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THEULTIMATED EDITIONUS 20170247762A1 TO THE MOUNTDOMAIN ( 19) United States (12 ) Patent Application Publication ( 10) Pub . No. : US 2017/ 0247762 A1 Heiman ( 43 ) Pub . Date: Aug . 31 , 2017 ( 54 ) COMPOSITIONS , METHODS AND USE OF Publication Classification SYNTHETIC LETHAL SCREENING (51 ) Int . CI. C120 1 /68 ( 2006 . 01 ) (71 ) Applicants : THE BOARD INSTITUTE INC ., C12N 15 / 113 ( 2006 .01 ) Cambridge, MA (US ) ; Massachusetts COZK 16 / 40 ( 2006 .01 ) Institute of Technology , Cambridge , A01K 67 /027 (2006 . 01 ) C12N 9 / 22 ( 2006 . 01 ) MA (US ) (52 ) U . S . CI. CPC . .. C12Q 1 /6883 (2013 . 01) ; A01K 67 /0278 (72 ) Inventor : Myriam Heiman , Newton , MA (US ) ( 2013 .01 ) ; C12N 9 / 22 ( 2013 .01 ) ; CO7K 16 / 40 ( 2013 .01 ) ; C12Y 111 /01009 ( 2013 . 01 ) ; C12N (21 ) Appl. No. : 15 /521 , 780 15 / 113 (2013 .01 ) ; AOIK 2267 / 0318 ( 2013 .01 ) ; C12Q 2600 / 118 ( 2013 . 01 ) ; C12Q 2600 / 158 (22 ) PCT Filed : Oct . 27 , 2015 (2013 .01 ) ; C120 2600 / 136 (2013 .01 ) ; C12N ( 86 ) PCT No. : PCT/ US2015 / 057567 2310 / 20 ( 2017 .05 ) ; CO7K 2317 / 34 (2013 .01 ) $ 371 ( C ) ( 1 ), (57 ) ABSTRACT Apr. 25 , 2017 The present invention generally relates to methods of iden ( 2 ) Date : tifying modulators of central nervous system diseases and the use of the modulators in treatment and diagnosis . The methods utilize a novel high throughput screen that includes Related U . S . Application Data injection of a library of barcoded viral vectors expressing (60 ) Provisional application No . 62/ 122, 686 , filed on Oct. shRNA ' s , CRISPR / Cas systems or cDNA ' s into animal 27 , 2014 . models of disease and detecting synthetic lethality . 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US 2017 /0247762 A1 Aug. 31, 2017 COMPOSITIONS , METHODS AND USE OF very difficult . Mental abilities generally decline into demen SYNTHETIC LETHAL SCREENING tia . Complications such as pneumonia , heart disease , and physical injury from falls reduce life expectancy to around RELATED APPLICATIONS AND twenty years from the point at which symptoms begin . There INCORPORATION BY REFERENCE is no cure for Huntington ' s disease , and full- time care is [ 0001] This application claims benefit of and priority to required in the later stages of the disease. U . S . provisional patent application Ser. No . 62 /122 ,686 , [ 0008 ] Treatments for Huntington ' s disease are available filed Oct. 27 , 2014 . to reduce the severity of some of its symptoms ( Frank et al . , [ 0002 ] The foregoing applications, and all documents (2010 ) Drugs 70 ( 5 ): 561 -71 ) . Tetrabenazine was approved cited therein or during their prosecution ( " appln cited docu in 2008 for treatment of chorea in Huntington ' s disease in ments” ) and all documents cited or referenced in the appln the United States . Other drugs that help to reduce chorea cited documents , and all documents cited or referenced include neuroleptics and benzodiazepines . Compounds such herein (“ herein cited documents ” ) , and all documents cited as amantadine are still under investigation but have shown or referenced in herein cited documents , together with any preliminary positive results (Walker , ( 2007 ) Lancet 369 manufacturer ' s instructions , descriptions, product specifica ( 9557 ) : 218 - 28 ) . Hypokinesia and rigidity , especially in tions , and product sheets for any products mentioned herein juvenile cases, can be treated with anti -Parkinson drugs , and or in any document incorporated by reference herein , are myoclonic hyperkinesia can be treated with valproic acid . hereby incorporated herein by reference , and may be employed in the practice of the invention . More specifically , [00091 Huntington ' s disease is caused by a mutation in the all referenced documents are incorporated by reference to Huntingtin gene . Expansion of a CAG ( cytosine - adenine the same extent as if each individual document was specifi guanine ) triplet repeat stretch within the Huntingtin gene cally and individually indicated to be incorporated by ref results in a mutant form of the protein , which gradually damages cells in the brain , through mechanisms that are not erence . fully understood . The length of the trinucleotide repeat FEDERAL FUNDING LEGEND accounts for 60 % of the variation in the age symptoms appear and the rate they progress. The remaining variation is [0003 ) This invention was made with government support due to environmental factors and other genes that influence under grant number NS085880 awarded by the National the mechanism of the disease (Walker , ( 2007) Lancet 369 Institutes of Health . The government has certain rights in the (9557 ) : 218 - 28 ) . invention . [ 0010 ] The diagnosis of Huntington ' s disease is suspected FIELD OF THE INVENTION clinically in the presence of symptoms. The diagnosis can be confirmed through molecular genetic testing which identi [ 0004 ] The present invention generally relates to methods fies the expansion in the Huntingtin gene . Testing of adults of identifying modulators of central nervous system diseases at risk for Huntington disease who have no symptoms using a novel high throughput methodology that includes (asymptomatic ) of the disease has been available for over expressing CRISPR / Cas systems, shRNA ' s or cDNA ' s in ten years . However , this testing cannot accurately predict the animal models of disease . age a person found to carry a Huntington disease causing mutation will begin experiencing symptoms, the severity or BACKGROUND OF THE INVENTION type of symptoms they will experience , or rate of disease [0005 ] Currently there are no cures or effective treatments progression . Other markers for disease progression are for many neurodegenerative diseases . All of the major available , for example , loss of DARPP - 32 striatal expression neurodegenerative diseases display characteristic
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    Downloaded from http://www.jimmunol.org/ by guest on October 2, 2021 is online at: average * The Journal of Immunology , 13 of which you can access for free at: 2012; 189:3947-3956; Prepublished online 17 from submission to initial decision 4 weeks from acceptance to publication September 2012; doi: 10.4049/jimmunol.1200449 http://www.jimmunol.org/content/189/8/3947 Foxp3 Expression Is Required for the Induction of Therapeutic Tissue Tolerance Frederico S. Regateiro, Ye Chen, Adrian R. Kendal, Robert Hilbrands, Elizabeth Adams, Stephen P. Cobbold, Jianbo Ma, Kristian G. Andersen, Alexander G. Betz, Mindy Zhang, Shruti Madhiwalla, Bruce Roberts, Herman Waldmann, Kathleen F. Nolan and Duncan Howie J Immunol cites 35 articles Submit online. Every submission reviewed by practicing scientists ? is published twice each month by Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts http://jimmunol.org/subscription http://www.jimmunol.org/content/suppl/2012/09/17/jimmunol.120044 9.DC1 This article http://www.jimmunol.org/content/189/8/3947.full#ref-list-1 Information about subscribing to The JI No Triage! Fast Publication! Rapid Reviews! 30 days* Why • • • Material References Permissions Email Alerts Subscription Supplementary The Journal of Immunology The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2012 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. This information is current as of October 2, 2021.
  • Intra-Genomic GC Heterogeneity in Sauropsids

    Intra-Genomic GC Heterogeneity in Sauropsids

    Matsubara et al. BMC Genomics 2012, 13:604 http://www.biomedcentral.com/1471-2164/13/604 RESEARCH ARTICLE Open Access Intra-genomic GC heterogeneity in sauropsids: evolutionary insights from cDNA mapping and GC3 profiling in snake Kazumi Matsubara1,7*, Shigehiro Kuraku2,3, Hiroshi Tarui3,8, Osamu Nishimura3,4, Chizuko Nishida5, Kiyokazu Agata4, Yoshinori Kumazawa1 and Yoichi Matsuda6 Abstract Background: Extant sauropsids (reptiles and birds) are divided into two major lineages, the lineage of Testudines (turtles) and Archosauria (crocodilians and birds) and the lineage of Lepidosauria (tuatara, lizards, worm lizards and snakes). Karyotypes of these sauropsidan groups generally consist of macrochromosomes and microchromosomes. In chicken, microchromosomes exhibit a higher GC-content than macrochromosomes. To examine the pattern of intra-genomic GC heterogeneity in lepidosaurian genomes, we constructed a cytogenetic map of the Japanese four-striped rat snake (Elaphe quadrivirgata) with 183 cDNA clones by fluorescence in situ hybridization, and examined the correlation between the GC-content of exonic third codon positions (GC3) of the genes and the size of chromosomes on which the genes were localized. Results: Although GC3 distribution of snake genes was relatively homogeneous compared with those of the other amniotes, microchromosomal genes showed significantly higher GC3 than macrochromosomal genes as in chicken. Our snake cytogenetic map also identified several conserved segments between the snake macrochromosomes and the chicken microchromosomes. Cross-species comparisons revealed that GC3 of most snake orthologs in such macrochromosomal segments were GC-poor (GC3 < 50%) whereas those of chicken orthologs in microchromosomes were relatively GC-rich (GC3 ≥ 50%). Conclusion: Our results suggest that the chromosome size-dependent GC heterogeneity had already occurred before the lepidosaur-archosaur split, 275 million years ago.