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(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date WO 2015/035367 Al 12 March 2015 (12.03.2015) P O P C T (51) International Patent Classification: (72) Inventors; and C12Q 1/68 (2006.01) (71) Applicants : SALOMON, Daniel [US/US]; 4728 Reedley Terrace, San Diego, CA 92130 (US). KURIAN, Sunil, M. (21) International Application Number: [IN/US]; 10963 Tobago Road, San Diego, CA 92126 (US). PCT/US2014/054735 HEAD, Steven [US/US]; 11673 Valle Vista Road, (22) International Filing Date: Lakeside, CA 92040 (US). ABECASSIS, Michael, M. >September 2014 (09.09.2014) [US/US]; 1975 Keats Court, Highland Park, IL 60035 (US). FRIEDEWALD, John, J. [US/US]; 3315 N . Lake- (25) Filing Language: English wood Avenue, Chicago, IL 60657 (US). LEVITSKY, (26) Publication Language: English Josh [US/US]; 1308 Judson, Evanston, IL 60201 (US). (30) Priority Data: (74) Agents: FITTING, Thomas et al; The Scripps Research 61/875,276 ' September 2013 (09.09.2013) US Institute, 10550 North Torrey Pines Road, TPC-8, La Jolla, 61/965,040 16 January 2014 (16.01.2014) US CA 92037 (US). 62/001,889 22 May 2014 (22.05.2014) US (81) Designated States (unless otherwise indicated, for every 22 May 2014 (22.05.2014) US 62/001,909 kind of national protection available): AE, AG, AL, AM, 62/001,902 22 May 2014 (22.05.2014) US AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, 62/029,038 25 July 2014 (25.07.2014) US BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, (71) Applicants: THE SCRIPPS RESEARCH INSTITUTE DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, [US/US]; 10550 North Torrey Pines Road, La Jolla, CA HN, HR, HU, ID, IL, IN, IR, IS, JP, KE, KG, KN, KP, KR, 92037 (US). NORTHWESTERN UNIVERSITY KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, MG, [US/US]; 633 Clark Street, Evanston, IL 60208 (US). MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, SC, [Continued on nextpage] (54) Title: METHODS AND SYSTEMS FOR ANALYSIS OF ORGAN TRANSPLANTATION Fig. 1 (57) Abstract: Disclosed herein are methods of detecting, predicting or monitoring a status or outcome of a transplant in a transplant recipient. In some aspects, a method for detecting or predicting a condition of a transplant recipient comprises a) 110. Obtain sample from a obtaining a sample, wherein the sample comprises one or transplant recipient more gene expression products from the transplant recipient; b) performing an assay to determine an expression level of the one or more gene expression products from the transplant re cipient; and c) detecting or predicting the condition of the transplant recipient by applying an algorithm to the expres 120. Perform assay to sion level determined in step (b), wherein the algorithm is a determine gene expression classifier capable of distinguishing between at least two con level ditions that are not normal conditions, and wherein one of the at least two conditions is transplant rejection or transplant dysfunction. 130. Apply computer algorithm to tire gene expression level 140. Classification Class A Class C based on the results © o o w o 2015/035367 AI Iinn iiiiiii 1mil i mil il i 1ill inn i l i i i imill i i i SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. LU, LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, (84) Designated States (unless otherwise indicated, for every GN, GQ, GW, KM, ML, MR, NE, SN, TD, TG). kind of regional protection available): ARIPO (BW, GH, GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, Published: TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, — with international search report (Art. 21(3)) TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, METHODS AND SYSTEMS FOR ANALYSIS OF ORGAN TRANSPLANTATION CROSS REFERENCE TO RELATED APPLICATIONS [0002] This application claims the benefit of U.S. Provisional Application No. 61/875,276 filed on September 9, 2013, U.S. Provisional Application No. 61/965,040 filed on January 16, 2014, U.S. Provisional Application No. 62/001,889 filed on May 22, 2014, U.S. Provisional Application No. 62/029,038 filed on July 25, 2014, U.S. Provisional Application No. 62/001,909 filed on May 22, 2014, and U.S. Provisional Application No. 62/001,902 filed on May 22, 2014, all of which are incorporated herein by reference in their entireties. GOVERNMENT RIGHTS [0003] This invention was made with government support under Grant Numbers AI052349, AI084146, and AI063603 awarded by the National Institutes of Health. The government has certain rights in the invention. BACKGROUND [0004] The current method for detecting organ rejection in a patient is a biopsy of the transplanted organ. However, organ biopsy results can be inaccurate, particularly if the area biopsied is not representative of the health of the organ as a whole (e.g., as a result of sampling error). There can be significant differences between individual observors when they read the same biopsies independently and these discrepancies are particularly an issue for complex histologies that can be challenging for clinicians. Biopsies, especially surgical biopsies, can also be costly and pose significant risks to a patient. In addition, the early detection of rejection of a transplant organ may require serial monitoring by obtaining multiple biopsies, thereby multiplying the risks to the patients, as well as the associated costs. [0005] Transplant rejection is a marker of ineffective immunosuppression and ultimately if it cannot be resolved, a failure of the chosen therapy. The fact that 50% of kidney transplant patients will lose their grafts by ten years post transplant reveals the difficulty of maintaining adequate and effective longterm immunosuppression. There is a need to develop a minimally invasive, objective metric for detecting, identifying and tracking transplant rejection. In particular, there is a need to develop a minimally invasive metric for detecting, identifying and tracking transplant rejection in the setting of a confounding diagnosis, such as acute dysfunction with no rejection. This is especially true for identifying the rejection of a transplanted kidney. For example, elevated creatinine levels in a kidney transplant recipient may indicate either that the patient is undergoing an acute rejection or acute dysfunction without rejection. A minimally- invasive test that is capable of distinguishing between these two conditions would therefore be extremely valuable and would diminish or eliminate the need for costly, invasive biopsies. SUMMARY [0006] The methods and systems disclosed herein may be used for detecting or predicting a condition of a transplant recipient (e.g., acute transplant rejection, acute dysfunction without rejection, subclinical acute rejection, hepatitis C virus recurrence, etc.). In some aspects, a method for detecting or predicting a condition of a transplant recipient comprises a) obtaining a sample, wherein the sample comprises one or more gene expression products from the transplant recipient; b) performing an assay to determine an expression level of the one or more gene expression products from the transplant recipient; and c) detecting or predicting the condition of the transplant recipient by applying an algorithm to the expression level determined in step (b), wherein the algorithm is a classifier capable of distinguishing between at least two conditions that are not normal conditions, and wherein one of the at least two conditions is transplant rejection or transplant dysfunction. In another embodiment, a method for detecting or predicting a condition of a transplant recipient comprises a) obtaining a sample, wherein the sample comprises one or more gene expression products from the transplant recipient; b) performing an assay to determine an expression level of the one or more gene expression products from the transplant recipient; and c) detecting or predicting the condition of the transplant recipient by applying an algorithm to the expression level determined in step (b), wherein the algorithm is a classifier capable of distinguishing between at least two conditions that are not normal conditions, and wherein one of the at least two conditions is transplant rejection. In another embodiment, a method for detecting or predicting a condition of a transplant recipient comprises a) obtaining a sample, wherein the sample comprises one or more gene expression products from the transplant recipient; b) performing an assay to determine an expression level of the one or more gene expression products from the transplant recipient; and c) detecting or predicting the condition of the transplant recipient by applying an algorithm to the expression level determined in step (b), wherein the algorithm is a classifier capable of distinguishing between at least two conditions that are not normal conditions, and wherein one of the at least two conditions is transplant dysfunction. In some cases, the transplant recipient is a kidney transplant recipient. In some cases, the transplant recipient is a liver transplant recipient. [0007] In some embodiments, a method of detecting or predicting a condition of a transplant recipient comprises: a) obtaining a sample, wherein the sample comprises one or more gene expression products from the transplant recipient; b) performing an assay to determine an expression level of the one or more gene expression products from the transplant recipient; and c) detecting or predicting the condition of the transplant recipient by applying an algorithm to the expression level determined in step (b), wherein the algorithm is capable of distinguishing between acute rejection and transplant dysfunction with no rejection.
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  • Diversification of AID/APOBEC-Like Deaminases in Metazoa: Multiplicity

    Diversification of AID/APOBEC-Like Deaminases in Metazoa: Multiplicity

    Diversification of AID/APOBEC-like deaminases in PNAS PLUS metazoa: multiplicity of clades and widespread roles in immunity Arunkumar Krishnana, Lakshminarayan M. Iyera, Stephen J. Hollandb, Thomas Boehmb, and L. Aravinda,1 aNational Center for Biotechnology Information, National Library of Medicine, National Institutes of Health, Bethesda, MD 20894; and bDepartment of Developmental Immunology, Max Planck Institute of Immunobiology and Epigenetics, 79108 Freiburg, Germany Edited by Anjana Rao, La Jolla Institute and University of California San Diego, La Jolla, CA, and approved February 23, 2018 (received for review November 30, 2017) AID/APOBEC deaminases (AADs) convert cytidine to uridine in viruses and retrotransposons through hypermutation of DNA during single-stranded nucleic acids. They are involved in numerous muta- reverse transcription (APOBEC3s) (21). genic processes, including those underpinning vertebrate innate and The deaminase superfamily displays a conserved β-sheet with adaptive immunity. Using a multipronged sequence analysis strategy, five β-strands arranged in 2-1-3-4-5 order interleaved with three we uncover several AADs across metazoa, dictyosteliida, and algae, α-helices forming an α/β-fold (the deaminase fold) (22), which it including multiple previously unreported vertebrate clades, and shares with JAB/RadC, AICAR transformylase, formate de- versions from urochordates, nematodes, echinoderms, arthropods, hydrogenase accessory subunit (FdhD), and Tm1506 superfamilies lophotrochozoans, cnidarians, and porifera. Evolutionary analysis sug- of proteins. The active site consists of two zinc (Zn)-chelating gests a fundamental division of AADs early in metazoan evolution into motifs, respectively typified by the signatures HxE/CxE/DxE at secreted deaminases (SNADs) and classical AADs, followed by diver- the end of helix 2 and CxnC (where x is any amino acid and n is ≥2) sification into several clades driven by rapid-sequence evolution, gene located in loop 5 and the beginning of helix 3 (Fig.
  • Insights Into the Structures and Multimeric Status of APOBEC Proteins Involved in Viral Restriction and Other Cellular Functions

    Insights Into the Structures and Multimeric Status of APOBEC Proteins Involved in Viral Restriction and Other Cellular Functions

    viruses Review Insights into the Structures and Multimeric Status of APOBEC Proteins Involved in Viral Restriction and Other Cellular Functions Xiaojiang S. Chen 1,2,3 1 Molecular and Computational Biology, Departments of Biological Sciences, Chemistry, University of Southern California, Los Angeles, CA 90089, USA; [email protected]; Tel.: +1-213-740-5487 2 Genetic, Molecular and Cellular Biology Program, Keck School of Medicine, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA 90089, USA 3 Center of Excellence in NanoBiophysics/Structural Biology, University of Southern California, Los Angeles, CA 90089, USA Abstract: Apolipoprotein B mRNA editing catalytic polypeptide-like (APOBEC) proteins belong to a family of deaminase proteins that can catalyze the deamination of cytosine to uracil on single- stranded DNA or/and RNA. APOBEC proteins are involved in diverse biological functions, including adaptive and innate immunity, which are critical for restricting viral infection and endogenous retroelements. Dysregulation of their functions can cause undesired genomic mutations and RNA modification, leading to various associated diseases, such as hyper-IgM syndrome and cancer. This review focuses on the structural and biochemical data on the multimerization status of individual APOBECs and the associated functional implications. Many APOBECs form various multimeric complexes, and multimerization is an important way to regulate functions for some of these proteins at several levels, such as deaminase activity, protein stability, subcellular localization, protein storage Citation: Chen, X.S. Insights into and activation, virion packaging, and antiviral activity. The multimerization of some APOBECs is the Structures and Multimeric Status more complicated than others, due to the associated complex RNA binding modes.