.7-fold ‘haploid’ coverage (98 billion bases) was obtained for the tumor genome, and 13.9-fold coverage (41.8 billion bases) was obtained for the normal sample. Of 2,647,695 well-supported Single Nucleotide Variants (SNVs) found in the tumor genome, 2,588,486 (97.7%) also were detected in the patient’s skin genome, limiting the number of variants that required further study. For the purposes of this initial study, we restricted our downstream analysis to the coding sequences of annotated genes: we found only eight heterozygous, non-synonymous somatic SNVs in the entire genome. All were novel, including mutations in protocadherin/cadherin family members (CDH24 and PCLKC), G-protein coupled receptors (GPR123 and EBI2), a protein phosphatase (PTPRT), a potential guanine nucleotide exchange factor (KNDC1), a peptide/drug transporter (SLC15A1), and a glutamate receptor gene (GRINL1B). We also detected previously described, recurrent somatic insertions in the FLT3 and NPM1 genes. Based on deep readcount data, we determined that all of these mutations (except FLT3) were present in nearly all tumor cells at presentation, and again at relapse 11 months later, suggesting that the patient had a single dominant clone containing all of the mutations. These results demonstrate the power of whole genome sequencing to discover novel cancer-associated mutations.
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            Identification of small-molecule inhibitors of Zika virus infection and induced neural cell death via a drug repurposing screen.

            In response to the current global health emergency posed by the Zika virus (ZIKV) outbreak and its link to microcephaly and other neurological conditions, we performed a drug repurposing screen of ∼6,000 compounds that included approved drugs, clinical trial drug candidates and pharmacologically active compounds; we identified compounds that either inhibit ZIKV infection or suppress infection-induced caspase-3 activity in different neural cells. A pan-caspase inhibitor, emricasan, inhibited ZIKV-induced increases in caspase-3 activity and protected human cortical neural progenitors in both monolayer and three-dimensional organoid cultures. Ten structurally unrelated inhibitors of cyclin-dependent kinases inhibited ZIKV replication. Niclosamide, a category B anthelmintic drug approved by the US Food and Drug Administration, also inhibited ZIKV replication. Finally, combination treatments using one compound from each category (neuroprotective and antiviral) further increased protection of human neural progenitors and astrocytes from ZIKV-induced cell death. Our results demonstrate the efficacy of this screening strategy and identify lead compounds for anti-ZIKV drug development.
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              Homozygosity mapping: a way to map human recessive traits with the DNA of inbred children.

              An efficient strategy for mapping human genes that cause recessive traits has been devised that uses mapped restriction fragment length polymorphisms (RFLPs) and the DNA of affected children from consanguineous marriages. The method involves detection of the disease locus by virtue of the fact that the adjacent region will preferentially be homozygous by descent in such inbred children. A single affected child of a first-cousin marriage is shown to contain the same total information about linkage as a nuclear family with three affected children. Calculations show that it should be practical to map a recessive disease gene by studying DNA from fewer than a dozen unrelated, affected inbred children, given a complete RFLP linkage map. The method should make it possible to map many recessive diseases for which it is impractical or impossible to collect adequate numbers of families with multiple affected offspring.
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                Author and article information

                Journal
                0404511
                7473
                Science
                Science
                Science (New York, N.Y.)
                0036-8075
                1095-9203
                18 January 2018
                01 June 2017
                07 July 2017
                05 February 2018
                : 357
                : 6346
                : 83-88
                Affiliations
                [1 ]Cancer Research UK Cambridge Institute, Li Ka Shing Centre, University of Cambridge, Robinson Way, Cambridge CB2 0RE, UK
                [3 ]Division of Virology, Department of Pathology, University of Cambridge, Addenbrookes Hospital, Cambridge, UK
                [4 ]Department of Medical Genetics, Cambridge Institute for Medical Research, University of Cambridge, Hills Road, Cambridge, CB2 0XY, UK
                [5 ]Department of Medicine, University of Cambridge, Hills Road, Cambridge, CB2 2QQ, UK
                [6 ]Faculty of Biological Sciences, Astbury Centre for Structural Molecular Biology, University of Leeds, Leeds, LS2 9JT, UK
                [7 ]Department of Human Genetics, Radboud University Medical Centre, Nijmegen, The Netherlands
                [8 ]Institute of Genetic Medicine, Newcastle University, International Centre for Life, Central Parkway, Newcastle upon Tyne, NE1 3BZ, UK
                Author notes
                [* ]Corresponding author. Fanni.Gergely@ 123456cruk.cam.ac.uk
                [2]

                Current address: MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge CB2 0QH, UK

                Article
                PMC5798584 PMC5798584 5798584 ems75691
                10.1126/science.aam9243
                5798584
                28572454
                b7e75013-b92b-4918-ac8d-2357cd45c209
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