2016-10-14T12:56:29-05:00 2015-11-30 861065772 DELOITTE TAX LLP 200 RENAISSANCE CENTER STE 3900 DETROIT MI 48243 990 2014-12-01 522000823 VAN ANDEL RESEARCH INSTITUTE VANA 6162345000 333 BOSTWICK AVENUE NE GRAND RAPIDS MI 49503 TIMOTHY J MYERS VICE PRESIDENT & CFO 6162345368 2016-10-14 1 ANNE FULTON P00941863 3133963000 2014 2017-02-10 21:41:12Z TIMOTHY J MYERS 333 BOSTWICK AVENUE NE GRAND RAPIDS MI 49503 72413434 0 X WWW.VAI.ORG X 1996 MI MEDICAL RESEARCH ORGANIZATION 4 2 399 0 112851 29059 67009142 56036129 1460533 1466232 260434 456048 6325873 7489858 75055982 65448267 201907 764340 0 0 29232885 32131259 0 0 1066552 37139975 36245067 66574767 69140666 8481215 -3692399 251725432 250842142 327697622 338375403 -75972190 -87533261 X MEDICAL RESEARCH ORGANIZATION VAN ANDEL RESEARCH INSTITUTE IS AN INDEPENDENT BIOMEDICAL RESEARCH ORGANIZATION COMMITTED TO IMPROVING THE HEALTH AND ENHANCING THE LIVES OF CURRENT AND FUTURE GENERATIONS. 0 0 10257392 237942 901159 CENTER FOR CANCER AND CELL BIOLOGY SCHEDULE O PROVIDES FURTHER INFORMATION REGARDING THIS PROGRAM'S ACCOMPLISHMENTS. 6153116 520190 0 CENTER FOR EPIGENETICSSCHEDULE O PROVIDES FURTHER INFORMATION REGARDING THIS PROGRAM'S ACCOMPLISHMENTS. 4180425 6208 192143 CENTER FOR NEURODEGENERATIVE SCIENCESEE SCHEDULE O FOR FURTHER INFORMATION ABOUT THIS PROGRAM'S ACCOMPLISHMENTS. 26043187 0 372930 26043187 372930 46634120 1 1 0 1 0 0 0 0 0 0 1 0 0 1 1 1 0 1 0 1 1 1 0 0 1 0 0 1 1 1 1 0 0 0 0 0 0 0 0 0 1 0 0 0 0 1 1 1 1 0 0 1 117 0 399 1 1 1 0 0 0 0 0 0 0 0 0 X 4 2 1 0 0 0 0 1 0 1 1 0 0 1 1 1 1 1 1 1 1 0 MI X TIMOTHY J MYERS VICE PRESIDENT & CFO 6162345368 333 BOSTWICK AVENUE NE GRAND RAPIDS MI 495032518 DAVID VAN ANDEL CHAIRMAN / CEO 36.00 17.00 X X 445515 0 136845 DR GEORGE VANDE WOUDE TRUSTEE/ INVESTIGATOR 45.00 0.00 X 302486 0 27326 DR JAMES FAHNER TRUSTEE 1.00 1.00 X 10000 2000 0 DR RALPH WEICHSELBAUM TRUSTEE 1.00 0.00 X 9000 0 0 DR GARY TARPLEY DONE 10715 TRUSTEE 1.00 0.00 X 10000 0 0 DR JANA HALL CHIEF OPERATIONS OFFICER 50.00 3.00 X 354023 0 106110 DAVID WHITESCARVER SECRETARY/V.P. & CHIEF LEGAL OFFICER 50.00 3.00 X 372187 0 105189 TIMOTHY MYERS V.P. & CHIEF FINANCIAL OFFICER 50.00 3.00 X 256638 0 83296 DR PETER JONES START 21714 CHIEF SCIENTIFIC OFFICER & RES. DIR. 53.00 0.00 X 432331 0 194171 KATHY VOGELSANG CHIEF INVESTMENT OFFICER 45.00 0.00 X 410046 0 216167 DR PATRIK BRUNDIN VARI ASSOCIATE DIRECTOR OF RESEARCH 45.00 0.00 X 502889 0 99267 DR GERALD CALLAHAN V.P., INNOVATIONS & COLLABORATIONS 45.00 0.00 X 311438 0 118810 DR SCOTT JEWELL INVESTIGATOR 45.00 0.00 X 354571 0 60446 DR H ERIC XU INVESTIGATOR 45.00 0.00 X 308932 0 50718 4080056 2000 1198345 60 0 1 0 CLARIENT DIAGNOSTIC SERVICES PO BOX 748196 LOS ANGELES CA 900748196 SCIENTIFIC SERVICES 560280 DK SECURITY INC 5160 FALCONVIEW AVE SE KENTWOOD MI 49512 SECURITY SERVICES 390529 FEDERAL EXPRESS PO BOX 223125 PITTSBURGH PA 152512125 SHIPPING 255699 BLUEWATER TECHNOLOGIES INC 24050 NORTHWESTERN HWY SOUTHFIELD MI 48075 AUDIO VISUAL SERVICES 196462 HOGAN LOVELLS US LLP COLUMBIA SQUARE 555 THIRTEENTH ST WASHINGTON DC 20004 LEGAL / CONSULTING 165119 16 49013 37825510 14181319 3980287 19286 56036129 RESEARCH BILLED REV 541700 1466232 1353381 112851 1466232 388556 388556 624474 624474 1505857 1400515 105342 105342 105342 5453960 170114 5465277 91305 -11317 78809 67492 67492 0 49013 8070 -8070 -8070 ALLOCATED ADMIN. EXP. 561000 6458393 6458393 REIMBURSED EXPENSES 900099 191104 191104 118615 118615 6768112 65448267 1353381 112851 7945906 352667 352667 261494 261494 150179 150179 2686112 1061907 1624205 23149989 13725800 8657351 766838 1683543 1007752 631268 44523 3014640 1804565 1130924 79151 1596975 955987 599763 41225 444805 47991 396814 128300 128300 45500 45500 2839850 2331875 499790 8185 1002668 81114 843854 77700 98687 55224 43130 333 257773 119336 133361 5076 2224334 1971415 251199 1720 761554 389266 358539 13749 263443 209003 54440 8630838 7180473 1450365 9304114 7999395 1304719 471162 286218 184944 LAB SUPPLIES & SERVICES 3636360 3614210 22150 0 EQUIPMENT & SOFTWARE 2753651 1320986 1426318 6347 BAD DEBT EXPENSE 614600 0 614600 0 ALLOCATED EXPENSES 550593 550593 0 0 2216835 1156670 1038460 21705 69140666 46634120 21439994 1066552 12177780 9808077 2575159 2205839 2523497 2855772 9657 0 1555278 1516647 1522498 1460528 272522203 83690445 193472540 188831758 1268817 1154264 36620206 43009257 251725432 250842142 44640472 51117987 2206247 1092693 220000000 220000000 60850903 66164723 327697622 338375403 X -78281142 -90432320 2215852 2794926 93100 104133 -75972190 -87533261 251725432 250842142 X -3692399 -114553 5955 -7760074 X 0 1 X 1 1 1 X SPECTRUM HEALTH GRAND RAPIDS MI RESTRICTED RESTRICTED RESTRICTED RESTRICTED RESTRICTED RESTRICTED RESTRICTED RESTRICTED 165579 165579 68975087 69140666 1000000 250000 0 0 1000000 1000000 1000000 1000000 4000000 6000000 68133 85680 367563 165579 686955 250000 250000 250000 250000 1000000 1500000 5288315 5288315 222174587 49169393 173005194 43739193 34504551 9234642 1320108 16501 1303607 188831758 BOND ISSUANCE COSTS NET OF ACCUMULATED AMORTIZATION 299257 PLEDGED SECURITIES 42710000 43009257 ACCRUED POSTRETIREMENT BENEFIT OBLIGATION 2036797 UNREALIZED LOSS ON INTEREST RATE SWAP 64074672 CAPITAL LEASE 53254 66164723 X 60289861 -114553 5955 1408585 1299987 58989874 6458393 6458393 65448267 71850932 9168659 9168659 62682273 6458393 6458393 69140666 PART X, LINE 2: PART X, LINE 1(1) AND LINE 2: THERE ARE NO UNCERTAIN TAX POSITIONS RELATED TO VARI. PART XI, LINE 2D - OTHER ADJUSTMENTS: RENTAL EXPENSES 1,400,515. FUNDRAISING EVENT EXPENSE 8,070. PART XI, LINE 4B - OTHER ADJUSTMENTS: NET ALLOCATED 6,458,393. PART XII, LINE 2D - OTHER ADJUSTMENTS: LOSS ON INTERST RATE SWAP 7,760,074. RENTAL EXPENSES 1,400,515. FUNDRAISING EVENT EXPENSE 8,070. PART XII, LINE 4B - OTHER ADJUSTMENTS: NET ALLOCATED 6,458,393. PART V THE VAN ANDEL INSTITUTE (A RELATED ORGANIZATION) MAINTAINS ENDOWED FUNDS FOR THE BENEFIT OF BOTH VARI AND THE VAN ANDEL EDUCATION INSTITUTE (A RELATED ORGANIZATION) TO FUND OPERATING EXPENSES. PART XI AND XII, LINE 4B EXPENSE ALLOCATIONS PRESENTED WITHIN REVENUE. 1 EAST ASIA & THE PACIFIC 0 0 PROGRAM SERVICES RESEARCH COLLABORATION - RESEARCH SERVICES 134783 EUROPE 0 0 GENERAL EXPENSES SOFTWARE LICENSING FEES 1065 EUROPE 0 0 UNRELATED TRADE OR BUSINESS FEE FOR SERVICES EUROPE 0 0 RESEARCH SERVICES LICENSING FEES 0 0 0 0 0 0 135848 0 135848 EUROPE RESEARCH COLLABORATION 150179 WIRE TRANSFER 1 0 0 0 0 0 0 PART I, LINE 2: GRANT FUNDS ARE MONITORED BY QUARTERLY EXPENDITURE REPORTS BEFORE DISBURSING INCREMENTAL FUNDING. PROGRESS REPORTS ARE REQUIRED ANNUALLY AND REVIEWED BY VAN ANDEL RESEARCH INSTITUTE AND A THIRD PARTY. SCHEDULE F, PART II, LINE 1 ORGANIZATION PROVIDED ASSISTANCE IS MONITORED WITH QUARTERLY EXPENDITURE REPORTING. 5K RACE 49013 49013 8070 49013 49013 8070 8070 -8070 1 JOHNS HOPKINS UNIVERSITY 3400 N CHARLES STREET BALTIMORE MD 21218 520595110 501C3 200000 RESEARCH COLLABORATION FOX CHASE CANCER CENTER 333 COTTMAN AVENUE PHILADELPHIA PA 19111 232003072 501C3 100000 RESEARCH COLLABORATION MEMORIAL SLOAN-KETTERING CANCER CENTER 1275 YORK AVENUE NEW YORK NY 10065 131924236 501C3 50000 RESEARCH COLLABORATION 3 0 GRADUATE STUDENT STIPENDS FOR MICHIGAN STATE UNIVERSITY STUDENTS 5 134127 GRADUATE STUDENT STIPENDS VAN ANDEL INSTITUTE GRADUATE SCHOOL 3 47503 FOREIGN NATIONAL STIPENDS 6 79864 PART I, LINE 2: STIPENDS ARE PROVIDED TO THE RESEARCH STUDENTS FOR LIVING AND INSURANCE ASSISTANCE. GRANT FUNDS TO INSTITUTIONS ARE MONITORED BY QUARTERLY EXPENDITURE REPORTS BEFORE DISBURSING INCREMENTAL FUNDING. PROGRESS REPORTS ARE REQUIRED ANNUALLY AND REVIEWED BY VAN ANDEL RESEARCH INSTITUTE AND A THIRD PARTY. X 1 1 X X X X X 0 0 0 0 0 0 0 1 0 DAVID VAN ANDEL CHAIRMAN / CEO 315000 0 107730 0 22785 0 136250 0 595 0 582360 0 107730 0 DR GEORGE VANDE WOUDE TRUSTEE/ INVESTIGATOR 282514 0 0 0 19972 0 26000 0 1326 0 329812 0 0 0 DR JANA HALL CHIEF OPERATIONS OFFICER 292928 0 59294 0 1801 0 97343 0 8767 0 460133 0 59294 0 DAVID WHITESCARVER SECRETARY/V.P. & CHIEF LEGAL OFFICER 270910 0 82096 0 19181 0 96422 0 8767 0 477376 0 82096 0 TIMOTHY MYERS V.P. & CHIEF FINANCIAL OFFICER 215939 0 40091 0 608 0 74529 0 8767 0 339934 0 40091 0 DR PETER JONES START 21714 CHIEF SCIENTIFIC OFFICER & RES. DIR. 397346 0 0 0 34985 0 186500 0 7671 0 626502 0 0 0 KATHY VOGELSANG CHIEF INVESTMENT OFFICER 204180 0 187500 0 18366 0 207400 0 8767 0 626213 0 0 0 DR PATRIK BRUNDIN VARI ASSOCIATE DIRECTOR OF RESEARCH 401680 0 86040 0 15169 0 90500 0 8767 0 602156 0 86040 0 DR GERALD CALLAHAN V.P., INNOVATIONS & COLLABORATIONS 245257 0 54263 0 11918 0 110043 0 8767 0 430248 0 54263 0 DR SCOTT JEWELL INVESTIGATOR 266775 0 67569 0 20227 0 61679 0 8767 0 425017 0 32312 0 DR H ERIC XU INVESTIGATOR 288693 0 19297 0 942 0 41951 0 8767 0 359650 0 19297 0 PART I, LINE 1A VARI ALLOWS FOR FIRST-CLASS OR CHARTER TRAVEL FOR OFFICERS AND TRUSTEES. PART I, LINE 7 ONE NON-FIXED BONUS WAS PAID AT THE DISCRETION OF THE CEO. A MICHIGAN STRATEGIC FUND 521417332 2013-04-01 220000000 REFUND BOND ISSUE 4/10/08 0 0 0 A 220000000 220000000 1 0 1 1 A 0 1 1 1 1 1 0.00890 0.00890 0 0 1 A 0 0 0 1 1 0 0 0 1 A 1 DATE REBATE COMPUTATION PERFORMED ISSUER NAME: MICHIGAN STRATEGIC FUND DATE THE REBATE COMPUTATION WAS PERFORMED: 11/30/2014 DONOR VENDOR 189366 SUPPLIES 0 FORM 990, PART VI, SECTION A, LINE 2 VARI, VAI, VAEI, AND VAIGS SHARE COMMON MANAGEMENT. DAVID VAN ANDEL, DR. JANA HALL, TIMOTHY MYERS AND DAVID WHITESCARVER ARE ALSO OFFICERS OF VAI, AND DAVID VAN ANDEL, TIMOTHY MYERS AND DAVID WHITESCARVER ARE OFFICERS OF VAEI AND VAIGS. FORM 990, PART VI, SECTION A, LINE 7A THE TRUSTEES OF VAN ANDEL INSTITUTE HAVE THE AUTHORITY TO ELECT ONE OR MORE MEMBERS OF VARI'S GOVERNING BODY. FORM 990, PART VI, SECTION B, LINE 11 FOLLOWING COMPLETION OF THE FINANCIAL STATEMENT AUDIT, THE FORM 990 IS PREPARED AND REVIEWED BY MANAGEMENT. IT IS THEN CIRCULATED TO THE FULL BOARD FOR REVIEW AND FINAL APPROVAL PRIOR TO FILING WITH THE IRS. FORM 990, PART VI, SECTION B, LINE 12C VARI HAS WRITTEN CONFLICT OF INTEREST ("COI") POLICIES AND PROCEDURES (ADMINISTERED BY VAN ANDEL INSTITUTE) WHICH ADMINISTER AND ENFORCE A PROCESS TO IDENTIFY, EVALUATE, AND MANAGE POTENTIAL CONFLICTS OF INTEREST. THESE POLICIES HAVE BEEN BOARD APPROVED. VAI ADMINISTERS THE COI POLICIES AND PROCEDURES THROUGH TWO COMMITTEES: THE CONFLICTS COMMITTEE ("CC") AND THE INSTITUTIONAL COI COMMITTEE ("ICOIC"). THE COI POLICIES AND PROCEDURES APPLY TO AND SERVE AS A GUIDE FOR EVERYONE IN THE ORGANIZATION. THEY 1) PROVIDE A USEFUL RESOURCE WHEN DEVELOPING ACTIVITIES OR RELATIONSHIPS WITH OUTSIDE ENTITIES OR PERSONS, AND 2) ESTABLISH COMMITTEES TO REVIEW AND MANAGE POTENTIAL CONFLICTS OF INTEREST AS THEY MAY ARISE. THE CC, CHAIRED BY THE CHIEF LEGAL OFFICER, REQUIRES ANNUAL AND UPDATED DISCLOSURES BY COVERED PERSONS AND REVIEWS AND APPROVES MANAGEMENT PLANS. THE INSTITUTIONAL COI POLICIES AND PROCEDURES SERVE AS A GUIDE FOR MEMBERS OF THE BOARDS OF TRUSTEES AND SENIOR EXECUTIVES. IN THE EVENT A POTENTIAL COI ARISES AT THE BOARD OR SENIOR EXECUTIVE LEVEL, THE ICOIC MEETS TO REVIEW AND DECIDE HOW TO MANAGE SUCH POTENTIAL CONFLICTS OF INTEREST IN ACCORDANCE WITH THE COI POLICIES AND PROCEDURES. FORM 990, PART VI, SECTION B, LINE 15 COMPARABILITY DATA FROM EXPERT THIRD PARTY IS OBTAINED AND REVIEWED BY THE INDEPENDENT, JOINT COMPENSATION COMMITTEE OF VAN ANDEL RESEARCH INSTITUTE AND RELATED ORGANIZATIONS TO DETERMINE APPROPRIATE COMPENSATION FOR THE CEO, EXECUTIVE MANAGEMENT OFFICIALS, OFFICERS, AND KEY EMPLOYEES, ON BEHALF OF VAN ANDEL RESEARCH INSTITUTE. FORM 990, PART VI, SECTION C, LINE 19 THE CONFLICT OF INTEREST POLICY AND FINANCIAL STATEMENTS ARE AVAILABLE TO THE PUBLIC UPON REQUEST. FORM 990, PART XI, LINE 9: LOSS ON INTEREST RATE SWAP -7,760,074. FORM 990, PART III, LINE 2 VAN ANDEL RESEARCH INSTITUTE (VARI) IS DEDICATED TO DETERMINING THE EPIGENETIC, GENETIC, MOLECULAR, AND CELLULAR ORIGINS OF CANCER, PARKINSON'S DISEASE, AND OTHER ILLNESSES AND TO TRANSLATING THOSE FINDINGS INTO EFFECTIVE THERAPIES. THE INSTITUTE'S SCIENTISTS WORK IN ON-SITE LABORATORIES AND PARTICIPATE IN COLLABORATIONS THAT SPAN THE GLOBE. WITH EPIGENETICS AS ITS COMMON THREAD, THE INSTITUTE IS ORGANIZED INTO THE CENTER FOR CANCER AND CELL BIOLOGY, THE CENTER FOR EPIGENETICS, AND THE CENTER FOR NEURODEGENERATIVE SCIENCE. THE CORE TECHNOLOGIES AND SERVICES GROUP PROVIDES A VIVARIUM, A BIOREPOSITORY, AND VALUABLE ON-SITE CAPABILITIES IN IMAGING, PATHOLOGY, BIOINFORMATICS, GENOMICS AND FLOW CYTOMETRY. RESEARCH BY VARI SCIENTISTS IS PUBLISHED IN MAJOR PEER-REVIEWED JOURNALS, INCLUDING, IN 2015, SCIENCE, NATURE, CELL, CELL RESEARCH, NEW ENGLAND JOURNAL OF MEDICINE, CIRCULATION RESEARCH, EXPERIMENTAL CELL RESEARCH, JOURNAL OF TRANSLATION MEDICINE, EXPERIMENTAL NEUROLOGY, GENOME BIOLOGY, GENOME RESEARCH, AMERICAN JOURNAL OF CANCER RESEARCH, AMERICAN JOURNAL OF SURGICAL PATHOLOGY, ANALYTICAL CHEMISTRY, BONE RESEARCH, CANCER RESEARCH, INTERNATIONAL JOURNAL OF CANCER, INTERNATIONAL JOURNAL OF ONCOLOGY, JOURNAL OF BIOLOGICAL CHEMISTRY, JOURNAL OF BONE AND MINERAL RESEARCH, JOURNAL OF MEDICINAL CHEMISTRY, JOURNAL OF PARKINSON'S DISEASE, MOLECULAR CELL, NEUROBIOLOGY OF DISEASE, PLOS ONE, AND PSYCHONEUROENDOCRINOLOGY. FORM 990, PART III, LINE 4A LINE 4A - PROGRAM SERVICE ACTIVITY #1 CENTER FOR CANCER AND CELL BIOLOGY THE CENTER FOR CANCER AND CELL BIOLOGY, DIRECTED BY BART WILLIAMS, PH.D., COMPRISES 14 LABORATORIES ENGAGED IN BASIC RESEARCH IN MOLECULAR AND STRUCTURAL BIOLOGY AND IN TRANSLATIONAL RESEARCH ON CANCERS, THE TUMOR MICROENVIRONMENT, AND SKELETAL DISEASES. THE CENTER WELCOMED PATRICK GROHAR, M.D., PH.D., AS AN ASSOCIATE PROFESSOR IN JULY 2015. INVESTIGATORS WITHIN THE CENTER IN 2015 RECEIVED NEW R01 AND R21 AWARDS FROM THE NATIONAL INSTITUTES OF HEALTH, AND A RENEWAL AWARD FROM THE BREAST CANCER RESEARCH FOUNDATION. ALSO, A NEW RESEARCH CONTRACT WITH A PHARMACEUTICAL FIRM WAS SIGNED. VAN ANDEL RESEARCH INSTITUTE'S PATHWAY OF HOPE INITIATIVE PROGRESSED IN 2015 UNDER THE DIRECTION OF ASSOCIATE PROFESSOR JEFFREY MACKEIGAN, PH.D. TSC CAUSES NON-CANCEROUS TUMORS IN MAJOR ORGANS, AND PATIENTS AFFLICTED WITH DISEASE OFTEN SUFFER FROM EPILEPSY, LEARNING DISABILITIES, AND OTHER COMPLICATIONS. THE PATHWAY OF HOPE INITIATIVE INVOLVES TSC INVESTIGATORS FROM ACROSS THE UNITED STATES, WITH FUNDING FROM THE MICHIGAN STRATEGIC FUND, BLUE CROSS BLUE SHIELD OF MICHIGAN, GREAT LAKES SCRIP, ROCKFORD CONSTRUCTION, COLLIERS INTERNATIONAL, TEAM HANNAH TSC, AND INDIVIDUAL DONORS. THE TSC RESEARCH TEAM HAS SCREENED FOR GENES NEVER BEFORE LINKED TO TSC AND IS INVESTIGATING SEVERAL THAT ARE INTRIGUING. THE MACKEIGAN LAB PUBLISHED A COMPARISON OF TWO DRUGS, EVEROLIMUS AND SIROLIMUS, AND THE CLINICAL TRIAL OUTCOMES FOR MANAGING TSC USING THESE DRUGS (MACKEIGAN AND KRUEGER, NEURO-ONCOLOGY 17(12): 1550-1559). STUDIES OF THREE-DIMENSIONAL MOLECULAR STRUCTURES AND THEIR PHYSICAL INTERACTIONS HAVE BEEN PROCEEDING ON SEVERAL FRONTS IN 2015. G PROTEIN-COUPLED RECEPTORS FORM A LARGE, COMPLEX GROUP OF MOLECULAR RECEPTORS IN HUMANS, AND MANY IMPORTANT QUESTIONS ABOUT THEM REMAIN. ONE MAJOR QUESTION WAS ANSWERED WITH THE SOLUTION OF THE RHODOPSIN-ARRESTIN STRUCTURE BY THE XU AND MELCHER LABS, WHICH PROVIDES A BASIS FOR UNDERSTANDING GPCR-MEDIATED, ARRESTIN-BIASED SIGNALING. THE COMPLEX IS RESPONSIBLE FOR REGULATING VITAL PHYSIOLOGICAL FUNCTIONS AND SERVES AS A MAJOR PHARMACOLOGICAL DRUG TARGET. THE NEW FINDINGS PROVIDE SCIENTISTS WITH A ROADMAP FOR SELECTIVELY TARGETING CELLULAR PATHWAYS, WHICH MAY LEAD TO MORE-EFFECTIVE DRUGS WITH FEWER SIDE EFFECTS FOR DISEASES SUCH AS CANCER, HEART DISEASE, AND NEURODEGENERATIVE DISORDERS. THIS PROJECT ALSO EMPLOYED CUTTING-EDGE X-RAY LASER TECHNOLOGY TO SOLVE THE STRUCTURE OF THESE COMPLEX MOLECULES (KANG ET AL., NATURE 523(7562): 561-567). ANOTHER STUDY FROM THESE LABS UNCOVERED THE MECHANISM OF ALLOSTERIC REGULATION OF AMP-ACTIVATED PROTEIN KINASE; THIS ENZYME IS A PROMISING TARGET FOR TREATING DIABETES, OBESITY, AND CANCER (LI ET AL., CELL RESEARCH 25(1): 50-66). STRUCTURAL STUDIES OF PLANT MOLECULES HAVE ALSO ADVANCED. STRINGOLACTONES ARE PLANT HORMONES THAT PROMOTE ROOT SYMBIOSIS WITH NITROGEN-FIXING BACTERIA SUCH AS RHIZOBIUM. VARI LABS HAVE MODELED THE INTERACTION OF STRINGOLACTONE WITH THE DWARF3 PROTEIN, REVEALING THE MECHANISM OF RECEPTOR RECOGNITION AND SIGNALING, WHICH IS A STEP TOWARD IMPROVING THE CRUCIAL MYCORRHIZAL AND RHIZOBIUM SYMBIOSIS OF AGRICULTURAL PLANTS (ZHAO ET AL., CELL RESEARCH 25(11): 1219-1236). ANOTHER STUDY SHOWED PRONOUNCED CONFORMATION CHANGES IN THE MYC3 PROTEIN IN ARABIDOPSIS, IDENTIFYING THE DYNAMIC MECHANISM BY WHICH THE SIGNALING PATHWAY OF THE CRUCIAL PLANT HORMONE JASMONATE IS REPRESSED OR ACTIVATED (ZHANG ET AL., NATURE 525(7568): 269-273). JASMONATE SIGNALING REGULATES A VARIETY OF PLANT PROCESSES, INCLUDING SEED GERMINATION, ROOT GROWTH, FLOWERING, AND PHOTOSYNTHESIS. UNDERSTANDING INTERACTIONS BETWEEN THESE PLANT PROTEINS NOT ONLY HAS IMPLICATIONS FOR GLOBAL CROP PRODUCTION, BUT ALSO OFFERS INSIGHTS INTO MOLECULAR MECHANISMS THAT MAY PLAY A ROLE IN HUMAN DISEASES. MICRO-RNAS ARE AN INCREASINGLY INTERESTING AND RELEVANT AREA OF RESEARCH IN HEALTH AND DISEASE. THE SEMPERE LAB REPORTED A LARGE PROGNOSTIC STUDY OF BLADDER CANCER THAT IDENTIFIED THE MICRO-RNA MIR-34A AS A POTENTIAL BIOMARKER AND/OR THERAPEUTIC TARGET FOR THIS DISEASE (ANDREW ET AL., INTERNATIONAL JOURNAL OF CANCER 137(5): 1158-1166). ANOTHER STUDY PUBLISHED IN 2015 WAS A CRITICAL ANALYSIS OF THE POTENTIAL OF MICRO-RNAS AS BIOMARKERS IN BREAST CANCER MANAGEMENT (GRAVEEL ET AL., BREAST CANCER: TARGETS AND THERAPY 7: 59-79). YET ANOTHER STUDY PROVIDED NOVEL INSIGHT INTO POTENTIAL NEW THERAPEUTIC APPROACHES FOR TRIPLE-NEGATIVE BREAST CANCER, A PARTICULARLY DIFFICULT TO TREAT AND AGGRESSIVE FORM OF THE DISEASE (SAMENI ET AL., CLIN CANCER RES., IN PRESS). VARI ALSO TOOK PART IN ESTABLISHING A UNIFORM NAMING SYSTEM FOR MICRO-RNA GENES AND HELPED ESTABLISH A NEW OPEN-ACCESS DATABASE, MIRGENEDB, ON MICRO-RNAS (FROMM ET AL., ANNUAL REVIEW OF GENETICS 49: 213-242). PROGRESS CONTINUES IN OUR STUDIES OF PANCREATIC CANCER. WORK DONE IN THE HAAB LAB SHOWED THAT SIALYL-LEWIS X PROTEIN INCREASES IN PANCREATIC CANCERS THAT ARE NEGATIVE FOR THE TRADITIONAL MARKER, THE CA19-9 PROTEIN. THIS MAY HELP IN DIFFERENTIATING AMONG SUBGROUPS OF PATIENTS WITH PANCREATIC TUMORS SO THAT THE MOST EFFECTIVE TREATMENT CAN BE PROVIDED (TANG ET AL., MOLECULAR AND CELLULAR PROTEOMICS 14(5): 1323-1333). A SECOND STUDY SHOWED THAT A SUBSET OF PANCREATIC CANCERS HAS AN INCREASE IN CELL-SURFACE GLYCANS CONTAINING A 3'-FUCOSE SUGAR COMPONENT, WHICH MAY COMPLEMENT OTHER BIOMARKERS AND ALLOW IMPROVED DETECTION OF PANCREATIC CANCERS (SINGH ET AL., JOURNAL OF PROTEOME RESEARCH 14(6): 2594-2605). VARI RESEARCHERS HAVE DEVELOPED A KIDNEY-SPECIFIC MOUSE MODEL OF BIRT-HOGG-DUBE SYNDROME TUMORIGENESIS BY KNOCKING OUT THE FLCN GENE IN THE KIDNEY'S PROXIMAL TUBULES. THIS MODEL AVOIDS MANY PROBLEMS THAT NORMALLY OCCUR IN GENETIC KNOCK-OUTS AND ACCURATELY MODELS HUMAN BIRT-HOGG-DUBE SYNDROME (CHEN ET AL., KIDNEY INTERNATIONAL 88(5): 1057-1069). A PROJECT EXPLORING THE WNT/BETA-CATENIN PATHWAY AND THE HEPSIN PATHWAY IN PROSTATE CANCER FOUND THAT THE ACTIVITY OF BOTH IS INCREASED, AND THUS THEY COULD BECOME TARGETS OF CHEMOTHERAPY (VALKENBURG ET AL., THE PROSTATE 75(14): 1579-1585). A STUDY OF MELANOMA XENOGRAFT MODELS TREATED WITH THE DRUG VEMURAFENIB FOUND SEVERAL MECHANISMS BY WHICH THE CANCER CELLS BECAME RESISTANT TO THERAPY. HOWEVER, WHEN VEMURAFENIB WAS COMBINED WITH AN INHIBITOR OF THE MEK PROTEIN, THE TUMORS WERE ERADICATED (MONSMA ET AL., AMERICAN JOURNAL OF CANCER RESEARCH 5(4): 1507-1518). IN CLINICALLY RELATED RESEARCH, A STUDY OF HUMAN OSTEOSARCOMA (BONE CANCER) FOUND THAT THERE WERE SPECIFIC CHANGES IN GENE EXPRESSION IN CELLS THAT WERE HIGHLY RESISTANT TO CHEMOTHERAPY. SUCH CELLS ARE SENSITIVE TO TARGETED EPIGENETIC THERAPIES, AND TARGETING THOSE CHANGES MAY BE A VALUABLE THERAPEUTIC STRATEGY (FOLEY ET AL., JOURNAL OF TRANSLATIONAL MEDICINE 13: 110). A STUDY OF TISSUES FROM TWO INDIVIDUALS SUFFERING FROM OCULOECTODERMAL SYNDROME IDENTIFIED TWO MUTATIONS OF THE KRAS GENE. THE LOW FREQUENCIES OF THE MUTATIONS IN THE PATIENTS SUGGEST THAT THE DISEASE IS A MOSAIC RAS-RELATED DISORDER (PEACOCK ET AL., AMERICAN JOURNAL OF MEDICAL GENETICS A 167(7): 1429-1435). RESEARCH ON THE METABOLISM OF BOTH NORMAL AND PATHOLOGICAL BONE TISSUES HAS CONTINUED IN 2015. A STUDY OF THE WNTLESS PROTEIN, WHICH IS REQUIRED FOR THE SECRETION OF ALL WNT MOLECULES, FOUND THAT WNTLESS REGULATES THE FORMATION OF CARTILAGE AND BONE AND IS ACTIVE IN AFFECTING EMBRYONIC BONE DEVELOPMENT (ZHONG ET AL., DEVELOPMENTAL DYNAMICS 244(10): 1347-1355). IN A STUDY OF BONE HEALING, RADIOACTIVE TECHNETIUM-METHYLENE DIPHOSPHONATE ([99M]TC-MDP) WAS USED TO IMAGE THE HEALING PROCESS. THE UPTAKE OF THIS RADIOTRACER CORRESPONDED TO THE LOCATIONS OF OSTEOBLAST GENERATION IN HEALING OF BONES AND TO OSTEOBLAST CELL MATURATION IN CELL CULTURE (ZHONG ET AL., BONE RESEARCH 3: 15013). ANOTHER VARI STUDY PRODUCED THE FIRST REPORT OF THE FUNCTION OF THE CD82 TRANSMEMBRANE PROTEIN IN BLOOD PLATELETS. CD82 WAS FOUND TO FUNCTION IN MODULATING CLOT RETRACTION, INTEGRIN ALPHAIIB-BETA3 EXPRESSION, CELL ADHESION, AND TYROSINE KINASE SIGNALING (UCHTMANN ET AL., EXPERIMENTAL CELL RESEARCH 339(2): 261-269). IN CULTURES OF PROSTATE CANCER CELLS, CYTOPLASMIC ANDROGEN RECEPTOR, WHEN ACTED ON BY ANDROGEN, RAPIDLY STIMULATED THE SRC TYROSINE KINASE ENZYME. CANCER CELL INVASIVE BEHAVIOR IS STIMULATED BY A RAPID BUT SUSTAINED INCREASE IN SRC ACTIVITY (ZARIF ET AL., ONCOTARGET 6(9): 6862-6876). FORM 990, PART III, LINE 4B LINE 4B - PROGRAM SERVICE ACTIVITY #2 CENTER FOR EPIGENETICS THE CENTER, ESTABLISHED IN 2014 AND DIRECTED BY PETER JONES, PH.D., D.SC., COMPRISES EIGHT LABORATORIES STUDYING EPIGENETICS AND EPIGENOMICS AND THE ROLE OF EPIGENETIC DYSFUNCTION IN CANCER AND NEURODEGENERATIVE DISEASE, CARDIOVASCULAR DISEASE, AND VIRAL TRANSCRIPTION. TWO NEW FACULTY WERE RECRUITED TO THE CENTER IN 2015: DR. SCOTT ROTHBART WAS APPOINTED AS AN ASSISTANT PROFESSOR AND DR. STEPHEN BAYLIN OF JOHNS HOPKINS UNIVERSITY ACCEPTED A PART-TIME APPOINTMENT AS A PROFESSOR. IN 2015, CENTER RESEARCHERS RECEIVED A NEW NIH GRANT AWARD, AS WELL AS A MAJOR AWARD FROM THE MICHIGAN ECONOMIC DEVELOPMENT CORPORATION. THE VARI-SU2C EPIGENETICS DREAM TEAM, LED BY PETER JONES AND STEPHEN BAYLIN, CONTINUED ITS WORK IN 2015, WITH THE AIMS OF DEVELOPING NEW COMBINATION THERAPIES TO COMBAT CANCER AND MOVING PROMISING THERAPIES TO CLINICAL TRIALS. THE TEAM FOCUSES ON EPIGENETIC MECHANISMS IN CELLS, WHICH HELP CONTROL WHETHER GENES ARE TURNED ON OR OFF WITHOUT CHANGING THE DNA SEQUENCE ITSELF. A PRINCIPAL WAY THIS IS DONE IS BY THE ADDITION OR REMOVAL OF METHYL GROUPS TO THE DNA MOLECULES (DNA METHYLATION/DEMETHYLATION). CENTER FACULTY, AS PART OF THE CANCER GENOME ATLAS RESEARCH NETWORK, CONTRIBUTED TO COMPREHENSIVE STUDIES CHARACTERIZING DIFFUSE LOWER-GRADE GLIOMAS AND PRIMARY PROSTATE CANCERS (CANCER GENOME ATLAS RESEARCH NETWORK, NEW ENGLAND JOURNAL OF MEDICINE 372(26): 2481-2498; CANCER GENOME ATLAS RESEARCH NETWORK, CELL, 163(4): 1011-1025), AS WELL AS TO A STUDY OF INVASIVE LOBULAR BREAST CANCER (CIRIELLO ET AL., CELL 163(2): 506-519). THIS WORK WILL HELP LAY THE FOUNDATION FOR IMPROVING CANCER PREVENTION, EARLY DETECTION, AND TREATMENT. ANOTHER PROJECT MADE USE OF ELMER, A SOFTWARE TOOL THAT USES DNA METHYLATION TO IDENTIFY ENHANCERS OF DNA TRANSCRIPTION. THE RESEARCHERS IDENTIFIED NETWORKS REGULATED BY KNOWN CANCER DRIVERS AND NOVEL NETWORKS THAT HAVE PROGNOSTIC POTENTIAL (YAO ET AL., GENOME BIOLOGY 16: 105). AN ASSAY CALLED MIRA FOR ANALYZING DNA METHYLATION HAS BEEN DEVELOPED AND COMBINED WITH NEXT-GENERATION SEQUENCING. THE ASSAY IS RELIABLE, COST-EFFECTIVE, AND NOT LIMITED BY PRIMER OR PROBE DESIGN (JUNG ET AL., EPIGENOMICS 7(5): 695-706). USING THIS ASSAY, DNA METHYLATION IN METASTATIC MELANOMA CELLS AND IN NORMAL MELANOCYTES WAS CHARACTERIZED. A SERIES OF METHYLATION PEAKS FOUND TO BE PRESENT IN ALL MELANOMA SAMPLES MAY BE EFFECTIVE BIOMARKERS OF THE DISEASE (JIN ET AL., GENOMICS 106(6): 322-330). A VECTOR-BASED APPROACH TO GENE RANKING WAS DEVELOPED THAT INCORPORATES TEMPORAL DISTANCE, SIGNAL INTENSITY, AND VARIANCE INTO A SINGLE SCORE. THIS METHOD IDENTIFIED AN AGE-DEPENDENT DECREASE IN THE EXPRESSION OF GENES INVOLVED IN TRANSLATION AND RIBOSOME FUNCTION (JUNG ET AL., NUCLEIC ACIDS RESEARCH 43(15): E100). A STUDY OF ENDOCRINE-DISRUPTING CHEMICALS FOUND THAT THEY EXERT DIRECT EPIGENETIC EFFECTS IN EXPOSED FETAL GERM CELLS, ALTERING DNA METHYLATION AND TRANSCRIPTION. HOWEVER, THOSE CHANGES ARE CORRECTED BY REPROGRAMMING EVENTS IN THE NEXT GENERATION, SO THE EFFECTS ARE NOT PASSED ON TO LATER GENERATIONS (IQBAL ET AL., GENOME BIOLOGY 16: 59). THE NUCLEOSOME OCCUPANCY AND METHYLATION SEQUENCING (NOME-SEQ) METHOD WAS USED TO COMPARE THESE TWO DNA CHARACTERISTICS IN NORMAL AND CANCER CELL LINES OF THE BREAST AND PROSTATE. THIS STUDY PROVIDES CELL LINE PROFILES, A BIOINFORMATIC PIPELINE, AND TOOLS THAT WILL BE USEFUL TO SCIENTISTS IN THE FIELD IN FUTURE STUDIES (STATHAM ET AL., GENOMICS DATA 3: 94-96). IN A SEPARATE RESEARCH PROJECT, A HIGH-RESOLUTION ANALYSIS OF THE CHROMATIN STRUCTURE OF HCT116 COLON CANCER CELLS AND DNA-METHYLATION-DEFICIENT DERIVATIVE CELLS WAS CARRIED OUT USING THE NOME-SEQ ASSAY. IT SHOWED A NUANCED AND CONTEXT-DEPENDENT ROLE OF METHYLATION IN THE FUNCTIONAL ORGANIZATION OF CANCER CELL EPIGENOMES (LAY ET AL., GENOME RESEARCH 25(4): 467-477). IN A STUDY OF COLORECTAL CANCER-INITIATING CELLS (CICS), LOW-DOSE 5-AZA-CDR, WHICH INHIBITS THE PLACEMENT OF METHYL GROUPS ON DNA, CAUSED CELLS TO RESPOND AS THEY DO TO A VIRAL INFECTION, WITH THE INDUCTION OF DSRNAS AND ACTIVATION OF THE MDA5/MAVS RNA RECOGNITION PATHWAY, THUS TRICKING CANCER CELLS INTO DYING. THE STUDY DENOTES A MAJOR SHIFT IN THE UNDERSTANDING OF ANTI-TUMOR MECHANISMS, IDENTIFYING THE MDA5/MAVS/IRF7 PATHWAY AS A POTENTIALLY DRUGGABLE TARGET AGAINST CICS (ROULOIS ET AL., CELL 162(5): 961-973). A COMPLEMENTARY STUDY WITH SIMILAR FINDINGS, COAUTHORED BY DR. STEPHEN BAYLIN, WHO HOLDS A JOINT APPOINTMENT AT VARI AND AT JOHNS HOPKINS UNIVERSITY, WAS PUBLISHED IN THE SAME JOURNAL ISSUE (CHIAPPINELLI ET AL., CELL 162(5): 961-973). THESE TWO STUDIES WERE INCLUDED AMONG THE DISCOVERIES HIGHLIGHTED AS TOP BIOMEDICAL ADVANCES OF 2015 BY NATURE MEDICINE. A PROJECT ON CELL GENERATION AND CELL TURNOVER IN THE HUMAN HEART PUBLISHED IN 2015 FOUND THAT THE TOTAL NUMBER OF HEART CELLS IS ESTABLISHED JUST AFTER BIRTH, BUT HEART CELLS ARE CONTINUALLY GENERATED THROUGHOUT LIFE TO REPLACE CELLS THAT DIE. UNDERSTANDING HOW THIS REGENERATION OF CELLS OCCURS WOULD LAY THE FOUNDATION FOR HARNESSING THIS CAPABILITY TO HELP DAMAGED HEARTS HEAL. (BERGMANN ET AL., CELL 161(7): 1566-1575). USING SINGLE-CELL EXPRESSION PROFILING, ANOTHER STUDY FOUND THAT A COMBINATION OF N-CADHERIN PLUS THE INTEGRINS ALPHA-1, ALPHA-5, AND ALPHA-6 ALLOWS THE ISOLATION OF REGENERATION-COMPETENT MURINE CARDIOMYOCYTES. OTHER SUBTYPES OF HEART CELLS COULD ALSO BE ISOLATED (TARNAWSKI ET AL., PLOS ONE 10(8): E0135880). THIS STUDY WAS ALSO INCLUDED IN NATURE MEDICINE'S LIST OF TOP ADVANCES OF 2015. THE HISTONE ANTIBODY SPECIFICITY DATABASE IS AN ONLINE AND EXPANDING RESOURCE CATALOGING THE BEHAVIOR OF WIDELY USED, COMMERCIALLY AVAILABLE HISTONE ANTIBODIES BY PEPTIDE MICROARRAY. THIS RECENTLY ANNOUNCED DATABASE HAS AN INTERACTIVE WEB PORTAL AND PROVIDES A VALUABLE RESOURCE FOR RESEARCHERS WHO USE THESE ANTIBODIES AS DETECTION REAGENTS (ROTHBART ET AL., MOLECULAR CELL 59(3): 502-511). FORM 990, PART III, LINE 4C LINE 4C - PROGRAM SERVICE ACTIVITY #3 CENTER FOR NEURODEGENERATIVE SCIENCE THE CENTER FOR NEURODEGENERATIVE SCIENCE WAS ESTABLISHED IN 2011 UNDER PATRIK BRUNDIN, M.D., PH.D., WHO IS ALSO ASSOCIATE DIRECTOR OF VARI. THE CENTER CURRENTLY HAS SIX LABORATORIES STUDYING PARKINSON'S DISEASE, AGING, PRIONS, AND THE RELATIONSHIP BETWEEN DEPRESSION, SUICIDE, AND BRAIN INFLAMMATION. ONE NEW FACULTY MEMBER, GARHARD COETZEE, PH.D., JOINED THE CENTER IN 2015. CENTER RESEARCHERS IN 2015 RECEIVED NEW R13 AND R01 AWARDS THE NATIONAL INSTITUTES OF HEALTH, A NEW AWARD FROM THE CURE PARKINSON'S TRUST, AND A POSTDOCTORAL FELLOWSHIP GRANT FROM THE AMERICAN PARKINSON DISEASE ASSOCIATION. TWO NEW RESEARCH CONTRACTS WERE SIGNED WITH PRIVATE FIRMS. VARI CONTINUES THE LINKED CLINICAL TRIALS INITIATIVE BEGUN IN 2014 WITH THE CURE PARKINSON'S TRUST, A UK-BASED RESEARCH CHARITY, TO IDENTIFY NEW TREATMENTS FOR PARKINSON'S DISEASE. THE COLLABORATION FOCUSES ON REPOSITIONING MEDICATIONS APPROVED TO TREAT OTHER DISEASES THAT ALSO HAVE PROMISE FOR TREATING PARKINSON'S DISEASE. THE LCT INITIATIVE COULD SIGNIFICANTLY REDUCE THE TIME AND COST OF MOVING NEW PARKINSON'S TREATMENTS FROM THE LAB TO CLINICAL USE. OUR STUDIES OF PARKINSON'S DISEASE INCLUDE A PROJECT ON THE ENGRAILED GENE. POLYMORPHISMS IN THE HUMAN ENGRAILED1 (EN1) GENE ARE ASSOCIATED WITH SPORADIC PARKINSON'S DISEASE. THE RESEARCH HAS FOUND EARLY TERMINAL DEFECTS IN THE DOPAMINERGIC NIGROSTRIATAL PATHWAY IN EN1+/- MICE. SUCH HETEROZYGOUS MICE SHOULD BE USEFUL IN UNCOVERING NEW KEYS TO PD PATHOGENESIS (NORDSTROM ET AL., NEUROBIOLOGY OF DISEASE 73(1): 70-82). ANOTHER STUDY HAS DEVELOPED A MODEL CELL CULTURE SYSTEM FOR MONITORING THE TRANSFER OF THE PROTEIN ALPHA-SYNUCLEIN BETWEEN CELLS. THIS PROVIDES RESEARCHERS WITH A TOOL FOR IDENTIFYING GENETIC MODIFIERS OR SMALL MOLECULES THAT CAN INHIBIT SUCH TRANSFER (REYES ET AL., NEUROBIOLOGY OF DISEASE 77: 266-275). A THIRD PROJECT STUDIED HOW SMALL VESICLES CALLED EXOSOMES CAN ACCELERATE THE AGGREGATION OF ALPHA-SYNUCLEIN PROTEIN. THE RESULTS SHOWED THAT EXOSOMES PROVIDE A CATALYTIC ENVIRONMENT FOR ACCELERATING THE AGGREGATION OF ALPHA-SYNUCLEIN AND THAT THE GANGLIOSIDE LIPIDS GM1 AND GM3 ARE IMPORTANT IN THE PROCESS (GREY ET AL., JOURNAL OF BIOLOGICAL CHEMISTRY 290(5): 2969-2982). A STUDY OF QUINONE-PROTEIN ADDUCTS IN THE SUBSTANTIA NIGRA FOUND THAT THE ENZYMATIC ACTIVITY OF TWO DEHYDROGENASE ENZYMES, LDH AND MDH, CAN BE COMPROMISED BY MODIFICATION OF THE QUINONE. THIS RESULT SUGGESTS THAT IMPAIRMENT OF ENERGY METABOLISM IS IMPORTANT IN THE VULNERABILITY OF AGED DOPAMINERGIC NEURONS TO PARKINSON'S DISEASE (YU ET AL., EXPERIMENTAL NEUROLOGY 271: 13-24). THE PARK9 GENE CAN PROTECT AGAINST ALPHA-SYNUCLEIN-INDUCED TOXICITY IN CELLULAR AND INVERTEBRATE MODELS OF PD, AND IT IS EXPRESSED AT A MODESTLY INCREASED LEVEL IN THE CINGULATE CORTEX OF PARKINSON'S DISEASE PATIENTS. HOWEVER, IN A RODENT MODEL, RESEARCH SHOWED A LACK OF PARK9-MEDIATED PROTECTION AGAINST ALPHA-SYNUCLEIN-INDUCED NEUROTOXICITY (DANIEL ET AL., NEUROBIOLOGY OF DISEASE 73(1): 229-243). THE LRRK2 PROTEIN CARRYING THE G2019S MUTATION PRODUCES NEUROTOXICITY IN THE BRAIN STRIATUM. A FURTHER MUTATION TO THE LRRK2 GENE THAT INACTIVATES THE PROTEIN'S KINASE ACTIVITY ELIMINATED THE TOXIC EFFECTS, SUGGESTING THAT KINASE INHIBITORS MAY HAVE POTENTIAL AS A THERAPEUTIC APPROACH TO PARKINSON'S DISEASE (TSIKA ET AL., NEUROBIOLOGY OF DISEASE 77: 49-61). ANOTHER VARI PROJECT STUDIED THE PATHOGENIC PROPERTIES OF SYNTHETICALLY GENERATED PRION (REC-PRION). THE REC-PRION HAS A TITRATABLE INFECTIVITY AND CAN CAUSE PRION DISEASE VIA ROUTES OTHER THAN DIRECT INTRACEREBRAL CHALLENGE. THE REC-PRION DISEASE IS PATHOGENICALLY AND PATHOLOGICALLY IDENTICAL TO NATURALLY OCCURRING, CONTAGIOUS, TRANSMISSIBLE SPONGIFORM ENCEPHALOPATHIES (WANG ET AL., PLOS PATHOGENS 11(7): E1004958). BECAUSE AGING IS THE GREATEST RISK FACTOR FOR THE DEVELOPMENT OF PARKINSON'S DISEASE (PD), CHANGES DURING THE AGING PROCESS MAY MAKE CELLS SUSCEPTIBLE TO DISEASE-CAUSING MUTATIONS THAT ARE TOLERATED AT YOUNGER AGES. IN A C. ELEGANS WORM MODEL, THE DAF-2 MUTATION INCREASED THE LIFE SPAN OF WORMS BEARING PD-RELATED MUTATIONS AND RESCUED THE DEGENERATION OF DOPAMINE NEURONS. THIS STUDY SUGGESTS THAT SLOWING THE AGING PROCESS MAY BE AN EFFECTIVE TREATMENT FOR PD (COOPER ET AL., NPJ PARKINSON'S DISEASE 1: 15022). ANOTHER STUDY IN C. ELEGANS SHOWED THAT THE LOCATION OF REACTIVE OXYGEN SPECIES (ROS) CAUSES DIFFERENT EFFECTS ON THE ORGANISM'S LIFE SPAN. HIGHER LEVELS OF ROS IN MITOCHONDRIA INCREASE LIFE SPAN, WHILE HIGHER LEVELS IN THE CYTOPLASM DECREASE IT. THIS KNOWLEDGE MAY EVENTUALLY BE USED TO PROMOTE LONGEVITY, AS WELL AS TO UNDERSTAND THE ROLE OF ROS IN AGE-RELATED CONDITIONS SUCH AS PARKINSON'S DISEASE (SCHAAR ET AL., PLOS GENETICS 11(2): E1004972). VARI PUBLISHED SEVERAL REPORTS ON DEPRESSION, SUICIDAL BEHAVIOR, AND BRAIN INFLAMMATION IN 2015 THAT MAY PROVIDE NEW THERAPEUTIC APPROACHES FOR MANAGING SUICIDAL BEHAVIOR. ONE STUDY SUGGESTS THAT THE MACROPHAGE MIGRATION INHIBITORY PROTEIN IS INVOLVED IN DEPRESSIVE-LIKE SYMPTOMS, POSSIBLY THROUGH INTERFERON-GAMMA EFFECTS ON DOPAMINE METABOLISM. THE EFFECTS MAY BE SEX-SPECIFIC (BAY-RICHTER ET AL., JOURNAL OF NEUROINFLAMMATION 12: 163). ANOTHER STUDY FOUND THAT AGGRESSION AND IMPULSIVITY ARE ASSOCIATED WITH LATENT INFECTION BY TOXOPLASMA GONDII PARASITES AND THAT THERE ARE GENDER- AND AGE-SPECIFIC DIFFERENCES IN THESE TRAITS. SUBSEQUENT STUDIES OF THE TRAITS MAY PROVIDE ADVANCES IN PROGNOSIS AND THERAPY FOR INFECTED INDIVIDUALS (COOK ET AL., JOURNAL OF PSYCHIATRIC RESEARCH 60: 87-94) BASED ON A COMPREHENSIVE LITERATURE REVIEW, THE EFFECTS OF BRAIN INFLAMMATION ON SUICIDAL BEHAVIOR MAY BE IN PART MEDIATED BY KYNURENINE PATHWAY COMPONENTS (BRUNDIN ET AL., ACTA PSYCHIATRICA SCANDINAVICA 132(3): 192-203). A SEPARATE STUDY FOUND DYSREGULATION OF KYNURENINE METABOLISM IN DEPRESSED AND SUICIDAL PATIENTS. HIGHER CONCENTRATIONS OF INFLAMMATORY CYTOKINES IN THE CEREBROSPINAL FLUID WERE ASSOCIATED WITH MORE-SEVERE SYMPTOMS. THE GLUTAMATE N-METHYL-D-ASPARTATE (NMDA) RECEPTOR MAY BE A TARGET FOR DEVELOPING NOVEL THERAPIES (BAY-RICHTER ET AL., BRAIN, BEHAVIOR, AND IMMUNITY 43: 110-117). A THIRD STUDY FOUND THAT MAJOR DEPRESSIVE DISORDER WAS NOT ASSOCIATED WITH HIGHER PLASMA LEVELS OF KYNURENINE PATHWAY MARKERS IN PATIENTS RECEIVING CYTOKINE THERAPY FOR DEPRESSION, SUGGESTING A DIFFERENT MECHANISM FROM THAT OF INTERFERON-INDUCED DEPRESSION (DAHL ET AL., PSYCHONEUROENDOCRINOLOGY 56: 12-22). FORM 990, PART IX, COLUMN D FUNDRAISING EXPENSES AT VARI WERE INCURRED TO SUPPORT THE MISSION OF THE RESEARCH INSTITUTE THROUGH DONOR SOLICITATION, GRANT SOLICITATION AND EXTRAMURAL PROPOSAL PREPARATION. FORM 990, PART X, LINE 33 VARI NET ASSETS ARE CONSIDERED ON A CONSOLIDATED BASIS WITH VAN ANDEL INSTITUTE (VAI), VAN ANDEL EDUCATION INSTITUTE (VAEI), AND RELATED PARTIES. ON A CONSOLIDATED BASIS, NET ASSETS ARE $1,312,631,000 PER AUDITED FINANCIAL STATEMENTS. THE NEGATIVE NET ASSET BALANCE AT VARI IS DUE TO VAI FUNDING EXPENSES ON A CASH BASIS AND THE UNREALIZED LOSS RECORDED IN ASSOCIATION WITH THE INTEREST RATE SWAP. 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