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Pathway Analysis Report This report contains the pathway analysis results for the submitted sample ''. Analysis was per- formed against Reactome version 73 on 02/08/2020. The web link to these results is: https://reactome.org/PathwayBrowser/#/ANALYSIS=MjAyMDA4MDIxNDU3NTRfNzM4NDA%3D Please keep in mind that analysis results are temporarily stored on our server. The storage period depends on usage of the service but is at least 7 days. As a result, please note that this URL is only valid for a limited time period and it might have expired. Table of Contents 1. Introduction 2. Properties 3. Genome-wide overview 4. Most significant pathways 5. Pathways details 6. Identifiers found 7. Identifiers not found 1. Introduction Reactome is a curated database of pathways and reactions in human biology. Reactions can be con- sidered as pathway 'steps'. Reactome defines a 'reaction' as any event in biology that changes the state of a biological molecule. Binding, activation, translocation, degradation and classical bio- chemical events involving a catalyst are all reactions. Information in the database is authored by expert biologists, entered and maintained by Reactome’s team of curators and editorial staff. Re- actome content frequently cross-references other resources e.g. NCBI, Ensembl, UniProt, KEGG (Gene and Compound), ChEBI, PubMed and GO. Orthologous reactions inferred from annotation for Homo sapiens are available for 17 non-human species including mouse, rat, chicken, puffer fish, worm, fly, yeast, rice, and Arabidopsis. Pathways are represented by simple diagrams follow- ing an SBGN-like format. Reactome's annotated data describe reactions possible if all annotated proteins and small mo- lecules were present and active simultaneously in a cell. By overlaying an experimental dataset on these annotations, a user can perform a pathway over-representation analysis. By overlaying quantitative expression data or time series, a user can visualize the extent of change in affected pathways and its progression. A binomial test is used to calculate the probability shown for each result, and the p-values are corrected for the multiple testing (Benjamini–Hochberg procedure) that arises from evaluating the submitted list of identifiers against every pathway. To learn more about our Pathway Analysis, please have a look at our relevant publications: Fabregat A, Sidiropoulos K, Garapati P, Gillespie M, Hausmann K, Haw R, … D’Eustachio P (2016). The reactome pathway knowledgebase. Nucleic Acids Research, 44(D1), D481–D487. https://doi.org/10.1093/nar/gkv1351. Fabregat A, Sidiropoulos K, Viteri G, Forner O, Marin-Garcia P, Arnau V, … Hermjakob H (2017). Reactome pathway analysis: a high-performance in-memory approach. BMC Bioinformatics, 18. https://reactome.org Page 2 2. Properties • This is an overrepresentation analysis: A statistical (hypergeometric distribution) test that de- termines whether certain Reactome pathways are over-represented (enriched) in the submit- ted data. It answers the question ‘Does my list contain more proteins for pathway X than would be expected by chance?’ This test produces a probability score, which is corrected for false discovery rate using the Benjamani-Hochberg method. • 214 out of 1185 identifiers in the sample were found in Reactome, where 1329 pathways were hit by at least one of them. • All non-human identifiers have been converted to their human equivalent. • IntAct interactors were included to increase the analysis background. This greatly increases the size of Reactome pathways, which maximises the chances of matching your submitted identifiers to the expanded pathway, but will include interactors that have not undergone manual curation by Reactome and may include interactors that have no biological signific- ance, or unexplained relevance. • This report is filtered to show only results for species 'Homo sapiens' and resource 'all re- sources'. • The unique ID for this analysis (token) is MjAyMDA4MDIxNDU3NTRfNzM4NDA%3D. This ID is valid for at least 7 days in Reactome’s server. Use it to access Reactome services with your data. https://reactome.org Page 3 3. Genome-wide overview Chromatin Metabolism organization Immune System of RNA Programmed DNA Replication Cell Cycle Cell Death Digestion and absorption DNA Repair Circadian Clock 0 Muscle Reproduction contraction Cellular responses Developmental to external stimuli Biology Signal Metabolism Transport of Transduction small molecules Organelle biogenesis Autophagy and maintenance Protein localization Extracellular matrix organization 0.05 Neuronal System Vesicle-mediated Metabolism transport of proteins Disease Hemostasis Gene expression (Transcription) Cell-Cell communication This figure shows a genome-wide overview of the results of your pathway analysis. Reactome path- ways are arranged in a hierarchy. The center of each of the circular "bursts" is the root of one top- level pathway, for example "DNA Repair". Each step away from the center represents the next level lower in the pathway hierarchy. The color code denotes over-representation of that pathway in your input dataset. Light grey signifies pathways which are not significantly over-represented. https://reactome.org Page 4 4. Most significant pathways The following table shows the 25 most relevant pathways sorted by p-value. Entities Reactions Pathway name found ratio p-value FDR* found ratio Interleukin-33 signaling 2 / 6 2.87e-04 0.06 1 2 / 2 1.54e-04 GABA synthesis 2 / 6 2.87e-04 0.06 1 2 / 2 1.54e-04 Defective SLC2A1 causes GLUT1 1 / 2 9.56e-05 0.123 1 1 / 1 7.71e-05 deficiency syndrome 1 (GLUT1DS1) Defective MGAT2 causes MGAT2- 1 / 3 1.43e-04 0.179 1 1 / 1 7.71e-05 CDG (CDG-2a) Defective GALK1 can cause 1 / 3 1.43e-04 0.179 1 1 / 1 7.71e-05 Galactosemia II (GALCT2) Evasion of Oncogene Induced Senescence Due to Defective 1 / 3 1.43e-04 0.179 1 1 / 1 7.71e-05 p16INK4A binding to CDK4 and CDK6 Defective SLC20A2 causes idiopathic 1 / 3 1.43e-04 0.179 1 1 / 1 7.71e-05 basal ganglia calcification 1 (IBGC1) Evasion of Oxidative Stress Induced Senescence Due to Defective 1 / 3 1.43e-04 0.179 1 1 / 1 7.71e-05 p16INK4A binding to CDK4 and CDK6 Defective SLC22A5 causes systemic 1 / 3 1.43e-04 0.179 1 1 / 1 7.71e-05 primary carnitine deficiency (CDSP) Proton-coupled monocarboxylate 2 / 12 5.74e-04 0.187 1 2 / 2 1.54e-04 transport Serotonin receptors 2 / 13 6.21e-04 0.211 1 2 / 3 2.31e-04 Defective ABCB6 causes isolated colobomatous microphthalmia 7 1 / 4 1.91e-04 0.231 1 1 / 1 7.71e-05 (MCOPCB7) Utilization of Ketone Bodies 2 / 15 7.17e-04 0.259 1 1 / 3 2.31e-04 Defective SLCO2A1 causes primary, autosomal recessive hypertrophic 1 / 5 2.39e-04 0.28 1 1 / 1 7.71e-05 osteoarthropathy 2 (PHOAR2) Defective SLC3A1 causes cystinuria 1 / 6 2.87e-04 0.326 1 1 / 1 7.71e-05 (CSNU) Defective SLC7A9 causes cystinuria 1 / 6 2.87e-04 0.326 1 1 / 1 7.71e-05 (CSNU) NTF4 activates NTRK2 (TRKB) 1 / 6 2.87e-04 0.326 1 2 / 3 2.31e-04 signaling Adenylate cyclase inhibitory 2 / 18 8.60e-04 0.331 1 5 / 5 3.86e-04 pathway Hormone ligand-binding receptors 3 / 18 8.60e-04 0.331 1 2 / 4 3.09e-04 Defective SLC16A1 causes symptomatic deficiency in lactate 1 / 7 3.35e-04 0.369 1 1 / 1 7.71e-05 transport (SDLT) https://reactome.org Page 5 Entities Reactions Pathway name found ratio p-value FDR* found ratio BDNF activates NTRK2 (TRKB) 1 / 7 3.35e-04 0.369 1 2 / 3 2.31e-04 signaling NTF3 activates NTRK2 (TRKB) 1 / 7 3.35e-04 0.369 1 2 / 3 2.31e-04 signaling Proton-coupled neutral amino acid 1 / 7 3.35e-04 0.369 1 1 / 2 1.54e-04 transporters Cellular hexose transport 3 / 34 0.002 0.387 1 5 / 17 0.001 Activation of GABAB receptors 4 / 49 0.002 0.402 1 8 / 8 6.17e-04 * False Discovery Rate https://reactome.org Page 6 5. Pathways details For every pathway of the most significant pathways, we present its diagram, as well as a short sum- mary, its bibliography and the list of inputs found in it. 1. Interleukin-33 signaling (R-HSA-9014843) https://reactome.org Page 7 Interleukin-33 (IL33) cytokine is a member of the Interleukin-1 family. It can be classified as an alarmin because it is released into the extracellular space during cell damage. It acts as an endo- genous danger signal (Liew et al. 2010).] The gene product is biologically active (full-length IL33). Its potency has been reported to increase significantly (up to 30x) after cleavage at the N-terminus by inflammatory proteases such as Cathep- sin G (CTSG) and Neutrophil elastase (ELANE) (Lefrançais et al. 2012, Lefrançais et al. 2014) but oth- ers have suggested that processing inactivates IL33 (Cayrol & Girard 2009). IL33 can act as an extra- cellular ligand and an intracellular signaling molecule (Martin et al. 2013, 2016). Full-length IL33 has a nuclear localization sequence and can translocate to the nucleus, where it binds heterochro- matin (Moussion et al. 2008, Carriere et al. 2007, Roussel et al. 2008, Kuchler et al. 2008, Sundli- saeter et al. 2012, Baekkevold et al. 2003). IL33 that has undergone proteolytic processing is unable to translocate to the nucleus (Martin et al. 2013, Ali et al. 2010). Binding of extracellular IL33 to its receptor Interleukin-1 receptor-like 1 (IL1RL1, suppression of tu- morigenicity 2, ST2) initiates several cellular signaling pathways. Cell injury or death are the dom- inant mechanisms by which IL33 reaches the extracellular environment, IL33 is not actively secreted by cells (Martin et al.
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  • (12) United States Patent (10) Patent No.: US 9,163,078 B2 Rao Et Al

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    US009 163078B2 (12) United States Patent (10) Patent No.: US 9,163,078 B2 Rao et al. (45) Date of Patent: *Oct. 20, 2015 (54) REGULATORS OF NFAT 2009.0143308 A1 6, 2009 Monk et al. 2009,0186422 A1 7/2009 Hogan et al. (75) Inventors: Anjana Rao, Cambridge, MA (US); 2010.0081129 A1 4/2010 Belouchi et al. Stefan Feske, New York, NY (US); Patrick Hogan, Cambridge, MA (US); FOREIGN PATENT DOCUMENTS Yousang Gwack, Los Angeles, CA (US) CN 1329064 1, 2002 EP O976823. A 2, 2000 (73) Assignee: Children's Medical Center EP 1074617 2, 2001 Corporation, Boston, MA (US) EP 1293569 3, 2003 WO 02A30976 A1 4, 2002 (*) Notice: Subject to any disclaimer, the term of this WO O2/O70539 9, 2002 patent is extended or adjusted under 35 WO O3/048.305 6, 2003 U.S.C. 154(b) by 0 days. WO O3/052049 6, 2003 WO WO2005/O16962 A2 * 2, 2005 This patent is Subject to a terminal dis- WO 2005/O19258 3, 2005 claimer. WO 2007/081804 A2 7, 2007 (21) Appl. No.: 13/161,307 OTHER PUBLICATIONS (22) Filed: Jun. 15, 2011 Skolnicket al., 2000, Trends in Biotech, vol. 18, p. 34-39.* Tomasinsig et al., 2005, Current Protein and Peptide Science, vol. 6, (65) Prior Publication Data p. 23-34.* US 2011 FO269174 A1 Nov. 3, 2011 Smallwood et al., 2002, Virology, vol. 304, p. 135-145.* • - s Chattopadhyay et al., 2004. Virus Research, vol. 99, p. 139-145.* Abbas et al., 2005, computer printout pp. 2-6.* Related U.S.