1 00:00:05,040 --> 00:00:07,280 >> I WOULD LIKE TO WELCOME 2 00:00:07,280 --> 00:00:09,920 EVERYBODY BACK FOR DAY 2 OF OUR 3 00:00:09,920 --> 00:00:12,280 NIH COMMON FUND SYMPOSIUM. 4 00:00:12,280 --> 00:00:15,120 GLYCO INFORMATICS AT THE 5 00:00:15,120 --> 00:00:16,200 INTERFACE OF DISEASE AND DATA. 6 00:00:16,200 --> 00:00:18,440 WE HAVE STWO SESSIONS TODAY. 7 00:00:18,440 --> 00:00:20,280 THE MORNING SESSION WILL BE 8 00:00:20,280 --> 00:00:23,080 HOSTED BY MICHAEL PIERCE AND 9 00:00:23,080 --> 00:00:24,080 GENERALLY ORGANIZED AROUND 10 00:00:24,080 --> 00:00:25,960 CANCER GLYCO BIOLOGY WITH OTHER 11 00:00:25,960 --> 00:00:27,320 IMPORTANT TOPICS THROWN IN AND 12 00:00:27,320 --> 00:00:30,080 THEN THE SECOND SESSION THIS 13 00:00:30,080 --> 00:00:32,480 AFTERNOON, CHAIRED BY NANCY 14 00:00:32,480 --> 00:00:34,520 DAHMs, ON RARE DISEASES AND 15 00:00:34,520 --> 00:00:38,240 INFORMATICS ASSOCIATED WITH 16 00:00:38,240 --> 00:00:38,880 UNDERSTANDING RARE DISEASES. 17 00:00:38,880 --> 00:00:40,680 I'M GOING TO TURN IT OVER TO 18 00:00:40,680 --> 00:00:42,080 MICHAEL PIERCE TO INTRODUCE OUR 19 00:00:42,080 --> 00:00:45,080 SPEAKERS FOR THE FIRST SESSION. 20 00:00:45,080 --> 00:00:46,760 THANKS, MICHAEL. 21 00:00:46,760 --> 00:00:47,560 >> THANKS, MIKE. 22 00:00:47,560 --> 00:00:49,760 YEAH, SO I'M MICHAEL PIERCE, 23 00:00:49,760 --> 00:00:50,680 UNIVERSITY OF GEORGIA AND IT'S 24 00:00:50,680 --> 00:00:52,880 MY PLEASURE TO INTRODUCE OUR 25 00:00:52,880 --> 00:00:59,000 FIRST SPEAKER IN OUR CANCER 26 00:00:59,000 --> 00:01:01,080 GLYCO BIOLOGY SESSION, DR. AVERY 27 00:01:01,080 --> 00:01:05,320 POSEY WHO WILL TELL US ABOUT 28 00:01:05,320 --> 00:01:06,640 EXPLOITING TRUNCATED 29 00:01:06,640 --> 00:01:12,360 O-GLYCOSYLATION IN TUMORS FOR 30 00:01:12,360 --> 00:01:12,680 IMMUNOTHERAPY. 31 00:01:12,680 --> 00:01:13,080 >> THANK YOU. 32 00:01:13,080 --> 00:01:14,600 I WOULD LIKE TO THANK THE 33 00:01:14,600 --> 00:01:16,200 ORGANIZERS FOR THE INVITATION TO 34 00:01:16,200 --> 00:01:16,680 SPEAK HERE TODAY. 35 00:01:16,680 --> 00:01:18,680 THE BULK OF MY LAB'S WORK 36 00:01:18,680 --> 00:01:21,920 FOCUSES ON A SYNTHETIC IMMUNO 37 00:01:21,920 --> 00:01:26,480 GLOBUE LYNN MOLECULE THAT 38 00:01:26,480 --> 00:01:28,560 IS--IT'S AN ARTIFICIAL T-CELL 39 00:01:28,560 --> 00:01:33,800 RECEPTOR AND IT UTILIZES 40 00:01:33,800 --> 00:01:35,680 COMPONENTS OF 2 DIFFERENT 41 00:01:35,680 --> 00:01:38,120 ADAPTIVE IMMUNE RELATED 42 00:01:38,120 --> 00:01:39,680 MOLECULES OF T-CELL RECEPTOR, OR 43 00:01:39,680 --> 00:01:41,400 PORTIONS OF THE T-CELL RECEPTOR 44 00:01:41,400 --> 00:01:42,840 THAT ARE IMPORTANT FOR 45 00:01:42,840 --> 00:01:44,840 ACTIVATING A T-CELL AND 46 00:01:44,840 --> 00:01:47,560 VERITABLE DOMAINS FROM 47 00:01:47,560 --> 00:01:48,720 MONOCLONAL ANTIBODIES AND THESE 48 00:01:48,720 --> 00:01:51,280 WHEN COMBINED IN A KHIHIGH 49 00:01:51,280 --> 00:01:53,960 MERRIC MOLECULE CAN REDIRECT 50 00:01:53,960 --> 00:01:55,080 T-CELL ACTIVATION AND 51 00:01:55,080 --> 00:01:56,080 SPECIFICITY TOWARDS THE ANTIGEN 52 00:01:56,080 --> 00:02:00,080 THAT IS THE TARGET OF THAT 53 00:02:00,080 --> 00:02:02,160 MONOCLONAL ANTIBODY THAT THE 54 00:02:02,160 --> 00:02:03,480 EXTRA CELLULAR DOMAIN IS DERIVED 55 00:02:03,480 --> 00:02:03,680 FROM. 56 00:02:03,680 --> 00:02:04,800 IN THE FIRST GENERATIONS OF 57 00:02:04,800 --> 00:02:06,760 THESE MOLECULES THIS WAS THE 58 00:02:06,760 --> 00:02:08,480 FORMAT OF THOSE KHIHIGH MERRIC 59 00:02:08,480 --> 00:02:11,280 ANTIGEN RECEPTORS AND THEY HAVE 60 00:02:11,280 --> 00:02:15,520 THE BENEFIT OF BEING NONMHC 61 00:02:15,520 --> 00:02:17,040 RESTRICTED AND SO THESE 62 00:02:17,040 --> 00:02:21,720 MOLECULES CAN NOW BE TRANSFERRED 63 00:02:21,720 --> 00:02:24,360 INTO T-CELLS REGARDLESS OF AN 64 00:02:24,360 --> 00:02:25,520 INDIVIDUAL'S HLA AND IN ADDITION 65 00:02:25,520 --> 00:02:29,240 THEY CAN OPERATE IN CD4 AND CD8 66 00:02:29,240 --> 00:02:30,200 T-CELLS SIMILARLY REGARDLESS OF 67 00:02:30,200 --> 00:02:34,200 WHAT THE COAL O RECEPTOR IS, CD4 68 00:02:34,200 --> 00:02:34,880 OR CD8. 69 00:02:34,880 --> 00:02:36,880 ANOTHER BENEFIT THAT I ALWAYS 70 00:02:36,880 --> 00:02:39,640 LIKE TO POINT OUT TO MY CAR 71 00:02:39,640 --> 00:02:41,800 T-CELL PEOPLE IS THAT ANTIBODIES 72 00:02:41,800 --> 00:02:43,560 HAVE A BROADER REPERTOIRE OF THE 73 00:02:43,560 --> 00:02:46,760 MOLECULES THEY CAN TARGET BEYOND 74 00:02:46,760 --> 00:02:48,720 WHAT A T-CELL RECEPTOR CAN 75 00:02:48,720 --> 00:02:51,240 TARGET, SO THESE CAN TARGET 76 00:02:51,240 --> 00:02:55,080 PEPTIDES AND NUCLEIC ACIDS, 77 00:02:55,080 --> 00:02:55,520 LIPIDS, CARBOHYDRATES, 78 00:02:55,520 --> 00:02:58,240 PHOSPHORALATED TARGETS AS WELL 79 00:02:58,240 --> 00:02:58,680 AS OTHER CHEMICALS. 80 00:02:58,680 --> 00:02:59,680 MULTIPLE GENERATIONS OF THESE 81 00:02:59,680 --> 00:03:01,000 MOLECULES HAVE NOW BEEN 82 00:03:01,000 --> 00:03:03,080 DEVELOPED, EVOLVED OVER THE LAST 83 00:03:03,080 --> 00:03:04,560 30 YEARS, INCLUDING THE 84 00:03:04,560 --> 00:03:08,080 INCLUSION OF A CO-STIMLATTORY 85 00:03:08,080 --> 00:03:10,720 DOMAIN INSISTS IN THIS MOLECULE 86 00:03:10,720 --> 00:03:12,280 OR MULTIPLE STIMLATTORY DOMAINS 87 00:03:12,280 --> 00:03:13,560 AND INCLUSION OF THESE MOLECULES 88 00:03:13,560 --> 00:03:16,880 HAVE BEEN SHOWN TO ENHANCE THE 89 00:03:16,880 --> 00:03:19,240 SURVIVAL OF CAR T-CELLS AND 90 00:03:19,240 --> 00:03:21,280 PROLIFERATION AND AUGMENT 91 00:03:21,280 --> 00:03:24,160 EFFECTOR FUNCTIONS. 92 00:03:24,160 --> 00:03:26,640 WE GENERATE THESE NOW 93 00:03:26,640 --> 00:03:28,600 COMMERCIALLY BUT ALSO 94 00:03:28,600 --> 00:03:30,480 PRECLINICALLY USING VIRAL 95 00:03:30,480 --> 00:03:30,840 VECTORS. 96 00:03:30,840 --> 00:03:31,360 THESE T-CELLS, PROJECTION 97 00:03:31,360 --> 00:03:32,840 NEURONS OR PIONS O CLONAL 98 00:03:32,840 --> 00:03:35,280 T-CELLS FROM THE PATIENTS OR 99 00:03:35,280 --> 00:03:37,480 NORMAL DONORS ARE TRANSDUCED AND 100 00:03:37,480 --> 00:03:39,000 CODING IF THIS NEW MOLECULE 101 00:03:39,000 --> 00:03:40,680 THAT'S BEEN EXPRESSED ON THE 102 00:03:40,680 --> 00:03:43,840 SURFACE OF THOSE T-CELLS AND 103 00:03:43,840 --> 00:03:45,160 DEPENDING ON THE SPECIFICITY OF 104 00:03:45,160 --> 00:03:47,320 THE MONOCLONAL ANTIBODY FROM 105 00:03:47,320 --> 00:03:50,160 WHICH THE SCFB WAS DERIVED, THE 106 00:03:50,160 --> 00:03:51,480 T-CELLS ARE DIRECTED TOWARDS A 107 00:03:51,480 --> 00:03:53,680 NEW TARGET AND IN THIS CASE, THE 108 00:03:53,680 --> 00:03:56,040 SCHEMATIC CD19 AND USING 109 00:03:56,040 --> 00:03:58,520 ANTICD19 CAR CONSTRUCT AND THAT 110 00:03:58,520 --> 00:03:59,640 ILLICITS ACTIVATION OF THE 111 00:03:59,640 --> 00:04:01,480 T-CELLS AND LEADS TO EFFECTOR 112 00:04:01,480 --> 00:04:02,400 FUNCTIONS SUCH AS SIGNIFY 113 00:04:02,400 --> 00:04:03,480 TOLL-LIKE RECEPTOR SIS AND 114 00:04:03,480 --> 00:04:05,480 KILLING OF THE CD19 POSITIVE 115 00:04:05,480 --> 00:04:08,440 CELLS, THERE ARE NOW 6 FDA 116 00:04:08,440 --> 00:04:09,680 APPROVED CAR T-CELL THERAPY FIST 117 00:04:09,680 --> 00:04:12,760 ARE THE TARGET CD19 AND 2 THAT 118 00:04:12,760 --> 00:04:15,000 TARGET BCMA FOR THE TREATMENT OF 119 00:04:15,000 --> 00:04:15,720 MULTIPLE MYELOMA. 120 00:04:15,720 --> 00:04:16,640 THE FIRST PATIENT WHO WAS 121 00:04:16,640 --> 00:04:20,960 TREATED WITH THESE TYPES OF 122 00:04:20,960 --> 00:04:21,960 THERAPEUTICS, HIS DATA IS 123 00:04:21,960 --> 00:04:24,120 PRESENTED BEFORE YOU ON THIS 124 00:04:24,120 --> 00:04:26,520 SCREEN, 1 DAY BEFORE INFUSION, 125 00:04:26,520 --> 00:04:29,360 LARGE NUMBER OF CIRCULATING CD19 126 00:04:29,360 --> 00:04:31,920 POSITIVE B-CELLS IN THIS 127 00:04:31,920 --> 00:04:32,920 INDIVIDUAL LEUKEMIC B-CELLS 128 00:04:32,920 --> 00:04:34,640 MOSTLY, 1 MONTH AFTER INFUSION 129 00:04:34,640 --> 00:04:37,960 OF THEIR T-CELLS, COMPLETE 130 00:04:37,960 --> 00:04:41,040 ABLATION SHOWING THE POTENCY OF 131 00:04:41,040 --> 00:04:41,720 THESE THERAPEUTICS, HOWEVER 132 00:04:41,720 --> 00:04:44,960 THOSE DO COME WITH SOME RISK, SO 133 00:04:44,960 --> 00:04:46,360 THERE'S AN INCREASE RISK OF 134 00:04:46,360 --> 00:04:50,040 INFECTION OF PATIENTS WHO HAVE 135 00:04:50,040 --> 00:04:51,080 EXPERIENCED B-CELL PLASSIA DUE 136 00:04:51,080 --> 00:04:54,960 TO TREATMENT WITH THESE KINDS OF 137 00:04:54,960 --> 00:04:55,720 CAR T-CELLS INCLUDING VIRAL 138 00:04:55,720 --> 00:04:57,720 INFECTION, SOME OF WHICH CAN BE 139 00:04:57,720 --> 00:05:00,680 SEVERE, LIFE THREATENING OR EVEN 140 00:05:00,680 --> 00:05:00,960 FATAL. 141 00:05:00,960 --> 00:05:02,600 IN ADDITION WE KNOW THAT WHILE 142 00:05:02,600 --> 00:05:04,480 THESE T-CELLS MAY PERSIST FOR A 143 00:05:04,480 --> 00:05:06,880 LONG TIME IN INDIVIDUALS LESS 144 00:05:06,880 --> 00:05:09,240 SHOWN IN THE RED AND BLUE 145 00:05:09,240 --> 00:05:13,960 TRIANGLES AND BLUE CIRCLES AND 146 00:05:13,960 --> 00:05:15,600 CAN LEAD TO COMPLETE LOSS OF 147 00:05:15,600 --> 00:05:17,160 B-CELLS SHOWN WITH THE BLUE 148 00:05:17,160 --> 00:05:18,680 SQUARES OVER A DECADE, THIS WAS 149 00:05:18,680 --> 00:05:20,800 REPORTED IN THE FIRST 2 150 00:05:20,800 --> 00:05:22,320 INDIVIDUALS TREATED WHO ACHIEVED 151 00:05:22,320 --> 00:05:23,360 A COMPLETE RESPONSE, OUR FIRST 152 00:05:23,360 --> 00:05:25,880 PATIENT DID DIE OF COVID-19 LAST 153 00:05:25,880 --> 00:05:27,760 YEAR AND I THINK THAT ALSO 154 00:05:27,760 --> 00:05:30,640 POINTS TO A VULNERABILITY OF 155 00:05:30,640 --> 00:05:32,080 TARGETING A MOLECULE THAT'S NOT 156 00:05:32,080 --> 00:05:35,920 TUMOR SPECIFIC AND LASTLY, MY 157 00:05:35,920 --> 00:05:37,360 LAB RECENTLY SHOWED THAT THERE'S 158 00:05:37,360 --> 00:05:39,920 THE PRESENCE OF CD19 TRANSCRIPTS 159 00:05:39,920 --> 00:05:42,440 AND PROTEIN O A SUBSET OF BRAIN 160 00:05:42,440 --> 00:05:45,240 PERISIGHTS THAT MAY BE A 161 00:05:45,240 --> 00:05:46,120 CONTRIBUTOR TO NEUROTOXICITY 162 00:05:46,120 --> 00:05:47,280 RELATED TO THESE THERAPEUTICS 163 00:05:47,280 --> 00:05:49,480 AND SO ALL OF THAT TAKEN INTO 164 00:05:49,480 --> 00:05:50,960 CONSIDERATION, TELLS US THAT WE 165 00:05:50,960 --> 00:05:53,080 STILL NEED TUMOR SPECIFIC 166 00:05:53,080 --> 00:05:54,760 TARGETS FOR B-SELMA LIGNANCYS 167 00:05:54,760 --> 00:05:56,040 FOR OTHER LEUKEMIAS AND WE KNOW 168 00:05:56,040 --> 00:05:58,760 THAT WE NEED THESE 4 GLEEL CELLS 169 00:05:58,760 --> 00:06:00,200 O BLASTOMA AND OTHER SOLID 170 00:06:00,200 --> 00:06:02,520 TUMORS SO THAT TAKES ME TO THE 171 00:06:02,520 --> 00:06:03,680 CRUX OF THIS PRESENTATION WHICH 172 00:06:03,680 --> 00:06:06,880 IS HOW DO WE GET TOWARDS A TUMOR 173 00:06:06,880 --> 00:06:07,360 SPECIFIC TARGET. 174 00:06:07,360 --> 00:06:08,920 FIRST WE WERE INTERESTED IN HOW 175 00:06:08,920 --> 00:06:12,880 TO GET TOWARDS A SOLID TUMOR 176 00:06:12,880 --> 00:06:14,800 SPECIFIC TARGET BUT REALLY WE 177 00:06:14,800 --> 00:06:18,040 STILL NEED THESE FOR HEME OOT O 178 00:06:18,040 --> 00:06:19,640 POETIC MALLIGNANCYS AS WELL, SO 179 00:06:19,640 --> 00:06:21,440 MY LAB IS INTERESTED IN THESE 180 00:06:21,440 --> 00:06:24,200 WAYS SO WE CAN EXPLORE THE 181 00:06:24,200 --> 00:06:24,880 DIFFERENTIATED GLYCOSYLATION 182 00:06:24,880 --> 00:06:26,680 THAT OCCURS IN TUMORS IN THE 183 00:06:26,680 --> 00:06:28,440 CONTEXT OF TUMOR ASSOCIATED 184 00:06:28,440 --> 00:06:31,080 PROTEINS OR REALLY FAVORABLE 185 00:06:31,080 --> 00:06:33,880 IMMUNOTHERAPY TARGETS FOR 186 00:06:33,880 --> 00:06:35,880 TARGETING MORE SPECIFICALLY A 187 00:06:35,880 --> 00:06:37,440 MALIGNANT CELL WHILE SPARING 188 00:06:37,440 --> 00:06:40,640 NORMAL CELLS, SO WE FOCUS ON THE 189 00:06:40,640 --> 00:06:41,560 GLYCANS, REALLY BECAUSE FOR US 190 00:06:41,560 --> 00:06:46,280 THIS IS VERY SIMPLE, SO IT'S A 191 00:06:46,280 --> 00:06:49,280 SIMPLE MONODISCIPLINARY 192 00:06:49,280 --> 00:06:50,600 SACCHARIDE THAT WE KNOW THERE 193 00:06:50,600 --> 00:06:52,480 ARE ANTIBODIES THAT CAN 194 00:06:52,480 --> 00:06:53,680 ACCOMMODATE THE CARBOHYDRATE AS 195 00:06:53,680 --> 00:06:55,040 WELL AS PROTEIN BACKBONE LEADING 196 00:06:55,040 --> 00:06:58,680 TO MORE SPECIFIC TARGETING OF 197 00:06:58,680 --> 00:06:59,040 THESE MOLECULES. 198 00:06:59,040 --> 00:07:00,960 SO THE FIRST STORY I WANT TO 199 00:07:00,960 --> 00:07:02,040 TELL YOU ABOUT IS WORK THAT 200 00:07:02,040 --> 00:07:05,080 WE'VE DONE TO TRY TO UNDERSTAND 201 00:07:05,080 --> 00:07:07,160 HOW THIS CHANGE IN GLYCOSYLATION 202 00:07:07,160 --> 00:07:10,040 AFFECTS TUMOR GROWTH AS WELL AS 203 00:07:10,040 --> 00:07:11,480 THE CONTRIBUTION OF THE IMMUNE 204 00:07:11,480 --> 00:07:12,400 MICROENVIRONMENT AND THIS IS 205 00:07:12,400 --> 00:07:20,240 WORK BY A NEW POST DOC IN MY LAB 206 00:07:20,240 --> 00:07:20,680 DR. SHAWNA BROOKENS. 207 00:07:20,680 --> 00:07:23,560 SO WE KNOW THIS IS EXPRESSED IN 208 00:07:23,560 --> 00:07:25,720 MEAN EPITHELIAL TUMORS THAT IT 209 00:07:25,720 --> 00:07:27,040 CAN BE QUITE UBIQUITOUS IN 210 00:07:27,040 --> 00:07:31,200 EXPRESSION IN SOME TUMORS AND 211 00:07:31,200 --> 00:07:33,960 NOT FOUND IN HEALTHY TUMORS. 212 00:07:33,960 --> 00:07:36,960 WE ALSO KNOW THAT THE SUGARS 213 00:07:36,960 --> 00:07:39,480 THAT I JUST POINTED OUT, THESE 214 00:07:39,480 --> 00:07:43,320 TRUNCATED DPLI KAN--KANAS ARE 215 00:07:43,320 --> 00:07:47,480 THE--GLYCANS ARE THE LIGANDS FOR 216 00:07:47,480 --> 00:07:51,520 THE SUGAR BINDING RECEPTORS LIKE 217 00:07:51,520 --> 00:07:54,080 THE SIGLECs, AND THESE ARE 218 00:07:54,080 --> 00:07:56,040 PRESENT ON INNATE IMMUNE SEISS, 219 00:07:56,040 --> 00:07:59,960 SOME ARE ON ADAPTIVE IMMUNE 220 00:07:59,960 --> 00:08:03,880 CELLS, SOME LEAD AS LEPTIN LIKE 221 00:08:03,880 --> 00:08:05,840 MACROPHAGE, AND LEPTIN WHICH 222 00:08:05,840 --> 00:08:08,600 BINDS TO THE TN-ANTIGEN AND 223 00:08:08,600 --> 00:08:12,160 BINDING OF THE TN-ANTIGEN BY 224 00:08:12,160 --> 00:08:14,120 EXPRESSING NGL CAN LEAD TO'MUNE 225 00:08:14,120 --> 00:08:15,400 O SUPPRESSIVE FUNCTION SO 226 00:08:15,400 --> 00:08:19,280 SKEWING OF T-CELLS TO IL10 227 00:08:19,280 --> 00:08:20,320 PRODUCING T-CELLS, MORE 228 00:08:20,320 --> 00:08:21,400 IMMUNOSUPPRESSIVE, AS WELL AS 229 00:08:21,400 --> 00:08:25,360 THIS HAS ALSO BEEN SHOWN FOR AN 230 00:08:25,360 --> 00:08:27,280 IMPORTANT IRPT ACTION FOR GLYCO 231 00:08:27,280 --> 00:08:28,480 PEPTIDES BY DENDRITIC CELLS AND 232 00:08:28,480 --> 00:08:30,600 THIS IS ALSO THOUGHT TO BE 233 00:08:30,600 --> 00:08:31,760 IMMUNOSUPPRESSIVE BECAUSE THE 234 00:08:31,760 --> 00:08:34,160 DENDRITIC CELLS THAT EXPRESS NGL 235 00:08:34,160 --> 00:08:37,600 ARE THOUGHT TO BE IMMATURE OR 236 00:08:37,600 --> 00:08:38,760 TOLL-LIKE RECEPTORRER GENIC, SO 237 00:08:38,760 --> 00:08:39,760 PRESENTATION OF THESE PEPTIDES 238 00:08:39,760 --> 00:08:41,200 CAN LEAD TO A TOLL-LIKE RECEPTOR 239 00:08:41,200 --> 00:08:42,000 RAISING IMMUNE RESPONSE WHICH IS 240 00:08:42,000 --> 00:08:46,600 NOT WHAT WE WANT FOR ANTITUMOR 241 00:08:46,600 --> 00:08:46,920 RESPONSE. 242 00:08:46,920 --> 00:08:48,240 AND SO I ACTUALLY WILL SKIP THIS 243 00:08:48,240 --> 00:08:50,080 SLIDE IN THE INTEREST OF TIME 244 00:08:50,080 --> 00:08:55,160 BECAUSE I THINK THAT THIS CROWD 245 00:08:55,160 --> 00:08:56,680 APPRECIATES HOW O-GLUE MARIOUS 246 00:08:56,680 --> 00:08:58,840 COSCALCULATIONS CAN BE DISRUPTED 247 00:08:58,840 --> 00:09:01,480 THROUGH COSMIC OR T-CELL SIPGHT 248 00:09:01,480 --> 00:09:04,480 ACE ASK THAT CAN LEAD TO THE TN 249 00:09:04,480 --> 00:09:07,800 ANTIGEN ORSILATION OF THAT FORM 250 00:09:07,800 --> 00:09:08,160 [INDISCERNIBLE]. 251 00:09:08,160 --> 00:09:10,600 WE DO KNOW THAT LOSS OF COSMIC 252 00:09:10,600 --> 00:09:12,800 DUE TO SILENCING IS A MAJOR 253 00:09:12,800 --> 00:09:16,960 CONTRIBUTOR TO THE PRESENTATION 254 00:09:16,960 --> 00:09:20,680 OF THE TN-ANTIGENOT CELL SURFACE 255 00:09:20,680 --> 00:09:23,800 OR SIL-TN-AND THIS IS SHOWN BY A 256 00:09:23,800 --> 00:09:27,840 GROUP IN COPENHAGEN, OF PATIENTS 257 00:09:27,840 --> 00:09:28,760 WITH PANCREATIC CANCERS AND THIS 258 00:09:28,760 --> 00:09:32,240 CAN BE A CONTRIBUTE TO DECREASED 259 00:09:32,240 --> 00:09:33,640 EXPRESSION WITH BOTH THE 260 00:09:33,640 --> 00:09:36,200 CHAPERON FOR THE SYNTHASE AND 261 00:09:36,200 --> 00:09:39,240 THE T-SYNTHASE, ASK TNF ALPHA, 262 00:09:39,240 --> 00:09:43,360 IL17 AND IL4 OR TGF BETA OR LPS 263 00:09:43,360 --> 00:09:45,080 OR SEVERAL MICRORNAs HAVE BEEN 264 00:09:45,080 --> 00:09:45,840 DEMONSTRATED TO DECREASE 265 00:09:45,840 --> 00:09:47,720 EXPRESSION OF COSMIC AS WELL AS 266 00:09:47,720 --> 00:09:52,360 T-SYNTHASE AND SO WE THINK THAT 267 00:09:52,360 --> 00:09:54,000 AN EARLY INSULT, EARLY 268 00:09:54,000 --> 00:09:56,720 INFLAMMATION CAN LEAD TO CHANGE 269 00:09:56,720 --> 00:09:59,560 IN OGLYCOSYLATION THAT MAY BE 270 00:09:59,560 --> 00:10:02,360 RELEVANT TO WOUND HEALING THAT 271 00:10:02,360 --> 00:10:04,560 MACROPHAGES AND DENDRITIC CELLS 272 00:10:04,560 --> 00:10:08,280 EXPRESSING NGL CAN COME INTO AN 273 00:10:08,280 --> 00:10:10,480 INFLAMED TISSUE AND THAT LEADS 274 00:10:10,480 --> 00:10:12,440 TO RESOLUTION OF THAT 275 00:10:12,440 --> 00:10:17,000 INFLAMMATION BUT IN A TUMOR WITH 276 00:10:17,000 --> 00:10:20,800 ONCO GENIC MUTATIONS AND 277 00:10:20,800 --> 00:10:23,480 INCREASED PROLIFERATION, THIS 278 00:10:23,480 --> 00:10:24,120 IMMUNE SUPPRESSION IS ACTUALLY 279 00:10:24,120 --> 00:10:26,080 COULD YOU WANTER TO AN ANTITUMOR 280 00:10:26,080 --> 00:10:28,600 RESPONSE AND WE DO KNOW THAT 281 00:10:28,600 --> 00:10:30,280 FROM WORK FROM OTHERS IN THE 282 00:10:30,280 --> 00:10:33,640 FIELD THAT IN DPLEEL BLASTOMA 283 00:10:33,640 --> 00:10:35,520 AND LUIS LUNG CARCINOMA AND 284 00:10:35,520 --> 00:10:37,920 COLORECTAL CANCER MODELS THAT 285 00:10:37,920 --> 00:10:41,120 THE INVASION OF MGL POSITIVE 286 00:10:41,120 --> 00:10:42,200 INNATE IMMUNE CELLS HAPPEN IN 287 00:10:42,200 --> 00:10:44,440 TUMORS THAT EXPRESS THE 288 00:10:44,440 --> 00:10:46,480 TN-ANTIGEN AND IF YOU DEPLETE 289 00:10:46,480 --> 00:10:48,320 THOSE CELLS BOTH THE DENDRITIC 290 00:10:48,320 --> 00:10:52,360 CELLS AND MACROPHAGESSA THE SAME 291 00:10:52,360 --> 00:10:56,360 TIME IN THIS MODEL YOU DO 292 00:10:56,360 --> 00:10:59,800 REDUCED TUMOR GROWTH WHEREAS 293 00:10:59,800 --> 00:11:00,640 TN-POSITIVE DEPLETE TUMOR 294 00:11:00,640 --> 00:11:02,880 GROWTH, IF YOU DEPLETE THE TN2 295 00:11:02,880 --> 00:11:05,960 POSITIVE CELLS CAN YOU RESTORE 296 00:11:05,960 --> 00:11:07,920 WILD TYPE GROWTH IN THOSE 297 00:11:07,920 --> 00:11:08,160 TUMORS. 298 00:11:08,160 --> 00:11:10,800 SO FOR OUR WORK, WE UTILIZED THE 299 00:11:10,800 --> 00:11:14,640 KPC MODEL AND A PANCREATIC MODEL 300 00:11:14,640 --> 00:11:16,320 THAT DEVELOPED SPONSPONTANEOUS 301 00:11:16,320 --> 00:11:19,200 TUMOR. 302 00:11:19,200 --> 00:11:20,720 THESE TUMORS HAVE BEEN SINGLE 303 00:11:20,720 --> 00:11:22,400 CELL CLONED AND LIMITING 304 00:11:22,400 --> 00:11:24,680 SOLUTION TO IDENTIFY TUMORS THAT 305 00:11:24,680 --> 00:11:26,280 REPRODUCIBLY ROUGH ATOM DUCE A 306 00:11:26,280 --> 00:11:29,920 T-CELL LOW OR T-CELL HIGH 307 00:11:29,920 --> 00:11:32,000 MICROENVIRONMENT AND WE'VE 308 00:11:32,000 --> 00:11:35,720 UTILIZED SOME OF THESE SINGLE 309 00:11:35,720 --> 00:11:37,600 CELL CLONE LINES TO INVESTIGATE 310 00:11:37,600 --> 00:11:39,160 HOW THE TN ANTIGEN PRESENT IN 311 00:11:39,160 --> 00:11:40,920 THESE TYPES OF TUMORS MIGHT 312 00:11:40,920 --> 00:11:41,920 CHANGE THE MICROENVIRONMENT BOTH 313 00:11:41,920 --> 00:11:45,160 IN A T-CELL HIGH AND A T-CELL 314 00:11:45,160 --> 00:11:45,520 LOW ENVIRONMENT. 315 00:11:45,520 --> 00:11:55,280 SO MY POST DOC HAS KNOCKED OUT 316 00:11:55,280 --> 00:11:57,480 COSMIC USING CRISPR/CAS 9, AND 317 00:11:57,480 --> 00:11:59,160 LOOKING FOR THE TN ANTIGEN AND 318 00:11:59,160 --> 00:12:01,280 THEN WE'VE DONE SOME EVALUATION 319 00:12:01,280 --> 00:12:03,200 OF THEIR GROWTH. 320 00:12:03,200 --> 00:12:05,480 INSHALLLY THE GROWTH DIFFERENCE 321 00:12:05,480 --> 00:12:06,240 BECAME APPARENT THROUGH CHANGE 322 00:12:06,240 --> 00:12:08,840 IN THE COLOR OF THE FEIGNILE RED 323 00:12:08,840 --> 00:12:11,160 IN THE MEDIA A FEW CELLS, WHERE 324 00:12:11,160 --> 00:12:13,880 THOSE CELLS THAT ARE TN POSITIVE 325 00:12:13,880 --> 00:12:18,080 THAT ARE NOT COSMIC SEEM TO HAVE 326 00:12:18,080 --> 00:12:20,480 INCREASED GLYCOLYTIC ACTIVITY, 327 00:12:20,480 --> 00:12:25,000 THE IMMEDIATE COLLAR CHANGE IS 328 00:12:25,000 --> 00:12:27,760 FASTEST, AND WE PLATE THE CELLS 329 00:12:27,760 --> 00:12:28,880 AND MEASURED THEIR ADHERENCE 330 00:12:28,880 --> 00:12:29,640 OVER TIME SO OVERALL STRATEGY 3 331 00:12:29,640 --> 00:12:32,320 DAYS WE CAN SEE THERE'S AN 332 00:12:32,320 --> 00:12:32,960 INCREASE PROLIFERATION INCREASED 333 00:12:32,960 --> 00:12:35,120 GROWTH, OF THE CELLS THAT HAVE 334 00:12:35,120 --> 00:12:37,440 COSMIC KNOCK OUT AND TNANTIGEN 335 00:12:37,440 --> 00:12:39,440 EXPRESSION AND WE ALSO MEASURED 336 00:12:39,440 --> 00:12:41,680 THIS IN AN WOUND HEALING ASSAY 337 00:12:41,680 --> 00:12:43,600 WHERE WE DO A SCRATCH TO A 338 00:12:43,600 --> 00:12:48,200 CONFLUENT PLATE AND WATCH THOSE 339 00:12:48,200 --> 00:12:49,640 CELLS MIGRATE BACK TO FILL THAT 340 00:12:49,640 --> 00:12:51,000 SCRATCH AND THOSE THAT HAVE A 341 00:12:51,000 --> 00:12:54,640 KNOCK OUT OF COSMIC OF INCREASED 342 00:12:54,640 --> 00:12:55,480 PROLIFERATION, INCREASED 343 00:12:55,480 --> 00:12:57,080 MIGRATION, WE SEE THAT BOTH FOR 344 00:12:57,080 --> 00:13:00,880 THE T-CELL LOW LINE AS WELLsA 345 00:13:00,880 --> 00:13:03,000 T-CELL HIGH LINES, IT'S MORE 346 00:13:03,000 --> 00:13:04,160 EXAGGERATED FOR THE T-CELL LOW 347 00:13:04,160 --> 00:13:06,920 LINES AND WE'VE TAKEN THESE 348 00:13:06,920 --> 00:13:08,000 PARENTAL AND COSMIC KNOCK OUT 349 00:13:08,000 --> 00:13:10,520 CELL LINES OF WHICH WE HAVE 4 350 00:13:10,520 --> 00:13:15,880 DIFFERENT CELL LINES THAT ARE 351 00:13:15,880 --> 00:13:17,520 PARENTAL OR COSMIC KNOCK OUT AND 352 00:13:17,520 --> 00:13:18,920 WE ARE CURRENTLY VALIDATING 353 00:13:18,920 --> 00:13:21,760 THESE RESULTS WITH SOME OF THE 354 00:13:21,760 --> 00:13:25,400 GENES THAT WERE OF INTEREST TO 355 00:13:25,400 --> 00:13:28,560 US ARE INVOLVED IN MONOCYTE 356 00:13:28,560 --> 00:13:31,440 RECRUITMENT AND DIFFERENTIATION, 357 00:13:31,440 --> 00:13:34,800 LIKE IL34 AND LIFT ARE INVOLVED 358 00:13:34,800 --> 00:13:39,360 IN EMT LIKE SNIWE 2 AND EMT, ARE 359 00:13:39,360 --> 00:13:44,920 INVOLVED, WE ALSO SEE CHANGES IN 360 00:13:44,920 --> 00:13:49,960 RESPONSE TO HYPOXIA, TNF ALPHA 361 00:13:49,960 --> 00:13:51,680 SIGNALING WHICH WE THINK MIGHT 362 00:13:51,680 --> 00:13:57,120 BE MODELING OR MIMICKING AN 363 00:13:57,120 --> 00:13:59,000 INFLAMED ENVIRONMENT, BECAUSE WE 364 00:13:59,000 --> 00:14:03,640 KNOCKED OUT COSMIC HE WE LOOKED 365 00:14:03,640 --> 00:14:04,480 WHAT INFLAMMATION MIGHT BE 366 00:14:04,480 --> 00:14:05,720 CONTRIBUTED TO THESE CELLS. 367 00:14:05,720 --> 00:14:07,440 WE SEE CHANGES IN THE PPEAEVER 368 00:14:07,440 --> 00:14:09,600 PATHWAY AND ALSO CHANGES IN 369 00:14:09,600 --> 00:14:11,280 CHECK POINT DECREASED CHECK 370 00:14:11,280 --> 00:14:15,400 POINT EXPRESSION SO THESE CELLS 371 00:14:15,400 --> 00:14:16,280 ARE PROLIFERATING MORE AS WELL 372 00:14:16,280 --> 00:14:18,080 AS CHANGES IN THE UNFOLDED 373 00:14:18,080 --> 00:14:18,880 PROTEIN RESPONSE. 374 00:14:18,880 --> 00:14:21,640 WE'VE INJECTED THESE TUMORS 375 00:14:21,640 --> 00:14:26,080 INVIVO AND BLACK 6 MICE AND SEEN 376 00:14:26,080 --> 00:14:27,640 THAT THERE'S INCREASED GROWTH OF 377 00:14:27,640 --> 00:14:30,160 THE TN POSITIVE TUMORS BOTH BY 378 00:14:30,160 --> 00:14:32,560 VOLUME AND WEIGHT. 379 00:14:32,560 --> 00:14:35,240 IN ADDITION, WHEN WE EXTRACT THE 380 00:14:35,240 --> 00:14:39,000 CD45 CELLS FROM A TUMOR, WE SEE 381 00:14:39,000 --> 00:14:42,600 THERE ARE DIFFERENCES IN BOTH 382 00:14:42,600 --> 00:14:44,120 THE T-CELLS THAT ACTUALLY 383 00:14:44,120 --> 00:14:45,680 EFFECTOR AND MEMORY CD8 T-CELLS 384 00:14:45,680 --> 00:14:47,360 AS WELL AS IN THE MYELOID CELLS 385 00:14:47,360 --> 00:14:51,200 SO WE SEE THERE'S A DIFFERENCE 386 00:14:51,200 --> 00:14:53,280 IN MONOSITTIC MDSCs, WE 387 00:14:53,280 --> 00:14:54,960 REPRODUCIBLY SEE THIS IN 388 00:14:54,960 --> 00:14:56,680 MULTIPLE TUMOR MODELS, WE ALSO 389 00:14:56,680 --> 00:14:59,600 SEE A DIFFERENCE IN Foxp3 390 00:14:59,600 --> 00:15:01,320 EXPRESSION SO TREGULATORY CELLS 391 00:15:01,320 --> 00:15:03,080 AS WELL AS SOME DENDRITIC CELL 392 00:15:03,080 --> 00:15:04,480 RETINAL LOCATIONIC CELLS, SO 393 00:15:04,480 --> 00:15:06,920 WE'RE NOW MOVING TOWARD RNA 394 00:15:06,920 --> 00:15:08,760 SINGLE CELL SEQUENCING TO 395 00:15:08,760 --> 00:15:10,440 PROVIDE A SYNTHESIS OF WHAT ARE 396 00:15:10,440 --> 00:15:11,640 CELL POPULATIONS PRESCRIBINGENT 397 00:15:11,640 --> 00:15:13,680 WHO ARE THE INNATE IMMUNE CELLS 398 00:15:13,680 --> 00:15:15,560 THAT ARE RESPONDING TO THIS 399 00:15:15,560 --> 00:15:16,400 CHANGE IN GLYCOSYLATION, AND 400 00:15:16,400 --> 00:15:18,280 THEN WITH HOPES WE COULD TARGET 401 00:15:18,280 --> 00:15:23,280 THOSE CELLS ARE RESOLUTION OF 402 00:15:23,280 --> 00:15:24,080 INCREASED TUMOR GROWTH. 403 00:15:24,080 --> 00:15:25,160 SO THOSE, WHAT I JUDGE UTV 404 00:15:25,160 --> 00:15:26,520 EXPLAINED TO YOU ARE APPROACHES 405 00:15:26,520 --> 00:15:33,880 HERE THAT WE PLAN TO TAKE NEXT 406 00:15:33,880 --> 00:15:34,120 STEPS. 407 00:15:34,120 --> 00:15:35,240 AND THEN ON THE OTHER SIDE OF 408 00:15:35,240 --> 00:15:38,680 THE STORY WE WORKED ON DIFFERENT 409 00:15:38,680 --> 00:15:40,400 THERAPEUTICS THAT TARGETED TUMOR 410 00:15:40,400 --> 00:15:43,720 ASSOCIATED ANTIGENS OR IMMUNE OR 411 00:15:43,720 --> 00:15:45,400 THERAPY TARGETS USING 412 00:15:45,400 --> 00:15:46,560 CAR-T-CELLS BUT I WON'T DISCUSS 413 00:15:46,560 --> 00:15:50,280 THAT BUT IT WAS TARGETING TNF 1 414 00:15:50,280 --> 00:15:52,000 AND WE DEMONSTRATE THAD A 415 00:15:52,000 --> 00:15:53,880 SIGNALING DIFFERENCE IN THOSE 416 00:15:53,880 --> 00:15:55,200 KHIHIGH MERRIC RECEPTORS COULD 417 00:15:55,200 --> 00:15:56,600 ENHANCE THE CO STIMULATION OF 418 00:15:56,600 --> 00:15:58,200 THESE CAR T-CELLS AND LEAD TO 419 00:15:58,200 --> 00:15:59,360 ENHANCED PERSISTENCE AND WE MOVE 420 00:15:59,360 --> 00:16:00,320 THIS TO A CLINICAL TRIAL. 421 00:16:00,320 --> 00:16:02,520 OUR SECOND VERSION OF THIS 422 00:16:02,520 --> 00:16:04,360 TARGETS FIBER NECTIN AND THIS 423 00:16:04,360 --> 00:16:05,240 WAS VERY NOSTALGIC FOR US 424 00:16:05,240 --> 00:16:08,200 BECAUSE WE WERE INTERESTED IN 425 00:16:08,200 --> 00:16:10,200 ANTIBODIES THAT TARGET THE TN 426 00:16:10,200 --> 00:16:13,680 ANTIGEN OF GLYCO PROTEINS, THE 427 00:16:13,680 --> 00:16:15,600 FIRST KNOWN ANTIBODY OF THIS 428 00:16:15,600 --> 00:16:17,560 CLASS IS CALLED FDC6 IT WAS 429 00:16:17,560 --> 00:16:20,720 DEVELOPED IN THE 80S AT FRED 430 00:16:20,720 --> 00:16:21,600 HUTCH AND [INDISCERNIBLE] AND IT 431 00:16:21,600 --> 00:16:23,440 WAS SHOWN TO BE TUMOR SPECIFIC 432 00:16:23,440 --> 00:16:25,200 THAT IT COULD RECOGNIZE A 433 00:16:25,200 --> 00:16:27,080 SPECIFIC GLYCO FORM OF FIBER 434 00:16:27,080 --> 00:16:29,960 NECTIN, NOT PRESENT IN NORMAL 435 00:16:29,960 --> 00:16:33,080 PLASMA FIBER NECTIN AND ADULT 436 00:16:33,080 --> 00:16:33,920 SKIN, CONNECTED TISSUE, LARGE 437 00:16:33,920 --> 00:16:35,600 INTESTINE AND COULD BE 438 00:16:35,600 --> 00:16:36,760 IDENTIFIED IN FIBER BLASTS AS 439 00:16:36,760 --> 00:16:39,520 WELL AS IN TUMOR CELL LINES THAT 440 00:16:39,520 --> 00:16:41,840 THIS ANTIBODY COULD RECOGNIZE 441 00:16:41,840 --> 00:16:43,920 ORAL CARCINOMAS BUT NOT NORMAL 442 00:16:43,920 --> 00:16:46,080 ORAL MUCOSAL OR EVEN 443 00:16:46,080 --> 00:16:49,240 PREMALIGNANT LESIONS AND WHEN 444 00:16:49,240 --> 00:16:50,400 ISOLATED FROM NORMAL FIBER 445 00:16:50,400 --> 00:16:51,800 NECTIN THAT ONLY THIS FIBER 446 00:16:51,800 --> 00:16:55,080 NECTIN WAS SHOWN TO ENHANCE THE 447 00:16:55,080 --> 00:16:58,360 ENT PHENOTYPES OF TUMOR CELLS 448 00:16:58,360 --> 00:17:01,120 LIKE A549 LUNG CANCER CELLS THAT 449 00:17:01,120 --> 00:17:04,600 ONLY THE ONCO-FIBER NECTIN COULD 450 00:17:04,600 --> 00:17:07,080 DECREASE IN CADHERREN AND 451 00:17:07,080 --> 00:17:08,160 INCREASE [INDISCERNIBLE] WHEREAS 452 00:17:08,160 --> 00:17:09,760 NORMAL FIBER NECTIN COULD NOT 453 00:17:09,760 --> 00:17:12,120 SUGGESTING THIS IS A RELEVANT 454 00:17:12,120 --> 00:17:15,480 MOLECULE FOR TARGETING AND 455 00:17:15,480 --> 00:17:16,440 INHIBITING TO DECREASE 456 00:17:16,440 --> 00:17:21,040 METASTASIS, SO WE GENERATED CAR 457 00:17:21,040 --> 00:17:24,400 T-CELL UTILIZING SCFB, WE ALSO 458 00:17:24,400 --> 00:17:27,360 GENERATED CAR T-CELLS FOR A 459 00:17:27,360 --> 00:17:28,880 FIBER NECTIN, A DEFICIENTLY 460 00:17:28,880 --> 00:17:30,520 SPLICED DOMAIN BUT NOT A COSTLY 461 00:17:30,520 --> 00:17:30,760 DOMAIN. 462 00:17:30,760 --> 00:17:33,480 THEE SHOW THAT THESE CAR T-CELLS 463 00:17:33,480 --> 00:17:35,280 COULD SECRETE INTERFERON GAMMA, 464 00:17:35,280 --> 00:17:39,640 QUITE A LOT OF INTERFERON GAMMA 465 00:17:39,640 --> 00:17:40,880 AGAINST PLOOF THATE CANCER TUMOR 466 00:17:40,880 --> 00:17:42,600 CELLS AS WELL AS KILL THESE 467 00:17:42,600 --> 00:17:45,440 CELLS ENVITROW, IF WE TESTED 468 00:17:45,440 --> 00:17:47,400 THESE CAR T-CELLS AGAINST NORMAL 469 00:17:47,400 --> 00:17:49,840 PROSTATE T-CELLS THEY HAVE NO 470 00:17:49,840 --> 00:17:53,080 REACTIVITY, IF WE IMK OUT THE 471 00:17:53,080 --> 00:17:56,520 AXON THAT HAS THE BGHPTY 472 00:17:56,520 --> 00:17:59,400 EPITAUPE THAT IS RECOGNIZED BOO 473 00:17:59,400 --> 00:18:01,160 I THIS ANTIBODY, THERE IS NO 474 00:18:01,160 --> 00:18:04,360 SECRETION BY KILLING AS IF AS IF 475 00:18:04,360 --> 00:18:05,560 WE KNOCKED OUT GALIN T6 AND THIS 476 00:18:05,560 --> 00:18:11,280 IS SHOWN TO BE IMPORTANT FOR 477 00:18:11,280 --> 00:18:42,040 MODIFYING THE BTHPGY EPITOPE. 478 00:18:42,040 --> 00:18:46,000 INVIVO WE SEE THE SIMILARITY 479 00:18:46,000 --> 00:18:48,440 TREND WHERE THESE T-CELLS ARE 480 00:18:48,440 --> 00:18:51,960 QUITE POTENT AT REDUCING TUMOR 481 00:18:51,960 --> 00:18:53,040 BURDEN IN MICE. 482 00:18:53,040 --> 00:18:55,120 THE 5 D 5 CAR T-CELLS ARE JUST 483 00:18:55,120 --> 00:18:57,400 AS GOOD, WE SEE A REBOWBD OF 484 00:18:57,400 --> 00:18:59,680 TUMORS THAT WE'RE TARGETED BY 485 00:18:59,680 --> 00:19:01,040 FIBER NECTIN TARGETING CAR 486 00:19:01,040 --> 00:19:02,920 T-CELLS AND WE HAVE WO, TO DO TO 487 00:19:02,920 --> 00:19:05,680 UNDERSTAND WHAT ARE THOSE 488 00:19:05,680 --> 00:19:06,480 MECHANISMS OF ESCAPE. 489 00:19:06,480 --> 00:19:08,480 WE SEE QUITE A LOT OF 490 00:19:08,480 --> 00:19:10,400 INFILTRATION OF CAR T-CELLS 491 00:19:10,400 --> 00:19:11,360 TARGETING FIBER NECTIN AS WELL 492 00:19:11,360 --> 00:19:14,040 AS A CHANGE TO WHAT WE JUST 493 00:19:14,040 --> 00:19:15,520 GENERALLY ARE CONSIDERING THE 494 00:19:15,520 --> 00:19:17,400 CHANGE IN TUMOR TO MATE RICK 495 00:19:17,400 --> 00:19:19,680 COMCISION, WE'RE INTERESTED IN 496 00:19:19,680 --> 00:19:22,480 HOW CAR T-CELLS TARGETING FIBER 497 00:19:22,480 --> 00:19:23,440 NECTIN MIGHT BE AFFAIRS TEAM 498 00:19:23,440 --> 00:19:24,840 LEADERRERRING THE MATRIX, WE 499 00:19:24,840 --> 00:19:31,720 KNOW FROM VALERIE WEAVERS WORK 500 00:19:31,720 --> 00:19:35,480 AND OTHER WORK THAT COLLAGEN AND 501 00:19:35,480 --> 00:19:36,680 FIBERS ARE DIFFERENTIALLY 502 00:19:36,680 --> 00:19:37,800 ALIGNED IN TUMORS COMPARED TO 503 00:19:37,800 --> 00:19:39,200 NORMAL TISSUE, WE'RE INTERESTED 504 00:19:39,200 --> 00:19:40,880 IN WHETHER TARGETING FIBER 505 00:19:40,880 --> 00:19:44,080 NECTIN, WE COULD POTENTIALLY 506 00:19:44,080 --> 00:19:46,720 RESOLVE THOSE CHANGES IN THE 507 00:19:46,720 --> 00:19:48,880 STROMA. 508 00:19:48,880 --> 00:19:50,920 AND THEN LASTLY, WE WERE 509 00:19:50,920 --> 00:19:53,320 INTERESTED IN HOW CAR T-CELLS 510 00:19:53,320 --> 00:19:56,360 TARGETING EXTRA CELLULAR MATRIX 511 00:19:56,360 --> 00:19:57,480 PROTEIN KILL 1 OF THOSE 512 00:19:57,480 --> 00:19:58,640 MECHANISMS OF DEATH, THIS IS 513 00:19:58,640 --> 00:20:09,720 DIFFERENT THAN HOW T-CELLS 514 00:20:09,720 --> 00:20:10,880 NORMALLY TARGET THROUGH CELL 515 00:20:10,880 --> 00:20:13,160 SURFACE MECHANISM, AND WE CAN 516 00:20:13,160 --> 00:20:14,600 GET THAT THROUGH FAST 517 00:20:14,600 --> 00:20:15,560 INTERACTIONS AND INTERFERON 518 00:20:15,560 --> 00:20:17,800 GAMMA SIGNALING AND THESE ARE 519 00:20:17,800 --> 00:20:20,200 PREVIOUSLY BEEN DEMONSTRATED TO 520 00:20:20,200 --> 00:20:22,560 BE IMPORTANT FOR LOSS, IMPORTANT 521 00:20:22,560 --> 00:20:25,680 MECHANISMS OF HOW CAR T-CELLS 522 00:20:25,680 --> 00:20:28,680 HAD FOUND THAT IF YOU COMPLETELY 523 00:20:28,680 --> 00:20:30,200 LOSE THE SENSITIVITY TO 524 00:20:30,200 --> 00:20:31,880 INTERFERON GAMMA IN A TUMOR SO 525 00:20:31,880 --> 00:20:33,800 LOSS OF INTERFERON GAMMA 526 00:20:33,800 --> 00:20:35,040 RECEPTOR THAT OUR CAR T-CELLS 527 00:20:35,040 --> 00:20:36,840 COULD NO LONGER KILL THEM AND SO 528 00:20:36,840 --> 00:20:38,520 THIS WAS ACTUALLY RECENTLY 529 00:20:38,520 --> 00:20:41,040 REPORTED BY 3 SEPARATE GROUPS, 530 00:20:41,040 --> 00:20:41,960 SCIENCE IMMUNOLOGY, NATURE 531 00:20:41,960 --> 00:20:43,720 COMMUNICATIONS AND THEN MOST 532 00:20:43,720 --> 00:20:45,920 RECENTLY IN NATURE, WE ALSO 533 00:20:45,920 --> 00:20:50,120 FOUND THAT IF YOU ADD A TLR 2 OR 534 00:20:50,120 --> 00:20:53,560 TLR 6, TLR 26 OR 4 AGANIST, TO 535 00:20:53,560 --> 00:20:55,920 THESE CO-CULTURES THAT YOU COULD 536 00:20:55,920 --> 00:20:58,680 ACTUALLY SYNERGIZE AND OVERCOME 537 00:20:58,680 --> 00:20:59,640 THIS DEFICIENCY IN KILLING SO 538 00:20:59,640 --> 00:21:02,080 OUR WORK NOW IS TRYING TO 539 00:21:02,080 --> 00:21:03,680 UNDERSTAND HOW WE CAN ENHANCE 540 00:21:03,680 --> 00:21:06,280 THE KILLING OF CAR T-CELLS BY 541 00:21:06,280 --> 00:21:07,120 INCORPORATING THESE SIGNALING 542 00:21:07,120 --> 00:21:10,240 MECHANISMS INTO THE CAR OR INTO 543 00:21:10,240 --> 00:21:11,280 THE T-CELL THEMSELVES WITHOUT 544 00:21:11,280 --> 00:21:13,600 HAVING TO USE A TLR 4 AGANIST 545 00:21:13,600 --> 00:21:15,360 WHICH IN WHICH CASE IS LPS WHICH 546 00:21:15,360 --> 00:21:19,800 WE CANNOT USE IN PATIENTS. 547 00:21:19,800 --> 00:21:21,880 AND SO, OUR SUMMARY IS THAT 548 00:21:21,880 --> 00:21:28,480 WE'VE SHOWN THAT TRUNCATED 549 00:21:28,480 --> 00:21:29,280 OGLYCOSYLATION CONTRIBUTES TO 550 00:21:29,280 --> 00:21:32,400 ENHANCE TUMOR GROWTH IN T-CELLS 551 00:21:32,400 --> 00:21:34,320 BUT THE GLOS COSALATION DOES 552 00:21:34,320 --> 00:21:35,480 CHANGE THE MIKE O ENVIRONMENT 553 00:21:35,480 --> 00:21:36,680 AND BY TARGETING THE T-CELLS WE 554 00:21:36,680 --> 00:21:39,360 MAY BE ABLE TO NORMALIZE THE 555 00:21:39,360 --> 00:21:40,840 IMMUNE MICROENVIRONMENT AND 556 00:21:40,840 --> 00:21:41,440 DECREASE IMMUNO SUPPRESSION. 557 00:21:41,440 --> 00:21:43,880 WE'VE ALSO SHOWN THE CAR T-CELLS 558 00:21:43,880 --> 00:21:46,080 CAN TARGET EXTRA CELLULAR MATRIX 559 00:21:46,080 --> 00:21:47,920 PROTEINS AND HERE WE'VE SHOWN AN 560 00:21:47,920 --> 00:21:48,880 EXTRA CELLULAR MATRIX PROTEIN 561 00:21:48,880 --> 00:21:53,240 THAT,A PEERS TO BE IMPORTANT FOR 562 00:21:53,240 --> 00:21:55,400 EMT, THAT THESE CELLS ARE LYTIC, 563 00:21:55,400 --> 00:21:57,080 THEY CAN KILL TUMOR CELLS 564 00:21:57,080 --> 00:21:58,800 INVITRO AND INVIVO AND THEN, I 565 00:21:58,800 --> 00:22:03,040 JUST WANT TO HARKEN BACK TO MY 566 00:22:03,040 --> 00:22:06,560 FIRST INTRO AND TOP THAT TUMOR 567 00:22:06,560 --> 00:22:08,280 SPECIFIC AGENTS ARENY NEEDED FOR 568 00:22:08,280 --> 00:22:09,360 B-SELMA LIGNANCIES AND ALL OTHER 569 00:22:09,360 --> 00:22:11,040 TUMORS THAT ARE USED IF ARE 570 00:22:11,040 --> 00:22:12,400 IMMUNO THR ACTIVITIES AND 571 00:22:12,400 --> 00:22:13,960 PROJECTSY LIKE BY SPECIFIC 572 00:22:13,960 --> 00:22:14,640 ANTIBODIES IN CAR T-CELLS AND 573 00:22:14,640 --> 00:22:16,840 WITH THAT I WILL SAY THANK YOU 574 00:22:16,840 --> 00:22:18,760 TO MY LAB, COLLABORATORS AND 575 00:22:18,760 --> 00:22:19,000 FUNDING. 576 00:22:19,000 --> 00:22:22,000 I WILL TAKE ANY QUESTIONS YOU 577 00:22:22,000 --> 00:22:23,120 MIGHT HAVE. 578 00:22:23,120 --> 00:22:24,560 >> OKAY, WELL, THANK YOU AVERY, 579 00:22:24,560 --> 00:22:26,160 THAT WAS REALLY FANTASTIC. 580 00:22:26,160 --> 00:22:30,200 I THINK WE WILL HOLD QUESTIONS 581 00:22:30,200 --> 00:22:36,280 UNTIL AFTER THE NEXT TALK. 582 00:22:36,280 --> 00:22:38,920 DR. STACIE MALAKER, WAS 583 00:22:38,920 --> 00:22:40,080 ORIGINALLY SCHEDULED FOR 10:40 584 00:22:40,080 --> 00:22:42,480 AND SHE CAN'T BE WITH US TODAY 585 00:22:42,480 --> 00:22:42,960 UNEXPECTEDLY. 586 00:22:42,960 --> 00:22:48,840 SO WE WILL TAKE QUESTIONS 587 00:22:48,840 --> 00:22:51,880 DR. PAPPROXIMATE OSEY IS 588 00:22:51,880 --> 00:22:53,560 DR. HAENDALL, AFTER 589 00:22:53,560 --> 00:22:54,920 DR. HAENDAL'S TALK, SO IF HAVE 590 00:22:54,920 --> 00:23:01,440 YOU SPECIFIC QUESTIONS PLEASE 591 00:23:01,440 --> 00:23:04,400 PUT THEM IN THE SEND LIVE 592 00:23:04,400 --> 00:23:06,880 FEEDBACK AREA, IF YOU CLICK ON 593 00:23:06,880 --> 00:23:09,000 THAT, YOU CAN TYPE IN YOUR 594 00:23:09,000 --> 00:23:10,960 QUESTION AND THAT WILL BE 595 00:23:10,960 --> 00:23:12,280 TRANSFERRED TO OUR CHAT AND WE 596 00:23:12,280 --> 00:23:23,040 WILL BE LOOKING AT THOSE AFTER 597 00:23:23,040 --> 00:23:24,280 DR. HAENDAL'S TALK, SO THANK YOU 598 00:23:24,280 --> 00:23:26,080 AND I'M SURE THERE WILL BE VERY 599 00:23:26,080 --> 00:23:31,920 INTERESTING QUESTIONS IN JUST A 600 00:23:31,920 --> 00:23:36,280 FEW MINUTES. 601 00:23:36,280 --> 00:23:37,080 SO DR. HAENDEL. 602 00:23:37,080 --> 00:23:37,520 >> GOOD MORNING. 603 00:23:37,520 --> 00:23:39,040 >> THERE YOU ARE, WELCOME. 604 00:23:39,040 --> 00:23:43,280 SO THIS IS DR. MELISSA HAENDA 605 00:23:43,280 --> 00:23:44,920 LUNIVERSITY OF COLORADO SCHOOL 606 00:23:44,920 --> 00:23:46,120 OF MEDICINE SPEAKING ON WHY WE 607 00:23:46,120 --> 00:23:49,480 NEED ALL THE ORGANISMS, 608 00:23:49,480 --> 00:23:53,040 HARMONIZING PHENOTYPES AND GENO 609 00:23:53,040 --> 00:23:54,680 TYPES AND DISEASES. 610 00:23:54,680 --> 00:23:55,280 SO TAKE IT AWAY, THANK YOU. 611 00:23:55,280 --> 00:23:56,000 ALL RIGHT TODAY I WILL TALK 612 00:23:56,000 --> 00:23:58,880 ABOUT WHY WE NEED ALL THE 613 00:23:58,880 --> 00:24:00,680 ORGANISMS, WHY WE NEED GENO 614 00:24:00,680 --> 00:24:01,960 TYPES, PHENOTYPES AND DISEASES, 615 00:24:01,960 --> 00:24:05,720 THIS IS WORK THAT'S LED BY THE 616 00:24:05,720 --> 00:24:06,800 INTERNATIONAL CONSORTIUM AND 617 00:24:06,800 --> 00:24:07,640 WE'RE DELIGHTED TO PRESENT THIS 618 00:24:07,640 --> 00:24:08,800 WORK TO YOU TODAY. 619 00:24:08,800 --> 00:24:10,680 SO FIRST OF ALL I JUDGE UTV 620 00:24:10,680 --> 00:24:12,960 WANTED TO TALK ABOUT SOME 621 00:24:12,960 --> 00:24:13,880 FOUNDATIONAL IDEAS THAT WILL 622 00:24:13,880 --> 00:24:16,360 KIND OF BE A THEME THROUGHOUT 623 00:24:16,360 --> 00:24:16,640 THE TALK. 624 00:24:16,640 --> 00:24:20,080 SO THERE ARE A LOT OF YOU KNOW 625 00:24:20,080 --> 00:24:21,920 NEEDS TO KIND OF COAALATE 626 00:24:21,920 --> 00:24:25,000 KNOWLEDGE FROM AROUND THE WORLD 627 00:24:25,000 --> 00:24:27,280 FROM DIFFERENT SOURCES, FROM 628 00:24:27,280 --> 00:24:28,040 DIFFERENT ORGANISMS, FROM 629 00:24:28,040 --> 00:24:29,440 DIFFERENT DOMAINS AND WE LIVE IN 630 00:24:29,440 --> 00:24:31,160 THIS WORLD OF DISTRIBUTED DATA 631 00:24:31,160 --> 00:24:33,160 ON THE LEFT SO IF WE'RE PUTTING 632 00:24:33,160 --> 00:24:34,800 TOGETHER A PUZZLE, A BIOLOGY 633 00:24:34,800 --> 00:24:36,360 KNOWLEDGE PUZZLE WE CAN HAVE 634 00:24:36,360 --> 00:24:39,920 THIS ANALOGY OF PUTTING TOGETHER 635 00:24:39,920 --> 00:24:41,680 THIS PUZZLE THAT IS THE BRIDGE 636 00:24:41,680 --> 00:24:44,400 OF THE SAN FRANCISCO BAY. 637 00:24:44,400 --> 00:24:46,880 AND WE CAN HAVE DIFFERENT RICH 638 00:24:46,880 --> 00:24:49,600 HIGH QUALITY DATA ABOUT EACH 639 00:24:49,600 --> 00:24:50,480 INDIVIDUAL ELEMENT SUCH AS 640 00:24:50,480 --> 00:24:53,800 SPECIES SPECIFIC OR DID THEA 641 00:24:53,800 --> 00:24:54,440 TYPE SPECIFIC RESOURCES. 642 00:24:54,440 --> 00:24:56,600 WE CAN AGGREGATE THESE DATA AND 643 00:24:56,600 --> 00:24:58,680 ESSENTIALLY IT'S EQUIVALENT TO 644 00:24:58,680 --> 00:25:00,680 PUTTING THOSE PUZZLE PIECES ALL 645 00:25:00,680 --> 00:25:01,360 IN A BOX. 646 00:25:01,360 --> 00:25:03,120 AND THAT'S REALLY GREAT FOR A 647 00:25:03,120 --> 00:25:04,200 LARGE SCALE INDEXING SO FOR 648 00:25:04,200 --> 00:25:06,880 EXAMPLE, THE WAY IN WHICH GOOGLE 649 00:25:06,880 --> 00:25:08,920 SEARCH WORKS, WE CAN SEARCH 650 00:25:08,920 --> 00:25:10,760 BASED ON STRINGS AND FREQUENCY 651 00:25:10,760 --> 00:25:12,080 OF SEARCHES AND SEARCH CO 652 00:25:12,080 --> 00:25:13,760 OCCURRENCE AND THESE TYPES OF 653 00:25:13,760 --> 00:25:14,680 THINGS, BUT THAT'S VERY 654 00:25:14,680 --> 00:25:15,880 DIFFERENT THAN HAVING A FULLY 655 00:25:15,880 --> 00:25:17,080 INTEGRATED DAILY BASIS THEA 656 00:25:17,080 --> 00:25:18,680 ECOSYSTEM WHERE WE CAN ACTUALLY 657 00:25:18,680 --> 00:25:21,320 PUT ALL THE PUZZLES DISPGHT BY 658 00:25:21,320 --> 00:25:22,800 CAREFUL ALIGNMENT OF THESE 659 00:25:22,800 --> 00:25:25,280 DIFFERENT DISTRIBUTED DAT 660 00:25:25,280 --> 00:25:26,880 ARESOURCES, USING CONCEPTUAL 661 00:25:26,880 --> 00:25:28,000 FRAMEWORKS AND CONSISTENT 662 00:25:28,000 --> 00:25:29,720 IDENTIFIERS, WE CAN COME UP WITH 663 00:25:29,720 --> 00:25:31,280 A BIG PICTURE VIEW, UNDERSTAND 664 00:25:31,280 --> 00:25:32,880 WHERE THE GAPS ARE AND HAVE 665 00:25:32,880 --> 00:25:35,240 CROSS DOMAIN INSIGHT BY BOTH 666 00:25:35,240 --> 00:25:36,760 HUMANS AND MACHINES. 667 00:25:36,760 --> 00:25:38,880 AND SO, FUNDAMENTALLY WHAT THE 668 00:25:38,880 --> 00:25:42,480 MONARCH INITIATIVE AIMS TO DO IS 669 00:25:42,480 --> 00:25:43,960 THAT LATTER, IS TAKE ALL THE 670 00:25:43,960 --> 00:25:44,960 DIFFERENT KNOWLEDGE RESOURCES WE 671 00:25:44,960 --> 00:25:46,600 HAVE AND BRING THEM TOGETHER 672 00:25:46,600 --> 00:25:47,880 INTO A UNIFIED MANNER THAT WILL 673 00:25:47,880 --> 00:25:51,200 ALLOW US TO GAIN NEW INSIGHTS. 674 00:25:51,200 --> 00:25:58,080 SO SO MY EXAMPLE FOR TODAY IS A 675 00:25:58,080 --> 00:26:01,080 LITTLE BIT OF HOW DO WE USE THE 676 00:26:01,080 --> 00:26:02,040 DIAGNOSTIC FOR DATA. 677 00:26:02,040 --> 00:26:03,560 SO MONARCH WAS FOUNDATION IF HOW 678 00:26:03,560 --> 00:26:06,280 WE UNDERSTAND HOW WE USE 679 00:26:06,280 --> 00:26:07,320 PHENOTYPIC INFORMATION TO 680 00:26:07,320 --> 00:26:10,480 IMPROVE DIAGNOSTICS AND 681 00:26:10,480 --> 00:26:12,280 PREVAILING CLINICAL DIAGNOSTIC 682 00:26:12,280 --> 00:26:13,560 PIPELINES LEVERAGE ON ONLY A 683 00:26:13,560 --> 00:26:14,920 TINY FRACTION OF THE POTENTIAL 684 00:26:14,920 --> 00:26:15,880 DATA ABOUT AN INDIVIDUAL 685 00:26:15,880 --> 00:26:17,480 PATIENT, AS WELL AS ITS 686 00:26:17,480 --> 00:26:19,400 RELATIONSHIP TO POPULATION AND 687 00:26:19,400 --> 00:26:20,520 COHORT LEVEL INFORMATION. 688 00:26:20,520 --> 00:26:22,240 SO THAT INCLUDES PHENOTYPING, 689 00:26:22,240 --> 00:26:27,120 BUT ALSO MANY OMICS, PHENOTYPES, 690 00:26:27,120 --> 00:26:29,120 SOCIAL DETERMINANTS OF HEALTH, 691 00:26:29,120 --> 00:26:31,240 ENVIRONMENTAL HEALTH AND 692 00:26:31,240 --> 00:26:32,280 EXPOSURE, DISEASE SURVEILLANCE, 693 00:26:32,280 --> 00:26:33,480 SURVEY INSTRUMENTS AND MANY 694 00:26:33,480 --> 00:26:34,760 OTHER THINGS THAT WOULD HELP US 695 00:26:34,760 --> 00:26:36,600 BETTER CREATE A PICTURE OF THE 696 00:26:36,600 --> 00:26:37,720 INDIVIDUAL PATIENT AND IT'S 697 00:26:37,720 --> 00:26:38,880 RELATIONSHIP TO THE POPULATION 698 00:26:38,880 --> 00:26:40,880 OR COHORT WHICH IS REALLY 699 00:26:40,880 --> 00:26:44,920 FUNDAMENTALLY THE GOAL OF 700 00:26:44,920 --> 00:26:46,080 PRECISION MEDICINE. 701 00:26:46,080 --> 00:26:47,640 SO THE MONARCH INITIATIVE 702 00:26:47,640 --> 00:26:49,600 DEVELOPED A PHENOTYPE ONTOLOGY, 703 00:26:49,600 --> 00:26:52,280 ABOUT 12 YEARS AGO. 704 00:26:52,280 --> 00:26:54,240 IT'S NOW OVER 14,000 TERMS, THIS 705 00:26:54,240 --> 00:26:56,680 ONTOLOGY IS REPRESENTED AS A 706 00:26:56,680 --> 00:26:57,480 GRAPH. 707 00:26:57,480 --> 00:27:02,200 AND THIS GRAPH HAS TERMS SUCH AS 708 00:27:02,200 --> 00:27:03,640 HIPOSMIA OR DEEPLY SET EYES THAT 709 00:27:03,640 --> 00:27:05,880 CAN BE EXPRESSED IN TERMS OF 710 00:27:05,880 --> 00:27:07,080 LOGICAL INTERPRETATION IN 711 00:27:07,080 --> 00:27:09,360 RELATION TO OTHER ONTOLOGYS, SO 712 00:27:09,360 --> 00:27:12,840 FOR EXAMPLE, THE TERM HIPOSMA IS 713 00:27:12,840 --> 00:27:14,880 REPRESENTED AS A LACK OFERER 714 00:27:14,880 --> 00:27:16,880 ACCEPTION OF CELL USING THE 715 00:27:16,880 --> 00:27:17,880 GENOME ONTOLOGY TERM WHICH AT 716 00:27:17,880 --> 00:27:21,520 THE TIME I DID THIS QUERY HAD 34 717 00:27:21,520 --> 00:27:23,320 ANNOTATIONS AND 22 SPECIES. 718 00:27:23,320 --> 00:27:25,160 SO CREATING THIS 719 00:27:25,160 --> 00:27:25,880 INTEROPERABILITY ACROSS 720 00:27:25,880 --> 00:27:27,080 DIFFERENT CONTEXTS, SO THE HUMAN 721 00:27:27,080 --> 00:27:32,240 PHENOTYPE IS USED TO DESCRIBE 722 00:27:32,240 --> 00:27:35,560 THE ABNORMAL GENE FUNCTION 723 00:27:35,560 --> 00:27:36,920 WHEREAS THE GENE ONTOLOGY IS 724 00:27:36,920 --> 00:27:37,800 USED TO DESCRIBE THIS ABILITY 725 00:27:37,800 --> 00:27:39,280 BUT WE HAVE THE ABILITY TO 726 00:27:39,280 --> 00:27:41,120 EPITHELIAL GREAT DATA ACROSS 727 00:27:41,120 --> 00:27:42,200 MANY DIFFERENT SPECIES 728 00:27:42,200 --> 00:27:43,480 POTENTIALLY FOR HELP IN 729 00:27:43,480 --> 00:27:44,800 DIAGNOSTICS AND MECH INFORM 730 00:27:44,800 --> 00:27:47,240 DISCOVERY AND THE HPO IS NOW THE 731 00:27:47,240 --> 00:27:50,560 DEFACTOR STANDARD FOR DESCRIBING 732 00:27:50,560 --> 00:27:52,680 RARE DISEASE PATIENTS PHENOTYPES 733 00:27:52,680 --> 00:27:53,320 FOR DIAGNOSTIC PURPOSES. 734 00:27:53,320 --> 00:27:56,240 SO HERE'S AN EXAMPLE OF THAT, SO 735 00:27:56,240 --> 00:27:57,840 THIS IS 2 CHILDREN WHO CAME INTO 736 00:27:57,840 --> 00:27:59,040 THE SAME CLINIC WITHIN A FEW 737 00:27:59,040 --> 00:28:02,880 WEEKS OF EACH OTHER, 1 WAS A 3 738 00:28:02,880 --> 00:28:04,240 YEAR-OLD GIRL AND A 14 YEAR-OLD 739 00:28:04,240 --> 00:28:05,040 BOY ON THE RIGHT. 740 00:28:05,040 --> 00:28:06,440 AND IT'S IMPORTANT TO UNDERSTAND 741 00:28:06,440 --> 00:28:07,920 HOW THIS WORKS AS AN EXAMPLE 742 00:28:07,920 --> 00:28:09,360 EVEN THOUGH IT'S NOT GLYCO 743 00:28:09,360 --> 00:28:11,400 BIOLOGY BUT I WILL GET TO THAT 744 00:28:11,400 --> 00:28:11,680 IN A MINUTE. 745 00:28:11,680 --> 00:28:14,000 THIS THESE THIS CASE, THOO 2 746 00:28:14,000 --> 00:28:16,360 PATIENTS WERE NOT DIAGNOSEABLE 747 00:28:16,360 --> 00:28:18,560 BASED ON THE WHOLE EXOME 748 00:28:18,560 --> 00:28:20,480 SEQUENCING THAT WAS PERFORMED 749 00:28:20,480 --> 00:28:22,840 AND IT WAS UNTIL THE CLINICAL 750 00:28:22,840 --> 00:28:25,720 GENETICIST WENT THROUGH AND 751 00:28:25,720 --> 00:28:27,160 CAPTURED THE CLINICAL GENOTYPE 752 00:28:27,160 --> 00:28:29,880 IN GREEN ON THE LEFT AND 753 00:28:29,880 --> 00:28:31,720 YELLOWOT RIGHT THEY WERE ABLE TO 754 00:28:31,720 --> 00:28:32,280 DIAGNOSE THESE PATIENTS WITH 755 00:28:32,280 --> 00:28:32,920 DIFFERENT VALID AND RELIABLE 756 00:28:32,920 --> 00:28:38,200 YABTS IN THE SAME GENE, WHICH 757 00:28:38,200 --> 00:28:41,080 TURNS OUT TO BE CAUSAL FOR 758 00:28:41,080 --> 00:28:42,120 STIENER SYNDROME AND IT'S 759 00:28:42,120 --> 00:28:43,280 INTERESTING TO NOTE THAT THESE 760 00:28:43,280 --> 00:28:45,720 MATCHES ARE NOT EXACT. 761 00:28:45,720 --> 00:28:48,120 SO WE'RE USING A GRAPH MECHANISM 762 00:28:48,120 --> 00:28:52,480 THAT LOOKS TO FIND ALMOST OVER 763 00:28:52,480 --> 00:28:55,080 8000 DISEASE PROTILES SHOWN IN 764 00:28:55,080 --> 00:28:56,760 THE MIDDLE, WE LOOK FOR THE 1 765 00:28:56,760 --> 00:28:58,840 THAT'S MOST SIMILAR TO THE 766 00:28:58,840 --> 00:28:59,680 PHENOTYPIC FEATURES THAT ARE 767 00:28:59,680 --> 00:29:00,680 DESCRIBED ABOUT THE PATIENT. 768 00:29:00,680 --> 00:29:02,960 SO FOR EXAMPLE, THE LITTLE GIRL 769 00:29:02,960 --> 00:29:05,560 HAS CONE SHAPED SYNTHESIS OF THE 770 00:29:05,560 --> 00:29:09,760 FELL ANGIES OF THE HAND AND HAS 771 00:29:09,760 --> 00:29:12,880 A SHORTER MAX TO THE FINGER NOW 772 00:29:12,880 --> 00:29:20,000 A HUMAN CAN SEE THAT BUT WE NEED 773 00:29:20,000 --> 00:29:22,120 TO MAKE THAT MORE FOR THE 774 00:29:22,120 --> 00:29:22,600 MACHINE. 775 00:29:22,600 --> 00:29:23,320 NOW CLINICALLY THAT'S NOT 776 00:29:23,320 --> 00:29:24,960 ASSOCIATED AS MUCH AS YOU MIGHT 777 00:29:24,960 --> 00:29:27,080 THINK BUT IN THE GRAPH, IT'S 778 00:29:27,080 --> 00:29:28,120 ACTUALLY THESE ARE 2 SIBLING 779 00:29:28,120 --> 00:29:30,120 TERMS IN THE GRAPH SO THEY'RE 780 00:29:30,120 --> 00:29:31,360 QUITE CLOSELY RELATED BUT NOT 781 00:29:31,360 --> 00:29:32,480 EXACT. 782 00:29:32,480 --> 00:29:34,000 SO USING THIS ALGORITHM WE CAN 783 00:29:34,000 --> 00:29:36,000 THEN, DENTIFY THE MOST SIMILAR 784 00:29:36,000 --> 00:29:37,400 SET OF PHENOTYPIC FEATURES THAT 785 00:29:37,400 --> 00:29:39,840 A DIFFERENT PATIENT HAS TO OUR 786 00:29:39,840 --> 00:29:41,760 GOLD STANDARD PROFILES SUCH AS 787 00:29:41,760 --> 00:29:46,280 WIDER AND STIENER SYNDROME SHOWN 788 00:29:46,280 --> 00:29:47,280 IN THE MIDDLE. 789 00:29:47,280 --> 00:29:51,240 SO THIS AN EXAMPLE OF HOW WE CAN 790 00:29:51,240 --> 00:29:52,200 ACTUALLY IMPROVE DISEASE 791 00:29:52,200 --> 00:29:59,040 DIAGNOSTICS WITH THE MOLECULAR 792 00:29:59,040 --> 00:29:59,440 GLYCO PHENOTYPES. 793 00:29:59,440 --> 00:30:02,800 SO THAL CASE WE'RE LOOKING AT 794 00:30:02,800 --> 00:30:11,080 HOW USEFUL IS IT TO INCLUDE 795 00:30:11,080 --> 00:30:13,520 GLYCO PHENOTYPES, WE TOOK 18 OF 796 00:30:13,520 --> 00:30:16,400 THE MOST FREQUENTLY ASSOCIATED 797 00:30:16,400 --> 00:30:23,800 PHENOTYPES WITH FUCOSIDOSIS, AND 798 00:30:23,800 --> 00:30:25,280 THESE ARE COMPOSED OF A 799 00:30:25,280 --> 00:30:27,000 SELECTION OF 16 OF THESE 800 00:30:27,000 --> 00:30:31,880 PHENOTYPES. 801 00:30:31,880 --> 00:30:32,680 AND THEN ESSENTIALLY THESE ARE 802 00:30:32,680 --> 00:30:35,040 SHOWN AT THE BOTTOM, SO THOSE 803 00:30:35,040 --> 00:30:36,680 ORANGE 1S ON THE LEFT. 804 00:30:36,680 --> 00:30:38,400 SO WE BASICALLY LOOKED TO SEE 805 00:30:38,400 --> 00:30:41,480 WHAT WAS THE SORT OF PERCENTAGE 806 00:30:41,480 --> 00:30:44,520 OF A THOUSAND SIMULATED PROFILES 807 00:30:44,520 --> 00:30:45,840 WHICH FUCOSIDOSIS IS CORRECTLY 808 00:30:45,840 --> 00:30:47,480 MATCHED THAT IS RANKED NUMBER 1 809 00:30:47,480 --> 00:30:48,920 IN THE PROFILE SIMILARITY 810 00:30:48,920 --> 00:30:50,240 MATCHING ALGORITHM THAT I SHOWED 811 00:30:50,240 --> 00:30:52,320 YOU ON THE PRIOR--ON THE PRIOR 812 00:30:52,320 --> 00:30:53,640 SCREEN AND YOU CAN SEE THAT JUST 813 00:30:53,640 --> 00:30:57,280 THE INCLUSION OF THOSE 2 GLYCO 814 00:30:57,280 --> 00:30:58,880 PHENOTYPES REALLY GREATLY 815 00:30:58,880 --> 00:30:59,560 IMPROVED THE DIAGNOSTIC 816 00:30:59,560 --> 00:31:00,920 EFFICIENCY, SO THIS IS JUST A 817 00:31:00,920 --> 00:31:02,560 VALIDATION OF WHAT WE ALREADY 818 00:31:02,560 --> 00:31:05,040 KNEW THAT ESSENTIALLY BECAUSE 819 00:31:05,040 --> 00:31:10,400 GLYCO PHENOTYPES ARE VERY 820 00:31:10,400 --> 00:31:12,240 SPECIFIC AND NOT COMMONLY SEEN 821 00:31:12,240 --> 00:31:14,320 ACROSS MANY DISEASES AT THAT 822 00:31:14,320 --> 00:31:15,280 LEVEL OF GRANULARITY, THAT IS 823 00:31:15,280 --> 00:31:18,280 DEEP IN THE GRAPH, THEY CAN BE 824 00:31:18,280 --> 00:31:21,880 EXTRAORDINARILY HELPFUL IN A 825 00:31:21,880 --> 00:31:22,320 DIAGNOSTIC SETTING. 826 00:31:22,320 --> 00:31:25,400 SO I WANT TO TALK A LITTLE BIT 827 00:31:25,400 --> 00:31:27,280 ABOUT WHAT IS THE MOST 828 00:31:27,280 --> 00:31:28,120 CLINICALLY USEFUL WAY TO DEFINE 829 00:31:28,120 --> 00:31:31,880 A GROUP OF DISEASES AND THE WORK 830 00:31:31,880 --> 00:31:34,200 TO DEVELOP THE MONDO ONTOLOGY 831 00:31:34,200 --> 00:31:36,280 WHICH IS A DISEASE ONTOLOGY THAT 832 00:31:36,280 --> 00:31:38,480 UNITES A VARIETY OF DIFFERENT 833 00:31:38,480 --> 00:31:41,280 DISEASE ONTOLOGY RESOURCES FOR 834 00:31:41,280 --> 00:31:42,560 COMPLEX DISEASES, CANCER, 835 00:31:42,560 --> 00:31:44,680 INFECTIOUS DISEASES, RARE 836 00:31:44,680 --> 00:31:45,720 DISEASES, MENDELIAN DISEASES AND 837 00:31:45,720 --> 00:31:47,480 WE REALLY NEEDED A SYSTEMATIC 838 00:31:47,480 --> 00:31:49,040 WAY OF RELATING THESE IN ORDER 839 00:31:49,040 --> 00:31:51,280 TO BE THE HANDLE FOR THOSE HPO 840 00:31:51,280 --> 00:31:53,480 PROFILES I SHOWED EARLIER ACROSS 841 00:31:53,480 --> 00:31:55,640 DIFFERENT SOURCES SO WHY NOT 842 00:31:55,640 --> 00:31:57,280 JUST USE MAPPINGS ACROSS 843 00:31:57,280 --> 00:31:57,680 SOURCES. 844 00:31:57,680 --> 00:31:58,800 MANY PEOPLE MAP ACROSS 845 00:31:58,800 --> 00:32:00,400 TERMINOLOGIES AND THE PROBLEM IS 846 00:32:00,400 --> 00:32:05,040 THAT THOSE, THOSE MAPPINGS AND 847 00:32:05,040 --> 00:32:07,360 TERMINOLOGIES ARE OFTEN MUTUALLY 848 00:32:07,360 --> 00:32:08,760 INCONSISTENT, THEY CAN BE IN THE 849 00:32:08,760 --> 00:32:10,880 SQUARED SET OF MAPPINGS, 1 TO 1 850 00:32:10,880 --> 00:32:12,080 EQUIVALENCE AND FURTHER MORE 851 00:32:12,080 --> 00:32:14,080 THEY'RE VERY OFTEN LACKS 852 00:32:14,080 --> 00:32:15,920 PROVIDENCE IN DEFINING WHAT WAS 853 00:32:15,920 --> 00:32:17,720 TRULY EQUIVALENT AND WHAT THOSE 854 00:32:17,720 --> 00:32:21,080 CURATION RULES FOR THE MAPPINGS 855 00:32:21,080 --> 00:32:21,640 REALLY WERE. 856 00:32:21,640 --> 00:32:22,560 FURTHER MODEL CITIZENNER WHEN 857 00:32:22,560 --> 00:32:27,040 YOU THINK ABOUT DISEASE ENDITYS 858 00:32:27,040 --> 00:32:28,880 AS HANDLES, THEY'RE REALLY 859 00:32:28,880 --> 00:32:31,080 HANDLES FOR ANNOTATIONS AGAINST 860 00:32:31,080 --> 00:32:32,120 FOR DIFFERENT RELATIONSHIPS, AT 861 00:32:32,120 --> 00:32:33,920 DIFFERENT LEVELS OF GRANULARITY 862 00:32:33,920 --> 00:32:35,840 AND DIFFERENT CONTEXTS, USING 863 00:32:35,840 --> 00:32:36,760 DIFFERENT VOCABULARIES, SO THIS 864 00:32:36,760 --> 00:32:38,720 IS JUST A SMATTERING OF THE FEW 865 00:32:38,720 --> 00:32:40,040 OF THE RESOURCES THAT WE 866 00:32:40,040 --> 00:32:45,320 INTEGRATE WHEN WE THINK ABOUT 867 00:32:45,320 --> 00:32:49,080 DISEASE, SUCH AS WEIDERMAN 868 00:32:49,080 --> 00:32:51,440 STIENER SYNDROME, DIFFERENT 869 00:32:51,440 --> 00:32:53,640 VARIANTS, DIFFERENT DISEASES TO 870 00:32:53,640 --> 00:32:55,680 GENES TYPE, VARIANTS AND VAIRMT 871 00:32:55,680 --> 00:32:56,400 ENVIRONMENTAL FACTORS SUCH AS 872 00:32:56,400 --> 00:32:58,880 THOSE SHOWN ON THE RIGHT, 873 00:32:58,880 --> 00:33:00,200 ANNOTATE BAR DISEASES TO 874 00:33:00,200 --> 00:33:04,000 VARIANTS WHERE AS ONEM ANNOTATES 875 00:33:04,000 --> 00:33:05,160 DECS TO GENES AND FENNISTERATION 876 00:33:05,160 --> 00:33:08,000 O TYPES AND THEN THE COMPARATIVE 877 00:33:08,000 --> 00:33:10,920 TOXIC O GENOMICS TO DISEASES TO 878 00:33:10,920 --> 00:33:11,440 GENES AND ENVIRONMENTS. 879 00:33:11,440 --> 00:33:12,680 SO EACH OF THESE DIFFERENT 880 00:33:12,680 --> 00:33:14,280 RESOURCES CONTRIBUTES TO A 881 00:33:14,280 --> 00:33:17,280 DIFFERENT ASPECT OF THE MODEL IN 882 00:33:17,280 --> 00:33:20,960 THESE DISEASES SUCH AS WEIDERMAN 883 00:33:20,960 --> 00:33:23,040 STIENER ISIN DROAM SO WE TRY TO 884 00:33:23,040 --> 00:33:24,320 COAALATE ALL THOSE INTO A MODEL 885 00:33:24,320 --> 00:33:26,200 TO INTEGRATE THESE DATA FOR 886 00:33:26,200 --> 00:33:27,600 MECHANISTIC DISCOVERY AND 887 00:33:27,600 --> 00:33:28,040 DIAGNOSTIC PURPOSES. 888 00:33:28,040 --> 00:33:33,840 SO THIS IS JUST AN EXAMPLE OF 889 00:33:33,840 --> 00:33:41,280 HOW THIS WORKS FOR FOR A GLYCO 890 00:33:41,280 --> 00:33:41,560 PHENOTYPE. 891 00:33:41,560 --> 00:33:44,120 I WAS TRYING TO FIND MY NOTES 892 00:33:44,120 --> 00:33:44,320 HERE. 893 00:33:44,320 --> 00:33:48,080 SO THIS IS A GRAPH 894 00:33:48,080 --> 00:33:50,080 REPRESENTATION OF THE 895 00:33:50,080 --> 00:33:50,880 DYSFUNCTIONAL COSMIC GENE WE 896 00:33:50,880 --> 00:33:53,520 JUST HEARD ABOUT AND A MOLECULAR 897 00:33:53,520 --> 00:33:55,240 CHAPERON FOR GLYCO TRANSFER ACE 898 00:33:55,240 --> 00:33:56,480 AND WHAT WE CAN SEE IS THAT OVER 899 00:33:56,480 --> 00:33:59,080 THERE ON THE LEFT, WE HAVE A 900 00:33:59,080 --> 00:34:00,480 VARIETY OF DIFFERENT PHENOTYPES, 901 00:34:00,480 --> 00:34:01,960 THAT ARE ASSOCIATED WITH A 902 00:34:01,960 --> 00:34:05,160 VARIETY OF DIFFERENT DISEASES AS 903 00:34:05,160 --> 00:34:06,920 INDICATED IN THE GREEN IN THE 904 00:34:06,920 --> 00:34:09,760 SECOND FROM THE LEFT THAT MAY 905 00:34:09,760 --> 00:34:11,400 HAVE IMPLICATIONS FOR GLYCO 906 00:34:11,400 --> 00:34:12,080 TRANSFER ACE. 907 00:34:12,080 --> 00:34:14,200 THERE'S THAT 1 DYSFUNCTIONAL 908 00:34:14,200 --> 00:34:15,400 GENE IN ORANGE. 909 00:34:15,400 --> 00:34:17,360 WE HAVE EPIGENETIC FAGHTORS SUCH 910 00:34:17,360 --> 00:34:19,520 AS HYPER METHYLATION AND 911 00:34:19,520 --> 00:34:20,760 FUNDAMENTALLY THAT GLYCO 912 00:34:20,760 --> 00:34:22,680 PHENOTYPE IS AN ABNORMALITY OF 913 00:34:22,680 --> 00:34:25,480 OGLYCANS WHICH ARE THE AFFECTED 914 00:34:25,480 --> 00:34:27,480 BIOLOGICAL ENTITIES WHICH WE 915 00:34:27,480 --> 00:34:28,840 ALSO KNOW MAY AFFECT GUT 916 00:34:28,840 --> 00:34:30,480 MICROBIOME AND SO THIS KIND OF 917 00:34:30,480 --> 00:34:34,400 SHOWS YOU JUST SORT OF HOW WE 918 00:34:34,400 --> 00:34:35,320 WOULD NAVIGATE THE GRAPH THAT 919 00:34:35,320 --> 00:34:37,120 WAS PUT TOGETHER IN TERMS OF 920 00:34:37,120 --> 00:34:39,640 MODELING ON THE PRIOR SLIDE. 921 00:34:39,640 --> 00:34:42,880 AND SO, WE CREATED MONDO TO 922 00:34:42,880 --> 00:34:44,040 BASICALLY BRING TOGETHER ALL 923 00:34:44,040 --> 00:34:46,600 THESE DIFFERENT DISEASE 924 00:34:46,600 --> 00:34:49,880 RESOURCES SUCH AS OMICS AND CIT, 925 00:34:49,880 --> 00:34:51,640 GUARD FOR RARE DISEASES, ET 926 00:34:51,640 --> 00:34:58,240 CETERA USING AN ALGORITHM CALLED 927 00:34:58,240 --> 00:34:59,680 KBOOM AND THIS WAS TO INITIALLY 928 00:34:59,680 --> 00:35:01,120 SEE THE ONTOLOGY AND IT 929 00:35:01,120 --> 00:35:03,880 BASICALLY USES A VARIETY OF 930 00:35:03,880 --> 00:35:06,400 LOGICAL AND PROBABLISTIC 931 00:35:06,400 --> 00:35:06,920 INFERENCE TO DETERMINE 932 00:35:06,920 --> 00:35:07,600 EQUIVALENCES ACROSS THESE 933 00:35:07,600 --> 00:35:08,960 DIFFERENT RESOURCES AND THEN A 934 00:35:08,960 --> 00:35:10,840 CURATOR, YOU KNOW WE HAVE A 935 00:35:10,840 --> 00:35:11,880 NUMBER OF CURATORS WHO GO 936 00:35:11,880 --> 00:35:17,000 THROUGH THE LOW PROBABILITY OF 937 00:35:17,000 --> 00:35:19,000 EQUIVALENCE, TO UNDERSTAND WHICH 938 00:35:19,000 --> 00:35:20,440 ARE EQUIV LEAPT AND WHICH ARE 939 00:35:20,440 --> 00:35:20,720 NOT. 940 00:35:20,720 --> 00:35:22,920 SO WHAT WE FOUND IS THAT 941 00:35:22,920 --> 00:35:24,840 ESSENTIALLY THERE'S A LOT OF 942 00:35:24,840 --> 00:35:27,480 ERRORS IN RECONCILING THESE 943 00:35:27,480 --> 00:35:28,080 DIFFERENT DISEASE RESOURCES 944 00:35:28,080 --> 00:35:29,240 UMPIRES STREAM AND WE WORK WITH 945 00:35:29,240 --> 00:35:31,320 EACH SOURCE TO TRY TO FRO 946 00:35:31,320 --> 00:35:32,520 PROVIDE FEEDBACK TO EACH SOURCE 947 00:35:32,520 --> 00:35:33,880 SO FOR EXAMPLE, WITH MESH WE 948 00:35:33,880 --> 00:35:36,600 HAPPEN TO FIND THAT THERE WERE 2 949 00:35:36,600 --> 00:35:38,920 BRANCHES OF MESH, 1 THAT WERE 950 00:35:38,920 --> 00:35:42,160 EQUIVALENT BUT WERE DUPLICATED, 951 00:35:42,160 --> 00:35:43,400 1 HAD ALPHANUMERIC NUMBERING 952 00:35:43,400 --> 00:35:54,080 SYSTEM AND 1 HAD A ROMAN 953 00:35:54,080 --> 00:35:55,400 NIEWMERAL MEMBERS, AND IT WAS 954 00:35:55,400 --> 00:35:57,080 FED BACK TO MESH AND THEY 955 00:35:57,080 --> 00:35:58,280 CORRECTED IT AND THOSE TERMS 956 00:35:58,280 --> 00:36:01,880 HAVE BEEN MERGED IN MESH AND IN 957 00:36:01,880 --> 00:36:02,080 MONDO. 958 00:36:02,080 --> 00:36:05,200 AND SO THIS IS JUST AN EXAMPLE 959 00:36:05,200 --> 00:36:20,480 OF HOWAN OITATIONS CAN WORK IN 960 00:36:20,480 --> 00:36:20,800 CONTEXT. 961 00:36:20,800 --> 00:36:23,080 SO THIS IS BASED ON GLUE MARIOUS 962 00:36:23,080 --> 00:36:28,320 O BIOLOGY OR KEVI, SO THIS CAN 963 00:36:28,320 --> 00:36:32,320 BE BOUND TO MOLECULES AND THE 964 00:36:32,320 --> 00:36:34,320 FREE 1S CAN BE SACCHARIDES OR 965 00:36:34,320 --> 00:36:36,880 DERIVATIVES AND SO HERE WE SHOW 966 00:36:36,880 --> 00:36:38,840 12 DISEASES WITH NAMES ALONG 967 00:36:38,840 --> 00:36:40,840 WITH THE MUTATED GENES AND THE 968 00:36:40,840 --> 00:36:42,160 MONDO ID AND WHETHER THE 969 00:36:42,160 --> 00:36:43,200 ACTIVITY IS INCREASED OR 970 00:36:43,200 --> 00:36:43,480 DECREASE. 971 00:36:43,480 --> 00:36:45,760 SO YOU CAN SEE JUST 972 00:36:45,760 --> 00:36:48,480 UNDERSTANDING ALL THE DIFFERENT 973 00:36:48,480 --> 00:36:51,480 DISEASE ENTITIES THAT ARE 974 00:36:51,480 --> 00:36:56,280 ALIGNED OR ANNOTATED HERE WITH 975 00:36:56,280 --> 00:36:58,560 DIFFERENT TYPES OF GLYCO 976 00:36:58,560 --> 00:37:00,800 BIOLOGY, SO FOR EXAMPLE, HERE WE 977 00:37:00,800 --> 00:37:03,880 HAVE GLYCO PROTEINS TO WORK WITH 978 00:37:03,880 --> 00:37:05,280 THE RATHER FAMOUS 979 00:37:05,280 --> 00:37:07,000 [INDISCERNIBLE] WHICH IS A 980 00:37:07,000 --> 00:37:08,360 DECREASE IN N-DPLE 1 DEFICIENCY 981 00:37:08,360 --> 00:37:11,600 AND YOU CAN SEE THE MONDO TERM 982 00:37:11,600 --> 00:37:11,880 FOR THAT. 983 00:37:11,880 --> 00:37:13,720 SIMILARLY HERE WE HAVE 984 00:37:13,720 --> 00:37:16,200 NUCLEOTIDE SUGARS WHERE WE HAVE 985 00:37:16,200 --> 00:37:17,040 HER EDUCATIONALITARY MYOPATHY 986 00:37:17,040 --> 00:37:19,280 AND THAT'S AN INCREASE AND SO, 987 00:37:19,280 --> 00:37:22,760 WE HAVE KIND OF A WAY OF SORT OF 988 00:37:22,760 --> 00:37:24,600 VISUALIZING INCREASES IN GLYCAN 989 00:37:24,600 --> 00:37:27,680 BY O SYNTHESIS AND DECREASES IN 990 00:37:27,680 --> 00:37:31,320 GLYCAN DEGRADATION AND PROBLEMS 991 00:37:31,320 --> 00:37:32,720 WITH GLYCAN TRANSPORTAN OITATED 992 00:37:32,720 --> 00:37:39,080 ACROSS THIS GRAPH OF GLYCO 993 00:37:39,080 --> 00:37:40,560 BIOLOGY SO WE CAN ALSO CAPTURE 994 00:37:40,560 --> 00:37:42,080 THIS INFORMATION FROM VARIOUS 995 00:37:42,080 --> 00:37:43,600 LAB TECHNIQUES SO FOR EXAMPLE, 996 00:37:43,600 --> 00:37:45,040 WE HAVE DIFFERENT SAMPLES 997 00:37:45,040 --> 00:37:46,560 COLLECTED FROM DIFFERENT 998 00:37:46,560 --> 00:37:49,640 ANATOMICAL STRUCTURES SUCH AS 999 00:37:49,640 --> 00:37:57,280 BLOOD, URINE, CEREBRAL 1000 00:37:57,280 --> 00:37:59,400 SPINAL--OR GLYCAN ANALYSIS, MASS 1001 00:37:59,400 --> 00:38:02,480 SPEC, GLYCO TRANSFER ACE, 1002 00:38:02,480 --> 00:38:04,960 ASSAYS, ET CETERA, AND THESE CAN 1003 00:38:04,960 --> 00:38:06,280 INFER THEN, GLYCO PHENOTYPES 1004 00:38:06,280 --> 00:38:10,760 SUCH AS REDUCED BLOOD, HEP A RIN 1005 00:38:10,760 --> 00:38:12,200 SULFATE CONITRATION, AND I 1006 00:38:12,200 --> 00:38:14,080 GLYCANS THESE ARE THE PHENOTYPES 1007 00:38:14,080 --> 00:38:15,240 WE WOULD USE FOR DESCRIBING 1008 00:38:15,240 --> 00:38:18,680 DISEASES THAT ARE ASSOCIATED 1009 00:38:18,680 --> 00:38:20,880 SUCH AS HEREDITARY OFTWOE 1010 00:38:20,880 --> 00:38:21,880 CONDROAMAS, AND SO CAN YOU KIND 1011 00:38:21,880 --> 00:38:25,240 OF SEE HOW WE RELATE THE 1012 00:38:25,240 --> 00:38:29,480 OUTCOMES OF GLYCO BIOLOGY ASSAYS 1013 00:38:29,480 --> 00:38:31,080 IN SPECIFIC ANATOMICAL CONTEXTS 1014 00:38:31,080 --> 00:38:32,960 TO THE GLYCO PHENOTYPES THAT ARE 1015 00:38:32,960 --> 00:38:35,080 THEN ASSOCIATED WITH THOSE MONDO 1016 00:38:35,080 --> 00:38:35,320 DISEASE. 1017 00:38:35,320 --> 00:38:36,880 SO KIND OF PUTTING TOGETHER THAT 1018 00:38:36,880 --> 00:38:40,760 WHOLE DISEASE MODEL THAT I 1019 00:38:40,760 --> 00:38:42,440 SHOWED EARLIER. 1020 00:38:42,440 --> 00:38:44,200 AND SO WHEN WE TRY TO DO THIS, 1021 00:38:44,200 --> 00:38:46,040 ACROSS THE MANY SOURCES OF 1022 00:38:46,040 --> 00:38:47,200 INFORMATION, SHOWN OVER ON THE 1023 00:38:47,200 --> 00:38:51,560 LEFT ARE MANY DIFFERENT SOURCES, 1024 00:38:51,560 --> 00:38:54,200 PUBLICATIONS, KEY HAVE KEVI, WE 1025 00:38:54,200 --> 00:38:56,040 HAVE GLYCO 2 KAN--KANA, WE HAVE 1026 00:38:56,040 --> 00:38:58,320 K, WE HAVE REACT OHM, WE HAVE 1027 00:38:58,320 --> 00:38:59,880 GLY CONNECT AND A VARIETY OF 1028 00:38:59,880 --> 00:39:02,080 OTHER SOURCES, WE CAN INTEGRATE 1029 00:39:02,080 --> 00:39:03,720 THOSE GLYKAN--KANA KNOWLEDGE 1030 00:39:03,720 --> 00:39:05,080 RELATED SOURCES USING SOME OF 1031 00:39:05,080 --> 00:39:06,400 THE MODELING TECHNIQUES I SHOWED 1032 00:39:06,400 --> 00:39:07,880 EARLIER, SUCH AS UNDERSTANDING 1033 00:39:07,880 --> 00:39:10,000 WHAT DPLI KAN--KANAS EXIST AND 1034 00:39:10,000 --> 00:39:12,240 THEIR DERIVATIVES AND WHAT 1035 00:39:12,240 --> 00:39:13,680 GLYCAN BINDINGS EXIST, WHAT 1036 00:39:13,680 --> 00:39:15,720 PRODUCTS ARE THERE AND HOW ARE 1037 00:39:15,720 --> 00:39:16,920 THESE ASSOCIATED TO DISEASES. 1038 00:39:16,920 --> 00:39:19,240 THOSE ARE ASSOCIATED VIA 1039 00:39:19,240 --> 00:39:19,840 SPECIFIC ONTOLOGYS AND 1040 00:39:19,840 --> 00:39:23,600 REPOSITORIES SUFFER FROM AS THE 1041 00:39:23,600 --> 00:39:25,240 GENE ONTOLOGY AND GLY-2 1042 00:39:25,240 --> 00:39:30,480 KAN--KANA, AND --CAN, AND THEN WE CAN 1043 00:39:30,480 --> 00:39:32,120 INTEGRATE ALL THIS IN DISEASE 1044 00:39:32,120 --> 00:39:34,040 DIAGNOSTICS AS I SHOWED EARLIER. 1045 00:39:34,040 --> 00:39:36,240 SO I WANT TO TALK ABOUT THE 1046 00:39:36,240 --> 00:39:37,200 CROSS SPECIES ASPECTS OF THIS, 1047 00:39:37,200 --> 00:39:40,080 SO AS YOU ALL KNOW, GLYCO 1048 00:39:40,080 --> 00:39:40,680 GIVING--YOUOLOGY AND WELL 1049 00:39:40,680 --> 00:39:43,880 CONSERVED ACROSS THE TREE OF 1050 00:39:43,880 --> 00:39:44,400 LIFE. 1051 00:39:44,400 --> 00:39:46,200 AND OTHER SPECIES AREN'T JUST 1052 00:39:46,200 --> 00:39:48,280 RELEVANT, EACH 1 HAS VERY UNIQUE 1053 00:39:48,280 --> 00:39:50,920 PHENOTYPES SO FOR EXAMPLE, NAKED 1054 00:39:50,920 --> 00:39:53,200 MOLE RATS DON'T GET CANCER, 1055 00:39:53,200 --> 00:39:56,960 ARMADILLOS ARE THE NATURAL HOST 1056 00:39:56,960 --> 00:39:57,840 OF LEPROSY, A MICROBACTERIUM 1057 00:39:57,840 --> 00:40:00,480 WHICH IS THE ONLY OTHER ORGANISM 1058 00:40:00,480 --> 00:40:04,480 THAT GETS LEPROSY BESIDES 1059 00:40:04,480 --> 00:40:13,200 HUMANS, AND TREE SHREWS ARE MORE 1060 00:40:13,200 --> 00:40:14,400 SIMILAR THAN MOUSE MODELS. 1061 00:40:14,400 --> 00:40:15,800 SO THIS IS DIFFERENT BIOLOGY 1062 00:40:15,800 --> 00:40:18,200 THAT WE MAY USE TO UNDERSTAND 1063 00:40:18,200 --> 00:40:19,280 THE DISEASE BETTER. 1064 00:40:19,280 --> 00:40:22,680 SO MODEL ORGANISMS MATTER TO 1065 00:40:22,680 --> 00:40:22,920 PATIENTS. 1066 00:40:22,920 --> 00:40:26,520 SO OVER HERE ON THE LEFT, WE 1067 00:40:26,520 --> 00:40:28,840 HAVE 19,201 CODING GENES IN THE 1068 00:40:28,840 --> 00:40:31,200 HUMAN GENOME AND APPROXIMATELILY 1069 00:40:31,200 --> 00:40:33,920 21% OF THOSE ARE ASSOCIATED WITH 1070 00:40:33,920 --> 00:40:37,080 A CAUSAL VARIATION THAT LEADS TO 1071 00:40:37,080 --> 00:40:38,320 A PHENOTYPIC OUTCOME. 1072 00:40:38,320 --> 00:40:41,600 IF WE TAKE THE ORTHOLOGS OF 1073 00:40:41,600 --> 00:40:42,760 THESE 19,201 GENES AND WE LOOK 1074 00:40:42,760 --> 00:40:46,160 AT THE 5 MOST COMMONLY UTILIZED 1075 00:40:46,160 --> 00:40:48,920 MODEL ORGANISMS SUCH AS YEEOF 1076 00:40:48,920 --> 00:40:53,800 THE, MOUSE, ELGANNAS, ZEBRA FISH 1077 00:40:53,800 --> 00:40:55,960 AND DROSOPHILA, AND WE LOOK AT 1078 00:40:55,960 --> 00:40:58,160 THE CURATED PHENOTYPES THAT IS 1079 00:40:58,160 --> 00:41:01,160 ABNORMAL TRAITS THAT BEEN 1080 00:41:01,160 --> 00:41:02,560 ATTRIBUTED TO THESE 19,201 1081 00:41:02,560 --> 00:41:04,080 ORTHOLOGS IN THESE SPECIES WE 1082 00:41:04,080 --> 00:41:06,680 HAVE 83% COVERAGE OF THE HUMAN 1083 00:41:06,680 --> 00:41:09,080 CODING GENOME AND IF WE COMBINE 1084 00:41:09,080 --> 00:41:11,400 THESE WE HAVE 84% OF THE HUMAN 1085 00:41:11,400 --> 00:41:12,920 COVERAGE CODING GENOME ANDEE 1086 00:41:12,920 --> 00:41:14,840 IT'S QUITE A LOT OF DATA THAT WE 1087 00:41:14,840 --> 00:41:16,680 MIGHT LEVERAGE GIVEN THE 1088 00:41:16,680 --> 00:41:19,480 CONSERVATION OF GLYCO BIOLOGY 1089 00:41:19,480 --> 00:41:20,080 ACROSS THE FIELD FUNCTIONS 1090 00:41:20,080 --> 00:41:23,400 LODGENY IF YOU LIKE. 1091 00:41:23,400 --> 00:41:25,040 SO THE INCLUSION OF JUST 5 1092 00:41:25,040 --> 00:41:28,080 SPECIES AND WE HAVE MANY, MANY 1093 00:41:28,080 --> 00:41:30,000 MORE IN THE RESOURCE BOOSTS 1094 00:41:30,000 --> 00:41:33,280 PHENOTYPIC COVERAGE OF GENES BY 1095 00:41:33,280 --> 00:41:34,080 63%. 1096 00:41:34,080 --> 00:41:35,800 SO THIS IS THE MONARCH KNOWLEDGE 1097 00:41:35,800 --> 00:41:37,200 GRAPH AND FOR THOSE WHO ARE MORE 1098 00:41:37,200 --> 00:41:38,160 TECHNICAL IN THE AUDIENCE, I 1099 00:41:38,160 --> 00:41:39,960 WANT TO PROVIDE THIS AS A 1100 00:41:39,960 --> 00:41:43,080 RESOURCE SO WE COLLECT DIFFERENT 1101 00:41:43,080 --> 00:41:44,920 INFORMATION ABOUT GENES 1102 00:41:44,920 --> 00:41:47,640 VARIANTS, MORPHOLOGY, MODEL 1103 00:41:47,640 --> 00:41:49,280 ORGANISMS, DISEASES, PHENOTYPES, 1104 00:41:49,280 --> 00:41:50,200 GENE FUNCTION, PROTEIN 1105 00:41:50,200 --> 00:41:51,280 INTERACTIONS AND EXPRESSION DATA 1106 00:41:51,280 --> 00:41:53,920 AND PATHWAYS FROM A VARIETY OF 1107 00:41:53,920 --> 00:41:56,320 DIFFERENT SOURCES SHOWN IN THE 1108 00:41:56,320 --> 00:41:57,640 MIDDLE SHOWING A VARIETY OF 1109 00:41:57,640 --> 00:41:58,440 DIFFERENT ONTOLOGIES AND 1110 00:41:58,440 --> 00:42:00,080 STANDARDS THAT CAN THEN ALL BE 1111 00:42:00,080 --> 00:42:01,240 LOADED INTO OUR KNOWLEDGE GRAPH 1112 00:42:01,240 --> 00:42:04,080 WHICH IS THE FUNDAMENTAL 1113 00:42:04,080 --> 00:42:06,520 RESOURCE THAT DRIVES OUR WEBSITE 1114 00:42:06,520 --> 00:42:10,680 AND OUR API SHOWN AT THE BOTTOM 1115 00:42:10,680 --> 00:42:11,760 FOR CROSS SPECIES QUERYING AND 1116 00:42:11,760 --> 00:42:14,480 INFERENCE AS WELL AS FOR 1117 00:42:14,480 --> 00:42:16,920 DIAGNOSTIC TOOLS. 1118 00:42:16,920 --> 00:42:18,400 THE GRAPH HAS 818,000 GENE 1119 00:42:18,400 --> 00:42:20,800 PHENOTYPE ASSOCIATIONS WITH OVER 1120 00:42:20,800 --> 00:42:22,880 9000 GENE-DISEASE ASSOCIATIONS 1121 00:42:22,880 --> 00:42:25,440 AND 30,000 NONCAUSAL 1122 00:42:25,440 --> 00:42:26,720 GENE-DISEASE ASSOCIATIONS FOR 1123 00:42:26,720 --> 00:42:31,480 MORE THAN 70 SPECSYS. 1124 00:42:31,480 --> 00:42:34,160 SO I WANTED TO JUST TO CLOSE OUR 1125 00:42:34,160 --> 00:42:36,440 CONVERSATION OFF TODAY TO BOLDLY 1126 00:42:36,440 --> 00:42:40,400 WHERE NO MAN, NO HUMAN, NO 1127 00:42:40,400 --> 00:42:45,200 ORGANISM HAS GONE BEFORE. 1128 00:42:45,200 --> 00:42:47,040 GLYCOBIOLOGY IS REALLY SOMETHING 1129 00:42:47,040 --> 00:42:48,440 THAT NEEDS TO BE THOUGHT ABOUT 1130 00:42:48,440 --> 00:42:51,080 IN A CROSS SPECIES MANNER AND WE 1131 00:42:51,080 --> 00:42:52,360 NEED TO LEVERAGE THE KNOWLEDGE 1132 00:42:52,360 --> 00:42:54,040 WE GAME FOR ALL THE ORGANISMS TO 1133 00:42:54,040 --> 00:42:55,800 HELP AND FOR OUR UNDERSTANDING 1134 00:42:55,800 --> 00:43:00,000 OF HUMAN DISEASE BIOLOGY, SIM 1135 00:43:00,000 --> 00:43:01,200 ABTIC DISEASE MORPHOLOGY IS 1 1136 00:43:01,200 --> 00:43:02,920 APPROACH AND 1 THING FROM A 1137 00:43:02,920 --> 00:43:04,240 TRANSLATIONAL CONTEXT IS IT 1138 00:43:04,240 --> 00:43:05,760 CONSIDERS THE PATIENT AS A 1139 00:43:05,760 --> 00:43:07,160 BIOLOGICAL SUBJECT THAT CAN BE 1140 00:43:07,160 --> 00:43:08,480 COMPARED TO THE DIFFERENT 1141 00:43:08,480 --> 00:43:09,640 ORGANISMSES THAT ARE'S DIFFERENT 1142 00:43:09,640 --> 00:43:11,160 THAN MOST CLINICAL SETTINGS 1143 00:43:11,160 --> 00:43:12,800 WHERE, YOU KNOW THE ELECTRONIC 1144 00:43:12,800 --> 00:43:14,680 HEALTH RECORD IS REALLY 1145 00:43:14,680 --> 00:43:18,480 GENERALLY VERY FOCUSED ON 1146 00:43:18,480 --> 00:43:20,600 CAPTURING FILLING AND CAPTURING 1147 00:43:20,600 --> 00:43:21,840 QUALITY OF CARE ISSUES AND NOT 1148 00:43:21,840 --> 00:43:22,880 NECESSARILY THE DATA WITH THE 1149 00:43:22,880 --> 00:43:24,600 GOAL OF THINKING ABOUT THE 1150 00:43:24,600 --> 00:43:27,160 PATIENT AS AN ORGANIZATIONS 1151 00:43:27,160 --> 00:43:27,440 ORGANISM. 1152 00:43:27,440 --> 00:43:28,880 PHENOTYPING ALL THE 1153 00:43:28,880 --> 00:43:30,880 ORGANIZATIONS INFORMS REALLY CAN 1154 00:43:30,880 --> 00:43:32,600 LEVERAGE THE DIVERSITY OF GENO 1155 00:43:32,600 --> 00:43:33,880 TYPE, PHENOTYPE OUTCOMES IN THE 1156 00:43:33,880 --> 00:43:34,840 DIFFERENT ORGANISMS FOR AGAIN 1157 00:43:34,840 --> 00:43:36,720 FOR INFERENCE IN OUR BEDDING OF 1158 00:43:36,720 --> 00:43:38,480 FLIEK O BIOLOGY, AND DATA 1159 00:43:38,480 --> 00:43:40,120 INTEGRATION ACROSS SOWSHESS AND 1160 00:43:40,120 --> 00:43:41,320 SPECIES IS ABSOLUTELY CRITICAL 1161 00:43:41,320 --> 00:43:43,520 FOR UNDERSTANDING FLIEK O 1162 00:43:43,520 --> 00:43:44,760 BIOLOGY GIVEN ITS CONSERVATION 1163 00:43:44,760 --> 00:43:48,400 ACROSS THE TREE OF LIFE. 1164 00:43:48,400 --> 00:43:51,880 I WANTED TO THANK A NUMBER OF 1165 00:43:51,880 --> 00:43:53,720 DIFFERENT PEOPLE, PETER 1166 00:43:53,720 --> 00:43:54,880 ROBINSON, CHRIS MUNGAL IN 1167 00:43:54,880 --> 00:43:56,000 PARTICULAR FOR THEIR PARTNERSHIP 1168 00:43:56,000 --> 00:44:00,880 OVER MANY YEARS IN CREATING THE 1169 00:44:00,880 --> 00:44:03,160 MONARCH INITIATIVE, I WOULD 1170 00:44:03,160 --> 00:44:06,920 ESPECIALLY LIKE TO THANK JB 1171 00:44:06,920 --> 00:44:09,320 GOURDINE, WHO LED THE LAB FOR 1172 00:44:09,320 --> 00:44:15,200 THE GLYCO BIOLOGY AND THE MONDO 1173 00:44:15,200 --> 00:44:15,480 ONTOLOGY. 1174 00:44:15,480 --> 00:44:16,920 I WANT TO THANK ALL OF THE MANY, 1175 00:44:16,920 --> 00:44:18,960 MANY RESOURCES THAT WE WELCOMER 1176 00:44:18,960 --> 00:44:21,960 WITH TO INTEGRATE THEIR DATA 1177 00:44:21,960 --> 00:44:24,160 THEY HAVE BEEN ABSOLUTELY 1178 00:44:24,160 --> 00:44:25,480 FUNDAMENTAL PARTNERS IN CREATING 1179 00:44:25,480 --> 00:44:26,640 THIS INTEGRATED RESOURCE AND 1180 00:44:26,640 --> 00:44:27,880 FINALLY OUR 3 MAJOR FUNDING 1181 00:44:27,880 --> 00:44:31,760 SOURCES FROM THE OFFICE OF THE 1182 00:44:31,760 --> 00:44:33,320 DIRECTOR AND NHGRI OR CENTER FOR 1183 00:44:33,320 --> 00:44:34,400 EXCELLENCE AND GENOME SCIENCES 1184 00:44:34,400 --> 00:44:37,240 IN OUR U24 FOR THE HUMAN 1185 00:44:37,240 --> 00:44:37,760 PHENOTYPE ONTOLOGY GRANT. 1186 00:44:37,760 --> 00:44:45,720 AND THANK YOU VERY MUCH. 1187 00:44:45,720 --> 00:44:48,520 >> OKAY, THANK YOU SO MUCH, MESS 1188 00:44:48,520 --> 00:44:49,720 MELISSA, THAT WAS REALLY 1189 00:44:49,720 --> 00:44:51,480 FASCINATING LET ME MENTION TO 1190 00:44:51,480 --> 00:44:54,520 EVERYONE, AGAIN, PLEASE SUBMIT 1191 00:44:54,520 --> 00:44:56,080 QUESTIONS USING THE LITTLE ICON 1192 00:44:56,080 --> 00:44:57,360 THAT SAYS SEND LIVE FEEDBACK AND 1193 00:44:57,360 --> 00:45:00,280 THOSE WILL COME UP IN OUR CHAT 1194 00:45:00,280 --> 00:45:02,040 AND I WILL LOOK AT THEM AS I 1195 00:45:02,040 --> 00:45:04,960 MENTIONED EARLIER IN CASE YOU 1196 00:45:04,960 --> 00:45:09,560 JOINED US A BIT LATE, 1197 00:45:09,560 --> 00:45:10,840 DR. MALAKER WILL NOT BE SPEAKING 1198 00:45:10,840 --> 00:45:15,720 THIS MORNING, WE WILL TAKE THE 1199 00:45:15,720 --> 00:45:18,640 OPPORTUNITY OF HER TIME TO ASK 1200 00:45:18,640 --> 00:45:21,360 QUESTIONS ABOUT THE FIRST 2 1201 00:45:21,360 --> 00:45:24,160 TALKS FROM DR. HAENDALL AND 1202 00:45:24,160 --> 00:45:26,040 DR. POSEY AND GO AHEAD AND SEND 1203 00:45:26,040 --> 00:45:30,840 QUESTIONS IN AND I WILL START 1204 00:45:30,840 --> 00:45:34,920 WITH THE FIRST QUESTION FROM 1205 00:45:34,920 --> 00:45:35,480 [INDISCERNIBLE]. 1206 00:45:35,480 --> 00:45:38,000 FOR DR. POSEY, GREAT TALK. 1207 00:45:38,000 --> 00:45:40,840 IS IT KNOWN IF TN ANTIGEN 1208 00:45:40,840 --> 00:45:44,000 MODIFIED FIBER NECTIN HAS 1209 00:45:44,000 --> 00:45:47,120 ALTERED SENSITIVITY TO VARIOUS 1210 00:45:47,120 --> 00:45:47,320 MMPs? 1211 00:45:47,320 --> 00:45:49,280 >> THAT'S A GREAT QUESTION. 1212 00:45:49,280 --> 00:45:50,600 I ACTUALLY JUST SPENT SOME TIME 1213 00:45:50,600 --> 00:45:52,800 LOOKING FOR THE ANSWER TO THAT 1214 00:45:52,800 --> 00:45:59,000 AND IT DOESN'T APPEAR THAT THAT 1215 00:45:59,000 --> 00:46:00,280 HAS IS KNOWN. 1216 00:46:00,280 --> 00:46:03,200 I THINK THAT THE--I THINK THAT 1217 00:46:03,200 --> 00:46:04,840 THE NEW--WELL THE ANTIBODY THAT 1218 00:46:04,840 --> 00:46:06,720 WAS DEVELOPED IN 2012 THAT 1219 00:46:06,720 --> 00:46:08,600 TARGETS NORMAL FIBER NECTIN, AND 1220 00:46:08,600 --> 00:46:10,600 CAN ALLOW ISOLATION OF THESE 2 1221 00:46:10,600 --> 00:46:12,520 DIFFERENT GLYCO FORMS WILL BE 1222 00:46:12,520 --> 00:46:14,080 REALLY IMPORTANT IN THAT WORK, 1223 00:46:14,080 --> 00:46:18,600 BUT THAT DOESN'T APPEAR TO BE 1224 00:46:18,600 --> 00:46:19,560 KNOWN. 1225 00:46:19,560 --> 00:46:23,400 >> OKAY, THANK YOU. 1226 00:46:23,400 --> 00:46:27,720 THE NEXT QUESTION FROM SIRIAM 1227 00:46:27,720 --> 00:46:28,680 [INDISCERNIBLE], THE ISSUE YOU 1228 00:46:28,680 --> 00:46:33,280 RAISED IS THAT TARGETING ALL 1229 00:46:33,280 --> 00:46:34,480 CD19 WILL DEPLETE B-CELLS AND 1230 00:46:34,480 --> 00:46:36,440 THUS THIS IS NOT, IDEAL 1231 00:46:36,440 --> 00:46:38,320 APPROACH, DO YOU SEE SIMILAR 1232 00:46:38,320 --> 00:46:39,200 LIMITATIONS WITH TN ANTIGEN 1233 00:46:39,200 --> 00:46:41,520 WHICH IS REDUCED IN A NUMBER OF 1234 00:46:41,520 --> 00:46:44,840 TUMOR TYPES THAT IS TO SAY NOT 1235 00:46:44,840 --> 00:46:46,280 COMPLETELY SPECIFIC AND PERHAPS 1236 00:46:46,280 --> 00:46:50,480 ALSO EXPRESSED ON SOME NORMAL 1237 00:46:50,480 --> 00:46:52,040 TISSUES, REGULATING GUT AND 1238 00:46:52,040 --> 00:46:57,680 MICROBIOTA AS SHOWN BY 1239 00:46:57,680 --> 00:46:59,200 DR. HAENDAL FOR EXAMPLE. 1240 00:46:59,200 --> 00:47:01,040 >> YES FOR SPECIFICITY OF CAR 1241 00:47:01,040 --> 00:47:02,840 T-CELLS IS AN ISSUE THAT WE TEND 1242 00:47:02,840 --> 00:47:05,480 TO OVERCOME BY UTILIZING THE TN 1243 00:47:05,480 --> 00:47:09,800 ANTIGEN IN COMBINATION OF TUMOR 1244 00:47:09,800 --> 00:47:10,280 ASSOCIATED IMMUNOTHERAPY 1245 00:47:10,280 --> 00:47:10,520 TARGETS. 1246 00:47:10,520 --> 00:47:12,520 TO GATE DATE WE HAVE NOT SEEN 1247 00:47:12,520 --> 00:47:14,440 OFF TARGET EFFECTS OF THESE 1248 00:47:14,440 --> 00:47:15,840 TYPES OF T-CELLS AND WE MEASURED 1249 00:47:15,840 --> 00:47:21,440 THAT IN OUR ANIMAL MODELS WHICH 1250 00:47:21,440 --> 00:47:24,640 EXPRESSES PROTEINS IN THE TN 18 1251 00:47:24,640 --> 00:47:27,080 GENT IN TN FIBER NECTIN BUT THEY 1252 00:47:27,080 --> 00:47:29,600 DO AS MENTIONED IN THE PREVIOUS 1253 00:47:29,600 --> 00:47:31,480 TALK, THE GLYCOSYLATION IS 1254 00:47:31,480 --> 00:47:33,680 CONSERVED AMONGST MANY OF THESE 1255 00:47:33,680 --> 00:47:34,680 ORGANISMS INCLUDING MICE AND SO 1256 00:47:34,680 --> 00:47:37,200 WE DON'T SEE TARGETING OF TN 1257 00:47:37,200 --> 00:47:39,960 ANTIGEN IN THE MOUSE MODEL AND 1258 00:47:39,960 --> 00:47:41,320 IN TERMS OF CONTRIBUTING TO 1259 00:47:41,320 --> 00:47:44,680 TOXICITY IN THE MOUSE MODEL, WE 1260 00:47:44,680 --> 00:47:46,960 ALSO MEASURED THIS INVITRO WITH 1261 00:47:46,960 --> 00:47:48,840 NORMAL HUMAN PRIMARY CELLS, 1262 00:47:48,840 --> 00:47:50,280 DON'T SEE INCREASED TOXICITY 1263 00:47:50,280 --> 00:47:51,280 AGAINST NORMAL HUMAN PRIMARY 1264 00:47:51,280 --> 00:47:53,120 CELLS ENCLUEDING THOSE FROM THE 1265 00:47:53,120 --> 00:47:57,600 KIDNEY AND COLON AND IN ADDITION 1266 00:47:57,600 --> 00:47:58,880 WE HAVE TREATED 18 PATIENTS NOW 1267 00:47:58,880 --> 00:48:01,680 IN A CLINICAL TRIAL TARGETING 1268 00:48:01,680 --> 00:48:03,280 TNF 1 AND DON'T SEE SEVERE 1269 00:48:03,280 --> 00:48:04,360 TOXICITY IN THESE PATIENTSA 1270 00:48:04,360 --> 00:48:04,600 WELL. 1271 00:48:04,600 --> 00:48:06,000 SOPHISTICATEDY WE THINK THAT WE 1272 00:48:06,000 --> 00:48:08,560 ARE ON THE PATH TOWARDS 1273 00:48:08,560 --> 00:48:10,120 DEVELOPING SPECIFIC REAGENTS, 1274 00:48:10,120 --> 00:48:11,680 HOWEVER, I THINK THAT MULTIPLE 1275 00:48:11,680 --> 00:48:14,760 OF THESE WILL BE NECESSARY 1276 00:48:14,760 --> 00:48:17,680 BECAUSE TUMOR SPECIFIC TARGETS 1277 00:48:17,680 --> 00:48:18,680 ARE HETEROGEANIOUS AND THAT'S 1278 00:48:18,680 --> 00:48:23,520 JUST THE NATURE OF THE TUMOR. 1279 00:48:23,520 --> 00:48:24,360 >> OKAY. 1280 00:48:24,360 --> 00:48:27,080 THANKS AVERY, I WILL SWITCH OVER 1281 00:48:27,080 --> 00:48:28,480 TO MELISSA NOW, THERE'S A 1282 00:48:28,480 --> 00:48:29,320 QUESTION, BASED ON YOUR 1283 00:48:29,320 --> 00:48:32,200 RESEARCH, DO YOU HAVE ANY 1284 00:48:32,200 --> 00:48:33,400 RECOMMENDATIONS AND WHAT TYPES 1285 00:48:33,400 --> 00:48:35,800 OF DATA FROM THE GLYCO 1286 00:48:35,800 --> 00:48:36,520 INFORMATICS SPACE WOULD HELP 1287 00:48:36,520 --> 00:48:40,200 FILL SOME OF THE GAPS THAT YOU 1288 00:48:40,200 --> 00:48:41,000 MENTIONED? 1289 00:48:41,000 --> 00:48:42,680 >> THAT'S A GREAT QUESTION, IT'S 1290 00:48:42,680 --> 00:48:48,160 BASICALLY HOW CAN WE ALL WORK 1291 00:48:48,160 --> 00:48:50,840 TOGETHER TO BE MORE 1292 00:48:50,840 --> 00:48:51,160 INTEROPERABLE. 1293 00:48:51,160 --> 00:48:53,200 I DO THINK AND THIS IS A FEW 1294 00:48:53,200 --> 00:48:54,600 YEARS AGO WHEN JP WROTE THE 1295 00:48:54,600 --> 00:48:55,800 SURVEY PAPER OF WHAT EXISTS AND 1296 00:48:55,800 --> 00:48:57,440 WHAT RESOURCES AND I CAN PUT THE 1297 00:48:57,440 --> 00:48:59,440 LINK INTO THE CHAT THAT SOME OF 1298 00:48:59,440 --> 00:49:00,600 THOSE GAPS STILL EXIST AND YOU 1299 00:49:00,600 --> 00:49:03,440 KNOW I THINK THE 1 SLIDE THAT I 1300 00:49:03,440 --> 00:49:05,120 THOUGHT WAS MOST IMPORTANT TO 1301 00:49:05,120 --> 00:49:06,600 SHOW IS REALLY THAT ASSAY SLIDE, 1302 00:49:06,600 --> 00:49:09,440 SO THE WAY IN WHICH WE DESCRIBE 1303 00:49:09,440 --> 00:49:11,400 GLYCO BIOLOGY ASSAYS IN THE 1304 00:49:11,400 --> 00:49:12,240 LITERATURE IS NOT DESCRIBING IN 1305 00:49:12,240 --> 00:49:15,280 SUCH A WAY THAT IT'S EASY TO 1306 00:49:15,280 --> 00:49:16,640 NECESSARILY CURATE INDIVIDUAL 1307 00:49:16,640 --> 00:49:18,440 PHENOTYPES WITH INDIVIDUAL 1308 00:49:18,440 --> 00:49:19,880 PATIENTS IN TERMS OF COHORTS AND 1309 00:49:19,880 --> 00:49:22,320 SO THERE'S KIND OF MULTIPLE 1310 00:49:22,320 --> 00:49:23,160 PROBLEMS THERE, 1 IS YOU KNOW 1311 00:49:23,160 --> 00:49:27,720 SORT OF HOW DO WE CREATE 1312 00:49:27,720 --> 00:49:28,200 COMPUTABLE PHENOTYPIC 1313 00:49:28,200 --> 00:49:29,800 INFORMATION IN THESE STUDIES MOW 1314 00:49:29,800 --> 00:49:31,320 MATTER WHICH ORGANISM IT COMES 1315 00:49:31,320 --> 00:49:33,280 FROM, WHEN WE PUBLISHED BUT THEN 1316 00:49:33,280 --> 00:49:36,040 ALSO HOW DO WE UNDERSTAND A 1317 00:49:36,040 --> 00:49:36,880 VARIATION ACROSS INDIVIDUALS AND 1318 00:49:36,880 --> 00:49:39,160 I DIDN'T TALK ABOUT IT TODAY BUT 1319 00:49:39,160 --> 00:49:41,880 WE'VE, IN THE GLOBAL ALLIANCE 1320 00:49:41,880 --> 00:49:43,080 FOR GENOMICS AND HEALTH WE 1321 00:49:43,080 --> 00:49:45,800 DEVELOPED A NEW STANDARD CALLED 1322 00:49:45,800 --> 00:49:48,280 PHENOPACKETS WHICH AIMS TO BE 1323 00:49:48,280 --> 00:49:49,800 INDIVIDUAL CASE LEVEL 1324 00:49:49,800 --> 00:49:50,960 INFORMATION AND SO, 1 OF THE BIG 1325 00:49:50,960 --> 00:49:52,280 CHALLENGES THAT WE HAVE WITH THE 1326 00:49:52,280 --> 00:49:53,560 GLYCO BIOLOGY IS THAT WE SEE 1327 00:49:53,560 --> 00:49:57,480 QUITE A LARGE SPECTRUM, EVEN IN 1328 00:49:57,480 --> 00:49:59,720 THE SAME DISEASE DIAGNOSIS THAT 1329 00:49:59,720 --> 00:50:02,720 THE GLYCO PHENOTYPES ARE 1330 00:50:02,720 --> 00:50:03,320 ACTUALLY QUITE HETEROGEANIOUS 1331 00:50:03,320 --> 00:50:04,600 DEPENDING ON WHICH TYPE OF 1332 00:50:04,600 --> 00:50:05,600 PHENOTYPE WE TALKING ABOUT AND 1333 00:50:05,600 --> 00:50:07,000 SO WE REALLY NEED THAT CASE 1334 00:50:07,000 --> 00:50:08,480 LEVEL INFORMATION ABOUT EACH 1335 00:50:08,480 --> 00:50:13,240 PATIENT SO WE CAN UNDERSTAND THE 1336 00:50:13,240 --> 00:50:15,680 SORT OF EXPRESSIVITY AND 1337 00:50:15,680 --> 00:50:17,440 PHENOTYPES AND PENETRANTS ON AN 1338 00:50:17,440 --> 00:50:19,280 INDIVIDUAL CASE LEVEL, AND THAT 1339 00:50:19,280 --> 00:50:21,120 RARELY GETS PUBLISHED IN 1340 00:50:21,120 --> 00:50:21,880 LITERATURE, IT'S USUALLY SUMMARY 1341 00:50:21,880 --> 00:50:23,600 TABLES LIKE THE AVERAGE WAS THIS 1342 00:50:23,600 --> 00:50:25,880 LEVEL OF SOME GLYCAN AND WANOT 1343 00:50:25,880 --> 00:50:27,800 SO THATIA WHERE THE BIGGEST GAP 1344 00:50:27,800 --> 00:50:29,760 IS AND HOW EACH INDIVIDUAL 1345 00:50:29,760 --> 00:50:31,520 RESOURCE THEN CURATES THAT 1346 00:50:31,520 --> 00:50:33,480 INFORMATION IS ALSO DIFFERENT 1347 00:50:33,480 --> 00:50:35,320 AND SO IT SORT OF PROMULGATES 1348 00:50:35,320 --> 00:50:39,280 THAT SAME PROBLEM AND SO WHEN WE 1349 00:50:39,280 --> 00:50:40,000 HARMONIZE THAT KNOWLEDGE, WE--IT 1350 00:50:40,000 --> 00:50:42,480 ENDS TO NOT HAVE THE FULL 1351 00:50:42,480 --> 00:50:44,080 PROMINENCE OF WHAT THAT SUMMARY 1352 00:50:44,080 --> 00:50:45,360 LEVEL INFORMATION WAS FROM THE 1353 00:50:45,360 --> 00:50:46,760 LITERATURE IN THE FIRST PLACE, 1354 00:50:46,760 --> 00:50:48,160 NEVER MINDING THE FACT THAT IT'S 1355 00:50:48,160 --> 00:50:49,720 NOT AT A CASE LEVEL, SO TO ME 1356 00:50:49,720 --> 00:50:51,160 THAT'S WHERE THE BIGGEST GAP IS 1357 00:50:51,160 --> 00:50:55,080 THAT SORT OF INDIVIDUAL ASSAY 1358 00:50:55,080 --> 00:50:58,480 RESULTS THE PIPELINE ALL THE WAY 1359 00:50:58,480 --> 00:51:01,240 TO KNOWLEDGE BASIS. 1360 00:51:01,240 --> 00:51:03,440 >> OKAY, GREAT. 1361 00:51:03,440 --> 00:51:05,000 >> MAYBE JAMBOREE OF 1362 00:51:05,000 --> 00:51:06,360 [INDISCERNIBLE] CURATION IN THE 1363 00:51:06,360 --> 00:51:08,520 NEXT GLUE MARIOUS O CURATION 1364 00:51:08,520 --> 00:51:08,760 MEETING. 1365 00:51:08,760 --> 00:51:09,800 >> I WOULD BE DELIGHTED. 1366 00:51:09,800 --> 00:51:11,080 >> ALL RIGHT, THERE YOU GO, 1367 00:51:11,080 --> 00:51:11,360 MIKE. 1368 00:51:11,360 --> 00:51:13,320 >> WE NEED TO ORGANIZE THAT. 1369 00:51:13,320 --> 00:51:14,920 >> IN ITALY, OKAY? 1370 00:51:14,920 --> 00:51:16,320 NYES, DEFINITELY IN ITALY WITH 1371 00:51:16,320 --> 00:51:17,480 WINE. 1372 00:51:17,480 --> 00:51:18,200 >> ALL RIGHT, SO,. 1373 00:51:18,200 --> 00:51:21,600 >> SO THAT'S THE PLAN. 1374 00:51:21,600 --> 00:51:27,680 >> OKAY, ANOTHER QUESTION FOR 1375 00:51:27,680 --> 00:51:27,920 MICHELLE,. 1376 00:51:27,920 --> 00:51:32,680 >> MICHAEL CAN I FOLLOW UP 1377 00:51:32,680 --> 00:51:33,800 QUICKLY WITH MELISSA? 1378 00:51:33,800 --> 00:51:34,240 >> SURE. 1379 00:51:34,240 --> 00:51:35,480 >> SO MELISSA I APPRECIATE THE 1380 00:51:35,480 --> 00:51:36,640 CROSS SPECIES DISCUSSION THAT 1381 00:51:36,640 --> 00:51:39,080 YOU PUT FORWARD, AND YOU KNOW 1382 00:51:39,080 --> 00:51:40,600 THE CORE FUNCTIONS OF DPLI 1383 00:51:40,600 --> 00:51:41,560 KAN--KANAS ARE CONSERVED ACROSS 1384 00:51:41,560 --> 00:51:43,280 SPECIES BUT THE STRUCTURE THAT 1385 00:51:43,280 --> 00:51:45,480 DOES SOMETHING IN 1 SPECIES 1386 00:51:45,480 --> 00:51:47,600 MIGHT BE DIFFERENT TO GLYCAN 1387 00:51:47,600 --> 00:51:50,680 STRUCTURE FOR INSTANCE, URONIC 1388 00:51:50,680 --> 00:51:53,240 ACIDS MIGHT SUBSTITUTE FOR 1389 00:51:53,240 --> 00:51:54,720 SIALIC ACIDS SO THE GENES MIGHT 1390 00:51:54,720 --> 00:51:59,280 NOT BE THE LENGTH TO LINK 1391 00:51:59,280 --> 00:52:03,080 TOGETHER GLYKAN--KANA SPECIES SO 1392 00:52:03,080 --> 00:52:05,880 IS THERE AN OBVIOUS WAY TO MAKE 1393 00:52:05,880 --> 00:52:07,480 GLYKAN--KANA STRUCTURES ACROSS, 1394 00:52:07,480 --> 00:52:10,320 AND NOT STRUCTURALLY HOMOLOGOUS 1395 00:52:10,320 --> 00:52:10,640 STRUCTURES. 1396 00:52:10,640 --> 00:52:11,480 >> YES, I SEE WHAT YOU MEAN AND 1397 00:52:11,480 --> 00:52:15,040 I THINK, YOU KNOW WE 1398 00:52:15,040 --> 00:52:16,480 FUNDAMENTALLY HAVE MADE A LOT OF 1399 00:52:16,480 --> 00:52:21,720 PROGRESS ON GENES AND VARIANTS 1400 00:52:21,720 --> 00:52:24,040 BUT BOTH FOR THE GLYCO BIOLOGY 1401 00:52:24,040 --> 00:52:28,800 BUT ALSO FOR GENOMICS IN GENERAL 1402 00:52:28,800 --> 00:52:31,600 HAVE BOTH THE SAME KINDS OF 1403 00:52:31,600 --> 00:52:34,320 ISSUES, YOU KNOW SAME THING WITH 1404 00:52:34,320 --> 00:52:35,600 LIPID OMICS AND OTHER FUNCTIONS 1405 00:52:35,600 --> 00:52:38,400 THAT REALLY, YOU KNOW WE NEED TO 1406 00:52:38,400 --> 00:52:41,880 BE TARGETING, YOU KNOW PROTEOMIC 1407 00:52:41,880 --> 00:52:45,200 AND LIPID OMIC AND 1408 00:52:45,200 --> 00:52:46,400 GLYCO-PROFILES NOT VARIANT AND 1409 00:52:46,400 --> 00:52:46,680 PROFILES. 1410 00:52:46,680 --> 00:52:48,760 AND SO I THINK YOU'RE ABSOLUTELY 1411 00:52:48,760 --> 00:52:48,960 RIGHT. 1412 00:52:48,960 --> 00:52:51,360 ONE THING THAT WE HAVE DONE A 1413 00:52:51,360 --> 00:52:53,920 LOT OF WORK ON THAT'S HELPFUL, 1414 00:52:53,920 --> 00:52:55,960 IS JUST THE FOCUS ON THE 1415 00:52:55,960 --> 00:52:57,560 PHENOTYPIC ASPECTS AND THE 1416 00:52:57,560 --> 00:53:06,240 ASSAYS BECAUSE THOSE ARE, YOU 1417 00:53:06,240 --> 00:53:07,400 KNOW REALLY INDEPENDENT AND ALSO 1418 00:53:07,400 --> 00:53:10,960 THAT ALLOWS US TO TAKE INTO THE 1419 00:53:10,960 --> 00:53:12,080 INFLUENCES OF THE ENVIRONMENT 1420 00:53:12,080 --> 00:53:13,480 AND I ALSO DIDN'T TALK ABOUT 1421 00:53:13,480 --> 00:53:15,760 THAT TODAY BUT WE HAVE AN 1422 00:53:15,760 --> 00:53:18,040 ONTOLOGY CALLED ECTO WHICH 1423 00:53:18,040 --> 00:53:18,880 FOCUSES ON ENVIRONMENTAL 1424 00:53:18,880 --> 00:53:22,680 CONDITIONS WHICH ARE INFLUENCERS 1425 00:53:22,680 --> 00:53:24,280 IN THIS CONTEXT AS WELL SO YOU 1426 00:53:24,280 --> 00:53:25,880 NEED THE BIG PICTURE OF WHAT ARE 1427 00:53:25,880 --> 00:53:29,280 ALL THE SORT OF PRESSURES ON AN 1428 00:53:29,280 --> 00:53:32,360 ORGANISM TO HAVE THAT CHANGED 1429 00:53:32,360 --> 00:53:33,880 GLYCO-BIOLOGY AND THEN HOW DO WE 1430 00:53:33,880 --> 00:53:34,880 MEASURE THAT GLYCO BIOLOGY. 1431 00:53:34,880 --> 00:53:38,120 SO 1 OF THE THINGS THAT HAVE 1432 00:53:38,120 --> 00:53:39,880 BEEN GOOD IS THAT SORT OF 1433 00:53:39,880 --> 00:53:42,160 REPRESENTATION GRAPH THAT I 1434 00:53:42,160 --> 00:53:45,880 SHOWED YOU OF THE GLYCAN BIOLOGY 1435 00:53:45,880 --> 00:53:47,800 CAN THE DISEASES WITH THOSE 1436 00:53:47,800 --> 00:53:48,920 DIFFERENTITYS, THAT DOES NOT 1437 00:53:48,920 --> 00:53:50,880 REQUIRE ANY GENE OR VARIANT 1438 00:53:50,880 --> 00:53:53,080 LEVEL INFORMATION TO MAKE THOSE 1439 00:53:53,080 --> 00:53:53,440 ASSOCIATIONS. 1440 00:53:53,440 --> 00:53:55,680 SO SO IT DOES HELP US AND THAT 1441 00:53:55,680 --> 00:53:58,000 GLIE O BIOLOGY REPRESENTATION 1442 00:53:58,000 --> 00:54:01,320 HAS HAD--YOU KNOW J. P. DID AN 1443 00:54:01,320 --> 00:54:04,200 INNORMOUS AMOUNT OF WORK WITH 1444 00:54:04,200 --> 00:54:06,120 [INDISCERNIBLE], AND SINCE KEVI 1445 00:54:06,120 --> 00:54:07,320 IS FOUNDATION FOR GENE ONTOLOGY 1446 00:54:07,320 --> 00:54:09,760 AT LEAST WE HAVE A BETTER 1447 00:54:09,760 --> 00:54:11,760 REPRESENTATION OF HOW THAT FLIEK 1448 00:54:11,760 --> 00:54:14,160 O BIOLOGY WORKS WHERE WE DO HAVE 1449 00:54:14,160 --> 00:54:16,280 CONSENSUS IN WHICH TAXA IT 1450 00:54:16,280 --> 00:54:17,800 APPLIES TO SO YOU KNOW THESE ARE 1451 00:54:17,800 --> 00:54:18,760 ALL THESE THINGS NEED 1452 00:54:18,760 --> 00:54:20,600 IMPROVEMENT BUT THERE ARE WAYS 1453 00:54:20,600 --> 00:54:22,480 TO CREATE THOSE STRUCTURAL 1454 00:54:22,480 --> 00:54:23,680 ASSOCIATIONS THAT DON'T RELY ON 1455 00:54:23,680 --> 00:54:27,000 THE GENETICS BUT WE HAVE NOT YET 1456 00:54:27,000 --> 00:54:28,760 CREATED GLYCO PROTILES FOR THE 1457 00:54:28,760 --> 00:54:29,080 DIAGNOSTICS. 1458 00:54:29,080 --> 00:54:30,560 THIS WORK WAS KIND OF EARLY IN 1459 00:54:30,560 --> 00:54:32,240 TERMS OF ASSESSING THE UTILITY 1460 00:54:32,240 --> 00:54:33,800 OF INCLUDING THE GLYCO PHENOTYPE 1461 00:54:33,800 --> 00:54:35,800 BUT I COMPLETELY AGREE WITH YOU, 1462 00:54:35,800 --> 00:54:37,760 I THINK AS THIS FIELD MOVES 1463 00:54:37,760 --> 00:54:38,480 FORWARD INTO PRECISION MEDICINE 1464 00:54:38,480 --> 00:54:41,520 THAT WE NEED TO GO BEYOND JUST 1465 00:54:41,520 --> 00:54:43,480 PHENOTYPIC MATCHING BUT ACTUALLY 1466 00:54:43,480 --> 00:54:44,360 LIKE GLUE MARIOUS COBIOLOGY 1467 00:54:44,360 --> 00:54:46,480 MATCHING IN TERMS OF THE 1468 00:54:46,480 --> 00:54:48,480 STRUCTURAL SIMILARITIES SO I 1469 00:54:48,480 --> 00:54:50,480 LOVE THAT IDEA. 1470 00:54:50,480 --> 00:54:52,280 >> YEAH, THANK YOU FOR REALLY 1471 00:54:52,280 --> 00:54:56,920 THOROUGH ANSWER THERE AND THANK 1472 00:54:56,920 --> 00:54:59,320 YOU FOR SEEING THE EXPERIENCE OF 1473 00:54:59,320 --> 00:55:00,120 GLYCO BIOLOGY PHENOTYPES. 1474 00:55:00,120 --> 00:55:07,080 SO RELATED TO THIS, MICHELLE 1475 00:55:07,080 --> 00:55:10,240 VAUGHN ASKS DO YOU HAVE DATA 1476 00:55:10,240 --> 00:55:11,520 THAT'S COLLECTED OR CATALOGED 1477 00:55:11,520 --> 00:55:15,400 THAT WOULD PROVE THE DATA 1478 00:55:15,400 --> 00:55:16,120 INTEGRATION YOU DESCRIBE? 1479 00:55:16,120 --> 00:55:16,960 NTHAT'S A GOOD QUESTION AND A 1480 00:55:16,960 --> 00:55:18,400 FOLLOW UP TO THE EARLIER 1 THAT 1481 00:55:18,400 --> 00:55:20,640 I TALKED ABOUT WITH PHENOPACKETS 1482 00:55:20,640 --> 00:55:23,600 ALREADY, I THINK ANOTHER THING, 1483 00:55:23,600 --> 00:55:26,160 SO WOE HAVE BEEN ALSO AGAIN I 1484 00:55:26,160 --> 00:55:30,000 DIDN'T TALK ABOUT IT TODAY BUT 1485 00:55:30,000 --> 00:55:33,040 WORKING ON A DATA MODELING 1486 00:55:33,040 --> 00:55:34,720 LANGUAGE CALLED [INDISCERNIBLE] 1487 00:55:34,720 --> 00:55:35,920 WHICH BASICALLY HELPS STRUCTURE 1488 00:55:35,920 --> 00:55:38,280 SCHEMAS IN SUCH A WAY THAT DATA 1489 00:55:38,280 --> 00:55:41,160 FROM KNOWLEDGE BASES CAN BE MADE 1490 00:55:41,160 --> 00:55:42,240 INTEROPERABLE, THIS WAS ORIGE 1491 00:55:42,240 --> 00:55:44,800 NAWILLLY DEVELOPED AS PART OF 1492 00:55:44,800 --> 00:55:46,760 THE NCATS BIOMEDICAL DATA 1493 00:55:46,760 --> 00:55:47,920 TRANSLATOR AND THE MONARCH 1494 00:55:47,920 --> 00:55:49,560 KNOWLEDGE GRAPH BUT IT'S USED 1495 00:55:49,560 --> 00:55:52,080 FOR A WIDE VARIETY OF DIFFERENT 1496 00:55:52,080 --> 00:55:55,720 RESOURCES, NOW EVERYTHING FROM 1497 00:55:55,720 --> 00:55:56,560 MICROBIOMES TO CANCER--SO WE 1498 00:55:56,560 --> 00:55:57,480 HAVE AA CANCER MODEL. 1499 00:55:57,480 --> 00:55:59,280 WE USE IT FOR LANGUAGE 1500 00:55:59,280 --> 00:56:00,760 TRANSLATIONS AND ALL KINDS OF 1501 00:56:00,760 --> 00:56:04,760 DIFFERENT THINGS AND IT'S 1502 00:56:04,760 --> 00:56:06,080 BASICALLY A MECHANISM TO KIND OF 1503 00:56:06,080 --> 00:56:08,720 HAVE A FOUNDATION OF HOW WE 1504 00:56:08,720 --> 00:56:09,880 ASSOCIATE--SO WE HAVE ONTOLOGYS 1505 00:56:09,880 --> 00:56:12,040 AND WE HAVE DATA MODELS, AND IT 1506 00:56:12,040 --> 00:56:14,280 SEEMS LIKE WHEN WE'RE 1507 00:56:14,280 --> 00:56:16,560 INTEGRATING DATA, WE REALLY 1508 00:56:16,560 --> 00:56:17,400 FUNDAMENTALLY ARE CHALLENGED BY 1509 00:56:17,400 --> 00:56:18,760 THE FACT THAT EVEN PEOPLE ARE 1510 00:56:18,760 --> 00:56:20,920 USING THE SAME ONTOLOGYS, THEY 1511 00:56:20,920 --> 00:56:22,680 ARE USING THEM IN VERY, VERY 1512 00:56:22,680 --> 00:56:24,000 DIFFERENT WAYS, DIFFERENT 1513 00:56:24,000 --> 00:56:25,400 COLLECTIONS OF ENUMERATIONS FOR 1514 00:56:25,400 --> 00:56:27,040 A GNCHT DATABASE FIELD. 1515 00:56:27,040 --> 00:56:29,200 IT'S VERY HARD TO MAP ACROSS 1516 00:56:29,200 --> 00:56:31,000 RESOURCES THAT USE VERY 1517 00:56:31,000 --> 00:56:31,840 DIFFERENT MODELING STRATEGIES, 1518 00:56:31,840 --> 00:56:33,880 AND IT'S REALLY NOT BEEN A 1519 00:56:33,880 --> 00:56:36,240 STANDARD FOR RESEARCH LIKE WE 1520 00:56:36,240 --> 00:56:39,120 MIGHT HAVE FOR EHR DATA FOR OMOP 1521 00:56:39,120 --> 00:56:41,280 FOR EXAMPLE SO THAT STARTING TO 1522 00:56:41,280 --> 00:56:44,600 HELP US CREATE MORE BOARN 1523 00:56:44,600 --> 00:56:46,280 INTEROPERABLE DATA BUT THEN 1524 00:56:46,280 --> 00:56:49,760 FUNDAMENTALLY IF COMES COME--IT COMES 1525 00:56:49,760 --> 00:56:51,880 BACK TO THE JOURNALS, THAT 1526 00:56:51,880 --> 00:56:53,320 AREN'T APLAYED TO THE LITERATURE 1527 00:56:53,320 --> 00:56:54,880 AND SO MUCH OF OUR DATA 1528 00:56:54,880 --> 00:56:56,680 REGARDLESS OF WHICH OF THOSE 1529 00:56:56,680 --> 00:56:57,960 REPOSITORIES WE'RE TALKING ABOUT 1530 00:56:57,960 --> 00:56:59,680 IS CURATED FROM THE LITERATURE 1531 00:56:59,680 --> 00:57:01,880 SO GETTING JOURNALS TO ADOPT ANY 1532 00:57:01,880 --> 00:57:04,240 OF THESE STANDARDS, I THINK AS A 1533 00:57:04,240 --> 00:57:06,400 COMMUNITY LEVEL CHALLENGE THAT 1534 00:57:06,400 --> 00:57:07,800 WOULD HELP EVERYBODY CURATE 1535 00:57:07,800 --> 00:57:10,880 THEIR PIECES OF THAT SORT OF 1536 00:57:10,880 --> 00:57:15,480 PIECE MEAL DATA MODEL THAT WE'RE 1537 00:57:15,480 --> 00:57:17,880 TRYING TO CORRELATE. 1538 00:57:17,880 --> 00:57:18,160 >> GREAT. 1539 00:57:18,160 --> 00:57:20,280 THANK WE HAVE ANOTHER COUPLE 1540 00:57:20,280 --> 00:57:20,960 QUESTIONS. 1541 00:57:20,960 --> 00:57:23,880 THIS 1'S FOR DR. POSEY, CAN YOU 1542 00:57:23,880 --> 00:57:25,800 PROVIDE MORE INFORMATION ABOUT 1543 00:57:25,800 --> 00:57:30,560 HOW TRUNCATED OGLUE MARIOUS CANS 1544 00:57:30,560 --> 00:57:32,080 AFFECT THE CELLULAR 1545 00:57:32,080 --> 00:57:32,560 PROLIFERATION. 1546 00:57:32,560 --> 00:57:34,680 >> SO WE'RE DIGGING INTO OUR 1547 00:57:34,680 --> 00:57:36,320 RNASEQ DATA TRYING TO VALIDATE 1548 00:57:36,320 --> 00:57:39,600 THE JEEP CHANGES THAT WE SEE 1549 00:57:39,600 --> 00:57:44,560 BEFORE GOING MORE INTO WHICH 1550 00:57:44,560 --> 00:57:46,760 PROCESSES MAY BE ENHANCING TUMOR 1551 00:57:46,760 --> 00:57:50,560 GROWTH AS WELL AS CHANGE IN 1552 00:57:50,560 --> 00:57:51,160 IMMUNE CONTRIBUTIONS, IMMUNE 1553 00:57:51,160 --> 00:57:52,760 PLIEK ROUGH ATOM ENVIRONMENT, 1554 00:57:52,760 --> 00:57:55,160 BUT OTHER VS DEMONSTRATE THAD A 1555 00:57:55,160 --> 00:57:58,080 LOSS OF COSMIC INCREASE IN 1556 00:57:58,080 --> 00:57:59,880 TN ANTIGEN EXPRESSION, INDUCES 1557 00:57:59,880 --> 00:58:01,160 INKREETIONED MAP KINASE 1558 00:58:01,160 --> 00:58:04,160 SIGNALING AND THIS IS 1559 00:58:04,160 --> 00:58:06,160 PRESIEWBLABLY CAUSED BY A CHANGE 1560 00:58:06,160 --> 00:58:08,400 IN RECEPTOR AGGREGATION, CELL 1561 00:58:08,400 --> 00:58:08,840 SURFACE SIGNALING. 1562 00:58:08,840 --> 00:58:11,680 YOU CAN IMAGINE THAT 1563 00:58:11,680 --> 00:58:13,280 CARBOHYDRATES DEFINITELY ARE 1564 00:58:13,280 --> 00:58:16,800 INVOLVED IN RECEPTOR 1565 00:58:16,800 --> 00:58:18,080 INTERACTIONS, AND THAT BY 1566 00:58:18,080 --> 00:58:20,600 CHANGING THAT YOU AFFAIRS TEAM 1567 00:58:20,600 --> 00:58:22,280 LEADERRER THE SIGNALING, WE--YOU 1568 00:58:22,280 --> 00:58:25,920 ALTER THE SIGNALING AND WE 1569 00:58:25,920 --> 00:58:27,680 DEFINITELY CHANGES IN LOSS OF 1570 00:58:27,680 --> 00:58:29,840 GENES WHEN WE CHANGE CELL 1571 00:58:29,840 --> 00:58:35,720 SURFACE ON THE THE GLYCANS. 1572 00:58:35,720 --> 00:58:37,920 >> ONE OTHER QUESTION FROM 1573 00:58:37,920 --> 00:58:39,520 [INDISCERNIBLE]: DO YOU OFTEN 1574 00:58:39,520 --> 00:58:42,200 USE IMMUNE DEFICIENT OR IMMUNE 1575 00:58:42,200 --> 00:58:45,280 COMPETENT MOUSE MODEL FIST YOUR 1576 00:58:45,280 --> 00:58:47,040 XENOGRAPH STUDIES AND HOW 1577 00:58:47,040 --> 00:58:49,680 VARIABLE IS TUMOR UPTAKE AND 1578 00:58:49,680 --> 00:58:53,480 GLYCOSYLATION BETWEEN THESE 2 1579 00:58:53,480 --> 00:58:53,880 DIFFERENT MODELS? 1580 00:58:53,880 --> 00:58:56,160 >> YEAH, SO WE USE BOTH IMMUNE 1581 00:58:56,160 --> 00:58:57,280 COMP TEBT AND IMMUNO DEFICIENT 1582 00:58:57,280 --> 00:59:00,680 MODELS IF ARE OUR IMMUNE COMTENT 1583 00:59:00,680 --> 00:59:03,000 MODELS WE'RE USING MOUSE TUMOR 1584 00:59:03,000 --> 00:59:04,440 LINES AND REALLY TRYING TO 1585 00:59:04,440 --> 00:59:07,280 UNDERSTAND THE CONTRIBUTIONS TO 1586 00:59:07,280 --> 00:59:08,600 THE TUMOR MICROENVIRONMENT, 1587 00:59:08,600 --> 00:59:09,880 IMMUNE MICROENVIRONMENT, FOR THE 1588 00:59:09,880 --> 00:59:11,200 XENO GRAPH STUDIES WE'RE USING 1589 00:59:11,200 --> 00:59:14,360 HUMAN CELL LINES AND WE TEST OUR 1590 00:59:14,360 --> 00:59:15,800 HUMAN CAR T-CELLS AND WE'RE 1591 00:59:15,800 --> 00:59:20,280 PROBING FOR EFFICACY AS WELL AS 1592 00:59:20,280 --> 00:59:26,680 SOME TOXICITY OR TOXICOLOGY FOR 1593 00:59:26,680 --> 00:59:27,480 THE ANIMALS. 1594 00:59:27,480 --> 00:59:28,520 VARIABILITY AND UPTAKE, WE DON'T 1595 00:59:28,520 --> 00:59:29,840 SEE A DIFFERENCE IN UPTAKE OF 1596 00:59:29,840 --> 00:59:33,040 THE TUMORS IF WE HAVE EITHER 1597 00:59:33,040 --> 00:59:35,200 WILD TYPE DPLI COSALATION OR 1598 00:59:35,200 --> 00:59:37,960 WE'VE KNOCKED OUT COSMIC. 1599 00:59:37,960 --> 00:59:41,400 AND IN TERMS OF ANTIGEN LOSS, SO 1600 00:59:41,400 --> 00:59:42,360 WE--WE HAVEN'T SEEN ANTIGEN LOSS 1601 00:59:42,360 --> 00:59:44,720 FOR THE TARGETS THAT I TOLD I 1602 00:59:44,720 --> 00:59:47,440 ABOUT, THE TNF 1 OR THE TN FIBER 1603 00:59:47,440 --> 00:59:48,960 NECTIN, ALTHOUGH THE TN FIBER 1604 00:59:48,960 --> 00:59:50,080 NECTIN STORY IS EVOLVING SO 1605 00:59:50,080 --> 00:59:51,640 WE'RE TRYING TO UNDERSTAND HOW 1606 00:59:51,640 --> 00:59:55,880 TUMORS ARE ESCAPING THERE, FOR 1607 00:59:55,880 --> 00:59:57,280 A--A RELATED MOLECULE 1608 00:59:57,280 --> 00:59:59,560 [INDISCERNIBLE] AS A TARGET FOR 1609 00:59:59,560 --> 01:00:03,360 CAR T-CELLS WE DEFINITELY SEE 1610 01:00:03,360 --> 01:00:06,640 LOSS OF MESOTHELIN AS WELL AS 1611 01:00:06,640 --> 01:00:08,720 CAR T-CELL EXHAUSTION BUT FOR 1612 01:00:08,720 --> 01:00:09,880 THE EXHAUSTION WE ARE INTERESTED 1613 01:00:09,880 --> 01:00:10,840 IN WAYS OF AFFAIRS TEAM 1614 01:00:10,840 --> 01:00:12,560 LEADERRER THE SIGNALING OF THE 1615 01:00:12,560 --> 01:00:13,760 MOLECULES TO ENHANCE PERSISTENCE 1616 01:00:13,760 --> 01:00:15,880 OF CELLS AND OVERCOME 1617 01:00:15,880 --> 01:00:16,200 EXHAUSTION. 1618 01:00:16,200 --> 01:00:17,360 I THINK IT IS AN INTERESTING 1619 01:00:17,360 --> 01:00:24,680 QUESTION OF HOW CHANGES IN TUMOR 1620 01:00:24,680 --> 01:00:27,840 GLYCOSYLATION CAN PROMOTE OR 1621 01:00:27,840 --> 01:00:29,840 OVERCOME T-CELL EXHAUSTION AS 1622 01:00:29,840 --> 01:00:30,080 WELL. 1623 01:00:30,080 --> 01:00:31,520 >> SO AVERY ANY OF THE CLEANS 1624 01:00:31,520 --> 01:00:33,880 THAT YOU IDENTIFIED FOR THE 1625 01:00:33,880 --> 01:00:34,960 PANCREATIC CANCER SINGLE CELL 1626 01:00:34,960 --> 01:00:36,480 CLONES, WOULD YOU CALL ANY OF 1627 01:00:36,480 --> 01:00:40,880 THOSE CANCER STEM CELLS OR 1628 01:00:40,880 --> 01:00:42,160 OTHER--CAR T STRATEGIES THAT ARE 1629 01:00:42,160 --> 01:00:44,760 TRYING TO TARGET CANCER STEM 1630 01:00:44,760 --> 01:00:45,040 CELLS. 1631 01:00:45,040 --> 01:00:47,760 THERE ARE SO CD133 IS THOUGHT TO 1632 01:00:47,760 --> 01:00:50,680 BE A GOOD TARGET FOR CANCER STEM 1633 01:00:50,680 --> 01:00:54,000 CELL, ALTHOUGH YOU KNOW IT'S A 1634 01:00:54,000 --> 01:00:56,360 GLYCO FORM OF CS D133 THAT'S 1635 01:00:56,360 --> 01:01:00,200 ONLY RECOGNIZED BY THE MULTANI 1636 01:01:00,200 --> 01:01:02,200 ANTIBODY, NOT ALL--NOT ANY OF 1637 01:01:02,200 --> 01:01:03,480 THE OTHER CD133 ANTIBODIES THAT 1638 01:01:03,480 --> 01:01:06,120 HAS BEEN ASSOCIATE WIDE CANCER 1639 01:01:06,120 --> 01:01:06,480 [INDISCERNIBLE]. 1640 01:01:06,480 --> 01:01:08,840 ALTHOUGH MANY IN THE FIELD ARE 1641 01:01:08,840 --> 01:01:11,720 RUNNING WITH ANTICD133 TARGETING 1642 01:01:11,720 --> 01:01:12,680 FOR--TO TARGET CANCER STEM CELLS 1643 01:01:12,680 --> 01:01:15,960 AS WELL AS I THINK A FEW OTHER 1644 01:01:15,960 --> 01:01:20,160 TARGETS AS WELL. 1645 01:01:20,160 --> 01:01:20,840 >> THANKS AVERY. 1646 01:01:20,840 --> 01:01:24,000 >> OKAY, WELL, THANKS TO BOTH OF 1647 01:01:24,000 --> 01:01:25,600 OUR SPEAKERS AND WHEN WE FINISH 1648 01:01:25,600 --> 01:01:29,240 THE REST OF THE TALKS, IF YOU 1649 01:01:29,240 --> 01:01:32,280 HAVE OTHER QUESTIONS FOR AVERY, 1650 01:01:32,280 --> 01:01:33,480 I THINK MELISSA IS GOING TO HAVE 1651 01:01:33,480 --> 01:01:35,240 TO LEAVE BUT GO AHEAD AND PUT 1652 01:01:35,240 --> 01:01:36,520 THOSE IN THE CHAT BOX AND WE 1653 01:01:36,520 --> 01:01:39,480 WILL GET TO THOSE A LITTLE BIT 1654 01:01:39,480 --> 01:01:39,760 LATER. 1655 01:01:39,760 --> 01:01:41,360 BOY THIS WENT BY REALLY QUICKLY, 1656 01:01:41,360 --> 01:01:46,560 SO, I THINK WE'RE READY FOR OUR 1657 01:01:46,560 --> 01:01:50,280 NEXT SPEAKER DR. RADOSLAV GOLD 1658 01:01:50,280 --> 01:01:52,640 MAN FROM GEORGETOWN UNIVERSITY, 1659 01:01:52,640 --> 01:02:00,480 HEP A RAN 6-0 ENDOSULF FAT AS IN 1660 01:02:00,480 --> 01:02:01,000 HNSCC AND OTHER CANCERS. 1661 01:02:01,000 --> 01:02:02,280 >> THANKS FOR THE INTRO. 1662 01:02:02,280 --> 01:02:05,040 NICE TO SEE EVERYBODY. 1663 01:02:05,040 --> 01:02:06,520 WELCOME TO THE MEETING, I AM 1664 01:02:06,520 --> 01:02:10,200 DPLAD I DON'T HAVE TO TALK ABOUT 1665 01:02:10,200 --> 01:02:11,920 [INDISCERNIBLE] AFTER STACIE AND 1666 01:02:11,920 --> 01:02:14,560 I AM SORRY YOU CANNOT HEAR HER. 1667 01:02:14,560 --> 01:02:22,080 SHE HAS REALLY EXCITING STORIES 1668 01:02:22,080 --> 01:02:26,280 TO TELL HER AND AT THE BEGINNING 1669 01:02:26,280 --> 01:02:27,640 OF UNIAND THAT COULD BE A GOOD 1670 01:02:27,640 --> 01:02:30,600 OPPORTUNITY FOR YOU TO CONNECT 1671 01:02:30,600 --> 01:02:32,120 WITH HER STORY. 1672 01:02:32,120 --> 01:02:38,160 I WILL--I WILL TELL BUT OUR 1673 01:02:38,160 --> 01:02:41,120 STUDIES ON 6-0 ENDOSULFATES IN 1674 01:02:41,120 --> 01:02:42,880 HEAD AND NECK CANCERS AND OTHER 1675 01:02:42,880 --> 01:02:53,400 MALIGNANCIES AND I HOPE YOU CAN 1676 01:02:53,400 --> 01:02:54,040 SEE MY SLIDES. 1677 01:02:54,040 --> 01:02:57,760 SO THIS IS A STORY THAT IS QUITE 1678 01:02:57,760 --> 01:02:58,080 SIMPLE. 1679 01:02:58,080 --> 01:03:04,040 >> RAJA J--RADO WE CAN'T SEE YOUR 1680 01:03:04,040 --> 01:03:04,280 SLIDES. 1681 01:03:04,280 --> 01:03:04,680 >> OKAY. 1682 01:03:04,680 --> 01:03:06,040 >> ALL WE SEE IS YOU. 1683 01:03:06,040 --> 01:03:07,320 >> THAT'S NOT BAD BUT I WILL TRY 1684 01:03:07,320 --> 01:03:28,800 TO MAKE IT EVEN BETTER. 1685 01:03:28,800 --> 01:03:30,520 I WILL TRY TO MAKE THE CASE AND 1686 01:03:30,520 --> 01:03:31,680 THEN TALK ABOUT HOW THEY'RE 1687 01:03:31,680 --> 01:03:32,960 IMPORTANT IN MANY DIFFERENT 1688 01:03:32,960 --> 01:03:33,200 CANCERS. 1689 01:03:33,200 --> 01:03:34,800 THE PEOPLE THAT DO CANCER WILL 1690 01:03:34,800 --> 01:03:37,040 BE IMMEDIATELY SKEPTICAL BECAUSE 1691 01:03:37,040 --> 01:03:39,000 CONNECTING 1 ENSIEM TO THE 1692 01:03:39,000 --> 01:03:41,280 ENTIRE CANCER FIELD IS A HIGH 1693 01:03:41,280 --> 01:03:44,320 BAR, EVEN THE P53 THAT WE HEAR 1694 01:03:44,320 --> 01:03:46,800 ABOUT FOR THE LAST 50 YEARS IS 1695 01:03:46,800 --> 01:03:51,280 CONNECTED TO MAYBE 50% OF THEM 1696 01:03:51,280 --> 01:03:57,760 AND SO, HOW IS THIS SO 1697 01:03:57,760 --> 01:03:58,040 IMPORTANT? 1698 01:03:58,040 --> 01:04:00,080 MAYBE 1 THING TO SAY IS 2 1699 01:04:00,080 --> 01:04:02,160 ENZYMES SO MAYBE I HAVE A BETTER 1700 01:04:02,160 --> 01:04:06,280 CHANCE GIVEN THAT, BUT THE SULFA 1701 01:04:06,280 --> 01:04:07,480 TAIS INHIBITORS ARE EXISTING IN 1702 01:04:07,480 --> 01:04:10,040 HUMAN AND 2 FORMS, SO THE SULF 1 1703 01:04:10,040 --> 01:04:13,280 AND 2, AND THEY ARE A CLASSIC 1704 01:04:13,280 --> 01:04:15,520 MEMBER OF THE SULFUR BASED 1705 01:04:15,520 --> 01:04:17,120 FAMILY OF ENZYMES THEY SHARE THE 1706 01:04:17,120 --> 01:04:20,040 SITE WITH THE OTHERS AND THEY 1707 01:04:20,040 --> 01:04:22,880 ARE DISTINGUISHED BY BEING THE 1708 01:04:22,880 --> 01:04:25,240 ONLY NEUTRAL PH ENDOSULFA TAIS 1709 01:04:25,240 --> 01:04:26,200 INHIBITORS, THEIR ACTIVITIES 1710 01:04:26,200 --> 01:04:28,880 OPTIMAL AND NEUTRAL PH AND THEY 1711 01:04:28,880 --> 01:04:31,640 ARE SECRETED ENZYMES, AND THEY 1712 01:04:31,640 --> 01:04:34,800 ACT IN THE EXTRA CELLULAR 1713 01:04:34,800 --> 01:04:36,080 ENVIRONMENT AS OPPOSE TO 1714 01:04:36,080 --> 01:04:37,360 MAJORITY OF THE OTHER SULFA TAIS 1715 01:04:37,360 --> 01:04:38,880 INHIBITORS WHICH ARE IS THE 1716 01:04:38,880 --> 01:04:42,240 LYSOSOMA AND THEY PARTICIPATE IN 1717 01:04:42,240 --> 01:04:48,400 DEGRADATION OF THE SULFATED 1718 01:04:48,400 --> 01:04:49,080 TARGETS. 1719 01:04:49,080 --> 01:04:50,600 THE ENDOSULFA TAIS INHIBITORS 1720 01:04:50,600 --> 01:04:54,400 DON'T DEGREAT THE POLYMERS, THEY 1721 01:04:54,400 --> 01:04:58,560 JUSTENT'RE END THE PATTERN, AND 1722 01:04:58,560 --> 01:05:00,520 THE SULFATION IS IMPORTANT AND 1723 01:05:00,520 --> 01:05:07,080 PROTEINS WITH THE H EP A RAN 1724 01:05:07,080 --> 01:05:11,920 SULFATE THE RTK LIGANDS AND 1725 01:05:11,920 --> 01:05:14,920 THEIR RECEPTORS, MANY PROYAISS, 1726 01:05:14,920 --> 01:05:18,520 MANY IMMUNE REGULATING MOLECULES 1727 01:05:18,520 --> 01:05:21,320 ARE SEQUESTERED ON THE HEP A RAN 1728 01:05:21,320 --> 01:05:23,160 SULFATES AND THE DISTRIBUTION, 1729 01:05:23,160 --> 01:05:25,720 REGULATION OF THEIR DISTRIBUTION 1730 01:05:25,720 --> 01:05:27,240 IS QUITE IMPORTANT. 1731 01:05:27,240 --> 01:05:30,960 THESE 2 ENZYMES ARE 65% 1732 01:05:30,960 --> 01:05:32,880 IDENTICAL AND YOU KNOW IF YOU 1733 01:05:32,880 --> 01:05:36,480 LOOK AT IF YOU LOOK AT KNOCK OUT 1734 01:05:36,480 --> 01:05:40,480 STUDIES, DOUBLE KNOCK OUT OF THE 1735 01:05:40,480 --> 01:05:43,840 SULF 2 IN MICE IS EMBRYONIC 1736 01:05:43,840 --> 01:05:45,200 LETHAL, NOT EXACTLY SO SOME OF 1737 01:05:45,200 --> 01:05:48,240 THE MICE GET BORN BUT MOST OF 1738 01:05:48,240 --> 01:05:52,120 THEM DIE NEAR BIRTH FROM 1739 01:05:52,120 --> 01:05:52,680 INABILITY TO SWALLOW. 1740 01:05:52,680 --> 01:05:56,320 AND IT'S INTERESTING TO NOTE 1741 01:05:56,320 --> 01:06:00,240 THAT THIS TOWBL KNOCK OUT 1742 01:06:00,240 --> 01:06:02,400 BASICALLY PREVENTS INNOVATION OF 1743 01:06:02,400 --> 01:06:05,640 THE ESOPHAGUS AND THE MICE 1744 01:06:05,640 --> 01:06:06,200 CANNOT SWALLOW. 1745 01:06:06,200 --> 01:06:08,480 SINGLE KNOCK OUTS ARE OKAY, THE 1746 01:06:08,480 --> 01:06:11,880 MICE SURVIVE SO THERE IS SOME 1747 01:06:11,880 --> 01:06:14,080 KIND OF ASSUMPTION THAT THE 1748 01:06:14,080 --> 01:06:17,080 ENSWRIMS MIGHT BE REDUNDANT AND 1749 01:06:17,080 --> 01:06:18,120 DO SIMILAR STUFF, BUT I WILL 1750 01:06:18,120 --> 01:06:24,600 MAKE THE CASE THAT MAYBE NOT THE 1751 01:06:24,600 --> 01:06:25,680 ONLY STORY. 1752 01:06:25,680 --> 01:06:27,080 AND RECENT STUDIES ACTUALLY 1753 01:06:27,080 --> 01:06:28,040 QUITE STRONGLY SUPPORT THE 1754 01:06:28,040 --> 01:06:29,080 IMPORTANCE OF ENZYME SO FOR 1755 01:06:29,080 --> 01:06:35,440 EXAMPLE, A STUDY THAT USED THE 1756 01:06:35,440 --> 01:06:37,280 SIMPLE ANTIBODIES 1757 01:06:37,280 --> 01:06:40,680 [INDISCERNIBLE] TO TREAT 1758 01:06:40,680 --> 01:06:42,320 COLOANGEALL CANCER IN A MOUSE 1759 01:06:42,320 --> 01:06:44,280 MODEL, SO THEY ARE INTERESTING, 1760 01:06:44,280 --> 01:06:45,360 WE STUMBLED ON THEM IN THE HEAD 1761 01:06:45,360 --> 01:06:48,160 AND NECK AND ON THE STUDY IS THE 1762 01:06:48,160 --> 01:06:49,600 LEFT SIDE, THE IMMUNO 1763 01:06:49,600 --> 01:06:50,280 HISTOCHEMIST RADIOY WILL SHOW 1764 01:06:50,280 --> 01:06:53,640 THAT YOU THE TUMOR TISSUES HAVE 1765 01:06:53,640 --> 01:06:57,160 QUITE NICE UPREGULATION OF THE 1766 01:06:57,160 --> 01:06:59,360 SULF 2 ENZYME COMPARED TO 1767 01:06:59,360 --> 01:07:01,080 ADJACENT NORMAL AND THAT 1768 01:07:01,080 --> 01:07:02,320 CORRELATES WITH THE KI-INCREASE 1769 01:07:02,320 --> 01:07:06,160 67 AND THE SAME AREAS OF THE 1770 01:07:06,160 --> 01:07:08,720 TUMORS THEN WE TRY TO MAKE AN 1771 01:07:08,720 --> 01:07:10,480 ADDITIONAL SENSE OUT OF THE 1772 01:07:10,480 --> 01:07:11,760 UPREGULATION OF THE ENZYMES IN 1773 01:07:11,760 --> 01:07:16,080 HEAD AND NECK TUMOR BASED ON ECG 1774 01:07:16,080 --> 01:07:18,400 DATA AND LOOKED AT ALL THE 1775 01:07:18,400 --> 01:07:20,160 ENZYMES THAT SYNTHESIZE THE 1776 01:07:20,160 --> 01:07:22,040 HEPATITIS EAR AN SULFATE 1777 01:07:22,040 --> 01:07:23,600 POLYMERS AND CHANGES IN HEAD AND 1778 01:07:23,600 --> 01:07:28,200 COMEK AND THE 1S THAT ARE MOST 1779 01:07:28,200 --> 01:07:30,040 CONSISTENTLY UPREGULATED IN THAT 1780 01:07:30,040 --> 01:07:31,040 DISEASE. 1781 01:07:31,040 --> 01:07:33,240 TOGETHER WITH SOME OF THE 1782 01:07:33,240 --> 01:07:35,320 EXTENSION ENZYMES THAT BUILD 1783 01:07:35,320 --> 01:07:37,400 LONGER AND HEPATITIS EAR AN 1784 01:07:37,400 --> 01:07:39,080 SULFATE CHANGES AND WHAT IS 1785 01:07:39,080 --> 01:07:41,960 DEFINITELY NOT INCREASED ARE THE 1786 01:07:41,960 --> 01:07:44,600 SULFUR TRANSFER ACES SO 1 CAN 1787 01:07:44,600 --> 01:07:46,240 SORT OF ASSUME THAT IN THE 1788 01:07:46,240 --> 01:07:47,560 CONTEXT OF HEAD AND NECK, WE 1789 01:07:47,560 --> 01:07:51,800 WILL BE BUILDING LONGER, 1790 01:07:51,800 --> 01:07:53,000 UNDERSULFATED POLYMERS OF HEP A 1791 01:07:53,000 --> 01:08:04,160 RAN AND WE THINK THAT IMPACTS 1792 01:08:04,160 --> 01:08:05,160 THE DISEASE PROGRESSION. 1793 01:08:05,160 --> 01:08:06,200 THE UPREGULATION HAPPENS NOT 1794 01:08:06,200 --> 01:08:08,880 ONLY IN THE LEVEL IN THE TCG 1795 01:08:08,880 --> 01:08:13,000 DATA BUT ALSO IN THE RECENT 1796 01:08:13,000 --> 01:08:26,560 CP TEX STUDIES, IT'S VERY CLEAR 1797 01:08:26,560 --> 01:08:28,160 THAT ARE UPREGULATED AND IT'S 1798 01:08:28,160 --> 01:08:29,360 ALSO THE CASE THAT WHAT IS 1799 01:08:29,360 --> 01:08:30,360 IMPACTED IS NOT JUST THE 1800 01:08:30,360 --> 01:08:31,720 EXPRESSION OF THE ENZYMES BUT 1801 01:08:31,720 --> 01:08:35,080 ALSO SURVIVAL OF THE PATIENTS. 1802 01:08:35,080 --> 01:08:36,800 SO, IF WE DO JOINT ANALYSIS OF 1803 01:08:36,800 --> 01:08:47,680 THE SULF 1 AND 2 IN THE 1804 01:08:47,680 --> 01:08:48,880 SCWAIMOUS CELL CARCINOMAS, YOU 1805 01:08:48,880 --> 01:08:50,480 SEE THOSE ARE POOR OUTCOMES, 1806 01:08:50,480 --> 01:08:53,880 THOSE ARE THE RED BARS AND THE 1807 01:08:53,880 --> 01:08:58,680 LOW, LOW ARE ASSOCIATED WITH 1808 01:08:58,680 --> 01:08:59,960 MUCH BETTER OUTCOMES INVARIABLY 1809 01:08:59,960 --> 01:09:01,600 FOR BOTH OF THE OVERALL 1810 01:09:01,600 --> 01:09:03,400 SURVIVALS AND THE PROGRESSION 1811 01:09:03,400 --> 01:09:05,480 FOR INTERVAL, IF WE BUILD A 1812 01:09:05,480 --> 01:09:09,120 MULTIVARIANT MODEL OF THE 1813 01:09:09,120 --> 01:09:10,120 SURVIVAL. 1814 01:09:10,120 --> 01:09:11,080 INCLUDING TUMOR STAGE, RADIATION 1815 01:09:11,080 --> 01:09:12,320 THERAPY AND OTHER IMPORTANT 1816 01:09:12,320 --> 01:09:14,160 FACTORS, YOU WILL SEE THAT 1817 01:09:14,160 --> 01:09:16,160 SOMETHING LIKE TUMOR STAGE IS 1818 01:09:16,160 --> 01:09:18,080 SIGNIFICANTLY ASSOCIATED WITH 1819 01:09:18,080 --> 01:09:20,520 OUTCOMES BUT INDEPENDENT OF 1820 01:09:20,520 --> 01:09:22,880 THAT, SULF 2 REMAINS AN 1821 01:09:22,880 --> 01:09:26,360 IMPORTANT FACTOR IN HEAD AND 1822 01:09:26,360 --> 01:09:26,680 NECK SURVIVAL. 1823 01:09:26,680 --> 01:09:30,760 BUT SULF 1 BECOMES 1824 01:09:30,760 --> 01:09:31,320 INSIGNIFICANT. 1825 01:09:31,320 --> 01:09:32,680 THIS IS AN INTERESTING 1826 01:09:32,680 --> 01:09:34,680 OBSERVATION BUT WHEN WE FURTHER 1827 01:09:34,680 --> 01:09:42,080 STUDY THE DATA, AND BREAK OUT 1828 01:09:42,080 --> 01:09:44,080 THE STUDY SETS INTO THE TUMORS 1829 01:09:44,080 --> 01:09:45,800 WHICH ARE EARLY STAGE AND LATE 1830 01:09:45,800 --> 01:09:47,680 STAGE WE NOTICE AN INTERESTING 1831 01:09:47,680 --> 01:09:49,080 PATTERN THERE. 1832 01:09:49,080 --> 01:09:50,800 THE SULF 1 ENZYME I AM NOT PACTS 1833 01:09:50,800 --> 01:09:52,760 SURVIVAL IN EARLY STAGE TUMORS 1834 01:09:52,760 --> 01:09:54,480 AND SULF 2 DOES NOT IMPACT THE 1835 01:09:54,480 --> 01:09:55,680 SURVIVAL AT THAT STAGE. 1836 01:09:55,680 --> 01:09:58,400 YOU CAN SEE IT ON THE HAZARD 1837 01:09:58,400 --> 01:10:03,280 RATIOS IN THE TABLE AND ON THE 1838 01:10:03,280 --> 01:10:04,320 LEFT-HAND SIDE, THE ENZYME 1839 01:10:04,320 --> 01:10:06,320 BECOMES IMPORTANT IN LATER STAGE 1840 01:10:06,320 --> 01:10:09,200 AND IT IS ACTUALLY MORE 1841 01:10:09,200 --> 01:10:09,760 IMPACTFUL OVERALL, MOSTLY 1842 01:10:09,760 --> 01:10:11,600 BECAUSE MOST OF THE TUMORS 1843 01:10:11,600 --> 01:10:13,280 REPRESENTED IN THOSE STUDY SETS 1844 01:10:13,280 --> 01:10:17,920 ARE ACTUALLY ADVANCED TUMORS, SO 1845 01:10:17,920 --> 01:10:19,720 THEY ARE THE 3-1 RATIO OF THE 1846 01:10:19,720 --> 01:10:21,440 LATE STAGE WHERE COMPARED TO THE 1847 01:10:21,440 --> 01:10:23,400 EARLY STAGE TUMORS AND WHAT YOU 1848 01:10:23,400 --> 01:10:25,120 ALSO CAN SEE ON THE GRAPH ON THE 1849 01:10:25,120 --> 01:10:27,680 RIGHT HAND SIDE IS THAT THE SULF 1850 01:10:27,680 --> 01:10:29,280 1 IS UPREGULATED AT AN EARLY 1851 01:10:29,280 --> 01:10:31,080 STAGE OF THE DISEASE. 1852 01:10:31,080 --> 01:10:34,200 SO, CONSISTENT WITH THAT, IT 1853 01:10:34,200 --> 01:10:39,480 ALSO IMPACTS SURVIVAL AT AN 1854 01:10:39,480 --> 01:10:39,920 EARLY STAGE. 1855 01:10:39,920 --> 01:10:41,720 SO NOW I WILL TURN A BIT TO THE 1856 01:10:41,720 --> 01:10:46,120 ENZYMES THEMSELVES AND HOW THEY 1857 01:10:46,120 --> 01:10:47,320 FUNCTION AND THE FIRST SLIDE IS 1858 01:10:47,320 --> 01:10:50,680 INTENDED TO SHOW YOU THE 1859 01:10:50,680 --> 01:10:53,480 COMMONALITIES BETWEEN THE 2 1860 01:10:53,480 --> 01:10:53,680 ENZYMES. 1861 01:10:53,680 --> 01:10:55,240 THE SCHEMATIC AT THE BOTTOM 1862 01:10:55,240 --> 01:10:58,520 SHOWS THE ORGANIZATION OF THAT 1863 01:10:58,520 --> 01:11:01,120 ENZYME, IT HAS A INTERIM 1864 01:11:01,120 --> 01:11:02,440 CATALYTIC DOMAIN, A HYDROPHILIC 1865 01:11:02,440 --> 01:11:04,480 DOMAIN AND A C-TERMINAL DOMAIN 1866 01:11:04,480 --> 01:11:10,080 WHICH ALSO IS IMPORTANT FOR 1867 01:11:10,080 --> 01:11:10,680 CATALYST. 1868 01:11:10,680 --> 01:11:11,480 THIS ARCHITECTURE IS CONSERVED 1869 01:11:11,480 --> 01:11:15,160 WITH THE SULF 1 AND 2 THE 1870 01:11:15,160 --> 01:11:18,520 ENZYMES ARE BOTH PROCESSED, THEY 1871 01:11:18,520 --> 01:11:20,280 ARE HEAVILY N-GLYCOSYLATED BY 1872 01:11:20,280 --> 01:11:22,280 INTERFER KNOW FOR SUBUNITS AND 1873 01:11:22,280 --> 01:11:23,760 THOSE SUBCOMMUNITIES REMAIN 1874 01:11:23,760 --> 01:11:27,440 LINKED BY DISCIPLINARY SULFIDES 1875 01:11:27,440 --> 01:11:28,160 IN 1 PIECE. 1876 01:11:28,160 --> 01:11:30,400 SO WHEN WE WORKED OUT THE 1877 01:11:30,400 --> 01:11:32,240 OVEREXPRESSION OF THE ENZYMES 1878 01:11:32,240 --> 01:11:34,440 YOU CAN SEE ALL THOSE CHANNELS 1879 01:11:34,440 --> 01:11:36,880 ON TOP, THAT THE FULL LENGTH 1880 01:11:36,880 --> 01:11:41,440 PROTEIN MIGRATES AS SOMETHING 1881 01:11:41,440 --> 01:11:44,080 AROUND 150 KILODALTONS, AND CAN 1882 01:11:44,080 --> 01:11:46,000 BE PURIFIED BY LEATHAL AFFINITY 1883 01:11:46,000 --> 01:11:48,840 THAT IS QUITE ABOUT WITH PURITY, 1884 01:11:48,840 --> 01:11:49,720 THAT OVEREXPRESSION SYSTEM IS 1885 01:11:49,720 --> 01:11:51,120 ACTUALLY A BREAK THROUGH FOR US, 1886 01:11:51,120 --> 01:11:54,960 WE STRUGGLED FOR A LONG TIME 1887 01:11:54,960 --> 01:11:56,880 WITH LOW ABUNDANCE OF THE 1888 01:11:56,880 --> 01:11:59,000 ENZYMES, THEY ARE ALL ABUNDANT 1889 01:11:59,000 --> 01:12:00,840 IN MOST OF THE CONTEXT OF HUMAN 1890 01:12:00,840 --> 01:12:03,000 BIOLOGY AND THEY DON'T EXPRESS 1891 01:12:03,000 --> 01:12:04,680 VERY WELL, PROBABLY BECAUSE OF 1892 01:12:04,680 --> 01:12:08,840 ALL THE BTMs THAT THEY'RE 1893 01:12:08,840 --> 01:12:12,120 ASSOCIATED WITH THEM AND THEY 1894 01:12:12,120 --> 01:12:13,280 EXPRESS QUITEENTIOUS FICIENT AND 1895 01:12:13,280 --> 01:12:18,680 WE GET MILLIGRAMS FROM THEM FROM 1896 01:12:18,680 --> 01:12:21,080 A HEX 293 SYSTEM PENSION SYSTEM 1897 01:12:21,080 --> 01:12:21,640 WITHULENTY VIRAL CONSTRUCTS. 1898 01:12:21,640 --> 01:12:25,480 THE STRUCTURE ON THE RIGHT HAND 1899 01:12:25,480 --> 01:12:26,920 SIDE POINTS OUT THAT THAT THE 1900 01:12:26,920 --> 01:12:28,800 MOLDLES OF THESE ENZYMES BUILT 1901 01:12:28,800 --> 01:12:31,080 BY ALPHA FOLD ARE VERY SIMILAR, 1902 01:12:31,080 --> 01:12:32,880 THEY ARE NOT CRYSTAL STRUCTURES 1903 01:12:32,880 --> 01:12:34,880 BUT ALPHA FOLD PREDICTS QUITE 1904 01:12:34,880 --> 01:12:36,400 SIMILAR IN THE CATALYTIC END AND 1905 01:12:36,400 --> 01:12:39,400 THIS PIECE OVER HERE IS THAT 1906 01:12:39,400 --> 01:12:40,600 CONSERVED DPLI SEEN RESIDUE IN 1907 01:12:40,600 --> 01:12:43,480 THE ACTIVE SITE WHICH IS 1908 01:12:43,480 --> 01:12:44,280 ESSENTIALLY FOR CATTAL SIS. 1909 01:12:44,280 --> 01:12:46,200 SO, SO FAR THEY ARE QUITE 1910 01:12:46,200 --> 01:12:48,280 SIMILAR TO ENZYMES AND THEY 1911 01:12:48,280 --> 01:12:50,000 MIGHT BE REDUNDANT. 1912 01:12:50,000 --> 01:12:51,760 BUT THE RECENT STUDIES ALSO 1913 01:12:51,760 --> 01:12:57,840 POINT OUT THAT WHEN YOU LOOK AT 1914 01:12:57,840 --> 01:12:59,040 THE [INDISCERNIBLE] AND THE 1915 01:12:59,040 --> 01:12:59,680 EXPRESSED PROTEINS YOU WILL 1916 01:12:59,680 --> 01:13:03,760 NOTICE THAT THE SULF 2 IS 1917 01:13:03,760 --> 01:13:06,120 ACTUALLY DISTINCTLY HIGHER 1918 01:13:06,120 --> 01:13:08,720 MOLECULAR WEIGHT THAN THE SULF 1919 01:13:08,720 --> 01:13:08,880 1. 1920 01:13:08,880 --> 01:13:11,080 AND IF YOU TREAT THAT WITH CHOND 1921 01:13:11,080 --> 01:13:12,880 REORGANIZATION OF THE 1922 01:13:12,880 --> 01:13:14,320 INSTITUTEIN, THE ENZYME SHIFTS 1923 01:13:14,320 --> 01:13:17,680 BY 50 KILO DALTONS TO A MASS OF 1924 01:13:17,680 --> 01:13:19,800 THE SULF 1 ENZYME. 1925 01:13:19,800 --> 01:13:22,880 AND IT WAS SHOWN BY A FRENCH 1926 01:13:22,880 --> 01:13:27,400 GROUP IN A VERY NICE RECENT 1927 01:13:27,400 --> 01:13:30,240 PAPER THAT ACTUALLY THIS ENZYME 1928 01:13:30,240 --> 01:13:34,880 IS A CHONT REORGANIZATION OF THE 1929 01:13:34,880 --> 01:13:35,520 INSTITUTEIN SULFATED MOLECULE 1930 01:13:35,520 --> 01:13:38,280 AND THAT IS SOMETHING THAT TOOK 1931 01:13:38,280 --> 01:13:39,000 20 YEARS TO DISCOVER. 1932 01:13:39,000 --> 01:13:40,280 I THINK THAT THAT'S ALSO RELATED 1933 01:13:40,280 --> 01:13:41,760 TO THE FACT THAT THE EXPRESSION 1934 01:13:41,760 --> 01:13:44,200 OF THOSE ENSWROIMS IS QUITE 1935 01:13:44,200 --> 01:13:45,400 TRICKY AND SO NOBODY NOTICED FOR 1936 01:13:45,400 --> 01:13:50,520 A LONG TIME THAT ACTUALLY THE 1937 01:13:50,520 --> 01:13:54,520 HEP A RAN SULFATE PROCESSING 1938 01:13:54,520 --> 01:13:55,280 ENZYME IS ITSELF A CHOND 1939 01:13:55,280 --> 01:14:01,200 REORGANIZATION OF THE 1940 01:14:01,200 --> 01:14:01,880 INSTITUTEIN SULFATED MOLECULE 1941 01:14:01,880 --> 01:14:04,320 AND SO THAT POINTS OUT THE 1942 01:14:04,320 --> 01:14:04,920 DIFFERENCES BETWEEN THE 2 1943 01:14:04,920 --> 01:14:06,280 ENZYMES AND HERE ARE THE 1944 01:14:06,280 --> 01:14:07,760 MOLECULES IN THE ALPHA FOLD 1945 01:14:07,760 --> 01:14:11,880 MODEL AND THE SCHEMATICS SHOW 1946 01:14:11,880 --> 01:14:13,400 THAT THE TERMINAL AGENTS 1947 01:14:13,400 --> 01:14:17,160 DISPLAYED IN RED, TOGETHER WITH 1948 01:14:17,160 --> 01:14:23,680 THE VERY C-TERMINAL PART, FORM 1949 01:14:23,680 --> 01:14:25,000 THE CATALYTIC ACTIVE DOMAIN AND 1950 01:14:25,000 --> 01:14:30,280 IN ADDITION TO THAT, THAT IS 1951 01:14:30,280 --> 01:14:33,520 THIS LARGELY DISORDERED 1952 01:14:33,520 --> 01:14:35,480 HYDRAULIC DOMAIN WHICH 1953 01:14:35,480 --> 01:14:38,000 PARTICIPATES IN THE CATALYST AS 1954 01:14:38,000 --> 01:14:39,560 WELL. 1955 01:14:39,560 --> 01:14:43,640 THE DATA AVAILABLE FROM FROM 1956 01:14:43,640 --> 01:14:45,760 [INDISCERNIBLE] GROUP AND HIS 1957 01:14:45,760 --> 01:14:47,880 [INDISCERNIBLE] THE FRENCH GROUP 1958 01:14:47,880 --> 01:14:49,400 AS WELL, ROMAN [INDISCERNIBLE] 1959 01:14:49,400 --> 01:14:54,480 IS THE PI THERE, SHOWED THAT THE 1960 01:14:54,480 --> 01:14:55,800 ENZYMES ARE PROCESSIVE BECAUSE 1961 01:14:55,800 --> 01:14:57,880 THEY MAKE MULTIPLE COMPLEX WITH 1962 01:14:57,880 --> 01:15:01,480 THE HEP A RAN SULFATE POLYMERS 1963 01:15:01,480 --> 01:15:03,000 THANKS TO INTERACTIONS MEDIATED 1964 01:15:03,000 --> 01:15:05,560 BY THE CATALYTIC DOMAIN, AT THE 1965 01:15:05,560 --> 01:15:09,520 SAME TIME THE HYDROPHILIC DOMAIN 1966 01:15:09,520 --> 01:15:10,600 ISSUESS, THE HYDROPHILIC DOMAINS 1967 01:15:10,600 --> 01:15:12,480 ARE MORE DIVERGENT AND THE 1968 01:15:12,480 --> 01:15:14,440 HYDROPHILIC DOMAIN ARE ALSO THE 1969 01:15:14,440 --> 01:15:15,680 SUGMENTORSHIP SKILL OF THE 1970 01:15:15,680 --> 01:15:18,240 SULFATE 2 PROTEIN WHICH IS 1971 01:15:18,240 --> 01:15:18,720 DECORATED BY THE CHOND 1972 01:15:18,720 --> 01:15:19,800 REORGANIZATION OF THE 1973 01:15:19,800 --> 01:15:20,880 INSTITUTEIN SULFATE CHAIN. 1974 01:15:20,880 --> 01:15:22,000 SO THANKS TO DIFFERENCE IN THESE 1975 01:15:22,000 --> 01:15:25,640 SPECIES THERE IS QUITE A BIT OF 1976 01:15:25,640 --> 01:15:26,880 DIFFERENCE IN SUBSTRATES. 1977 01:15:26,880 --> 01:15:28,000 AND THAT'S SOMETHING UNDER 1978 01:15:28,000 --> 01:15:33,280 INTENSE INVESTIGATION IN MY LAB 1979 01:15:33,280 --> 01:15:34,920 AND OTHER LABS, AND IT IS AT 1980 01:15:34,920 --> 01:15:37,040 THIS POINT UNKNOWN SO USING 1981 01:15:37,040 --> 01:15:40,120 SMALL MOLECULES AS A SUBSTRATE, 1982 01:15:40,120 --> 01:15:42,360 THE DIFFERENCES BETWEEN 1983 01:15:42,360 --> 01:15:43,840 [INDISCERNIBLE] ARE SUBTLE BUT 1984 01:15:43,840 --> 01:15:45,760 USING OTHER SUBSTRATES WE HOPE 1985 01:15:45,760 --> 01:15:48,840 TO DISTINGUISH THEIR ACTIVITIES 1986 01:15:48,840 --> 01:15:49,200 IN VITROW. 1987 01:15:49,200 --> 01:15:51,200 IN FACT WHAT IS QUITE 1988 01:15:51,200 --> 01:15:54,720 INTERESTING IS THAT THE 1989 01:15:54,720 --> 01:15:55,320 CHONDROITIN SULFATE MODULES 1990 01:15:55,320 --> 01:15:57,080 ACTIVITY HEAVILY AND IF YOU 1991 01:15:57,080 --> 01:15:57,680 REMOVE THE CHOND REORGANIZATION 1992 01:15:57,680 --> 01:15:58,720 OF THE INSTITUTEIN SULFATE THE 1993 01:15:58,720 --> 01:16:03,400 ACTIVITY OF THE ENZYME 1994 01:16:03,400 --> 01:16:04,760 INCREASES, NEARLY DOUBLES AND 1995 01:16:04,760 --> 01:16:07,440 SOOOSE NOT ONLY INTERESTING WHEN 1996 01:16:07,440 --> 01:16:09,160 IT'S MODIFIED BUT IT ALSO 1997 01:16:09,160 --> 01:16:09,560 IMPACTS FUNCTION. 1998 01:16:09,560 --> 01:16:12,680 WHAT WE DID NEXT IS TO DETERMINE 1999 01:16:12,680 --> 01:16:14,120 THE GLYCO FORMS OF THE SULF 1 2000 01:16:14,120 --> 01:16:17,400 AND 2 ENZYMES IN THE 2001 01:16:17,400 --> 01:16:18,400 OVEREXPRESSION SYSTEM AND 2002 01:16:18,400 --> 01:16:20,640 BECAUSE THE ENZYMES ARE 65% 2003 01:16:20,640 --> 01:16:29,080 IDENTICAL, 1 EXPECTS THAT THE IN 2004 01:16:29,080 --> 01:16:29,720 GLYCOSYLATION WOULD BE SIMILAR 2005 01:16:29,720 --> 01:16:31,680 AND THAT'S THE CASE, THE ONLY 2006 01:16:31,680 --> 01:16:32,920 DIFFERENCE WE NOTICE IS THAT THE 2007 01:16:32,920 --> 01:16:37,280 SEQUENCE AT THE N-TERMINUS 1 OF 2008 01:16:37,280 --> 01:16:38,640 THEM IS ASSOCIATED ONLY WITH 2009 01:16:38,640 --> 01:16:45,880 SULF 2 AND THAT 1 IS DECORATED 2010 01:16:45,880 --> 01:16:48,760 BY THE C-TERMINUS, AND THE OTHER 2011 01:16:48,760 --> 01:16:52,920 WOKNOW IS ON THE SULF 1 AND IT 2012 01:16:52,920 --> 01:16:54,520 IS NOT OCCUPIED UNDER SULF 2 2013 01:16:54,520 --> 01:16:55,880 OTHERWISE ALL THE OTHER SITES 2014 01:16:55,880 --> 01:16:57,920 ARE OCCUPIED AND THEY ARE 2015 01:16:57,920 --> 01:17:00,880 OCCUPIED BY SIMILAR STRUCTURES 2016 01:17:00,880 --> 01:17:05,920 IN TERMS OF IF SULF 2 COMPLEX 2017 01:17:05,920 --> 01:17:09,120 GLYCANS WITH AT THAT SITE OR 2018 01:17:09,120 --> 01:17:09,600 HIGH [INDISCERNIBLE]. 2019 01:17:09,600 --> 01:17:14,160 SO THERE IS QUITE A BIT OF 2020 01:17:14,160 --> 01:17:16,040 SIMILARITY IN THAT BPN AND 2021 01:17:16,040 --> 01:17:17,480 THAT'S SUMMARIZED IN THIS 2022 01:17:17,480 --> 01:17:20,360 SCHEMATIC, YOU CAN SEE THAT MOST 2023 01:17:20,360 --> 01:17:23,440 OF THE NGLUE MARIOUS CANS SIT ON 2024 01:17:23,440 --> 01:17:25,440 THE KACCT THEA LYTIC DOMAIN AND 2025 01:17:25,440 --> 01:17:26,400 THERE IS NO INFORMATION SOINAR 2026 01:17:26,400 --> 01:17:29,640 IN TERMS OF IMMEDIATIFYING 2027 01:17:29,640 --> 01:17:30,680 CATALYTIC ACTIVITY DIRECTLY BUT 2028 01:17:30,680 --> 01:17:35,480 YOU KNOW THAT REMAINS TO BE 2029 01:17:35,480 --> 01:17:35,720 STUDIED. 2030 01:17:35,720 --> 01:17:39,280 WELL, IT'S QUITE CLEAR FROM THIS 2031 01:17:39,280 --> 01:17:40,800 IS DEPENDING ON WHICH CELL WILL 2032 01:17:40,800 --> 01:17:41,960 BE EXPRESSING THESE ENZYMES, 2033 01:17:41,960 --> 01:17:47,000 THEY WILL BE QUITE DIFFERENT. 2034 01:17:47,000 --> 01:17:48,960 THE GLYCOSYLATION IS CELL 2035 01:17:48,960 --> 01:17:50,320 DEPENDENT SO WHAT IS QUITE 2036 01:17:50,320 --> 01:17:51,840 INTERESTING IS ALSO TO LOOK AT 2037 01:17:51,840 --> 01:17:52,920 THE DISTRIBUTION OF THE 2038 01:17:52,920 --> 01:17:55,400 PRODUCTION OF THESE ENZYMES, IN 2039 01:17:55,400 --> 01:17:59,720 SINGLE CELL RNA SEQ DATA, THIS 2040 01:17:59,720 --> 01:18:01,840 DATA SET THAT I AM SHOWING YOU 2041 01:18:01,840 --> 01:18:03,840 IS RELATED TO THE HEAD AND NECK 2042 01:18:03,840 --> 01:18:09,080 CANCER, AND THE AUTHORS SHOW 2043 01:18:09,080 --> 01:18:11,280 THAT THE SULF 1 ENZYME DERIVES 2044 01:18:11,280 --> 01:18:13,840 PRIMARILY FROM FIBRO BLASTS 2045 01:18:13,840 --> 01:18:15,480 WHEREAS THE SULF 2 ENZYME IS 2046 01:18:15,480 --> 01:18:18,280 USED BY THE CANCER CELLS, AND 2047 01:18:18,280 --> 01:18:21,440 SOME OTHER CANCER CELL TYPES 2048 01:18:21,440 --> 01:18:22,720 INCLUDING THE FIBRO BLASTS AS 2049 01:18:22,720 --> 01:18:23,720 WELL, BUT IT'S QUITE STRIKING AS 2050 01:18:23,720 --> 01:18:25,480 YOU CAN SEE ON THE GRAPH ON THE 2051 01:18:25,480 --> 01:18:29,720 RIGHT HAND SIDE, THAT THE SULF 1 2052 01:18:29,720 --> 01:18:31,760 DERIVES ALMOST EXCLUSIVELY FROM 2053 01:18:31,760 --> 01:18:34,840 THE FIBRO BLAST CELLS AND THE 2054 01:18:34,840 --> 01:18:37,480 SULF 2 IS DOMINANT IN THE TUMOR 2055 01:18:37,480 --> 01:18:37,840 CELLS. 2056 01:18:37,840 --> 01:18:46,240 THIS IS SOMETHING THAT WAS 2057 01:18:46,240 --> 01:18:47,560 ACTUALLY NEVER DESCRIBED AND 2058 01:18:47,560 --> 01:18:49,760 MOST OF THE STUDIES THAT ANALYZE 2059 01:18:49,760 --> 01:18:52,400 THE SULF IN TUMORS SHOWS IT 2060 01:18:52,400 --> 01:18:53,560 IMPACTS TUMOR CELLS BUT THEN 2061 01:18:53,560 --> 01:18:56,120 THERE IS SOMEWHAT CONFUSING 2062 01:18:56,120 --> 01:18:57,080 LITERATURE AT SULF 1 IMPACT ON 2063 01:18:57,080 --> 01:19:06,400 THE CANCER CELLS WHICH IS IN MY 2064 01:19:06,400 --> 01:19:08,040 OPINION AND WE NEED TO DO 2065 01:19:08,040 --> 01:19:09,280 STUDIES WITH THE FIBRO BLASTS 2066 01:19:09,280 --> 01:19:11,360 ARE INCLUDED IN THE PICTURE. 2067 01:19:11,360 --> 01:19:13,920 WE DID CONFIRM THAT OBSERVATION 2068 01:19:13,920 --> 01:19:16,000 ACTUALLY BY INSITUE 2069 01:19:16,000 --> 01:19:16,840 HYBRIDIZATION STUDIES AND THIS 2070 01:19:16,840 --> 01:19:18,360 IS A HEAD AND NECK TUMOR AND 2071 01:19:18,360 --> 01:19:26,880 WHAT YOU CAN SEE IN GREEN IS ON 2072 01:19:26,880 --> 01:19:28,680 TUMOR CELLS AND NORMAL 2073 01:19:28,680 --> 01:19:29,840 EPITEALIA, THE REST OF THE SLIDE 2074 01:19:29,840 --> 01:19:31,280 IS SOME KIND OF STROMA AND ON 2075 01:19:31,280 --> 01:19:35,040 THE RIGHT HAND SIDE OF THAT 2076 01:19:35,040 --> 01:19:39,880 SLIDE, IS TUMOR WITH TUMOR 2077 01:19:39,880 --> 01:19:41,840 STROMA, WHERE THE SULF ENZYME IS 2078 01:19:41,840 --> 01:19:42,080 RICH. 2079 01:19:42,080 --> 01:19:45,240 YOU CAN SEE IT IN THE PINK OR 2080 01:19:45,240 --> 01:19:46,920 WHATEVER COLOR AND ON THE 2081 01:19:46,920 --> 01:19:51,840 LEFT-HAND SIDE, THESE ARE 2082 01:19:51,840 --> 01:19:55,480 STRUCTURES OF NORMAL GLANDS AND 2083 01:19:55,480 --> 01:19:56,920 IN THAT--IN THAT PART OF THE 2084 01:19:56,920 --> 01:20:00,480 SLIDE, THE SULF 1 IS NOT PRESENT 2085 01:20:00,480 --> 01:20:02,360 SO THAT'S THE CANCER ASSOCIATED 2086 01:20:02,360 --> 01:20:06,120 STROMA THAT IS RICH IN THOSE 2087 01:20:06,120 --> 01:20:06,320 CELLS. 2088 01:20:06,320 --> 01:20:08,040 AND IF YOU ZOOM INTO THAT SLIDE, 2089 01:20:08,040 --> 01:20:10,600 YOU START SEEING THE SULF 2 2090 01:20:10,600 --> 01:20:13,360 EXPRESSION AND THAT'S AGAIN 2091 01:20:13,360 --> 01:20:15,040 INSIGHTUE HYBRIDIZATION ON TOP 2092 01:20:15,040 --> 01:20:16,560 OF THE IMMUNO HISTOIN YELLOW AND 2093 01:20:16,560 --> 01:20:19,200 YOU SEE THOSE YELLOW DOTS MOSTLY 2094 01:20:19,200 --> 01:20:22,000 ON THE TUMOR BUT ALSO IN THE 2095 01:20:22,000 --> 01:20:26,720 STROMA NEXT TO THE SULF 1. 2096 01:20:26,720 --> 01:20:28,040 FROM THAT POINT OF VIEW, IT'S 2097 01:20:28,040 --> 01:20:29,680 QUITE INTERESTING TO LOOK AT THE 2098 01:20:29,680 --> 01:20:33,840 CORRELATION OF OTHER GENES WITH 2099 01:20:33,840 --> 01:20:37,200 THE SULF. 2100 01:20:37,200 --> 01:20:40,280 IN THE IN THE EXPRESSION HAD BY 2101 01:20:40,280 --> 01:20:41,320 MRNA OR PROTEOMICS, THERE IS A 2102 01:20:41,320 --> 01:20:44,000 SET OF GENES WHICH ARE STRONGLY 2103 01:20:44,000 --> 01:20:46,160 CORRELATED WITH THE SULF 1 2104 01:20:46,160 --> 01:20:47,680 ENZYME AND MUCH MORE WITH THE 2105 01:20:47,680 --> 01:20:52,080 SULF 2 ENZYME, THE CORRELATION 2106 01:20:52,080 --> 01:20:55,440 CO EFFICIENTS, FOR EACH POINT 2107 01:20:55,440 --> 01:20:57,080 AND WHAT TURNS OUT TO BE TRUE IS 2108 01:20:57,080 --> 01:20:58,720 THAT MOST OF THOSE ADDITIONAL 2109 01:20:58,720 --> 01:21:00,120 PROTEINS ARE HIGHLY CORRELATED 2110 01:21:00,120 --> 01:21:03,840 WITH SULF 1 COME FROM THE CANCER 2111 01:21:03,840 --> 01:21:06,600 ASSOCIATED FIBRO BLASTS, ALL 2112 01:21:06,600 --> 01:21:14,080 THESE PROTEINS LISTED IN THE 2113 01:21:14,080 --> 01:21:14,680 TABLE COME FROM [INDISCERNIBLE] 2114 01:21:14,680 --> 01:21:19,000 AND MANY OF THEM ARE HEP A RAN 2115 01:21:19,000 --> 01:21:21,280 SULFATE BINDING PROTEINS. 2116 01:21:21,280 --> 01:21:22,120 THIS IS STATISTICALLY 2117 01:21:22,120 --> 01:21:24,280 SIGNIFICANCE DIFFERENCE WHEN YOU 2118 01:21:24,280 --> 01:21:25,720 BUILD THOSE HISTOGRAMS OF 2119 01:21:25,720 --> 01:21:27,760 CORRELATION COENTIOUS FICIENTS 2120 01:21:27,760 --> 01:21:30,840 IN THE CAF GENES VERSUS ANY 2121 01:21:30,840 --> 01:21:32,720 OTHER GENE, YOU SEE THE SHIFT TO 2122 01:21:32,720 --> 01:21:37,400 THE MUCH HIGHER CORRELATION, AND 2123 01:21:37,400 --> 01:21:38,680 AND WHEN YOU LOOK AT EXPRESSION 2124 01:21:38,680 --> 01:21:40,400 OF THE PROTEINS IN THE HEAD AND 2125 01:21:40,400 --> 01:21:42,840 NECK DATA SETS, THERE IS A GROUP 2126 01:21:42,840 --> 01:21:46,280 PROTEINS WHICH ARE HIGHLY 2127 01:21:46,280 --> 01:21:48,280 UPREGULATED SIGNIFICANTLY AND TO 2128 01:21:48,280 --> 01:21:52,440 A GREAT DEGREE THAT ARE ALL 2129 01:21:52,440 --> 01:21:55,200 HEPATITIS EAR AN SULFATE BINDING 2130 01:21:55,200 --> 01:21:57,160 PROTEINS THAT COULD BE BINDING 2131 01:21:57,160 --> 01:22:00,680 BY THE REAC IV THERAPY OF THE 2132 01:22:00,680 --> 01:22:00,960 SULFS. 2133 01:22:00,960 --> 01:22:02,440 IN FACT, SULF 1 IS 1 OF THEM. 2134 01:22:02,440 --> 01:22:03,520 SOPHISTICATEDY THERE'S A SET OF 2135 01:22:03,520 --> 01:22:05,760 PROTEINS WHICH ARE QUITE 2136 01:22:05,760 --> 01:22:07,880 COMMONLY DERIVED FROM CANCER 2137 01:22:07,880 --> 01:22:09,040 ASSOCIATED FIBRO BLASTS, THERE 2138 01:22:09,040 --> 01:22:12,640 ARE SUPPLIED TO THE TUMORS BY 2139 01:22:12,640 --> 01:22:15,720 THAT CELL TYPE AND THAT ARE 2140 01:22:15,720 --> 01:22:17,280 REGULATED IN QUITE IMPACTFUL 2141 01:22:17,280 --> 01:22:25,080 WAYS BY THAT SULF 1 ENZYME AND 2142 01:22:25,080 --> 01:22:26,720 BASED ON THAT WE BRO POSED THIS 2143 01:22:26,720 --> 01:22:28,120 MODEL IN WHAT HAPPENS IN THE 2144 01:22:28,120 --> 01:22:32,360 HEAD AND NECK TUMOR TISSUES 2145 01:22:32,360 --> 01:22:34,440 WHERE THE SULF 1 IS SUPPLIED BY 2146 01:22:34,440 --> 01:22:37,840 THE FIBRO BLAST, THAT'S ITS JOB, 2147 01:22:37,840 --> 01:22:39,640 THE SULF 2 THAT COMES FROM TUMOR 2148 01:22:39,640 --> 01:22:40,720 CELLS WILL BE MODIFIED 2149 01:22:40,720 --> 01:22:41,880 DIFFERENTLY AND WILL HAVE 2150 01:22:41,880 --> 01:22:44,720 SOMEWHAT DIFFERENT TARGET ANDS 2151 01:22:44,720 --> 01:22:47,280 ACTIVITIES AND JOINTLY THEY EDIT 2152 01:22:47,280 --> 01:22:48,320 THE EXTRA CELLULAR MATRIX IN 2153 01:22:48,320 --> 01:22:51,640 SUCH WAYS THAT PRACTICE PLOATS 2154 01:22:51,640 --> 01:22:57,280 TUMOR INVASION AND IS CONNECTED 2155 01:22:57,280 --> 01:23:00,840 TO MISREGULATED IMMUNE RESPONSES 2156 01:23:00,840 --> 01:23:04,680 IN THE TUMORS, TUMOR 2157 01:23:04,680 --> 01:23:05,000 ENVIRONMENT. 2158 01:23:05,000 --> 01:23:08,560 SO I SHOWED YOU THAT THE SULFS 2159 01:23:08,560 --> 01:23:09,840 ARE UPREGULATED QUITE COMMONLY 2160 01:23:09,840 --> 01:23:11,000 AND CONSISTENTLY IN THE HEAD AND 2161 01:23:11,000 --> 01:23:14,080 NECK TUMORS THAT THE SULF 1 2162 01:23:14,080 --> 01:23:16,680 COMES FROM THE CAFs AND THEY 2163 01:23:16,680 --> 01:23:18,480 REGULATE MANY PATHWAYS. 2164 01:23:18,480 --> 01:23:20,680 THAT AT THIS POINT, WE GET 2165 01:23:20,680 --> 01:23:23,480 INVARIABLY ASKED BY VIEWERS OR 2166 01:23:23,480 --> 01:23:26,040 COLLEAGUES, WHAT IS THE PATHWAY 2167 01:23:26,040 --> 01:23:28,560 THAT IS IMPORTANT IN THIS CASE. 2168 01:23:28,560 --> 01:23:30,480 AND I THINK THAT IT'S ACTUALLY, 2169 01:23:30,480 --> 01:23:35,080 YOU KNOW A LITTLE BIT OF AN 2170 01:23:35,080 --> 01:23:35,680 OVERLIMP LIAISONIFICATION OF 2171 01:23:35,680 --> 01:23:39,360 THAT PROBLEM, I DON'T THINK THAT 2172 01:23:39,360 --> 01:23:40,560 THOSE ROUGHLY 600 INTERACTIONS 2173 01:23:40,560 --> 01:23:42,240 REGULATED BY THESE INTERACTIONS 2174 01:23:42,240 --> 01:23:44,080 CAN BE TRANSLATED INTO 1 SINGLE 2175 01:23:44,080 --> 01:23:47,160 EVENT THAT IS IMPORTANT; WE HAVE 2176 01:23:47,160 --> 01:23:51,240 HERE INTERACTION OF MANY CELL 2177 01:23:51,240 --> 01:23:53,800 TYPES WITH MATRIX AND WITH THOSE 2178 01:23:53,800 --> 01:23:55,480 CELLS AND DEPENDING ON WHICH 2179 01:23:55,480 --> 01:23:59,880 STAGE OF THE PROGRESSION OF THE 2180 01:23:59,880 --> 01:24:02,120 TUMOR, WE ARE AT AND DEPENDING 2181 01:24:02,120 --> 01:24:06,480 ON THE SPECIFIC PATIENT CONTEXT, 2182 01:24:06,480 --> 01:24:08,000 THIS MAY DIFFER, BUT WHAT DOES 2183 01:24:08,000 --> 01:24:09,840 PROBABLY HAPPEN IS THAT THE 2184 01:24:09,840 --> 01:24:12,880 SULFs BECOME SORT OF A HELP OF 2185 01:24:12,880 --> 01:24:14,320 COMMON REGULATORY EVENTS THAT 2186 01:24:14,320 --> 01:24:18,520 TRANSLATE INTO THE SURVIVAL 2187 01:24:18,520 --> 01:24:19,880 [INDISCERNIBLE]. 2188 01:24:19,880 --> 01:24:22,800 AND THERE WE NOW STARTED USING 2189 01:24:22,800 --> 01:24:25,120 TUMOR BIOLOGY MODELS TO CAPTURE 2190 01:24:25,120 --> 01:24:28,240 THIS COMPLEX SET OF INTERACTIONS 2191 01:24:28,240 --> 01:24:30,280 AND WE STARTED LOOKING ACTUALLY 2192 01:24:30,280 --> 01:24:31,720 AT WHOLE CULTURES OF THE TUMOR 2193 01:24:31,720 --> 01:24:37,080 CELLS WITH THE CANCER ASSOCIATED 2194 01:24:37,080 --> 01:24:39,400 FIBRO BLASTS IN [INDISCERNIBLE] 2195 01:24:39,400 --> 01:24:39,840 MODELS. 2196 01:24:39,840 --> 01:24:42,080 THOSE ARE NICE MODELS WHERE WE 2197 01:24:42,080 --> 01:24:47,880 MIX 6000 CANCER CELLS EMBEDDED 2198 01:24:47,880 --> 01:24:50,840 IN MATRIGEL AND LOOK AT THEIR 2199 01:24:50,840 --> 01:24:54,360 PROGRESSION OR INCREASE OVER 5 2200 01:24:54,360 --> 01:24:55,080 DAYS. 2201 01:24:55,080 --> 01:24:58,160 THE CELLS ARE FLUORESCENTLY 2202 01:24:58,160 --> 01:24:59,360 LABELINGED, THEY FORM THOSE 2203 01:24:59,360 --> 01:25:00,680 SPHEROID STRUCTURES AND IN THE 2204 01:25:00,680 --> 01:25:03,520 CULTURE OF THE SKC35 HEAD AND 2205 01:25:03,520 --> 01:25:05,800 NECK CELL CANCER LINE ALONE OVER 2206 01:25:05,800 --> 01:25:08,440 3 DAYS YOU CAN SEE THEY DON'T 2207 01:25:08,440 --> 01:25:09,480 INCREASE, THEY ACTUALLY SHRINK A 2208 01:25:09,480 --> 01:25:12,880 LITTLE BIT BECAUSE THE SPHEROID 2209 01:25:12,880 --> 01:25:15,760 IS SOMEWHAT LOOSE IN DAY 1 AND 2210 01:25:15,760 --> 01:25:21,120 IN THE CONTEXT OF CO-CULTURES 2211 01:25:21,120 --> 01:25:22,440 WHERE WE ADD 300 CANCER 2212 01:25:22,440 --> 01:25:24,000 ASSOCIATED FIBRO BLASTS AND 3000 2213 01:25:24,000 --> 01:25:28,000 TUMOR CELLS, THERE IS A QUITE 2214 01:25:28,000 --> 01:25:32,000 DISTINCT PROLIFERATION OF THAT 2215 01:25:32,000 --> 01:25:34,080 STRUCTURE, CO CULTURE, INCLUDING 2216 01:25:34,080 --> 01:25:35,800 INCLUSION INTO THE MATRIGEL, SO 2217 01:25:35,800 --> 01:25:37,040 CAN YOU SEE HOW DIFFERENT THE 2218 01:25:37,040 --> 01:25:38,680 FINE O TYPE IS WHEN YOU CULTURE 2219 01:25:38,680 --> 01:25:40,560 THE CELLS ISSUES THE CANCER 2220 01:25:40,560 --> 01:25:42,040 CELLS,A LONE OR ADD THE FIBRO 2221 01:25:42,040 --> 01:25:54,680 BLAST INTO THE PICTURE. 2222 01:25:54,680 --> 01:25:56,840 AND THIS THAT WE WANT TO EXPAND 2223 01:25:56,840 --> 01:26:01,560 S&P ACTUALLY THE FACT THAT WHEN 2224 01:26:01,560 --> 01:26:03,080 WE KNOCK OUT THE TOOLS IN THE 2225 01:26:03,080 --> 01:26:06,040 CANCER CELL AND WHEN WE KNOCK 2226 01:26:06,040 --> 01:26:11,640 OUT 1 IN THE CANCER ASSOCIATED 2227 01:26:11,640 --> 01:26:16,520 FIEB ON BLASTS IS INCREASED AS I 2228 01:26:16,520 --> 01:26:18,280 SHOWED BEFORE BUT THE KNOCK OUT 2229 01:26:18,280 --> 01:26:30,560 CELLS NO LONGER STIMULATE EACH 2230 01:26:30,560 --> 01:26:32,880 OTHER. 2231 01:26:32,880 --> 01:26:37,040 SO I DO FIND THAT REALLY 2232 01:26:37,040 --> 01:26:38,680 INTERESTING, IN CONTEXT OF OTHER 2233 01:26:38,680 --> 01:26:41,120 TUMORS IN ANALYSIS OF THE CELL 2234 01:26:41,120 --> 01:26:43,840 LINES OVERALL IN THE CANCER CELL 2235 01:26:43,840 --> 01:26:45,560 LINE ENCYCLOPEDIA THAT WAS QUITE 2236 01:26:45,560 --> 01:26:47,240 NICELY THAT SULF 1 AND SULF 2 2237 01:26:47,240 --> 01:26:47,880 STORAGE. 2238 01:26:47,880 --> 01:26:54,800 IF YOU LOOK ACROSS ALL THE 2239 01:26:54,800 --> 01:26:56,960 TUMORS THEY EXPRESS SULF 1 BUT 2240 01:26:56,960 --> 01:26:58,480 MUCH MORE THAN FIBRO BLASTS, 2241 01:26:58,480 --> 01:26:59,880 THEY STAND OUT AS SOMETHING AS 2242 01:26:59,880 --> 01:27:01,600 AN IMPORTANT SOURCE OF THAT 2243 01:27:01,600 --> 01:27:06,000 INZEME, IF YOU LOOK AT SULF 2, 2244 01:27:06,000 --> 01:27:08,520 THAT'S NOT THE CASELET SULF 2 2245 01:27:08,520 --> 01:27:10,840 FIBRO BLASTS SOURCE IS SOMEWHERE 2246 01:27:10,840 --> 01:27:18,920 HERE IN THIS LEGION EMPLOY 2247 01:27:18,920 --> 01:27:29,400 FRESES IN HEAD AND NECK AND CELL 2248 01:27:29,400 --> 01:27:32,480 LINES THAT THAT PROVIDE A 2249 01:27:32,480 --> 01:27:32,680 SOURCE. 2250 01:27:32,680 --> 01:27:34,080 >> RADO, WE ARE A BIT OVER TIME, 2251 01:27:34,080 --> 01:27:35,520 CAN YOU GO FOR THE END. 2252 01:27:35,520 --> 01:27:36,120 >> YEAH. 2253 01:27:36,120 --> 01:27:37,720 SO HERE'S THE LAST SLIDE AND 2254 01:27:37,720 --> 01:27:39,360 THAT TELLS YOU THAT WHEN WE LOOK 2255 01:27:39,360 --> 01:27:45,680 AT EXPRESSION AND SURVIVAL OF 2256 01:27:45,680 --> 01:27:47,480 THOSE AND IT SHOWS SURVIVAL IN 2257 01:27:47,480 --> 01:27:49,200 DIFFERENT CANCERS AND MAYBE 2258 01:27:49,200 --> 01:27:51,160 THAT'S SUPPLIED BY THE CANCER 2259 01:27:51,160 --> 01:27:52,680 ASSOCIATED FIBRO BLAST IS THE 2260 01:27:52,680 --> 01:27:53,680 COMMON DENOMINATOR THERE IN 2261 01:27:53,680 --> 01:28:08,080 CONTEXT OF THE SULF 1. 2262 01:28:08,080 --> 01:28:09,520 SO I WANT TO THANK THE PEOPLE IN 2263 01:28:09,520 --> 01:28:11,560 MY LAB WHO DID THE WORK ON THIS, 2264 01:28:11,560 --> 01:28:13,080 THEY CONTINUE TO DO THE CO 2265 01:28:13,080 --> 01:28:17,120 CULTURES AND EXPRESSIONS, SO IN 2266 01:28:17,120 --> 01:28:33,080 THESE HEX CELLS AND I WANT TO 2267 01:28:33,080 --> 01:28:34,360 THANK ALSO COLLABORATORS AND A 2268 01:28:34,360 --> 01:28:37,720 NUMBER OF FUNDING SOURCES AND 2269 01:28:37,720 --> 01:28:38,320 ORGANIZATIONS. 2270 01:28:38,320 --> 01:28:40,800 >> THANK YOU VERY MUCH RADO, 2271 01:28:40,800 --> 01:28:41,520 THAT WAS REALLY, REALLY 2272 01:28:41,520 --> 01:28:42,280 INTERESTING, WE HAVE SOME 2273 01:28:42,280 --> 01:28:44,080 QUESTIONS IF YOU HAVE OTHER 2274 01:28:44,080 --> 01:28:45,760 QUESTIONS FOR RADO, WE WILL TAKE 2275 01:28:45,760 --> 01:28:49,560 THOSE AFTER OUR NEXT 2 TALKS. 2276 01:28:49,560 --> 01:28:52,680 SO I WOULD LIKE TO INTRODUCE OUR 2277 01:28:52,680 --> 01:28:59,440 NEXT SPEAKER DR. SRIRAM, 2278 01:28:59,440 --> 01:29:00,240 NEELAMEGHAM, STATE OF UNIVERSITY 2279 01:29:00,240 --> 01:29:03,160 OF NEW YORK BUFFALO, A 2280 01:29:03,160 --> 01:29:07,520 PAN-CANCER ANALYSIS OF GLYCO 2281 01:29:07,520 --> 01:29:12,200 GENE DISREGULATION. 2282 01:29:12,200 --> 01:29:12,600 SRIRIAM, ARE YOU-- 2283 01:29:12,600 --> 01:29:13,840 >> YOU CAN SEE MY SCREEN RIGHT? 2284 01:29:13,840 --> 01:29:24,760 >> WE CAN SEE YOU BUT NOT YOUR 2285 01:29:24,760 --> 01:29:26,240 SCREEN YET. 2286 01:29:26,240 --> 01:29:27,680 >> THAT'S YOU RUNNINGOT BEACH I 2287 01:29:27,680 --> 01:29:28,280 GUESS. 2288 01:29:28,280 --> 01:29:29,440 >> THAT'S ME WISHING I WAS 2289 01:29:29,440 --> 01:29:30,960 RUNNING ON THE BEACH ESPECIALLY 2290 01:29:30,960 --> 01:29:32,120 SINCE IT'S SNOWING HERE. 2291 01:29:32,120 --> 01:29:33,280 IS THIS GOOD FOR YOU. 2292 01:29:33,280 --> 01:29:34,240 >> THANK YOU VERY MUCH. 2293 01:29:34,240 --> 01:29:37,240 >> YEAH, WELL IT'S A PLEASURE TO 2294 01:29:37,240 --> 01:29:37,600 PRESENT. 2295 01:29:37,600 --> 01:29:40,240 I WANT TO THANK MIKE AND ROGER 2296 01:29:40,240 --> 01:29:41,680 FOR PUTTING THIS SYMPOSIUM 2297 01:29:41,680 --> 01:29:42,720 TOGETHER, I ENJOYED MANY OF THE 2298 01:29:42,720 --> 01:29:43,960 TALKS WHAT I WILL TALK ABOUT 2299 01:29:43,960 --> 01:29:45,800 TODAY IS A COUPLE THINGS WE'VE 2300 01:29:45,800 --> 01:29:46,840 BEEN WORKING ON IN THE GROUP. 2301 01:29:46,840 --> 01:29:49,360 ONE OF THEM IS ABOUT AN ONTOLOGY 2302 01:29:49,360 --> 01:29:51,000 TO DESCRIBE GLYCO ENZYMES 2303 01:29:51,000 --> 01:29:52,000 PARTICULARLY WITH FOCUS ON 2304 01:29:52,000 --> 01:29:52,840 HUMANS AND THE SECOND IS HOW 2305 01:29:52,840 --> 01:29:54,960 THIS CAN BE APPLIED TO LOOKING 2306 01:29:54,960 --> 01:29:56,600 AT TCB GATTA AND THE CANCER 2307 01:29:56,600 --> 01:30:04,320 GENOME IS SO THIS IS WORK DONE 2308 01:30:04,320 --> 01:30:06,320 LARGELY BY TED GROTH, AND COLLAB 2309 01:30:06,320 --> 01:30:07,520 IDENTITY ARES FROM THE ONTOLOGY 2310 01:30:07,520 --> 01:30:12,680 COMMUNITY THAT YOU HEARD FROM 2311 01:30:12,680 --> 01:30:13,840 TODAY AND THE COLLEAGUES OF 2312 01:30:13,840 --> 01:30:14,080 MINE. 2313 01:30:14,080 --> 01:30:17,760 THE WORK WE HAVE IS KINDLY 2314 01:30:17,760 --> 01:30:19,240 SUPPORTED BY NHLBI ASHES 2315 01:30:19,240 --> 01:30:19,920 CYSTANCE TECHNOLOGY PROGRAM 2316 01:30:19,920 --> 01:30:21,560 WHICH IS THE BREAD AND BUTTER 2317 01:30:21,560 --> 01:30:23,680 FOR THE LAB AND THE SUPPORT IS 2318 01:30:23,680 --> 01:30:25,320 APPRECIATED AND IT HELPS GET THE 2319 01:30:25,320 --> 01:30:26,600 ONTOLOGY WORK DONE AND SOME OF 2320 01:30:26,600 --> 01:30:29,880 THE CANCER WORK IS SUPPORTED BY 2321 01:30:29,880 --> 01:30:32,520 SUBCONTRACT AND FROM 2322 01:30:32,520 --> 01:30:34,600 [INDISCERNIBLE] AND IN TERMS OF 2323 01:30:34,600 --> 01:30:35,480 GLYCOSYLATION, IT'S A PROESES IS 2324 01:30:35,480 --> 01:30:37,600 BY WHICH YOU HAVE COMPLEX 2325 01:30:37,600 --> 01:30:39,280 CARBOHYDRATES AND THIS CAN TAKE 2326 01:30:39,280 --> 01:30:40,640 PLACE IN MULTIPLE SCAF OLDER 2327 01:30:40,640 --> 01:30:43,520 PEOPLE WOULDS ON AND LIPIDS 2328 01:30:43,520 --> 01:30:48,280 ONENDING GLUE MARIOUS CANS AND 2329 01:30:48,280 --> 01:30:49,920 ALL GLYCANS OF ALL TYPES AND 2330 01:30:49,920 --> 01:30:51,480 THESE ARE SORT OF 2331 01:30:51,480 --> 01:30:52,840 FUNCTIONALLIZED AND MADE BY 2332 01:30:52,840 --> 01:30:55,160 ENZYMES WHICH WE CALL GLYCO 2333 01:30:55,160 --> 01:30:56,640 ENZYMES AND THESE GLYCO ENZYMES 2334 01:30:56,640 --> 01:30:57,920 IN OUR DEFINITION DON'T JUST 2335 01:30:57,920 --> 01:31:00,240 INCLUDE THE ENZYMES THAT HAD THE 2336 01:31:00,240 --> 01:31:01,440 CAT LATTIC ACTIVITY BUT THEY 2337 01:31:01,440 --> 01:31:03,480 INCLUDE ENZYMES THAT ARE 2338 01:31:03,480 --> 01:31:05,800 METABOLT-ONTIC IN NATURE, HAVE 2339 01:31:05,800 --> 01:31:06,720 TRANSPORT PROCESSES, STRUCTURAL 2340 01:31:06,720 --> 01:31:07,480 RULES AND CO FACTOR FUNCTIONS 2341 01:31:07,480 --> 01:31:10,160 AND WHEN YOU STARTED LOOKING AT 2342 01:31:10,160 --> 01:31:11,400 YOU KNOW GLYCO GENE REGULATION, 2343 01:31:11,400 --> 01:31:13,960 WHAT WAS STRUCK WAS THERE WAS NO 2344 01:31:13,960 --> 01:31:15,640 ONTOLOGY ENZYMES IN A SYSTEMATIC 2345 01:31:15,640 --> 01:31:17,440 WAY IN A COMPLETE MANNER. 2346 01:31:17,440 --> 01:31:19,880 AND SO WE SET OUT TO SORT OF 2347 01:31:19,880 --> 01:31:21,840 START TO DEFINE WHAT THIS 2348 01:31:21,840 --> 01:31:23,240 ONTOLOGY IS AND WHAT WE DEFINED 2349 01:31:23,240 --> 01:31:27,120 SO FAR IS APPROXIMATE 286 HUGH 2350 01:31:27,120 --> 01:31:28,680 MAN GLIEM GLYCO ENZYMES THAT ARE 2351 01:31:28,680 --> 01:31:31,000 CURATE AND THESE ARE CLASSIFIED 2352 01:31:31,000 --> 01:31:33,040 INTO 134 MOLECULAR FUNCTIONS AND 2353 01:31:33,040 --> 01:31:34,840 134 BIOLOGICAL PROCESSES AND 2354 01:31:34,840 --> 01:31:35,400 MULTIPLE COMPARTMENTS, AND I 2355 01:31:35,400 --> 01:31:37,080 WILL SHOW YOU THIS IN A MINUTE. 2356 01:31:37,080 --> 01:31:38,920 THE REASON WE STARTED GET 2357 01:31:38,920 --> 01:31:40,680 INTERESTED IN THIS IS BECAUSE OF 2358 01:31:40,680 --> 01:31:42,040 THE LACK OF SYSTEMATIC 2359 01:31:42,040 --> 01:31:45,600 ORGANIZATION THAT WOULD HELP US 2360 01:31:45,600 --> 01:31:46,960 TO DO OVER PRESENTATION AND 2361 01:31:46,960 --> 01:31:47,360 ANALYSIS. 2362 01:31:47,360 --> 01:31:48,280 SOPHISTICATEDY MY LAB IS 2363 01:31:48,280 --> 01:31:49,120 INTERESTED IN CONNECTING THE 2364 01:31:49,120 --> 01:31:52,600 GENES IN THE CELL TO THE GLYCANS 2365 01:31:52,600 --> 01:31:59,760 THAT THEY WOULD PRODUCE AND FOR 2366 01:31:59,760 --> 01:32:02,960 THIS PARTICULAR PURPOSE WE AND 2367 01:32:02,960 --> 01:32:03,920 WE'RE WORKING WITH ROGER AND 2368 01:32:03,920 --> 01:32:08,480 MIKE IN GETTING THIS INTO THE 2369 01:32:08,480 --> 01:32:09,280 PROJECT PORTAL. 2370 01:32:09,280 --> 01:32:12,600 AND ALSO WE ARE USING THIS TO 2371 01:32:12,600 --> 01:32:13,960 SORT OF CREATE NETWORKS OF DPLI 2372 01:32:13,960 --> 01:32:14,680 COSALATION REACTION BECAUSE THIS 2373 01:32:14,680 --> 01:32:17,760 WOULD BE A NICE WAY IN WE COULD 2374 01:32:17,760 --> 01:32:18,600 OVERLAY EXPERIMENTAL DATA ON 2375 01:32:18,600 --> 01:32:20,120 TPHREU RACING COSALATION AND 2376 01:32:20,120 --> 01:32:21,240 STRUCTURE DATA ON TOP OF IT TO 2377 01:32:21,240 --> 01:32:32,240 GET MORE INSIGHT IN THE PROCESS. 2378 01:32:32,240 --> 01:32:38,240 AND THAT'S ARE CONNECTED TO 2379 01:32:38,240 --> 01:32:43,680 INFORMATION AVAILABLE AT UNIPROT 2380 01:32:43,680 --> 01:32:46,560 AND ENGL, SO ONCE IT'S CONNECTED 2381 01:32:46,560 --> 01:32:47,720 IT CONNECTED PRETTY MUCH 2382 01:32:47,720 --> 01:32:50,200 EVERYWHERE, SO WE ARE FOCUSED ON 2383 01:32:50,200 --> 01:32:51,600 PROCISELY WHAT THIS DOES IN 2384 01:32:51,600 --> 01:32:53,280 TERMS OF WHAT THEY REGULATE 2385 01:32:53,280 --> 01:32:57,240 BECAUSE IT WOULD BE A TERMINAL 2386 01:32:57,240 --> 01:32:58,280 GLYCOSYLATION AND GLYCOSYLATION 2387 01:32:58,280 --> 01:32:59,000 ADDITIONAL INFORMATION ABOUT 2388 01:32:59,000 --> 01:33:00,200 PATHWAYS TO ACT ON. 2389 01:33:00,200 --> 01:33:02,600 THIS IS RELATED TO THE GENE 2390 01:33:02,600 --> 01:33:03,760 ONTOLOGY SO NOW OUR GOAL 2391 01:33:03,760 --> 01:33:05,320 BASICALLY IN THE SHORT-TERM IS 2392 01:33:05,320 --> 01:33:07,720 TO SORT OF GET THIS ONTOLOGY 2393 01:33:07,720 --> 01:33:10,040 ACCEPTED AND SLOWLY MAKE OUR WAY 2394 01:33:10,040 --> 01:33:12,120 INTO THE GUEST INTEGRATED INTO 2395 01:33:12,120 --> 01:33:14,160 THE GENE ONTOLOGY, FOR EACH OF 2396 01:33:14,160 --> 01:33:15,720 THESE ENZYMES WE DEFINE ACTION 2397 01:33:15,720 --> 01:33:17,760 ROOTS WHICH WE WILL GO THROUGH 2398 01:33:17,760 --> 01:33:18,840 AND CONSTRAINTS, EVERYTHING IS 2399 01:33:18,840 --> 01:33:19,840 YELLOW IS OUR CONTRIBUTION AND 2400 01:33:19,840 --> 01:33:22,080 OUR GOAL IS NOT TO THE DUPLICATE 2401 01:33:22,080 --> 01:33:30,080 EFFORT BUT INTEGRATE INTO 2402 01:33:30,080 --> 01:33:30,520 EXISTING RESOURCES. 2403 01:33:30,520 --> 01:33:31,840 IF YOU WANT MORE INFORMATION, WE 2404 01:33:31,840 --> 01:33:33,920 HAVE A PAGE THAT DESCRIBES ALL 2405 01:33:33,920 --> 01:33:34,840 THESE IN DETAIL. 2406 01:33:34,840 --> 01:33:38,080 SO WE'VE TAKEN THESE GLYCO GENES 2407 01:33:38,080 --> 01:33:40,240 AND THESE ARE CLASSIFIED AND 2408 01:33:40,240 --> 01:33:42,640 OTHERS HAVE SYNTHESIS AND SOME 2409 01:33:42,640 --> 01:33:44,040 DO DEGRADATION OF OUR ENZYMES 2410 01:33:44,040 --> 01:33:47,000 AND IN TERMS OF PATHWAYS THAT I 2411 01:33:47,000 --> 01:33:49,000 HAVE DIVIDED THIS THAT CREATE 2412 01:33:49,000 --> 01:33:49,920 PATHWAYS ALONG ELONGATION AND 2413 01:33:49,920 --> 01:33:52,400 BRANCHING AND CAPPING AND THE 2414 01:33:52,400 --> 01:33:55,000 THESE ARE N-GLYCOSYLATION AND IN 2415 01:33:55,000 --> 01:33:57,880 THAT SUBCLASS OF SYNTHESIS AND 2416 01:33:57,880 --> 01:33:59,800 IN GLYCOSYLATION PROCESSING AND 2417 01:33:59,800 --> 01:34:01,600 ALL IN GLYCOSYLATION OF THE NECK 2418 01:34:01,600 --> 01:34:08,400 TYPE AND THE NECK TYPES BY 2419 01:34:08,400 --> 01:34:08,840 PATHWAYS. 2420 01:34:08,840 --> 01:34:10,720 AND AND THE SUGAR STRUCTURE IT 2421 01:34:10,720 --> 01:34:13,200 FOR THE SCAFFOLD AND FOLLOWING 2422 01:34:13,200 --> 01:34:20,440 THESE STRUCTURES WE INCLUDE 2423 01:34:20,440 --> 01:34:21,480 ENZYMES, DILACTENZYMES AND ALSO 2424 01:34:21,480 --> 01:34:23,240 AND THE CAPPING ENZYMES AND 2425 01:34:23,240 --> 01:34:25,080 SULFATIONS ARE A GOOD WHYED THAT 2426 01:34:25,080 --> 01:34:26,960 WE'VE TAKEN EVERY ENZYME AND 2427 01:34:26,960 --> 01:34:28,360 SAID WHICH PATHWAY DO THEY ACT 2428 01:34:28,360 --> 01:34:30,640 ON AND WHICH PART DO THEY ACT 2429 01:34:30,640 --> 01:34:30,840 ON? 2430 01:34:30,840 --> 01:34:32,680 I DON'T HAVE TIME TO GO THROUGH 2431 01:34:32,680 --> 01:34:34,760 THIS BUT WE'VE DONE A LOT OF THE 2432 01:34:34,760 --> 01:34:37,040 SAME THINGS AND OTHER TRANSFER 2433 01:34:37,040 --> 01:34:38,560 ACES, GLUE MARIOUS COSDACES 2434 01:34:38,560 --> 01:34:39,480 TRANSPORTS ET CETERA AND THE 2435 01:34:39,480 --> 01:34:41,600 NUMBERS HERE TELL YOU HOW MANY 2436 01:34:41,600 --> 01:34:44,640 OF THESE GENES HOW MANY ARE 2437 01:34:44,640 --> 01:34:45,480 MODIFYING ENZYMES, REGULATORS 2438 01:34:45,480 --> 01:34:46,920 AND, ET CETERA AND THE SAME 2439 01:34:46,920 --> 01:34:47,880 THING FOR COMPARTMENTS, THESE 2440 01:34:47,880 --> 01:34:51,000 HAVE BEEN CLASSIFIED IN THE ER, 2441 01:34:51,000 --> 01:34:52,760 GOLGY AND THE ADDITIONAL 2442 01:34:52,760 --> 01:34:55,680 COMPARTMENTS BASED ON SOME OF IT 2443 01:34:55,680 --> 01:34:56,840 AS MANUELLY CURATED ABOUT IA 2444 01:34:56,840 --> 01:34:58,920 LARGE PART OF IT AM CANS FROM 2445 01:34:58,920 --> 01:34:59,280 GENE ONTOLOGY. 2446 01:34:59,280 --> 01:35:00,120 SO AN IMPORTANT THING THAT WE 2447 01:35:00,120 --> 01:35:01,680 ARE TRYING TO GET DONE OVER HERE 2448 01:35:01,680 --> 01:35:03,760 IS SORT OF DEFINE, YOU KNOW HOW 2449 01:35:03,760 --> 01:35:06,680 DOES A GLOI COSALATION REACTION 2450 01:35:06,680 --> 01:35:08,240 AND WE'VE CREATED REACTION RULES 2451 01:35:08,240 --> 01:35:11,200 IN TERMS OF HOW TO DESCRIBE THIS 2452 01:35:11,200 --> 01:35:12,600 WHEN YOU HAVE GLYCOSYLATION 2453 01:35:12,600 --> 01:35:13,800 TAKING PLACE IN THE HUMAN 2454 01:35:13,800 --> 01:35:16,040 SYSTEM, THERE ARE ESSENTIALLY 5 2455 01:35:16,040 --> 01:35:18,400 TYPES OF REACTIONS THAT OCCUR. 2456 01:35:18,400 --> 01:35:21,400 IT CAN BE ADDITIONAL REACTIONS 2457 01:35:21,400 --> 01:35:24,560 WITH THE SALIC ACID IS ATTACHED 2458 01:35:24,560 --> 01:35:27,040 TO A GLUE MARIOUS COSMEAN CHAIN, 2459 01:35:27,040 --> 01:35:28,720 A BRACKET IS SHOWN BY THE A MARK 2460 01:35:28,720 --> 01:35:30,920 AND FLUICOSE IS MOVE FRIDAY THIS 2461 01:35:30,920 --> 01:35:34,640 CHAIN, A REVERSIBLE REACTION 2462 01:35:34,640 --> 01:35:37,600 WHERE YOU CAN HAVE GLUCOSE 1 2463 01:35:37,600 --> 01:35:38,240 PHOSPHATE AND GLUCOSE 6 2464 01:35:38,240 --> 01:35:40,920 PHOSPHATE AND CAN YOU HAVE A 2465 01:35:40,920 --> 01:35:41,760 SUBSIDIARY CONSTITUTION REACT 2466 01:35:41,760 --> 01:35:55,080 AND TO 2467 01:35:55,080 --> 01:35:56,400 HYULU RONNIC AND THOSE ENZYMES 2468 01:35:56,400 --> 01:35:58,040 DON'T GIST ACT ON 1 PARTICULAR 2469 01:35:58,040 --> 01:35:59,560 SUBSTRATE, THAT CAN ACT ON 2470 01:35:59,560 --> 01:36:01,920 MULTIPLE TYPES OF SUBSTRATE AND 2471 01:36:01,920 --> 01:36:03,080 THERE'S SUBSTRATE AMBIG WITY 2472 01:36:03,080 --> 01:36:04,480 WHICH IS USING THE QUESTION MARK 2473 01:36:04,480 --> 01:36:06,120 IF THE LINKAGE IS UNCERTAINTY, 2474 01:36:06,120 --> 01:36:07,880 IF ALL THE STRUCTURE CANS APPEAR 2475 01:36:07,880 --> 01:36:09,560 FOR EXAMPLE, AND THIS IS THE 2476 01:36:09,560 --> 01:36:15,760 CASE COULD BE A SUBSTRATE BUT 2477 01:36:15,760 --> 01:36:18,280 IT'S NOT NECESSARY THEN IF YOU 2478 01:36:18,280 --> 01:36:20,040 HAVE AN INTERNAL SITE, THEN WE 2479 01:36:20,040 --> 01:36:22,120 SEE THE SITE WHERE WE HAVE A 2480 01:36:22,120 --> 01:36:23,200 CHEMICAL REACTION AND THAT'S THE 2481 01:36:23,200 --> 01:36:24,880 3 DOT AND THERE'S A BRANCH IN 2482 01:36:24,880 --> 01:36:26,280 THE MIDDLE, THEY WILL PRODUCE 2483 01:36:26,280 --> 01:36:27,840 THE DOT LIKE THIS AND IF THE 2484 01:36:27,840 --> 01:36:30,040 REACTION TAKES PLACE IN THESE 2485 01:36:30,040 --> 01:36:32,480 PARTICULAR DOMAINS, THEN WE 2486 01:36:32,480 --> 01:36:33,080 BEDETECTION ANTIBODY THE TEXT. 2487 01:36:33,080 --> 01:36:37,600 SIMILAR TO THIS, THERE ARE 2488 01:36:37,600 --> 01:36:38,520 PRIMARY CLASSIFICATIONS OF OF 2489 01:36:38,520 --> 01:36:41,680 THOSE ENZYMES AND THESE ARE 2490 01:36:41,680 --> 01:36:42,960 BASED SO AN ENZYME MIGHT REQUIRE 2491 01:36:42,960 --> 01:36:47,320 THIS AND THIS WITH THE SUBSTRATE 2492 01:36:47,320 --> 01:36:48,680 IT'S REACTING WITH OR IT'S A 2493 01:36:48,680 --> 01:36:51,480 POSITION WHERE IT'S A 2-3, 6 AND 2494 01:36:51,480 --> 01:36:52,680 THE ENZYME DIDN'T CARE ABOUT IT 2495 01:36:52,680 --> 01:36:56,200 SO THESE RULES OF SUBSTRATE 2496 01:36:56,200 --> 01:36:57,480 AMBIG WIT SKPE BAKUGAN 2497 01:36:57,480 --> 01:36:58,760 DISCRIMINATION DESCRIBE LAWN 2498 01:36:58,760 --> 01:36:59,760 MOWER AN ENZYME SCRUTINIZED AND 2499 01:36:59,760 --> 01:37:02,280 I THINK IT HAS IMPLICATIONS NOT 2500 01:37:02,280 --> 01:37:04,080 ONLY FOR ENZYMATIC REACTION AND 2501 01:37:04,080 --> 01:37:06,160 DESCRIPTION OF ENZYMES BUT ALSO 2502 01:37:06,160 --> 01:37:07,600 DESCRIBING IN GENERAL HOW 2503 01:37:07,600 --> 01:37:10,160 MOLECULAR GENERATION OF PROTEINS 2504 01:37:10,160 --> 01:37:11,640 AND CARBOHYDRATES TAKE PLACE IN 2505 01:37:11,640 --> 01:37:13,280 THE CONTEXT OF LECTUREINS THAT 2506 01:37:13,280 --> 01:37:13,560 TAKE PLACE. 2507 01:37:13,560 --> 01:37:15,200 WHAT WE TRY TO DO IS ESSENTIA 2508 01:37:15,200 --> 01:37:17,080 WILY TAKE MANY OF THE RULES THAT 2509 01:37:17,080 --> 01:37:19,320 WERE PROAFIOUSLY DESCRIBED FOR 2510 01:37:19,320 --> 01:37:19,960 DESCRIBING THESE GLYCOSYLATIONY 2511 01:37:19,960 --> 01:37:22,080 ACTION IN TERMS OF SYMBOLS THAT 2512 01:37:22,080 --> 01:37:25,840 ARE USED BUT WE TEND THEM TO 2513 01:37:25,840 --> 01:37:30,520 LOOK AT IPAD INSTRUCTIONS YOU 2514 01:37:30,520 --> 01:37:32,080 DON'T NEED A COMPUTER AND IT'S 2515 01:37:32,080 --> 01:37:33,160 INTUITIVE ININATE AND YOU WE TRY 2516 01:37:33,160 --> 01:37:34,320 TO REDUCE THE NUMBER OF SIM BOOM 2517 01:37:34,320 --> 01:37:37,560 BOOM BOOM BOOMS TO THE BARE 2518 01:37:37,560 --> 01:37:40,280 MINIMUM, BUT IT SHOULD BE USEFUL 2519 01:37:40,280 --> 01:37:41,520 FOR LECTUREIN AND LOOKINGA THE 2520 01:37:41,520 --> 01:37:42,800 DPLI KAN--KANA AREAS AND OTHER 2521 01:37:42,800 --> 01:37:44,080 INFORMATION THAT BE RESORTED. 2522 01:37:44,080 --> 01:37:47,000 AND I THINK IF YOU CAN DECIDE ON 2523 01:37:47,000 --> 01:37:48,520 A COMMON FORMAT FOR DESCRIBING 2524 01:37:48,520 --> 01:37:51,200 THESE STRUCTURES, THEN IT CAN 2525 01:37:51,200 --> 01:37:52,040 MAKE SOFTWARES INTEROPERABLE 2526 01:37:52,040 --> 01:37:52,920 WHICH GOOD FOR US. 2527 01:37:52,920 --> 01:37:57,080 SO ONCE YOU JUST FIND THESE 2528 01:37:57,080 --> 01:37:57,760 PARTICULAR ENZYMES, IT'S 2529 01:37:57,760 --> 01:37:58,720 POSSIBLE TO LOOK AT WHAT THESE 2530 01:37:58,720 --> 01:38:00,520 ARE DOING IN A PATHWAY, IN THIS 2531 01:38:00,520 --> 01:38:02,320 PARTICULAR NATURE, AND YOU 2532 01:38:02,320 --> 01:38:03,600 CAN--STARTING WITH THE INITIAL 2533 01:38:03,600 --> 01:38:05,920 MOLECULE AND GIVEN CERTAIN 2534 01:38:05,920 --> 01:38:07,000 ENZYMES THE ONTOLOGY ALLOWS TO 2535 01:38:07,000 --> 01:38:08,600 YOU CREATE PATHWAYS AND SMALL 2536 01:38:08,600 --> 01:38:10,320 DESCRIPTION AS SHOWN OVER HERE. 2537 01:38:10,320 --> 01:38:12,080 MORE IMPORTANT WHAT WE REALLY 2538 01:38:12,080 --> 01:38:15,040 INTERESTED IN ONTOLOGY IS SORT 2539 01:38:15,040 --> 01:38:17,320 OF THE LINK GENE EXPRESSION DATA 2540 01:38:17,320 --> 01:38:18,480 TO GLYCAN STRUCTURE DATA SO THIS 2541 01:38:18,480 --> 01:38:21,120 IS AN EXAMPLE OF A BREAST CANCER 2542 01:38:21,120 --> 01:38:23,120 SYSTEM WHERE WE BASICALLY TAKEN 2543 01:38:23,120 --> 01:38:27,320 HER TBO FROM THE TCGA DATA SET 2544 01:38:27,320 --> 01:38:29,880 AND DOING OVERPRESENTATION 2545 01:38:29,880 --> 01:38:31,600 ANALYSIS, OVERPRESENTATION 2546 01:38:31,600 --> 01:38:32,840 ANALYSIS SAYS IF I HAVE THE 2547 01:38:32,840 --> 01:38:34,280 ENTIRE GENOME WITH ALL THE 2548 01:38:34,280 --> 01:38:36,320 JEERNS INSIDE IT, WHICH OF THESE 2549 01:38:36,320 --> 01:38:37,680 PATHWAYS OR WHICH OF THESE GLYCO 2550 01:38:37,680 --> 01:38:38,840 GENES ARE GOING UP IN THIS 2551 01:38:38,840 --> 01:38:39,880 PARTICULAR SYSTEM OR GOING DOWN 2552 01:38:39,880 --> 01:38:42,360 IN A PARTICULAR SYSTEM OR 2553 01:38:42,360 --> 01:38:44,360 DIFFERENTIALLY ALTERED AND WE 2554 01:38:44,360 --> 01:38:48,360 COMPARED THOSE ON TO THE CANNED 2555 01:38:48,360 --> 01:38:50,040 WHAT WITH THE GENE ONTOLOGY AND 2556 01:38:50,040 --> 01:38:51,800 REACT OHM AND WHAT I TRY TO 2557 01:38:51,800 --> 01:38:53,680 POINT OUT IS THAT THE GLYCO 2558 01:38:53,680 --> 01:38:55,280 ENZYME GIVES YOU A MUCH MORE 2559 01:38:55,280 --> 01:38:56,680 REFINED UNDERSTANDING OF 2560 01:38:56,680 --> 01:38:58,640 PATHWAYS THAT ARE DISREGULATED 2561 01:38:58,640 --> 01:38:59,840 DURING CANCER COMPARED TO THESE 2562 01:38:59,840 --> 01:39:00,880 OTHER ONTOLOGYS, FOR EXAMPLE IN 2563 01:39:00,880 --> 01:39:04,040 THIS CASE, WHAT'S GOING UP IS 2564 01:39:04,040 --> 01:39:04,880 NDPLI COSALATION PATHWAY AND 2565 01:39:04,880 --> 01:39:06,520 WHAT THIS TELLS YOU IS THAT THE 2566 01:39:06,520 --> 01:39:07,840 PATHWAY IS WHAT GOES UP AND NONE 2567 01:39:07,840 --> 01:39:10,040 OF THESE OTHER PATHWAYS ACTUALLY 2568 01:39:10,040 --> 01:39:10,280 CHANGE. 2569 01:39:10,280 --> 01:39:11,880 WE SHOULD PLOT THE ENZYME 2570 01:39:11,880 --> 01:39:14,560 CHANGES IN THE FULL CHANGES OF 2571 01:39:14,560 --> 01:39:15,560 BREAST CANCER VERSUS NORMAL, 2572 01:39:15,560 --> 01:39:16,960 WHAT YOU SEE IS THAT MOST OF 2573 01:39:16,960 --> 01:39:17,960 THESE ENZYMES THAT ARE SHOWN 2574 01:39:17,960 --> 01:39:20,960 HERE IN THE PATHWAY ARE ACTUALLY 2575 01:39:20,960 --> 01:39:22,720 INCREASED ALONG WITH SOME 2576 01:39:22,720 --> 01:39:24,480 [INDISCERNIBLE] THAT ARE STATIST 2577 01:39:24,480 --> 01:39:26,080 LIKE SIGNIFICANT INCREASED IF 2578 01:39:26,080 --> 01:39:38,160 YOU SEE THE AND SEE THIS 2579 01:39:38,160 --> 01:39:39,680 PARTICULARLY AND THIS IS A 2580 01:39:39,680 --> 01:39:40,960 SUBSTRATE FOR DPLI COSALATION 2581 01:39:40,960 --> 01:39:42,480 AND IF YOU GO AND TRIM DOWN AND 2582 01:39:42,480 --> 01:39:45,840 LOOK AT THE LIST OF DREAMS IN 2583 01:39:45,840 --> 01:39:46,680 THE GLYCOSYLATION PATHWAYS THEY 2584 01:39:46,680 --> 01:39:48,560 INCLUDE THINGS THAT ARE IN THE 2585 01:39:48,560 --> 01:39:54,720 CORE BY SYNTHETIC PATHWAY BUT 2586 01:39:54,720 --> 01:39:55,680 INCLUDE GENES LIKE AND 2587 01:39:55,680 --> 01:39:58,560 NECESSARILY FOR THE TYPE OF 2588 01:39:58,560 --> 01:39:59,600 UNDERSTANDING THAT AND WE NEED. 2589 01:39:59,600 --> 01:40:02,120 SO YOU CAN DO THIS AGAINST 2590 01:40:02,120 --> 01:40:04,800 ANTIGENOME OR CAN YOU DO IT FOR 2591 01:40:04,800 --> 01:40:06,360 SPECIFIC GLYCO JEERNS SO NOW 2592 01:40:06,360 --> 01:40:09,360 INSTEAD OF LOOKING AT THE WHOLE 2593 01:40:09,360 --> 01:40:11,120 GLUE MARIOUS COAND IN THE GENES 2594 01:40:11,120 --> 01:40:13,760 WHICH 1S ARE DISREG AUTOLOGY 2595 01:40:13,760 --> 01:40:14,960 WIDE RESPECT TO OTHER GLYCO 2596 01:40:14,960 --> 01:40:17,680 GENES IN THE SYSTEM AND WHAT 2597 01:40:17,680 --> 01:40:18,920 THIS PREDICTS IS THAT ALL 2598 01:40:18,920 --> 01:40:19,680 GLYCOSYLATION IS AFFAIRS TEAM 2599 01:40:19,680 --> 01:40:21,040 LEADERRERRED AND THE GENES 2600 01:40:21,040 --> 01:40:23,560 INVOLVED IN THE DECREASED OR 2601 01:40:23,560 --> 01:40:25,640 SCIENTIFIC INCREASE BECAUSE WE 2602 01:40:25,640 --> 01:40:27,720 GET MORE ANTIGENS AND THESE HAVE 2603 01:40:27,720 --> 01:40:29,240 [INDISCERNIBLE] TAKING PLACE AND 2604 01:40:29,240 --> 01:40:30,720 YOU HAVE CERTAIN [INDISCERNIBLE] 2605 01:40:30,720 --> 01:40:31,280 TAKING PLACE. 2606 01:40:31,280 --> 01:40:33,480 SO WHAT HAPPENS OVER HERE IS 2607 01:40:33,480 --> 01:40:34,400 ESSENTIALLY A NUANCE 2608 01:40:34,400 --> 01:40:36,480 UNDERSTANDING OF WHAT TPHREU 2609 01:40:36,480 --> 01:40:38,000 RACING COSALATION PATHWAYS ARE 2610 01:40:38,000 --> 01:40:40,160 ALTERED AND THIS IS PROVIEDMAN 2611 01:40:40,160 --> 01:40:48,640 BY SOME DEGREE BY K BUT IT'S NOT 2612 01:40:48,640 --> 01:40:50,160 JUST THE [INDISCERNIBLE], IT'S 2613 01:40:50,160 --> 01:40:52,880 ALSO THE SERIES AND THE SPECIFIC 2614 01:40:52,880 --> 01:40:54,000 GENES IN THE LACTOSERIES THAT 2615 01:40:54,000 --> 01:40:55,600 ARE REDUCED SO IT GIVES YOU A 2616 01:40:55,600 --> 01:40:57,680 BETTER UNDERSTANDING OF THE 2617 01:40:57,680 --> 01:40:58,360 GLYCOSYLATION PROCESS AND THE 2618 01:40:58,360 --> 01:41:00,080 GENES THAT ARE REGULATING. 2619 01:41:00,080 --> 01:41:01,840 SO WE WENT ON BEYOND THIS AND 2620 01:41:01,840 --> 01:41:03,720 SAYING WELL, YOU KNOW WE HAVE AN 2621 01:41:03,720 --> 01:41:06,440 ONTOLOGY NOW TO SORT OF LOOK AT 2622 01:41:06,440 --> 01:41:07,840 CLASSIFYING PATHWAYS, CAN WE 2623 01:41:07,840 --> 01:41:09,920 AMRI TO A MUCH LARGER DATA SET 2624 01:41:09,920 --> 01:41:13,040 SO WHAT TED'S DONE BASICALLY IS 2625 01:41:13,040 --> 01:41:15,160 TAKE AND THESE PATIENTS IN THE 2626 01:41:15,160 --> 01:41:17,280 RNA SEQ DATA THAT'S AVAILABLE AT 2627 01:41:17,280 --> 01:41:19,240 THE TCGA AND THESE ARE SORT OF 2628 01:41:19,240 --> 01:41:21,120 AND THE MOTIVATION FOR THIS IS 2629 01:41:21,120 --> 01:41:22,640 INVOLVED IN MANY DIFFERENT 2630 01:41:22,640 --> 01:41:23,920 PATHWAYS AND REGULATE THE 2631 01:41:23,920 --> 01:41:24,680 HALLMARKS OF CANCER AND IN 2632 01:41:24,680 --> 01:41:26,840 PARTICULAR, I WOULD LIKE TO 2633 01:41:26,840 --> 01:41:28,560 POINT OUT PROLIFERATION, IMMUNE 2634 01:41:28,560 --> 01:41:29,560 DESTRUCTION, AND INVASION AND 2635 01:41:29,560 --> 01:41:30,840 METASTASIS WHICH I THINK HAVE 2636 01:41:30,840 --> 01:41:32,480 BEEN DISCUSSED TODAY AND THESE 2637 01:41:32,480 --> 01:41:34,360 DATA SETS THAT ARE THERE FOR 2638 01:41:34,360 --> 01:41:35,560 THESE PATIENTS, EXIST FOR 33 2639 01:41:35,560 --> 01:41:36,680 DIFFERENT TYPES OF CANCERS. 2640 01:41:36,680 --> 01:41:38,160 NOW THE FIRST THING WE DID WAS 2641 01:41:38,160 --> 01:41:44,880 WE JUST SAID, LET'S PARSE OUT 2642 01:41:44,880 --> 01:41:47,280 THE GENES IN THESE CANCERS AND 2643 01:41:47,280 --> 01:41:49,960 THESE ALOAN CAN THEY ALONE 2644 01:41:49,960 --> 01:41:51,560 CLASSIFY TUMORS FROM COMING FROM 2645 01:41:51,560 --> 01:41:52,200 DIFFERENT AREAS. 2646 01:41:52,200 --> 01:41:56,560 SO WE TOOK THE DATA, PARSED OUT 2647 01:41:56,560 --> 01:41:57,640 GLYCO GENES AND PUT THEM ON THE 2648 01:41:57,640 --> 01:41:59,960 BLOT AND WHAT YOU SEE AMAZINGLY 2649 01:41:59,960 --> 01:42:01,640 IS THAT EVERY TOMB--EACH OF 2650 01:42:01,640 --> 01:42:04,280 THESE DOTS IS A PATIENT AND YOU 2651 01:42:04,280 --> 01:42:06,400 CAN SEE THAT THERE'S NICE 2652 01:42:06,400 --> 01:42:07,360 CLUSTERING OF THE TUMORS BASED 2653 01:42:07,360 --> 01:42:10,080 ON THE TYPE OF ORGANS THEY COME 2654 01:42:10,080 --> 01:42:13,520 IN, YOU KNOW THE BRACCA, ARE ALL 2655 01:42:13,520 --> 01:42:14,560 HERE, THE LUNGS ARE ALL OVER 2656 01:42:14,560 --> 01:42:15,480 HERE AND SO ON. 2657 01:42:15,480 --> 01:42:17,400 AND YOU LOOK AT THEM IN TERMS OF 2658 01:42:17,400 --> 01:42:18,240 JUST ORGAN SYSTEMS OVER HERE, 2659 01:42:18,240 --> 01:42:21,560 WHAT YOU CAN SEE IS THAT THESE 2660 01:42:21,560 --> 01:42:24,080 DIFFERENT ORGAN SYSTEMS SORT OF 2661 01:42:24,080 --> 01:42:24,840 CLASSIFY THEMSELVES TOGETHER. 2662 01:42:24,840 --> 01:42:27,560 FOR EXAMPLE, IF IF YOU HAVE C& 2663 01:42:27,560 --> 01:42:29,080 S, OVER HERE THERE'S DPLEE O 2664 01:42:29,080 --> 01:42:31,440 PLAOF THOMA AND LOWER GRADE 2665 01:42:31,440 --> 01:42:32,320 GLIOMAS, AND THEY CLUSTER 2666 01:42:32,320 --> 01:42:33,320 TOGETHER AND THESE THIS CANCER 2667 01:42:33,320 --> 01:42:35,760 FROM THE SKIN AND THE EYES, SORT 2668 01:42:35,760 --> 01:42:37,440 OF CLUSTERED TOGETHER FOR THE 2669 01:42:37,440 --> 01:42:40,080 LIVER, AND THE CARCINOMA AND THE 2670 01:42:40,080 --> 01:42:41,440 HEPATITIS EATIC CARCINOMA THEY 2671 01:42:41,440 --> 01:42:42,840 ARE BOTH CLUSTER TOGETHER. 2672 01:42:42,840 --> 01:42:43,680 SO INTERESTINGLY IT'S NOT JUST 2673 01:42:43,680 --> 01:42:46,120 THAT THE GENES AND THE FLIEK O 2674 01:42:46,120 --> 01:42:48,480 GENES DIFFERENTIATE DIFFERENT 2675 01:42:48,480 --> 01:42:50,640 TUMORS, ALSO ORGANS THAT HAVE 2676 01:42:50,640 --> 01:42:51,480 SIMILAR ORIGINS TEND TO CLUSTER 2677 01:42:51,480 --> 01:42:52,880 TOGETHER AND YOU CAN SEE THAT 2678 01:42:52,880 --> 01:42:54,640 FOR THESE 3 EXAMPLES, ARE 2679 01:42:54,640 --> 01:42:55,800 SOMETIMES YOU SEE DIFFERENCES 2680 01:42:55,800 --> 01:42:57,280 FOR EXAMPLES, IF YOU LOOK AT 2681 01:42:57,280 --> 01:42:59,320 LUNG CANCERS OF 2 TYPES THEY'RE 2682 01:42:59,320 --> 01:43:01,520 NOT QUITE OVERLAPPING EACH OTHER 2683 01:43:01,520 --> 01:43:02,800 AND SIMILARLY FOR--FOR JEEPS 2684 01:43:02,800 --> 01:43:04,680 THAT MIGHT BE INVOLVED IN OTHER 2685 01:43:04,680 --> 01:43:06,560 PATHWAYS FOR EXAMPLE, ENDOCRINE 2686 01:43:06,560 --> 01:43:07,320 PATHWAYS THAT ARE CLOSE TO EACH 2687 01:43:07,320 --> 01:43:09,000 OTHER AND THE SAME THING FOR 2688 01:43:09,000 --> 01:43:10,440 KIDNEY, 3 TYPES OF KIDNEY 2689 01:43:10,440 --> 01:43:12,080 CANCERS ARE CLOSE TO EACH OTHER 2690 01:43:12,080 --> 01:43:13,280 AND SOME CANCERS FOR EXAMPLE, IF 2691 01:43:13,280 --> 01:43:16,240 YOU LOOK AT BLOOD CANCERS LIKE 2692 01:43:16,240 --> 01:43:17,440 ACUTE MYELOID LEUKEMIA AND 2693 01:43:17,440 --> 01:43:19,640 THINGS THAT ARE INVOLVED IN 2694 01:43:19,640 --> 01:43:21,440 LEUKEMIA THESE ARE IN TERMS OF 2695 01:43:21,440 --> 01:43:23,720 GLYCO GENES AND SO THESE GLYCO 2696 01:43:23,720 --> 01:43:25,480 GENES IN THESE SYSTEMS DIFFERENT 2697 01:43:25,480 --> 01:43:28,040 AND YOU CAN CLASSIFY THEM BASED 2698 01:43:28,040 --> 01:43:30,280 ON MULTIOMICS FRAMEWORK USING 2699 01:43:30,280 --> 01:43:33,680 WHAT'S CALLED THE PAN-CANCER 2700 01:43:33,680 --> 01:43:35,280 CLASSIFICATION WHICH USES 2701 01:43:35,280 --> 01:43:36,000 PROTEOMICS GENOMICS AND 2702 01:43:36,000 --> 01:43:36,840 TRANSCRIPTOMICS AND YOU CAN SEE 2703 01:43:36,840 --> 01:43:38,400 THAT MANY OF THESE THINGS SORT 2704 01:43:38,400 --> 01:43:42,640 OF COME TOGETHER, ALL THE 2705 01:43:42,640 --> 01:43:45,560 GYNECOLOGICAL CANCERS BREAST 2706 01:43:45,560 --> 01:43:46,720 CANCER, OVARIAN CANCER, UTERINE 2707 01:43:46,720 --> 01:43:47,680 CANCER, CERVICAL CANCER IS OVER 2708 01:43:47,680 --> 01:43:49,280 HERE BECAUSE IT'S MORE OF A 2709 01:43:49,280 --> 01:43:50,960 SCWAIMOUS MORPHOLOGY AND YOU CAN 2710 01:43:50,960 --> 01:43:52,760 SEE THE GASTRO, RECTAL, 2711 01:43:52,760 --> 01:43:55,480 COLORECTAL, STOMACH ARE 2712 01:43:55,480 --> 01:43:58,080 TOGETHER, [INDISCERNIBLE] IS FAR 2713 01:43:58,080 --> 01:44:02,280 AWAY BECAUSE THAT'S MORE OF A 2714 01:44:02,280 --> 01:44:03,800 SCWAIMOUS MORPHOLOGY SO IT'S 2715 01:44:03,800 --> 01:44:06,400 REALLY INTERESTING YOU CAN CLASS 2716 01:44:06,400 --> 01:44:09,080 FLY TUMORS BASED ON JUST THE 2717 01:44:09,080 --> 01:44:11,480 FLIEK O GENES. 2718 01:44:11,480 --> 01:44:13,880 SO NOW, TD GLYCO GENES ARE 2719 01:44:13,880 --> 01:44:15,080 DIFFERENT IN DIFFERENT ORGANS SO 2720 01:44:15,080 --> 01:44:16,040 THAT MIGHT WELL EXPLAIN THESE 2721 01:44:16,040 --> 01:44:17,400 DIFFERENCES SO WE ASK THE 2722 01:44:17,400 --> 01:44:19,440 QUESTION, THIS IS INTERESTING, 2723 01:44:19,440 --> 01:44:21,400 BUT CAN YOU ACTUALLY CLASSIFY 2724 01:44:21,400 --> 01:44:23,760 DIFFERENT TUMOR TYPES AND 2725 01:44:23,760 --> 01:44:24,360 DIFFERENT MOLECULAR SUBTYPES, 2726 01:44:24,360 --> 01:44:25,640 BASED ON JUST THE FLIEK O JEEPS 2727 01:44:25,640 --> 01:44:27,400 SO WE PARSE OUT THE GLYCO GENES 2728 01:44:27,400 --> 01:44:29,360 AND THEN WE TOOK DIFFERENT TYPES 2729 01:44:29,360 --> 01:44:31,080 OF TUMORS AND TOOK MOLECULAR 2730 01:44:31,080 --> 01:44:32,320 CLASS UCHGS FOR EACH OF THEM AND 2731 01:44:32,320 --> 01:44:35,000 FOR EXAMPLE, THIS IS THE BREAST 2732 01:44:35,000 --> 01:44:36,280 CANCER TO EXPAND UPON IN A FEW 2733 01:44:36,280 --> 01:44:38,760 MINUTES AND THIS IS JUST SHOWING 2734 01:44:38,760 --> 01:44:40,360 THE PAN 50 CLASSIFICATION OF THE 2735 01:44:40,360 --> 01:44:41,800 GENES OVER HERE AND SHOWING THIS 2736 01:44:41,800 --> 01:44:43,880 IS THE NORMAL ALONG THE BASAL 2737 01:44:43,880 --> 01:44:45,840 AND LUMINAL A AND B AND THIS IS 2738 01:44:45,840 --> 01:44:47,240 A 2 D PLOT AND YOU CAN GET MORE 2739 01:44:47,240 --> 01:45:01,440 AS I WILL SHOW YOU IN A BIT. 2740 01:45:01,440 --> 01:45:02,720 IF YOU LOOK AT THE HISTOLOGY, 2741 01:45:02,720 --> 01:45:04,280 YOU WILL HAVE TO DESCRIBE WHAT'S 2742 01:45:04,280 --> 01:45:05,680 WITH THE TUMORS AND WHAT WILL DO 2743 01:45:05,680 --> 01:45:09,080 THIS THING AS WELL, IF YOU LOOK 2744 01:45:09,080 --> 01:45:10,600 AT BRAF MUTATION, YOU CAN SEE 2745 01:45:10,600 --> 01:45:12,840 THAT THE GLYCO GENES ALONE 2746 01:45:12,840 --> 01:45:15,040 WITHOUT ANYTHING ELSE CLASSIFY 2747 01:45:15,040 --> 01:45:18,040 DIFFERENTLY SO BRAF MUTATION 2748 01:45:18,040 --> 01:45:20,000 KAWS CANCER WHICH EXPRESS 2749 01:45:20,000 --> 01:45:20,560 PRESUMABLILY DIFFERENT 2750 01:45:20,560 --> 01:45:21,000 STRUCTURES ON THEM. 2751 01:45:21,000 --> 01:45:23,600 NOW WE'VE GONE AND THAT I CANNEN 2752 01:45:23,600 --> 01:45:25,680 ALL OF THESE TUMORS ABOUT 16 OF 2753 01:45:25,680 --> 01:45:27,680 THEM THAT HAVE SUFFICIENT 2754 01:45:27,680 --> 01:45:28,200 NORMALS AND DIFFERENTIAL 2755 01:45:28,200 --> 01:45:30,560 EXPRESSION ON ALL OF THEM AND 2756 01:45:30,560 --> 01:45:33,600 THIS IS AN EXAMPLE OF A HER 2 2757 01:45:33,600 --> 01:45:34,680 POSITIVE CANCER SHOWING SOME 2758 01:45:34,680 --> 01:45:37,040 GENES GO DOWN AND SOME GO UP 2759 01:45:37,040 --> 01:45:39,480 ANDA ABOUT A THIRD OF 2760 01:45:39,480 --> 01:45:40,280 DISREGULATED INVARIABLY IN A 2761 01:45:40,280 --> 01:45:43,000 CANCER WE'VE SEEN SO THEREYA A 2762 01:45:43,000 --> 01:45:44,080 PHENOMENAL CHANGE IN THE 2763 01:45:44,080 --> 01:45:46,480 STRUCTURES AND THE GLYCO ENZYMES 2764 01:45:46,480 --> 01:45:48,680 AND THEY AREN'T REALLY SPECIFIC 2765 01:45:48,680 --> 01:45:50,680 TO SPECIFIC GLYCAN TYPES THEY 2766 01:45:50,680 --> 01:45:51,840 JUST GENERALLY DISREGULATED IN 2767 01:45:51,840 --> 01:45:53,600 THESE CANCERS AND YOU CAN SEE 2768 01:45:53,600 --> 01:45:54,680 THAT FOR MULTILE CANCER TYPES 2769 01:45:54,680 --> 01:45:56,640 FOR ALL THE GENES THAT THEY'RE 2770 01:45:56,640 --> 01:45:58,160 LOOKING AT LONG WITH DIFFERENT 2771 01:45:58,160 --> 01:45:58,840 FAMILIES AND WHAT'S REALLY 2772 01:45:58,840 --> 01:46:00,280 INTERESTING ABOUT THIS IS THAT 2773 01:46:00,280 --> 01:46:01,880 TUMOR TYPES, SIMILAR TYPES ARE 2774 01:46:01,880 --> 01:46:03,320 CLUSTERED TOGETHER, THESE ARE 2775 01:46:03,320 --> 01:46:04,000 ALL NEUROLOGICAL CANCERS THAT 2776 01:46:04,000 --> 01:46:06,000 ARE CLOSE TO EACH OTHER. 2777 01:46:06,000 --> 01:46:07,840 IF YOU COMPARE THIS RECTAL AND 2778 01:46:07,840 --> 01:46:09,480 COLO CANCER THEY'RE ALL RED OVER 2779 01:46:09,480 --> 01:46:11,360 HERE, CAN YOU SEE THE RATE TO 2780 01:46:11,360 --> 01:46:13,000 EACH OTHER IF YOU TAKE THESE 2781 01:46:13,000 --> 01:46:14,600 FIGURES YOU CAN SEE ALL THESE 2782 01:46:14,600 --> 01:46:16,120 GENES ARE DOWN REGULATED IN 2783 01:46:16,120 --> 01:46:17,680 THESE PARTICULAR 2 TYPES OF SO 2784 01:46:17,680 --> 01:46:20,160 ON SO CAN YOU SEE 2785 01:46:20,160 --> 01:46:23,760 [INDISCERNIBLE] THAT SIMILAR 2786 01:46:23,760 --> 01:46:25,880 TUMORS BASED ON ORIGIN WILL HAVE 2787 01:46:25,880 --> 01:46:26,960 SIMILAR PATHWAY DISREGULATION 2788 01:46:26,960 --> 01:46:28,280 DURING CANCER WHICH I THOUGHT 2789 01:46:28,280 --> 01:46:29,200 WAS REALLY INTERESTING, I WON'T 2790 01:46:29,200 --> 01:46:30,720 GO INTO THIS IN MUCH DETAIL BUT 2791 01:46:30,720 --> 01:46:33,280 JUST THEY WE PULLED UP THE TOP 2792 01:46:33,280 --> 01:46:35,280 GENES IN EVERYONE 1 OF THESE 2793 01:46:35,280 --> 01:46:37,960 CLUSTERS AND KIDNEY AND GUIN 2794 01:46:37,960 --> 01:46:39,080 OICOLOGICAL AND THEY ARE CERTAIN 2795 01:46:39,080 --> 01:46:40,320 GENES THAT ARE GOING UP AND 2796 01:46:40,320 --> 01:46:42,160 GOING DOWN, AND THEY DON'T 2797 01:46:42,160 --> 01:46:43,960 BELONG TO ANY SPECIFIC PATHWAY, 2798 01:46:43,960 --> 01:46:44,960 THEY BELONG TO MULTIPLE PATHWAYS 2799 01:46:44,960 --> 01:46:46,240 IN THIS PARTICULAR SYSTEM, SO 2800 01:46:46,240 --> 01:46:47,800 THEY BELONG TO ALL SORTS OF 2801 01:46:47,800 --> 01:46:48,760 PATHWAYS THAT ARE ALTERED SO 2802 01:46:48,760 --> 01:46:50,760 THEN THE QUESTION AS YOU KNOW IS 2803 01:46:50,760 --> 01:46:52,400 WHICH PATHWAYS ARE ALTERED IN 2804 01:46:52,400 --> 01:46:58,000 THESE THINGS SO WE TOOK THE 2805 01:46:58,000 --> 01:46:58,920 GLYCO ENZYME MORPHOLOGY AND WE 2806 01:46:58,920 --> 01:47:00,480 USE THAT FOR THE EXPRESSION DAT 2807 01:47:00,480 --> 01:47:03,600 FAR ALL THESE PARTICULAR TUMORS 2808 01:47:03,600 --> 01:47:06,200 AND YOU LOOK AT ALL THE 2809 01:47:06,200 --> 01:47:08,480 DIFFERENT PATHWAYS WHAT ARE THE 2810 01:47:08,480 --> 01:47:09,640 PATHWAYS THAT ARE DISREGULATED 2811 01:47:09,640 --> 01:47:11,480 AND THESE ARE THE PATHWAYS THAT 2812 01:47:11,480 --> 01:47:12,760 ARE REDUCED, THESE ARE GOING UP 2813 01:47:12,760 --> 01:47:14,480 AND IT'S INTERESTING BECAUSE WE 2814 01:47:14,480 --> 01:47:17,120 HEARD A TALK ON OLD GIVING--YOU 2815 01:47:17,120 --> 01:47:18,080 COSALATION PATHWAYS, AND SOME OF 2816 01:47:18,080 --> 01:47:20,280 THE GENES ARE GOING DOWN AND 2817 01:47:20,280 --> 01:47:21,680 THAT'S CALLING TN ANTIGENS AND 2818 01:47:21,680 --> 01:47:23,560 THE OTHER PART WE HEARD ABOUT 2819 01:47:23,560 --> 01:47:24,640 AND EXTRA CELLULAR DEGRADATION, 2820 01:47:24,640 --> 01:47:27,840 SO THIS IS RADDA'S TALK TALKING 2821 01:47:27,840 --> 01:47:29,920 ABOUT DEGRADATION AND SULF 1 AND 2822 01:47:29,920 --> 01:47:31,000 2, THERE'S ALSO OTHER CHANGES 2823 01:47:31,000 --> 01:47:32,680 THAT TAKE PLACE IN THESE CANCERS 2824 01:47:32,680 --> 01:47:36,560 THAT ARE UNIFORM, FOR EXAMPLE, 2825 01:47:36,560 --> 01:47:37,840 [INDISCERNIBLE] IS GOING UP IN 2826 01:47:37,840 --> 01:47:39,520 MANY TYPES OF CANCERS AND 2827 01:47:39,520 --> 01:47:40,240 ADDITIONAL PATHWAYS THAT ARE 2828 01:47:40,240 --> 01:47:42,160 ALTERED AND YOU CAN FIND YOUR 2829 01:47:42,160 --> 01:47:43,040 FAVORITE GENE OVER HERE. 2830 01:47:43,040 --> 01:47:45,560 WE HAVE A WHOLE WEBSITE THAT 2831 01:47:45,560 --> 01:47:47,560 CURATES THAT IS PEOPLE CAN COME 2832 01:47:47,560 --> 01:47:50,240 IN AND CURE QUERY ALL THESE 2833 01:47:50,240 --> 01:47:51,840 THINGS IN THAT PARTICULAR 2834 01:47:51,840 --> 01:47:52,080 WEBSITE. 2835 01:47:52,080 --> 01:47:53,120 BUT WHAT'S REALLY INTERESTING IS 2836 01:47:53,120 --> 01:47:54,640 I THOUGHT THAT ALL THESE 2837 01:47:54,640 --> 01:47:56,840 DIFFERENT CANCERS THAT HAVE YOU 2838 01:47:56,840 --> 01:47:58,480 HAVE DIFFERENT PATHWAYS 2839 01:47:58,480 --> 01:47:59,280 DISREGULATED, SOME OF THEM ARE 2840 01:47:59,280 --> 01:48:00,400 READ HERE, PLURIBU IN OTHER 2841 01:48:00,400 --> 01:48:02,040 CANCERS AND SO ON, SO EVEN 2842 01:48:02,040 --> 01:48:04,160 THOUGH THE GLYCO GENES ARE 2843 01:48:04,160 --> 01:48:05,000 DISREGULATE INDEED MULTIPLE 2844 01:48:05,000 --> 01:48:06,200 CANCER TYPES, WHAT WE OBSERVING 2845 01:48:06,200 --> 01:48:09,360 OR WHAT WE THINK IS OBSERVING IS 2846 01:48:09,360 --> 01:48:13,120 THAT THE GENES, THE PATTERNS OF 2847 01:48:13,120 --> 01:48:13,840 CARBOHYDRATE STRUCTURES IS 2848 01:48:13,840 --> 01:48:14,920 ACTUALLY DIFFERENT BECAUSE 2849 01:48:14,920 --> 01:48:15,840 DIFFERENT PATHWAYS ARE 2850 01:48:15,840 --> 01:48:17,040 DISREGULATE INDEED DIFFERENT 2851 01:48:17,040 --> 01:48:18,600 KANGSER TYPES, YOU CAN ALSO SEE 2852 01:48:18,600 --> 01:48:20,480 CLOSE ASSOCIATION HERE FOR THE 2853 01:48:20,480 --> 01:48:21,600 RECTAL AND COLORECTAL OVER HERE, 2854 01:48:21,600 --> 01:48:23,080 CAN YOU SEE THAT THESE SORT OF 2855 01:48:23,080 --> 01:48:24,920 THINGS THAT ARE STOMACH AND 2856 01:48:24,920 --> 01:48:25,880 FIGURES ARE SIMILARLY 2857 01:48:25,880 --> 01:48:28,280 DIFFERENTIATED AND SO THE 2858 01:48:28,280 --> 01:48:30,280 PATHWAYS THAT SORT OF NEED 2859 01:48:30,280 --> 01:48:32,760 CHANGE OR ARE DOWN REGULATED OR 2860 01:48:32,760 --> 01:48:34,800 UPREGULATED ARE SIMILAR SO CAN 2861 01:48:34,800 --> 01:48:36,480 YOU SEE THAT HERE FOR THE KIDNEY 2862 01:48:36,480 --> 01:48:37,880 AND YOU SEE SIMILAR 2863 01:48:37,880 --> 01:48:40,280 DISREGULATION FOR CANCER TYPES 2864 01:48:40,280 --> 01:48:42,520 FOR THOSE BASED ON ORGAN SYSTEMS 2865 01:48:42,520 --> 01:48:44,040 BUT TOTALLY DIFFERENT PATTERNS 2866 01:48:44,040 --> 01:48:45,200 FOR EACH CANCER. 2867 01:48:45,200 --> 01:48:47,400 WE'VE GONE ON 1 STEP FURTHER AND 2868 01:48:47,400 --> 01:48:48,840 LOOKED AT LET'S SEE SO YOU CAN 2869 01:48:48,840 --> 01:48:51,360 STUDY 1 PARTICULAR CANCER IN 2870 01:48:51,360 --> 01:48:52,360 MOLECULAR CANCER AND BREAST 2871 01:48:52,360 --> 01:48:53,680 CANCER AND WE APLAYED MACHINE 2872 01:48:53,680 --> 01:48:56,600 LEARNING IN THESE THINGS TO 2873 01:48:56,600 --> 01:48:57,480 CLASSIFY 6 DIFFERENT TYPES OF 2874 01:48:57,480 --> 01:48:59,800 EXAMPLES THAT ARE EXISTING, THIS 2875 01:48:59,800 --> 01:49:01,680 IS BASAL, HER 2, LUMINAL, 2876 01:49:01,680 --> 01:49:05,480 LUMINAL AB AND YOU SAID, YES WE 2877 01:49:05,480 --> 01:49:07,520 HAVE 286 FLIEK O GENES BUT 2878 01:49:07,520 --> 01:49:09,080 MEASURED EXPRESSION IN THE 2879 01:49:09,080 --> 01:49:10,400 GENES, LET'S SEE WHAT IS A 2880 01:49:10,400 --> 01:49:11,520 MINIMUM NUMBER YOU NEED IN ORDER 2881 01:49:11,520 --> 01:49:12,960 TO EXPLAIN THE DIFFERENCES AMONG 2882 01:49:12,960 --> 01:49:15,800 THESE THINGS AND WE'VE DONE THIS 2883 01:49:15,800 --> 01:49:18,280 AND WE'VE SORT OF ABOUT 50 GLYCO 2884 01:49:18,280 --> 01:49:19,800 GENES IN ORDER TO EXPLAIN 2885 01:49:19,800 --> 01:49:20,840 DIFFERENCES IN ABOUT 85% 2886 01:49:20,840 --> 01:49:22,080 ACCURACY AND ALL THESE DIFFERENT 2887 01:49:22,080 --> 01:49:23,560 CANCERS THAT CAN YOU GET, AND 2888 01:49:23,560 --> 01:49:24,800 THESE ARE SOME OF THE GENES THAT 2889 01:49:24,800 --> 01:49:27,000 ARE INVOLVED IN THERE, APPEAR IN 2890 01:49:27,000 --> 01:49:37,120 THE GLYCO LIPID PATHWAY. 2891 01:49:37,120 --> 01:49:39,280 AND CANCER, WE CAN ALSO CREATE 2892 01:49:39,280 --> 01:49:40,600 THESE PROGRESSION MAPS WHERE YOU 2893 01:49:40,600 --> 01:49:41,880 CAN GO IN AND TAKE IT AND SAY 2894 01:49:41,880 --> 01:49:43,840 THIS IS THE CLUSTER OF PATTERNS 2895 01:49:43,840 --> 01:49:46,920 YOU'RE SEEING ON A PCA PLOT, AND 2896 01:49:46,920 --> 01:49:48,800 THIS IS A NORMAL TUMOR THAT 2897 01:49:48,800 --> 01:49:51,480 GOING INTO THE NIEWMOR TUMORS 2898 01:49:51,480 --> 01:49:53,240 BASAL OR LUMINAL A OR B AND YOU 2899 01:49:53,240 --> 01:49:54,640 CAN SEE DIFFERENT IF YOU TAKE 2900 01:49:54,640 --> 01:49:56,280 GLYCO GENE 50 AND YOU PLOT 2901 01:49:56,280 --> 01:49:57,680 PROGRESSION MAP, IT'S PRETTY 2902 01:49:57,680 --> 01:49:59,760 SIMILAR TO PAN 50, SO 2903 01:49:59,760 --> 01:50:01,720 GLYCOSYLATION HAS THE NEED TO 2904 01:50:01,720 --> 01:50:03,920 PLOT, NOT EXACTLY THE SAME 2905 01:50:03,920 --> 01:50:05,760 AMOUNT OF PAN 50 BUT COMPARABLE 2906 01:50:05,760 --> 01:50:07,840 LEVELS OF INFORMATION IS PAN 50 2907 01:50:07,840 --> 01:50:09,880 BECAUSE OF CLASSIFICATIONS WE 2908 01:50:09,880 --> 01:50:11,920 SEE OF USING GLYCO GENES ALONE 2909 01:50:11,920 --> 01:50:13,840 IN DIFFERENT TYPES OF CANCER 2910 01:50:13,840 --> 01:50:15,000 SUBTYPES IS QUITE COMPARABLE TO 2911 01:50:15,000 --> 01:50:16,680 WHAT WE SEE IN PAN 50. 2912 01:50:16,680 --> 01:50:18,520 CAN YOU USE IN INFORMATION TO 2913 01:50:18,520 --> 01:50:20,960 SORT OF LOOK AT PROGRESSION MAPS 2914 01:50:20,960 --> 01:50:23,720 HOW DO THESE STRUCTURES OR GLYCO 2915 01:50:23,720 --> 01:50:24,800 GENES CHANGE DURING CANCER AS IT 2916 01:50:24,800 --> 01:50:29,280 GOES FROM A NORMAL TO A TUMOR 2917 01:50:29,280 --> 01:50:31,720 USING BASAL FOR EXAMPLE, AND YOU 2918 01:50:31,720 --> 01:50:33,840 SEE THAT THESE GO UP FOR A 2919 01:50:33,840 --> 01:50:35,320 WHILE, THESE ARE IMPORTANT FOR 2920 01:50:35,320 --> 01:50:38,800 THE PATHWAY, YOU HAVE PATHWAYS 2921 01:50:38,800 --> 01:50:40,200 RELATED TO C& B CYTOTOLL-LIKE 2922 01:50:40,200 --> 01:50:41,400 RECEPTORIC ACIDS THAT GO UP AND 2923 01:50:41,400 --> 01:50:43,160 THESE GENES THAT ARE GOING UP 2924 01:50:43,160 --> 01:50:45,040 AND YOU CAN SEE THANKS TAKING 2925 01:50:45,040 --> 01:50:47,720 PLACE IN TRANSFER ACES OR 2926 01:50:47,720 --> 01:50:49,280 STRUCTURES, SOME GENES, LIKE 2927 01:50:49,280 --> 01:50:51,000 TRANSFERS 8 AND IN PARTICULAR 2928 01:50:51,000 --> 01:50:52,280 CASE, THE BASAL GOES UP FOR A 2929 01:50:52,280 --> 01:50:54,360 WHILE AND THEN GOES DOWN. 2930 01:50:54,360 --> 01:50:57,280 AND SO, THESE TUMOR 2931 01:50:57,280 --> 01:50:58,080 HETEROGENERATED AITYS THAT WE 2932 01:50:58,080 --> 01:50:59,280 TALKED ABOUT YESTERDAY THAT ARE 2933 01:50:59,280 --> 01:51:01,080 NOT ALL PATIENTS OF THE SAME ARE 2934 01:51:01,080 --> 01:51:02,160 REALLY BECAUSE WE CATCH SOME OF 2935 01:51:02,160 --> 01:51:03,560 THEM, AND WE CATCH OTHERS IN 2936 01:51:03,560 --> 01:51:05,000 THIS PARTICULAR STAGE AND SO THE 2937 01:51:05,000 --> 01:51:07,560 TUMORS HAVE A SORT OF SIGNATURE 2938 01:51:07,560 --> 01:51:11,960 OF TPHREU --GLYCAN STRUCTURE CHANGES AND 2939 01:51:11,960 --> 01:51:15,200 THESE COMMUNITIES COME TOGETHER 2940 01:51:15,200 --> 01:51:16,000 AND THE BIO-INFORMATICS COULD 2941 01:51:16,000 --> 01:51:16,480 CONTRIBUTE TO THIS. 2942 01:51:16,480 --> 01:51:18,360 SO I WILL JUST CLOSE OUT WITH 2943 01:51:18,360 --> 01:51:20,720 CONCLUSIONS WHAT WE'VE DONE IS 2944 01:51:20,720 --> 01:51:31,000 WE'VE GOT A GLYCO ENZYME 2945 01:51:31,000 --> 01:51:34,560 ONTOLOGY WHICH WHICH IN OUR 2946 01:51:34,560 --> 01:51:37,040 STUDIES ENHANCES IT IS GENE 2947 01:51:37,040 --> 01:51:37,720 ENRICHMENT ANALYSIS ACROSS 2948 01:51:37,720 --> 01:51:46,400 DPRIEK O BI--GLYCO BIOLOGICAL 2949 01:51:46,400 --> 01:51:46,680 PATHWAYS. 2950 01:51:46,680 --> 01:51:48,080 GEICO GENES CAN DIFFERENTIATE 2951 01:51:48,080 --> 01:51:52,160 TUMORS BUT THEY CAN DISTINGUISH 2952 01:51:52,160 --> 01:51:53,800 BETWEEN DIFFERENT MOLECULAR 2953 01:51:53,800 --> 01:51:55,400 TYPES, AND THEY SUGGEST THAT THE 2954 01:51:55,400 --> 01:51:59,120 EXPRESSION OF GENES IN DIFFERENT 2955 01:51:59,120 --> 01:52:00,440 CANCERS, THE DIFFERENCES IN THE 2956 01:52:00,440 --> 01:52:02,640 GLYCO GENES AND SPECIFIC CANCER 2957 01:52:02,640 --> 01:52:03,480 TYPES ALSO TRANSLATE IN 2958 01:52:03,480 --> 01:52:06,320 CHAIMPLES IN PATHWAYS TO 2959 01:52:06,320 --> 01:52:07,080 TENTIALLY IS LIGANDS IN 2960 01:52:07,080 --> 01:52:08,520 DIFFERENT CANCERS WHICH WILL BE 2961 01:52:08,520 --> 01:52:10,280 DIFFERENT BUT RELATED IN TERMS 2962 01:52:10,280 --> 01:52:12,240 OF ORGAN SYSTEMS AND ALSO 2963 01:52:12,240 --> 01:52:13,520 CREATED A SYSTEM IN A FRAMEWORK 2964 01:52:13,520 --> 01:52:14,840 IN WHICH WE CAN HAVE A 2965 01:52:14,840 --> 01:52:16,080 PROGRESSION MAP TO ELECTRIC AT 2966 01:52:16,080 --> 01:52:18,280 HOW DO GENES EVOLVE DURING 2967 01:52:18,280 --> 01:52:21,160 CANCER AND SO FAR TO THE EXTEND 2968 01:52:21,160 --> 01:52:24,800 THAT WE'VE DONE ANALYSIS THESE 2969 01:52:24,800 --> 01:52:26,880 GENES ARE SIMILAR AND POETIC 2970 01:52:26,880 --> 01:52:28,520 TEBTIAL TO DISTINGUISH DIFFERENT 2971 01:52:28,520 --> 01:52:30,880 CANCER TYPES AND TO LOOK AT 2972 01:52:30,880 --> 01:52:31,800 DIFFERENT MOLECULAR SUBTYPES 2973 01:52:31,800 --> 01:52:33,840 THAT COULD BE LOOK AT IT FROM A 2974 01:52:33,840 --> 01:52:34,480 SYSTEMS BIOLOGY PERSPECTIVE SO 2975 01:52:34,480 --> 01:52:35,800 THANK YOU IF ARE YOUR ATTENTION 2976 01:52:35,800 --> 01:52:41,480 AND WELCOME QUESTIONS AT THE 2977 01:52:41,480 --> 01:52:41,640 END. 2978 01:52:41,640 --> 01:52:44,240 >> THANK YOU SO MUCH, THAT'S 2979 01:52:44,240 --> 01:52:44,680 REALLY FASCINATING. 2980 01:52:44,680 --> 01:52:47,040 I'M SURE WE WILL HAVE QUESTIONS. 2981 01:52:47,040 --> 01:52:55,280 JUST PUT THOSE IN THE SEND LIVE 2982 01:52:55,280 --> 01:52:56,800 FEEDBACK LINK THERE AND SO WE'RE 2983 01:52:56,800 --> 01:52:58,440 BEHIND TIME SO LET'S MOVE 2984 01:52:58,440 --> 01:53:04,320 DIRECTLY TO OUR NEXT SPEAKER 2985 01:53:04,320 --> 01:53:06,640 DR. JOSHUA KLEIN, BOSTON 2986 01:53:06,640 --> 01:53:07,480 UNIVERSITY, REDUCING AMBIGUITY 2987 01:53:07,480 --> 01:53:10,200 IN GLYCO FORM ASSIGNMENT USING 2988 01:53:10,200 --> 01:53:12,280 RETENTION TIME MODELING AND 2989 01:53:12,280 --> 01:53:26,360 GLYCAN NETWORK SMOOTHING. 2990 01:53:26,360 --> 01:53:28,400 >> SO THAT I FIT IN TIME, I WILL 2991 01:53:28,400 --> 01:53:30,680 JUST TALK ABOUT REDUCING 2992 01:53:30,680 --> 01:53:36,200 AMBIGUITY THROUGH RETENTION TIME 2993 01:53:36,200 --> 01:53:36,480 MODELING. 2994 01:53:36,480 --> 01:53:43,680 SO THANK YOU EVERYONE FOR HAVING 2995 01:53:43,680 --> 01:53:44,840 THE PATIENCE TO SIT THROUGH MY 2996 01:53:44,840 --> 01:53:47,240 TALK TODAY AND THE ORGANIZERS 2997 01:53:47,240 --> 01:53:49,000 LETTING ME TALK TODAY AND MAY 2998 01:53:49,000 --> 01:53:52,080 YOU NOT REGRET IT. 2999 01:53:52,080 --> 01:53:59,560 SO KEY WORDS TO DEFINE A PREP SO 3000 01:53:59,560 --> 01:54:04,400 I WILL TALK EXCLUSIVELY ABOUT 3001 01:54:04,400 --> 01:54:06,680 LIQUID CHROMATOGRAPHY COUPLED 3002 01:54:06,680 --> 01:54:07,800 MASS SPECTROMETRY MASS 3003 01:54:07,800 --> 01:54:10,040 SPECTROMETRY, WE WILL TALK ABOUT 3004 01:54:10,040 --> 01:54:15,840 TYPES OF ADDUKS AND DPLIK O 3005 01:54:15,840 --> 01:54:18,880 PEPTIDE AND GLYCAN COMCISION 3006 01:54:18,880 --> 01:54:21,360 ASSIGNMENT USING RELATIVE 3007 01:54:21,360 --> 01:54:22,680 PRETENSION TRIEM PREDICTION. 3008 01:54:22,680 --> 01:54:24,080 ONE OF THE IMPORTANT THINGS TO 3009 01:54:24,080 --> 01:54:26,600 TALK ABOUT WHEN IDENTIFYING 3010 01:54:26,600 --> 01:54:29,360 FLIEK O PEPTIDES WITH MASS 3011 01:54:29,360 --> 01:54:31,080 SPECTROMETRY, HOW DO WE IDENTIFY 3012 01:54:31,080 --> 01:54:32,680 THEIR FRAGMENTS WE TAKE A 3013 01:54:32,680 --> 01:54:34,600 PEPTIDE PLUS 1 OR MORE LOCALIZED 3014 01:54:34,600 --> 01:54:35,680 GLYCANS SOMEWHERE IN THE 3015 01:54:35,680 --> 01:54:38,480 SEQUENCE AND WE GET A KIND OF 3016 01:54:38,480 --> 01:54:39,440 MASS SPECTRUM WITH MANY 3017 01:54:39,440 --> 01:54:41,280 DIFFERENT TYPES OF FRAGMENTS. 3018 01:54:41,280 --> 01:54:43,160 WHEN WE FRAGMENT THE DPLI 3019 01:54:43,160 --> 01:54:46,360 KAN--KANA, WE GET CHUNKS OF THE 3020 01:54:46,360 --> 01:54:48,000 GLYCAN SIS ASSOCIATED FROM THE 3021 01:54:48,000 --> 01:54:50,120 PEPTIDE AND THE REDUCING END OF 3022 01:54:50,120 --> 01:54:51,920 THE GLYCANS SILL ATTACHED TO THE 3023 01:54:51,920 --> 01:54:52,360 INTACT PEPTIDE. 3024 01:54:52,360 --> 01:54:54,240 WITH A BIT MORE ENERGY WE CAN 3025 01:54:54,240 --> 01:54:57,560 START TO SEE PEPTIDE BACKBONE 3026 01:54:57,560 --> 01:54:59,240 FRAG METROPOLITANS BEING Y-IONS 3027 01:54:59,240 --> 01:55:01,080 SOME OF THEM WILL HAVE A DPLI 3028 01:55:01,080 --> 01:55:02,400 KAN--KANA TO ATTACH AND THE MORE 3029 01:55:02,400 --> 01:55:03,960 ENERGY YOU PUT INTO THE 3030 01:55:03,960 --> 01:55:05,360 MOLECULE, THE DIFFERENT 3031 01:55:05,360 --> 01:55:08,560 PROPORTIONS OF THESE TYPES OF 3032 01:55:08,560 --> 01:55:09,400 PROTOTYPES YOU WILL GET. 3033 01:55:09,400 --> 01:55:14,640 SO THERE IS NOT 1 ENERGY TO USE 3034 01:55:14,640 --> 01:55:18,680 THAT WILL GIVE YOU PERFECT 3035 01:55:18,680 --> 01:55:19,960 FRAGMENT ANTICIPATION FOR ALL 3036 01:55:19,960 --> 01:55:23,360 PEPTIDES MEANING YOU WON'T GET 3037 01:55:23,360 --> 01:55:24,560 PERFECT FRAGMENTATION OF THE 3038 01:55:24,560 --> 01:55:27,480 DPLI KAN--KANAS AND YOU NOT 3039 01:55:27,480 --> 01:55:30,600 ACCURATELY SAVE WHAT IS ATTACHED 3040 01:55:30,600 --> 01:55:30,840 AND WHERE. 3041 01:55:30,840 --> 01:55:33,120 BUT WE CARE ABOUT ACCURATE 3042 01:55:33,120 --> 01:55:35,000 GLYCAN ASSIGNMENT, SAY WE HAVE 3043 01:55:35,000 --> 01:55:37,800 THIS DPLI KAN--KANA ON A 3044 01:55:37,800 --> 01:55:39,880 PEPTIDE,--DPLI CAN ON A PEPTIDE, 3045 01:55:39,880 --> 01:55:40,960 HOW WOULD WE IDENTIFY IT? 3046 01:55:40,960 --> 01:55:44,320 WE COULD LOOK AT THE TOTAL MASS 3047 01:55:44,320 --> 01:55:45,440 AND THE MASS SPECTROMETER CAN 3048 01:55:45,440 --> 01:55:48,040 TELL US WHAT THE INTACT MASS OF 3049 01:55:48,040 --> 01:55:50,120 THE PRECURSOR ION WAS. 3050 01:55:50,120 --> 01:55:52,400 IF WE'RE LUCKY WE CAN FRAGMENT 3051 01:55:52,400 --> 01:55:57,080 THE GLUE MARIOUS CAN AND 3052 01:55:57,080 --> 01:55:58,280 DETERMINE AND THE COMPOSITION BY 3053 01:55:58,280 --> 01:55:59,240 LOOKING AT PIECES THAT FALL 3054 01:55:59,240 --> 01:56:00,760 APART AND WHAT THEY ADDED UP TO 3055 01:56:00,760 --> 01:56:04,120 COME BACK TO TOGETHER BUT 3056 01:56:04,120 --> 01:56:05,680 THEY'RE ALSO LA BILE GROUP THAT 3057 01:56:05,680 --> 01:56:07,080 DON'T SHOW US THE BREAK DOWN 3058 01:56:07,080 --> 01:56:11,040 WHILE ATTACHED TO THE PEPTIDE. 3059 01:56:11,040 --> 01:56:14,120 SILIC ASITS AND AXONION IONS 3060 01:56:14,120 --> 01:56:23,200 DERIVED FROM ACID CONTAINING 3061 01:56:23,200 --> 01:56:23,440 IONS. 3062 01:56:23,440 --> 01:56:24,440 EVEN THOUGH THOSE AREN'T 3063 01:56:24,440 --> 01:56:27,720 ATTACHED TO THE PEPTIDE, WHEN WE 3064 01:56:27,720 --> 01:56:29,640 OBSERVE THEM, THEY CAN TELL US 3065 01:56:29,640 --> 01:56:32,240 THAT THE MONOSACCHARIDE FOR THE 3066 01:56:32,240 --> 01:56:34,800 WHOLE MONOSACCHARIDE ATTACHED TO 3067 01:56:34,800 --> 01:56:46,720 ANOTHER MONOSACCHARIDE 1, SAY WE 3068 01:56:46,720 --> 01:57:03,880 HAVE A AVE A GLYCAN THAT HAS--OR 3069 01:57:03,880 --> 01:57:08,280 IT COULD BE A GAL ALPHA GALL 3070 01:57:08,280 --> 01:57:09,680 WITH A DEOXYHEX OAZ ATTACHED 3071 01:57:09,680 --> 01:57:10,800 SOMEWHERE BUT FOR LACK OF A 3072 01:57:10,800 --> 01:57:12,360 BETTER PLACE TO DRAW IT WILL 3073 01:57:12,360 --> 01:57:18,040 SHOW IT ATTACHED TO THIS 3074 01:57:18,040 --> 01:57:18,560 TERMINAL. 3075 01:57:18,560 --> 01:57:19,880 THESE 2 BRANCHES ARE NEARLY THE 3076 01:57:19,880 --> 01:57:25,800 SAME PASS, THEY DIFFER BY ONLY 3077 01:57:25,800 --> 01:57:26,680 .11 DALTON WITHERSPOONERS, NOW 3078 01:57:26,680 --> 01:57:29,680 WE COULD SAY WHEN WE LOOK FOR 3079 01:57:29,680 --> 01:57:32,320 THE ION BUT THE REST OF OUR 3080 01:57:32,320 --> 01:57:34,600 STRUCTURE HAS SIALOGLYCANSIC 3081 01:57:34,600 --> 01:57:37,080 ACID ON THIS, SO IT'S NOT 3082 01:57:37,080 --> 01:57:39,480 INDICATIVE, SO SIMILARLY WE 3083 01:57:39,480 --> 01:57:43,080 CAN'T USE THE DEOXYHEXOSE AS THE 3084 01:57:43,080 --> 01:57:44,080 DISCRIMINATING FACTOR BECAUSE 3085 01:57:44,080 --> 01:57:46,120 THERE'S 1 ON THE ORIGINAL 3086 01:57:46,120 --> 01:57:47,240 STRUCTURE AND IF WE WERE TALKING 3087 01:57:47,240 --> 01:57:49,520 ABOUT MUSEUM MANS WE COULD SAY 3088 01:57:49,520 --> 01:57:52,520 WELL HUMANS DON'T DO ALPHA GAL 3089 01:57:52,520 --> 01:57:53,480 ALPHA GAL, WE DON'T CONSIDER 3090 01:57:53,480 --> 01:57:54,960 THIS BEING IN THE SEARCH SPACE 3091 01:57:54,960 --> 01:57:56,840 BUT MAYBE WE'RE NOT DEALING WITH 3092 01:57:56,840 --> 01:57:59,080 HUMAN DATA AND YOU COULD SAY 3093 01:57:59,080 --> 01:58:00,120 THAT MASS SPECTROMETRY ALL LOVED 3094 01:58:00,120 --> 01:58:02,320 TO TALK ABOUT HOW ACCURATE YOUR 3095 01:58:02,320 --> 01:58:04,840 INSTRUMENTS ARE, THEY CAN TELL 3096 01:58:04,840 --> 01:58:06,400 WHEN A PROTEIN SNEEZES, SURELY 3097 01:58:06,400 --> 01:58:09,080 THEY CAN TELL THE DIFFERENCE 3098 01:58:09,080 --> 01:58:10,080 BETWEEN .01 DALTONS AND MOST OF 3099 01:58:10,080 --> 01:58:13,760 THE TIME THEY CAN BUT UNLESS 3100 01:58:13,760 --> 01:58:15,600 THINGS ARE WORKING PERFECTLY, 3101 01:58:15,600 --> 01:58:20,160 THIS CAN STILL HAPPEN WITH THAT 3102 01:58:20,160 --> 01:58:20,480 EXPERIMENT. 3103 01:58:20,480 --> 01:58:23,720 WHAT'S MORE IS THIS IS NOT THE 3104 01:58:23,720 --> 01:58:25,280 ONLY SITUATION WHERE WE WOULD 3105 01:58:25,280 --> 01:58:26,280 OBSERVATION THIS AMBIGUITY, 3106 01:58:26,280 --> 01:58:29,160 THERE ARE MANY, MANY SITUATIONS 3107 01:58:29,160 --> 01:58:30,800 WHERE THIS CAN OCCUR, A COMMON 1 3108 01:58:30,800 --> 01:58:33,400 IS WHEN WE ACTUALLY HAVE AN 3109 01:58:33,400 --> 01:58:35,240 ERROR IN SELECTING MONOISOTOPIC 3110 01:58:35,240 --> 01:58:39,880 MASS AND WE SUBSTITUTE ASILIC 3111 01:58:39,880 --> 01:58:42,440 ACID FOR 2 DEOXYHEXODACES. 3112 01:58:42,440 --> 01:58:45,120 WE CAN ALSO HAVE MUCH LARGER 3113 01:58:45,120 --> 01:58:47,360 AMBIGUITYS WHEN WE HAVE LARGE 3114 01:58:47,360 --> 01:58:53,880 SUBSTITUTION EVENTS AND WE ARE 3115 01:58:53,880 --> 01:58:55,960 LOOKING AT BIGGER MASS ACCURACY 3116 01:58:55,960 --> 01:58:58,200 TOLERANCE WHERE WE TAKE THIS 3117 01:58:58,200 --> 01:59:01,680 HUGE CHUNK OF GLYCAN COMPOSITION 3118 01:59:01,680 --> 01:59:05,160 AND SUBSTITUTE IT FOR HOMOGENOUS 3119 01:59:05,160 --> 01:59:06,640 HEXES, BUT YOU COULD SAY THIS IS 3120 01:59:06,640 --> 01:59:10,280 UNCOMMON AND YOU WOULDN'T EXPECT 3121 01:59:10,280 --> 01:59:11,760 SUBSTITUTION COMPLEMENT HERE TO 3122 01:59:11,760 --> 01:59:14,280 BE PRESENT IN YOUR GLYCAN 3123 01:59:14,280 --> 01:59:16,640 DATABASE AND IF YOU'RE WORKING 3124 01:59:16,640 --> 01:59:18,760 WITH A REASONABLE CONSERVATIVE 3125 01:59:18,760 --> 01:59:19,400 DATABASE THAT'S PROBABLY TRUE, 3126 01:59:19,400 --> 01:59:21,640 ABOUT YOU AS WE SEE THE RISE OF 3127 01:59:21,640 --> 01:59:23,240 DATABASE FREE RADICALS 3128 01:59:23,240 --> 01:59:25,280 APPROACHES, THIS BECOMES MORE OF 3129 01:59:25,280 --> 01:59:25,720 A CONCERN. 3130 01:59:25,720 --> 01:59:28,880 WE MIGHT ALSO BE LOOKING FOR 3131 01:59:28,880 --> 01:59:30,720 THOSE INTERESTING MODIFICATIONS 3132 01:59:30,720 --> 01:59:37,880 LIKE SULFATION OR FOSTER NURSED 3133 01:59:37,880 --> 01:59:39,560 FARALATION AND SIGNATURE IONS TO 3134 01:59:39,560 --> 01:59:41,440 DISCRIMINATE THEM BUT THEY HAVE 3135 01:59:41,440 --> 01:59:42,680 DIFFERENT FEATURES THAT WE MIGHT 3136 01:59:42,680 --> 01:59:47,240 USE WHEN WE CAN'T RELY ON THOSE. 3137 01:59:47,240 --> 01:59:50,080 ALTERNATIVELY, YOU CAN HAVE A 3138 01:59:50,080 --> 01:59:53,760 SUBSTITUTION OF SULFATE PLUS 2 3139 01:59:53,760 --> 01:59:56,200 HEX ACTS AND REPLACE THAT WITH 3 3140 01:59:56,200 --> 02:00:02,080 HEXOSES AND WITH A RELATIVELY 3141 02:00:02,080 --> 02:00:04,320 NEAR THE SAME, COMPOSITION AT 3142 02:00:04,320 --> 02:00:07,680 THE ROOT OF THE GLYCAN. 3143 02:00:07,680 --> 02:00:09,680 AT A LARGE ENOUGH TOTAL DPLI 3144 02:00:09,680 --> 02:00:13,280 KAN--KANA MASS, THIS IS TOTALLY 3145 02:00:13,280 --> 02:00:20,400 FINE FOR--GLYCAN MASS THIS IS 3146 02:00:20,400 --> 02:00:22,560 TOTALLY FIEP FOR A MISMATCH 3147 02:00:22,560 --> 02:00:24,560 BECAUSE WE'RE UNRELIABLE TO 3148 02:00:24,560 --> 02:00:27,360 IDENTIFY SODIUM AS AN ION AND IF 3149 02:00:27,360 --> 02:00:29,000 YOU DON'T KNOW YOU'RE LOOKING AT 3150 02:00:29,000 --> 02:00:31,080 SOMETHING WITH SULFATION ON IT 3151 02:00:31,080 --> 02:00:33,000 YOU MIGHT VERY WELL ACCEPT THE 3152 02:00:33,000 --> 02:00:35,080 IDENTIFICATION OF THOSE 3 HEXES. 3153 02:00:35,080 --> 02:00:35,920 IT'S JUST THE FACT THAT 3154 02:00:35,920 --> 02:00:37,560 SULFATION IS NOT PART OF A 3155 02:00:37,560 --> 02:00:43,040 COMMON SEARCH SPACE COMPONENTS. 3156 02:00:43,040 --> 02:00:45,440 THE SAME THING WILL APPLY FOR 3157 02:00:45,440 --> 02:00:47,280 PHOSPHORYLATION, TOO, IF YOU'RE 3158 02:00:47,280 --> 02:00:48,360 DEALING WITH MAMMALIAN GLYCANS 3159 02:00:48,360 --> 02:00:50,680 YOU HAVE SO MANY MORE 3160 02:00:50,680 --> 02:00:52,640 OPPORTUNITIES TO MAKE MISTAKES 3161 02:00:52,640 --> 02:01:00,640 AS UGC AND UAC ARE DIRECT 3162 02:01:00,640 --> 02:01:02,880 SUBSTITUTIONS WITH HEXOSE, OR 3163 02:01:02,880 --> 02:01:04,200 DEOXYHEXOSE TO BE PAIRED WITH SO 3164 02:01:04,200 --> 02:01:06,680 ALL THE PROBLEMS WE HAVE WITH 3165 02:01:06,680 --> 02:01:11,360 SALIC ACID WE WILL HAVE WITH 3166 02:01:11,360 --> 02:01:11,520 UGC. 3167 02:01:11,520 --> 02:01:15,600 NOW IF WE WERE TO LOOK AT A 3168 02:01:15,600 --> 02:01:17,440 PROSTATE CANCER SERUM DATA SET, 3169 02:01:17,440 --> 02:01:19,080 TAKEN FROM THIS PUBLISHED DATA 3170 02:01:19,080 --> 02:01:20,720 SET, THANK TO YOU THE AUTHORS 3171 02:01:20,720 --> 02:01:22,360 WHO PROVIDED THIS DAT TO BE 3172 02:01:22,360 --> 02:01:27,400 FREELY AVAILABLE, YOU SEE THIS 3173 02:01:27,400 --> 02:01:28,040 BIMODAL CHROMEATOGRAPHIC PEAK 3174 02:01:28,040 --> 02:01:43,920 FOR THIS GRID SERVICES KAN--KANA 3175 02:01:43,920 --> 02:01:45,880 AND ANOTHER PEAK PRIMATES MORDAL 3176 02:01:45,880 --> 02:01:47,080 DPLI KAN--KANA, AND ANOTHER PEAK 3177 02:01:47,080 --> 02:01:52,720 BUT IT'S GAINED A HEXOSE AND A 3178 02:01:52,720 --> 02:01:55,120 FUCOSIDOSIS. 3179 02:01:55,120 --> 02:01:57,000 THEY HAVE ADENTICAL PEAK APEXS 3180 02:01:57,000 --> 02:01:58,480 EVEN FOR THE 2 DIFFERENT MODES 3181 02:01:58,480 --> 02:02:01,600 COULD THIS BE AN AMMONIUM 3182 02:02:01,600 --> 02:02:02,200 DEDUCTION FOLLOWED BY 3183 02:02:02,200 --> 02:02:05,480 SUBSTITUTION BECAUSE THIS WAS IN 3184 02:02:05,480 --> 02:02:07,120 OUR DATABASE? 3185 02:02:07,120 --> 02:02:08,800 HOW COULD WE DISTINGUISH THESE 2 3186 02:02:08,800 --> 02:02:11,200 STRUCTURES IF WE CAN'T SEE 3187 02:02:11,200 --> 02:02:17,800 RELIABLE FRAGMENTATION OF THE 3188 02:02:17,800 --> 02:02:18,160 GLYCAN. 3189 02:02:18,160 --> 02:02:20,240 WELL, MAYBE THAT'S A FLUKE BUT 3190 02:02:20,240 --> 02:02:22,240 WHAT IF WE WERE TO LOOK AT IT IN 3191 02:02:22,240 --> 02:02:25,680 THE CONTEXT OF THE ENTIRE 3192 02:02:25,680 --> 02:02:26,280 CHROMEATOGRAPHIC DISTRACTION 3193 02:02:26,280 --> 02:02:29,400 WITH ALL THE DPLI KAN--KANAS 3194 02:02:29,400 --> 02:02:30,240 ATTACHED TO IT. 3195 02:02:30,240 --> 02:02:32,880 WE THIS CLUSTER HERE OF 3196 02:02:32,880 --> 02:02:34,720 DISCIPLINARYSILATED FORMS AND 3197 02:02:34,720 --> 02:02:37,080 TRISILATED FORMS MUCH LATER AND 3198 02:02:37,080 --> 02:02:39,480 MONOSILATED FORMS MUCH EARLIER 3199 02:02:39,480 --> 02:02:41,040 BUT THAT MONOSILATED FORM WE 3200 02:02:41,040 --> 02:02:42,600 WERE JUST TALKING ABOUT AS 3201 02:02:42,600 --> 02:02:44,840 AMBIGUOUS SHOWS UP IN THE 3202 02:02:44,840 --> 02:02:46,400 DISCIPLINARYSILATED CLUSTER, IT 3203 02:02:46,400 --> 02:02:49,200 BE BE MISS PLACED OUR 3204 02:02:49,200 --> 02:02:50,680 CHROMATOGRAPHY IS WISHY WASHY WE 3205 02:02:50,680 --> 02:02:54,360 CAN'T TRUST IT ALL THE TIME. 3206 02:02:54,360 --> 02:02:57,040 WHAT IF WE LOOKED AT ANOTHER 3207 02:02:57,040 --> 02:02:57,280 DATA SET. 3208 02:02:57,280 --> 02:02:59,040 DO WE SEE THE SIMILAR PATTERN 3209 02:02:59,040 --> 02:03:03,440 THAT MAYBE WE COULD STRUOF THE 3210 02:03:03,440 --> 02:03:03,760 THIS FURTHER? 3211 02:03:03,760 --> 02:03:08,800 BUT WE HAVE THE SAME BUNDLING OF 3212 02:03:08,800 --> 02:03:10,680 TRI THAT WILLATED FORMS AND 3213 02:03:10,680 --> 02:03:11,600 DISCIPLINARY THAT WILLATED FORMS 3214 02:03:11,600 --> 02:03:14,840 BUT WE SEE THERE ARE FORMS IN 3215 02:03:14,840 --> 02:03:17,480 THE TRI THAT WILLATED CLUSTER 3216 02:03:17,480 --> 02:03:20,280 AND EVEN MONOCYTE FORMS IN THE 3217 02:03:20,280 --> 02:03:22,040 DISCIPLINARY THAT WILLATED 3218 02:03:22,040 --> 02:03:22,760 CLUSTER, DIFFERENT BACKBONE, 3219 02:03:22,760 --> 02:03:23,960 DIFFERENT DATA SETS ISSUES 3220 02:03:23,960 --> 02:03:24,800 DIFFERENT CANCER TYPES BUT STILL 3221 02:03:24,800 --> 02:03:27,960 WE SEE THE SAME THING. 3222 02:03:27,960 --> 02:03:31,680 CAN WE EXPLAIN THESE OVERLAPS. 3223 02:03:31,680 --> 02:03:34,520 WELL, WE CAN LOOK FOR SIGNATURE 3224 02:03:34,520 --> 02:03:36,600 IONS PERHAPS, WELL, HERE AT THE 3225 02:03:36,600 --> 02:03:38,640 2 TANDEM MASS SPECTRA, I 3226 02:03:38,640 --> 02:03:40,440 APOLOGIZE IN ADVANCE, THIS IS 3227 02:03:40,440 --> 02:03:47,320 GOING TO BE A COUPLE OF TEND 3228 02:03:47,320 --> 02:03:49,280 RAIN THIS TALK, SO THEY LOOK 3229 02:03:49,280 --> 02:03:53,240 SIMILAR, THERE'S MINOR VARIATION 3230 02:03:53,240 --> 02:03:55,560 IN THE IONS BUT FUNDAMENTALLY 3231 02:03:55,560 --> 02:04:00,440 ENOUGH, THERE ARE SALIC ACID TO 3232 02:04:00,440 --> 02:04:02,880 HEX NAC, TO THE IRON RATIO THAT 3233 02:04:02,880 --> 02:04:04,880 WERE CLOSE, SO IF THERE WERE A 3234 02:04:04,880 --> 02:04:06,000 WHOLE UNIT DIFFERENCE THERE 3235 02:04:06,000 --> 02:04:07,320 WOULD BE MORE PERCEPTIBLE 3236 02:04:07,320 --> 02:04:11,080 DIFFERENCE IN THE RATIO OF THOSE 3237 02:04:11,080 --> 02:04:11,680 2 IONS ABUNDANCES. 3238 02:04:11,680 --> 02:04:14,080 SOME CREDENCE THAT COULD BE 3239 02:04:14,080 --> 02:04:15,560 AMMONIA SUBSTITUTION, WHAT IF WE 3240 02:04:15,560 --> 02:04:19,400 LOOK AT ANOTHER PAIR OF GLYCO 3241 02:04:19,400 --> 02:04:22,640 FORMS FOR THIS SAME PEPTIDE 3242 02:04:22,640 --> 02:04:22,920 BACKBONE? 3243 02:04:22,920 --> 02:04:26,720 WELL, WE SEE PRETTY MUCH THE 3244 02:04:26,720 --> 02:04:29,880 SAME SITUATION, THERE'S NO FUCOS 3245 02:04:29,880 --> 02:04:33,880 E CONTAINING IONS AND THE RATIO, 3246 02:04:33,880 --> 02:04:36,440 AND THE SODIUM RATIO LOOKS 3247 02:04:36,440 --> 02:04:36,800 PRETTY SIMILAR. 3248 02:04:36,800 --> 02:04:39,680 IS THIS ENOUGH EVIDENCE TO CLAIM 3249 02:04:39,680 --> 02:04:45,920 THAT THIS IS THAT PESKY AMMONIUM 3250 02:04:45,920 --> 02:04:46,760 SUBSIDIARY TUITION AGAIN? 3251 02:04:46,760 --> 02:04:48,320 I WOULD ARGUE YES AND I HOPE TO 3252 02:04:48,320 --> 02:04:49,640 CONVINCE EVERYONE OF THAT SOON 3253 02:04:49,640 --> 02:04:51,160 BUT THE CONSEQUENCES OF NOT 3254 02:04:51,160 --> 02:04:52,800 CORRECTING THESE THINGS COULD 3255 02:04:52,800 --> 02:04:55,520 MEAN THAT YOUR QUANTIFICATION OF 3256 02:04:55,520 --> 02:04:58,680 GLYCO FORMS COULD BE OFF BY AS 3257 02:04:58,680 --> 02:04:59,880 MUCH AS 50%. 3258 02:04:59,880 --> 02:05:05,680 THE ASHES BUNKEDDANCE FROM THAT 3259 02:05:05,680 --> 02:05:08,840 CLAIM ADDUCT INCREASES THE 3260 02:05:08,840 --> 02:05:10,280 ABUNDANCE OVERALL FOR THE WHOLE 3261 02:05:10,280 --> 02:05:19,320 FLIEK O FORM CONSIDERABLY. 3262 02:05:19,320 --> 02:05:20,720 SO NOW I NEED TO CONVINCE YOU 3263 02:05:20,720 --> 02:05:21,080 THIS IS REAL. 3264 02:05:21,080 --> 02:05:23,280 SO FROM THE EARLIER DATA SET, WE 3265 02:05:23,280 --> 02:05:25,200 NEED TO SAY IF YOU WERE TO TAKE 3266 02:05:25,200 --> 02:05:27,520 2 PEPTIDES WITH GLYCANS THAT 3267 02:05:27,520 --> 02:05:29,080 DIFFER BY A SINGLE 3268 02:05:29,080 --> 02:05:31,240 MONOSACCHARIDE AND LOOK AT THEIR 3269 02:05:31,240 --> 02:05:32,680 DIFFERENCES IN RETENTION TIME, 3270 02:05:32,680 --> 02:05:37,400 WE OBSERVE A SYSTEMATIC OR 3271 02:05:37,400 --> 02:05:39,120 REGULAR RETENTION TIME CHANGE 3272 02:05:39,120 --> 02:05:41,800 ASSOCIATE WIDE THAT 3273 02:05:41,800 --> 02:05:43,200 MONOSACCHARIDE, HEX NAC AND 3274 02:05:43,200 --> 02:05:46,840 HEXOSE BOTH SHIFT A BIT EARLIER 3275 02:05:46,840 --> 02:05:48,840 AND FUCOSE HAS SLIGHTLY MORE 3276 02:05:48,840 --> 02:05:51,320 VARIATION EARLIER ON LATER, 3277 02:05:51,320 --> 02:05:53,000 HOWEVER SALIC ACID ALMOST CAN 3278 02:05:53,000 --> 02:05:56,080 ALWAYS SHIFT LATER BY A LARGE 3279 02:05:56,080 --> 02:05:56,680 AMOUNT. 3280 02:05:56,680 --> 02:05:57,840 BUT IT'S A PRETTY WIDE 3281 02:05:57,840 --> 02:05:59,800 DISTRIBUTION EMPLOY THAT WOULD 3282 02:05:59,800 --> 02:06:03,080 BE CONCERNING BECAUSE YOU WOULD 3283 02:06:03,080 --> 02:06:04,800 NOT WANT TO SEE ANY SUCH 3284 02:06:04,800 --> 02:06:08,680 VARIABILITY ANY TOOL YOU USE TO 3285 02:06:08,680 --> 02:06:09,240 CLASSIFY AN IDENTIFICATION. 3286 02:06:09,240 --> 02:06:11,480 BUT WE CAN EXPLAIN THAT BECAUSE 3287 02:06:11,480 --> 02:06:14,200 THE CHANGE IN RETENTION TIME FOR 3288 02:06:14,200 --> 02:06:16,640 A MONOSACCHARIDE VARIES OVER 3289 02:06:16,640 --> 02:06:19,840 TIME MUCH EARLY IN THE 3290 02:06:19,840 --> 02:06:21,880 EXPERIMENT, THE CHROMEATOGRAPHIC 3291 02:06:21,880 --> 02:06:23,760 RADIANT, THE RATIO OF THE ALPHA 3292 02:06:23,760 --> 02:06:25,160 COMPONENT IS AT SOME LEVEL BUT 3293 02:06:25,160 --> 02:06:27,240 LATER IN THE EXPERIMENT IT'S AT 3294 02:06:27,240 --> 02:06:34,680 ANOTHER LEVEL LEADING TO A 3295 02:06:34,680 --> 02:06:36,080 DRASTIC DIFFERENCE IN THE 3296 02:06:36,080 --> 02:06:36,920 CONDITIONS ON THE COLUMN, 3297 02:06:36,920 --> 02:06:42,800 LEADING TO THINGS FLOWING OUT A 3298 02:06:42,800 --> 02:06:43,760 DIFFERENT RATE. 3299 02:06:43,760 --> 02:06:46,280 WE CAN ALSO ENCOUNTER PROBLEMS 3300 02:06:46,280 --> 02:06:48,480 WHERE MANY DIFFERENT 3301 02:06:48,480 --> 02:06:49,400 MONOSACCHARIDES ARE DIFFERENT 3302 02:06:49,400 --> 02:06:52,040 AND MAYBE DIFFICULT TO 3303 02:06:52,040 --> 02:06:52,880 DISAMBIGUATE OR MAYBE THERE'S 3304 02:06:52,880 --> 02:06:55,080 NOT ENOUGH CONTRAST IN OUR DATA 3305 02:06:55,080 --> 02:06:58,520 TO ACCURATELY SOLVE 1 FROM THE 3306 02:06:58,520 --> 02:06:59,280 OTHER. 3307 02:06:59,280 --> 02:07:00,680 HOWEVER, THIS REGRESSION MODEL 3308 02:07:00,680 --> 02:07:02,040 THAT I'M SHOWING HERE EXPLAINS 3309 02:07:02,040 --> 02:07:06,480 95% OF THE VARIATION BETWEEN 3310 02:07:06,480 --> 02:07:12,840 PREDICTED AND OBSERVED 3311 02:07:12,840 --> 02:07:17,360 CHROMEATOGRAPHIC APEX TIMES. 3312 02:07:17,360 --> 02:07:19,400 SHOWN ANOTHER WAY, IF IF OUR 3313 02:07:19,400 --> 02:07:20,560 MODEL WERE PERFECT, EVERY DOT 3314 02:07:20,560 --> 02:07:22,720 HERE WOULD BE ALONG THIS MIDDLE 3315 02:07:22,720 --> 02:07:24,720 BEND OF THIS RESIDUAL PLOT BUT 3316 02:07:24,720 --> 02:07:29,200 WHAT WE'RE SEE SUGGEST THAT 3317 02:07:29,200 --> 02:07:30,680 WITHIN THESE CONFIDENCE 3318 02:07:30,680 --> 02:07:33,520 INTERVALS 95% OF THE VARIANCE IS 3319 02:07:33,520 --> 02:07:33,800 EXPLAINED. 3320 02:07:33,800 --> 02:07:35,080 WE HAVE A SMALL POPULATION OF 3321 02:07:35,080 --> 02:07:38,120 POINTS THAT ARE OUTSIDE OF OUR 3322 02:07:38,120 --> 02:07:41,000 PREDICTED INTERVAL, IT WAS MAYBE 3323 02:07:41,000 --> 02:07:45,160 MISIDEBTIFICATIONS, THEY MAY BE 3324 02:07:45,160 --> 02:07:49,080 CHROMEATOGRAPHIC ARTIFACTS, 3325 02:07:49,080 --> 02:07:50,160 REQUIRES FURTHER STUDY. 3326 02:07:50,160 --> 02:07:51,920 LET ME NOW DEFINE THE MODEL THAT 3327 02:07:51,920 --> 02:07:54,120 I'M USING, I WILL TALK ABOUT THE 3328 02:07:54,120 --> 02:07:57,080 APEX TIME OF A GLYCO PEPTIDE FOR 3329 02:07:57,080 --> 02:08:01,880 THE FUNCTION OF THE DPLI 3330 02:08:01,880 --> 02:08:02,480 --GLYCAN AND 3331 02:08:02,480 --> 02:08:04,480 THE FUNCTION IT'S ATTACHED TO. 3332 02:08:04,480 --> 02:08:06,120 EVERY PEPTIDE WILL HAVE ITS OWN 3333 02:08:06,120 --> 02:08:07,720 STARTING EVOLUTION TIME, THIS IS 3334 02:08:07,720 --> 02:08:08,920 THE SAME SORT OF STARTING POINT 3335 02:08:08,920 --> 02:08:11,040 YOU WOULD GET FROM 1 OF THOSE 3336 02:08:11,040 --> 02:08:13,840 NEW FANGLED DEEP LEARNING BASED 3337 02:08:13,840 --> 02:08:15,040 PEPTIDE RETENTION TIME 3338 02:08:15,040 --> 02:08:17,200 PREDICTERS THAT EVERYONE IS 3339 02:08:17,200 --> 02:08:20,680 USING IN NORMAL PROTEOMICS, BUT 3340 02:08:20,680 --> 02:08:23,120 FOR THE PURPOSES THE STARTING 3341 02:08:23,120 --> 02:08:24,680 POINT FOR THE EVOLUTION ORDER FF 3342 02:08:24,680 --> 02:08:26,840 ALL THE GLYCO FORMS OF THAT 3343 02:08:26,840 --> 02:08:29,880 PEPTIDE AS WELL, WE THEN ADD 3344 02:08:29,880 --> 02:08:32,280 SOME SHIFT, SPECIFIC TO 3345 02:08:32,280 --> 02:08:32,960 EACH,AMOUNT OF SACCHARIDE 3346 02:08:32,960 --> 02:08:34,600 COMPONENT IN THE DPLI KAN--KANA 3347 02:08:34,600 --> 02:08:35,840 COMPOSITION THAT IS MULTILIE 3348 02:08:35,840 --> 02:08:38,120 PLIED BY THE NUMBER OF TIME WEES 3349 02:08:38,120 --> 02:08:41,680 HAVE THAT MONOSACCHARIDE 3350 02:08:41,680 --> 02:08:43,880 COMPONENT PLUS AN ERROR. 3351 02:08:43,880 --> 02:08:44,920 BECAUSE THIS CHANGES OVER TIME, 3352 02:08:44,920 --> 02:08:49,600 WE NEED TO HAVE THE MODEL ALSO 3353 02:08:49,600 --> 02:08:51,000 CHANGE OVER TIME AND WHILE WE 3354 02:08:51,000 --> 02:08:56,560 COULD FIT A MODEL THAT USES 3355 02:08:56,560 --> 02:08:57,280 PRIOR INFORMATION SEQUENTIALLY 3356 02:08:57,280 --> 02:09:02,880 THAT RUNS THE RISK OF ABSORBING 3357 02:09:02,880 --> 02:09:05,480 ERRORS ON 1 END BUT NOT THE 3358 02:09:05,480 --> 02:09:09,840 OTHER END SO, FROM EARLIER BUT 3359 02:09:09,840 --> 02:09:10,680 NOT LATER. 3360 02:09:10,680 --> 02:09:12,160 ADDITIONALLY WE NEED A WAY TO 3361 02:09:12,160 --> 02:09:15,480 MAKE SURE THOSE AMENIUM ADDUCTS 3362 02:09:15,480 --> 02:09:18,000 DON'T CUE THE WAY THAT THE MODEL 3363 02:09:18,000 --> 02:09:21,120 LEARNS, SO WE NEED TO START BY 3364 02:09:21,120 --> 02:09:22,560 FITTING THE MODEL ON THE FLIEK O 3365 02:09:22,560 --> 02:09:29,360 PEPTIDES THAT ARE IDENTIFIED 3366 02:09:29,360 --> 02:09:31,400 BOTH AMMONIA OR ADDUCTED IF WE 3367 02:09:31,400 --> 02:09:34,160 DON'T SEARCH FOR AMMONIUM ADDUCT 3368 02:09:34,160 --> 02:09:34,880 WE CAN'T RULINNATED ANTIGENS 3369 02:09:34,880 --> 02:09:37,680 THEM OUT BUT WE EXPECT THE MODEL 3370 02:09:37,680 --> 02:09:38,000 TO BE ROBUST. 3371 02:09:38,000 --> 02:09:41,520 THAT ITERATIVELY FIT THE MODEL 3372 02:09:41,520 --> 02:09:44,320 THAT INCREASINGLY LESS CONFIDENT 3373 02:09:44,320 --> 02:09:46,840 OBSERVATIONS IN EACH OF THESE 3374 02:09:46,840 --> 02:09:50,160 TIME BUCKETS BY SAYING WELL, 3375 02:09:50,160 --> 02:09:55,120 THESE GLYCO FORMS WERE INCLUDED 3376 02:09:55,120 --> 02:09:56,560 IN THE LAST FIT SO WE BELIEVE 3377 02:09:56,560 --> 02:10:01,320 THE MODEL WILL BE BETTER AT 3378 02:10:01,320 --> 02:10:04,120 PREDICTING THE CORRECT 3379 02:10:04,120 --> 02:10:05,880 IDENTIFICATION FOR THIS NEW 3380 02:10:05,880 --> 02:10:08,720 GLYCO PEPTIDE THAT WE'RE NOT YET 3381 02:10:08,720 --> 02:10:11,360 CONFIDENT IN ANDA ADD THAT 3382 02:10:11,360 --> 02:10:13,320 INFORMATION TO THE NEXT MODEL 3383 02:10:13,320 --> 02:10:15,680 CAN TRAIN ON. 3384 02:10:15,680 --> 02:10:17,800 ADDITIONALLY WE CAN CORRECT GLUE 3385 02:10:17,800 --> 02:10:19,640 MARIOUS CAN IDENTIFICATIONS ON 3386 02:10:19,640 --> 02:10:25,000 EACH GLYCO PEPTIDE AS THE MODEL 3387 02:10:25,000 --> 02:10:25,560 RUNS PERFORMS INCREMENTAL 3388 02:10:25,560 --> 02:10:27,360 REVISION SO THAT WE CAN CORRECT 3389 02:10:27,360 --> 02:10:30,320 FOR ERRORS BEFORE WE LET THEM 3390 02:10:30,320 --> 02:10:39,280 PROPAGATE THROUGH THE MODEL. 3391 02:10:39,280 --> 02:10:41,120 SO SAY WE HAVE THAT SITUATION I 3392 02:10:41,120 --> 02:10:43,320 DESCRIBED EARLIER WHERE WE CAN'T 3393 02:10:43,320 --> 02:10:45,080 TELL THE DIFFERENCE BETWEEN THIS 3394 02:10:45,080 --> 02:10:47,200 ANTENNA AND THAT ANTENNA AND WE 3395 02:10:47,200 --> 02:10:49,040 HAVE RESERVED ATTENTION TIME FOR 3396 02:10:49,040 --> 02:10:51,120 THAT GLYCO PEPTIDE SO WE FIND 3397 02:10:51,120 --> 02:10:53,480 OUT WHICH CANDIDATE IS BEST, BUT 3398 02:10:53,480 --> 02:10:56,120 THIS MODEL IS SPECIFIED A AS 3399 02:10:56,120 --> 02:10:57,760 LINEAR MODEL SO WE CAN DEFINE 3400 02:10:57,760 --> 02:11:00,520 SOME SCORE AS A FUNCTION OF THE 3401 02:11:00,520 --> 02:11:02,400 PREDICTION INTERVAL SO JUST A 3402 02:11:02,400 --> 02:11:03,560 CONFIDENCE INTERVAL AROUND WHEN 3403 02:11:03,560 --> 02:11:04,680 THE EARLIEST POINT IS THAT IS 3404 02:11:04,680 --> 02:11:07,080 OBSERVED AND WHEN IT WOULD END, 3405 02:11:07,080 --> 02:11:08,480 OR WHEN WE WOULD NOT EXPECT IT 3406 02:11:08,480 --> 02:11:10,560 TO BE OBSERVED LATER. 3407 02:11:10,560 --> 02:11:14,040 IF WE WERE TO USE 1 GLYCAN WE 3408 02:11:14,040 --> 02:11:16,200 WILL GET A PREDICTION GIVEN IT'S 3409 02:11:16,200 --> 02:11:17,840 STARTING AT A CERTAIN TIME 3410 02:11:17,840 --> 02:11:20,400 SELECT THE MODEL AT 23 MINUTES 3411 02:11:20,400 --> 02:11:22,440 AND ANOTHER OF THE OTHER GLYCO 3412 02:11:22,440 --> 02:11:29,760 FORM AT 29 MINUTES WHICH GIVES 3413 02:11:29,760 --> 02:11:30,800 US THIS NEW TIME WHICH SUGGEST 3414 02:11:30,800 --> 02:11:32,680 THIS IS IS THE CORRECT 3415 02:11:32,680 --> 02:11:33,280 ADDITIONAL ANTENNA. 3416 02:11:33,280 --> 02:11:35,400 WE CAN DEFINE THE SCORE IN TERMS 3417 02:11:35,400 --> 02:11:37,280 OF THE PREDECLARATION INTERVAL 3418 02:11:37,280 --> 02:11:43,120 HERE, BUT THE SPECIFICS AREN'T 3419 02:11:43,120 --> 02:11:43,480 IMPORTANT. 3420 02:11:43,480 --> 02:11:45,480 TO AVOID LETTING THIS REVISION 3421 02:11:45,480 --> 02:11:47,000 PROCESS RUN RAM PANT, WE CAN 3422 02:11:47,000 --> 02:11:48,720 INCLUDE A CONSTRAINT THAT WE 3423 02:11:48,720 --> 02:11:50,120 CAN'T REDUCE THE AMOUNT OF 3424 02:11:50,120 --> 02:11:52,200 SIGNAL EXPLAIN BY MORE THAN 5% 3425 02:11:52,200 --> 02:11:55,480 SO WE CAN'T GET RID OF A SODIUM 3426 02:11:55,480 --> 02:11:57,040 IEKSON THAT'S ABUNDANT OR A 3427 02:11:57,040 --> 02:11:59,440 PEPTIDE PLUS 1 ION LIKE A 3428 02:11:59,440 --> 02:12:02,160 DPLUICOSE ATTACHMENT THAT WOULD 3429 02:12:02,160 --> 02:12:03,120 UNDERMINE THE CORRECT 3430 02:12:03,120 --> 02:12:05,240 IDENTIFICATION EVEN IF THE MODEL 3431 02:12:05,240 --> 02:12:06,400 IS REALLY CONFIDENT BECAUSE IT'S 3432 02:12:06,400 --> 02:12:14,280 NOT LEARNED THE RIGHT ANSWERS 3433 02:12:14,280 --> 02:12:14,520 YET. 3434 02:12:14,520 --> 02:12:16,680 SO IF WE HAVE THIS IN THE 3435 02:12:16,680 --> 02:12:19,440 ADDITIONAL CHANGE IN THE 3436 02:12:19,440 --> 02:12:21,200 RADIATION BECAUSE THE AUTHORS 3437 02:12:21,200 --> 02:12:22,920 DECIDED AT 180 MINUTES TO REALLY 3438 02:12:22,920 --> 02:12:24,480 SPEED UP THE CHANGE IN BETA TO 3439 02:12:24,480 --> 02:12:28,600 ALPHA WE CAN OBSERVE THE MODEL 3440 02:12:28,600 --> 02:12:31,960 PICKS THAT UP AND UPDATES 3441 02:12:31,960 --> 02:12:32,400 PRIMERS ACCORDINGLY. 3442 02:12:32,400 --> 02:12:34,200 IT DOES HOWEVER HAVE A POINT 3443 02:12:34,200 --> 02:12:37,480 WHERE, IT IS USHED DETERMINED TO 3444 02:12:37,480 --> 02:12:40,840 DIFFERENTIATE HEX NAT FROM 3445 02:12:40,840 --> 02:12:43,800 HEXOSE SO TD 2 PARAMETERS WORK 3446 02:12:43,800 --> 02:12:48,200 WELL TOGETHER AND THIS EXPLAINS 3447 02:12:48,200 --> 02:12:50,720 98% OF THE OPERATION OBSERVED. 3448 02:12:50,720 --> 02:12:53,640 SO LOOKING AT THOSE PLOTS WE CAN 3449 02:12:53,640 --> 02:12:59,160 SEE THE SAME TRENDS FOR FUCOSE 3450 02:12:59,160 --> 02:13:00,040 AND HEX NAC ARE PRESENT AND 3451 02:13:00,040 --> 02:13:03,240 DON'T CHANGE BY THAT MUCH BUT WE 3452 02:13:03,240 --> 02:13:07,280 CAN SEE THAT SALIC ACID DELTAS 3453 02:13:07,280 --> 02:13:07,880 ACTUALLY FORM ASKEWED 3454 02:13:07,880 --> 02:13:09,080 DISTRIBUTION INSTEAD OF A NORMAL 3455 02:13:09,080 --> 02:13:10,480 DISTRIBUTION WHICH WE SAW 3456 02:13:10,480 --> 02:13:13,160 EARLIER WHICH REFLECTS THAT 3457 02:13:13,160 --> 02:13:15,280 SHARP CHANGE IN ITS BEHAVIOR 3458 02:13:15,280 --> 02:13:18,600 WHEN THE GRADEIENT CHANGED NOW 3459 02:13:18,600 --> 02:13:21,480 WHAT ARE THE CONSEQUENCES IF YOU 3460 02:13:21,480 --> 02:13:24,480 USE THIS FOR IDENTIFICATION 3461 02:13:24,480 --> 02:13:24,760 PURPOSES. 3462 02:13:24,760 --> 02:13:28,640 IF YOU WERE TO RUN A DATABASE 3463 02:13:28,640 --> 02:13:30,600 SEARCH WITHOUT AMMONIUM ADDUCTS 3464 02:13:30,600 --> 02:13:34,480 OR RETENTION TIME CORRECTION, 3465 02:13:34,480 --> 02:13:37,720 YOU WOULD IDENTIFY OVER 580 3466 02:13:37,720 --> 02:13:38,560 DISTINCT GLYCO PEPTIDES AND YOU 3467 02:13:38,560 --> 02:13:41,040 LIKE THAT NUMBER BECAUSE IT'S 3468 02:13:41,040 --> 02:13:41,280 BIG. 3469 02:13:41,280 --> 02:13:44,560 BUT IT YOU WERE TO SEARCH FOR 3470 02:13:44,560 --> 02:13:45,920 AMMON CRUM ADDUCTS THAT NUMBER 3471 02:13:45,920 --> 02:13:48,280 WOULD FALL DOWN TO 474 BECAUSE 3472 02:13:48,280 --> 02:13:50,480 YOU TAKE GLYCANS LIKE THIS, AND 3473 02:13:50,480 --> 02:13:53,040 MERGE THEM INTO OTHER DPLI 3474 02:13:53,040 --> 02:13:54,760 KAN--KANAS LIKE THIS. 3475 02:13:54,760 --> 02:13:57,280 REDUCING THE TOTAL NUMBER OF 3476 02:13:57,280 --> 02:13:59,280 DISTINCT GLYCO FORMS THAT YOU 3477 02:13:59,280 --> 02:14:03,120 IDENTIFIED BUT HAVING A SMALLER 3478 02:14:03,120 --> 02:14:04,200 MORE CORRECT SUBSET. 3479 02:14:04,200 --> 02:14:06,480 AND ALSO IMPROVE YOUR 3480 02:14:06,480 --> 02:14:07,000 QUANTIFICATION ACCURACY. 3481 02:14:07,000 --> 02:14:08,520 LIKE I SAID BEFORE, YOU CAN SEE 3482 02:14:08,520 --> 02:14:11,560 UP TO A 50% INCREASE IN 3483 02:14:11,560 --> 02:14:13,880 ABUNDANCE OF RILE GLYCO FORMS 3484 02:14:13,880 --> 02:14:15,640 WHEN YOU CORRECT FOR ADDUCTS. 3485 02:14:15,640 --> 02:14:18,280 IF YOU FURTHER USE RETENTION 3486 02:14:18,280 --> 02:14:22,320 TIME MODELING, AND NOT JUST 3487 02:14:22,320 --> 02:14:23,520 EXACT OVERLAP TO CORRECT FOR 3488 02:14:23,520 --> 02:14:29,080 ADDUCTION, YOU CAN SEE A SET OF 3489 02:14:29,080 --> 02:14:29,680 38 ADDITIONAL CORRECTIONS 3490 02:14:29,680 --> 02:14:33,240 COMPARED TO WHAT YOU GET FROM 3491 02:14:33,240 --> 02:14:36,360 TOTAL INTERSECTION AND EVEN A 3492 02:14:36,360 --> 02:14:37,720 FEW MORE IDENTIFICATIONS GET 3493 02:14:37,720 --> 02:14:39,560 CORRECTED BY THE ABILITY TO 3494 02:14:39,560 --> 02:14:41,640 CORRECT THOSE OTHER AMBIGUITYS 3495 02:14:41,640 --> 02:14:44,880 LIKE MONOCISE O TOPIC PEAK 3496 02:14:44,880 --> 02:14:46,360 ERRORRORS OR THOSE LARGE 3497 02:14:46,360 --> 02:14:47,360 SUBSTITUTION SO CAN YOU SEE A 3498 02:14:47,360 --> 02:14:48,760 HUGE DIFFERENCE IN THE RESULTS 3499 02:14:48,760 --> 02:14:50,400 YOU GET, BUT YOU KNOW I CAN 3500 02:14:50,400 --> 02:14:52,480 CLAIM WHATEVER I LIKE IF I CAN'T 3501 02:14:52,480 --> 02:14:54,480 SHOW THAT THERE'S AN UNCERTAINTY 3502 02:14:54,480 --> 02:14:57,200 ESTIMATE THAT'S ASSOCIATED WITH 3503 02:14:57,200 --> 02:14:58,680 THE CORRECTIONS, IT DOESN'T 3504 02:14:58,680 --> 02:15:00,800 MATTER, HOWEVER, I CAN TAKE THE 3505 02:15:00,800 --> 02:15:03,880 PREDICTIONS THAT I'VE MADE AND 3506 02:15:03,880 --> 02:15:06,160 SHUFFLE THE ASSOCIATED LABELS 3507 02:15:06,160 --> 02:15:13,720 AND SHOW THAT THE MODEL STILL 3508 02:15:13,720 --> 02:15:17,080 PROVIDES USEFUL RESULTS EVEN AT 3509 02:15:17,080 --> 02:15:18,280 A RELATIVELY LARGE DISTANCE FROM 3510 02:15:18,280 --> 02:15:20,800 THE TRUSTEES, AND THE PREDICTION 3511 02:15:20,800 --> 02:15:21,160 INTERVAL. 3512 02:15:21,160 --> 02:15:22,240 HOWEVER, THE PREDICTION INTERVAL 3513 02:15:22,240 --> 02:15:25,280 IS ONLY A FEW MINUTES WIDE, SO 3514 02:15:25,280 --> 02:15:34,960 THIS ISN'T ENOUGH TO DRASTICALLY 3515 02:15:34,960 --> 02:15:35,480 DISIEW IDENTIFICATIONS. 3516 02:15:35,480 --> 02:15:37,960 TO BACK UP THAT CLAIM, THE 3517 02:15:37,960 --> 02:15:39,280 PREDICTION IS DRAWN HERE, 3518 02:15:39,280 --> 02:15:40,640 PREDICTION FROM THE CENTER OUT 3519 02:15:40,640 --> 02:15:42,760 TO THESE ORSWRONTAL LINES, IT'S 3520 02:15:42,760 --> 02:15:44,200 ONLY ABOUT 4 MINUTES AND WE CAN 3521 02:15:44,200 --> 02:15:46,160 SEE THERE ARE VERY FEW 3522 02:15:46,160 --> 02:15:52,280 ASSIGNMENTS THAT FALL OUTSIDE 3523 02:15:52,280 --> 02:15:52,640 THAT RANGE. 3524 02:15:52,640 --> 02:15:54,880 IF YOU DON'T USE RETENTION TIME 3525 02:15:54,880 --> 02:15:56,240 MODELING WITH THIS DATA SET YOU 3526 02:15:56,240 --> 02:15:59,000 COULD END UP MISSING FLIEK O 3527 02:15:59,000 --> 02:16:00,720 FORMS ENTIRELY BECAUSE ERRORS 3528 02:16:00,720 --> 02:16:04,640 LEAD TO THEM NOT BEING 3529 02:16:04,640 --> 02:16:05,440 ASSIGNABLE AT ALL. 3530 02:16:05,440 --> 02:16:08,120 THIS WOULD BE COMPLETELY 3531 02:16:08,120 --> 02:16:09,000 MISASSIGNED BECAUSE IT DOESN'T 3532 02:16:09,000 --> 02:16:10,680 HAVE SUFFICIENT EVIDENT IN THE 3533 02:16:10,680 --> 02:16:11,840 FRAGMENTATION ALONE TO CONVINCE 3534 02:16:11,840 --> 02:16:14,560 YOU OF THIS LARGE GLYCO FORM 3535 02:16:14,560 --> 02:16:17,040 EVEN THOUGH THE RETENTION TIME 3536 02:16:17,040 --> 02:16:17,280 FITS. 3537 02:16:17,280 --> 02:16:19,280 SIMILARLY, IT CAN HELP TO 3538 02:16:19,280 --> 02:16:22,280 SUPPORT THE PRESENCE OF OTHER 3539 02:16:22,280 --> 02:16:23,800 LOW QUALITY FRAGMENTATION EVENTS 3540 02:16:23,800 --> 02:16:25,560 ON OTHER GLYCO PEPTIDES, AGAIN 3541 02:16:25,560 --> 02:16:26,440 WE DON'T HAVE SUFFICIENT 3542 02:16:26,440 --> 02:16:29,360 EVIDENCE TO ASSIGN EXACTLY THIS 3543 02:16:29,360 --> 02:16:32,320 GLYCAN COMPOSITION. 3544 02:16:32,320 --> 02:16:34,000 BUT RETENTION TIME AND SUPPORT 3545 02:16:34,000 --> 02:16:36,680 EVIDENCE FROM OVERLAPPING FLIEK 3546 02:16:36,680 --> 02:16:39,120 O FORMS HIT, AND FINALLY NO 3547 02:16:39,120 --> 02:16:42,800 PRESENTATION IS COMPLETE WITHOUT 3548 02:16:42,800 --> 02:16:45,280 MENTIONING SARS-COV-2, GLYCO 3549 02:16:45,280 --> 02:16:50,720 PROTEOMICS HERE IS A SAMPLE FROM 3550 02:16:50,720 --> 02:16:54,000 1 OF TD ORGANIZERS VERY OWN DATA 3551 02:16:54,000 --> 02:16:55,080 SETS, THANK YOU VERY MUCH FOR 3552 02:16:55,080 --> 02:16:56,640 PROVIDING THIS SLIDE TO ME, WE 3553 02:16:56,640 --> 02:16:59,320 CAN SEE THAT IT PRODUCED LARGE 3554 02:16:59,320 --> 02:17:00,120 RETENTION TIME DELTASENTIOUS 3555 02:17:00,120 --> 02:17:02,960 SPECIALLY FOR THIS LONG RADIANT 3556 02:17:02,960 --> 02:17:04,720 OF OVER 400 MINUTE THIS IS MODEL 3557 02:17:04,720 --> 02:17:07,880 EXPLAINS 90% OF THE VARIABLE 3558 02:17:07,880 --> 02:17:09,080 ITSELF, AND PART OF THIS HAS TO 3559 02:17:09,080 --> 02:17:10,720 DO WITH JUST THE MAGNITUDE OF 3560 02:17:10,720 --> 02:17:14,680 THE DELTAS THAT WE SEE. 3561 02:17:14,680 --> 02:17:16,520 HERE'S THAT SAME RERIDDUAL PLOT 3562 02:17:16,520 --> 02:17:18,160 WHERE WE SEE THAT MOST OF THE 3563 02:17:18,160 --> 02:17:19,480 PREDICTIONS FOR THOSE 3564 02:17:19,480 --> 02:17:23,280 IDENTIFICATIONS FALL WITHIN THE 3565 02:17:23,280 --> 02:17:24,120 PREDICTION WITH APPROXIMATELY 10 3566 02:17:24,120 --> 02:17:25,200 MINUTES EVEN THOUGH WE HAVE A 3567 02:17:25,200 --> 02:17:28,880 HUGE SPREAD OF ADDITIONAL DIERKS 3568 02:17:28,880 --> 02:17:29,280 DENTIFICATIONS. 3569 02:17:29,280 --> 02:17:35,000 BECAUSE OF THE DEPTH OF COVERAGE 3570 02:17:35,000 --> 02:17:36,960 ON THIS DATA SET IT'S MUCH 3571 02:17:36,960 --> 02:17:40,080 EASIER FOR ANY SEARCH ENGINE TO 3572 02:17:40,080 --> 02:17:41,800 INCORRECTLY ACCEPT TOO MANY 3573 02:17:41,800 --> 02:17:46,000 IDs BECAUSE WE DON'T HAVE A 3574 02:17:46,000 --> 02:17:48,680 VERY STABLE FALSE DORPHY RATE 3575 02:17:48,680 --> 02:17:50,320 ESTIMATION PROCEDURE FOR GLYCO 3576 02:17:50,320 --> 02:17:54,560 PEPTIDES, HOWEVER, WE CAN USE 3577 02:17:54,560 --> 02:17:55,360 THIS ADDITIONAL COMPLIMENTARY 3578 02:17:55,360 --> 02:17:56,880 INFORMATION TOOL TO RILE OUT 3579 02:17:56,880 --> 02:17:59,200 SOME OF THESE REALLY WILD 3580 02:17:59,200 --> 02:18:01,000 OFFBASE IDENTIFICATIONS THAT IF 3581 02:18:01,000 --> 02:18:01,720 WE CHOOSE TO. 3582 02:18:01,720 --> 02:18:04,680 WE CAN ALSO USE IT TO SUPPORT 3583 02:18:04,680 --> 02:18:05,720 SULFATED GLYCO PEPTIDE 3584 02:18:05,720 --> 02:18:08,080 IDENTIFICATION, HERE WE CAN SEE 3585 02:18:08,080 --> 02:18:10,080 WE HAVE ENTIRELY NEUTRAL GLYCO 3586 02:18:10,080 --> 02:18:13,640 FORMS THIS PUNNEDLE CONTAINS 3587 02:18:13,640 --> 02:18:15,400 MONOSILLATED GLYCO FORMS AND 3588 02:18:15,400 --> 02:18:16,600 MONOSULFATED GLYCO FORMS AND 3589 02:18:16,600 --> 02:18:18,680 THEN WE HAVE A BUNDLE OF TBLIEK 3590 02:18:18,680 --> 02:18:21,240 O FORMS COMING OUT MUCH LATER 3591 02:18:21,240 --> 02:18:23,520 SULFATION DOESN'T REALLY HAVE A 3592 02:18:23,520 --> 02:18:29,080 GOOD RELIABLE SIGNATURE ION LIKE 3593 02:18:29,080 --> 02:18:30,600 HEXON NAC SULFATE BUT BASED ON 3594 02:18:30,600 --> 02:18:31,880 RETENTION TIME AND THIS TINY 3595 02:18:31,880 --> 02:18:33,520 LITTLE PEAK WE CAN SAY THIS IS 3596 02:18:33,520 --> 02:18:34,480 CORRECT DPLI KAN--KANA 3597 02:18:34,480 --> 02:18:38,080 ASSIGNMENT SO IN CONCLUSION, 3598 02:18:38,080 --> 02:18:39,000 RETENTION TIME IS ANOTHER 3599 02:18:39,000 --> 02:18:40,080 IMPORTANT DIMENSION FOR 3600 02:18:40,080 --> 02:18:42,360 CONTROLLING THE ACCURACY OF YOUR 3601 02:18:42,360 --> 02:18:45,120 GLYCO PEPTIDE ESTIMATION AND 3602 02:18:45,120 --> 02:18:46,400 IDENT IIVES, COMMON DPLI 3603 02:18:46,400 --> 02:18:48,280 KAN--KANA MODIFICATIONS MAY BE 3604 02:18:48,280 --> 02:18:49,400 CONCEALED BY NEARLY ISOBARIC 3605 02:18:49,400 --> 02:18:52,280 MASSES IF YOU DON'T LOOK FOR 3606 02:18:52,280 --> 02:18:54,560 DELTA RETENTION TIMES AND 3607 02:18:54,560 --> 02:18:56,760 UNKREKED ADDUCTS CAN CORRUPT OR 3608 02:18:56,760 --> 02:18:58,080 CONSEE SEAL QUANTITATIVE 3609 02:18:58,080 --> 02:18:59,480 MEASUREMENTS OF GLYCO FORM 3610 02:18:59,480 --> 02:19:01,480 ABUNDANCES, THANK YOU ALL FOR 3611 02:19:01,480 --> 02:19:02,280 YOUR PATIENCE IN SITTING THROUGH 3612 02:19:02,280 --> 02:19:02,680 THE TALK. 3613 02:19:02,680 --> 02:19:06,880 I WOULD LIKE TO THANK THE 3614 02:19:06,880 --> 02:19:08,840 RESEARCH GROUP AT BOSTON 3615 02:19:08,840 --> 02:19:12,240 UNIVERSITY, MY Ph.D. ADVISORS, 3616 02:19:12,240 --> 02:19:17,040 [INDISCERNIBLE] AND THE PEOPLE 3617 02:19:17,040 --> 02:19:18,400 WHO GENEROUSLY MADE THEIR 3618 02:19:18,400 --> 02:19:20,360 THEY'RE VALUABLE DATA PUB LIEBLY 3619 02:19:20,360 --> 02:19:21,080 AVAILABLE. 3620 02:19:21,080 --> 02:19:22,040 ALL THE SOFTWARE SHOWN HERE IS 3621 02:19:22,040 --> 02:19:23,800 FREE AND OPEN SOURCED, YOU CAN 3622 02:19:23,800 --> 02:19:26,840 GET THE SOURCE CODE AT THIS URL 3623 02:19:26,840 --> 02:19:27,440 AND PREBUILT GRAPHICALLY 3624 02:19:27,440 --> 02:19:31,080 INTERFACE AT THIS URL. 3625 02:19:31,080 --> 02:19:32,360 THANK YOU AGAIN FOR YOUR TIME 3626 02:19:32,360 --> 02:19:34,400 AND THANK YOU TO THE PRESENTERS 3627 02:19:34,400 --> 02:19:35,880 FOR NOT KICKING ME OFF. 3628 02:19:35,880 --> 02:19:41,720 >> THANK YOU JOSHUA, THAT WAS 3629 02:19:41,720 --> 02:19:42,560 REALLY A MAGNIFICENT AND I'M 3630 02:19:42,560 --> 02:19:46,280 GOING TO HAVE TO MOVE ON IT SEE 3631 02:19:46,280 --> 02:19:56,760 IF WE CAN PUT IN SOME QUESTIONS 3632 02:19:56,760 --> 02:19:58,480 HERE FOR THE MANLE MEMBERS FOR 3633 02:19:58,480 --> 02:20:00,280 JUST A FEW MINUTES. 3634 02:20:00,280 --> 02:20:03,800 THERE'S A QUESTION HERE FOR 3635 02:20:03,800 --> 02:20:04,960 SRIRIAM, CAN YOU VALIDATE THIS 3636 02:20:04,960 --> 02:20:08,480 FOR A SET OF GRIEK O GENES BY 3637 02:20:08,480 --> 02:20:11,360 OBSERVING A GEICO CHANGE IN THE 3638 02:20:11,360 --> 02:20:12,080 GLUE MARIOUS CONE? 3639 02:20:12,080 --> 02:20:15,600 HOW IS THIS DONE EXPERIMENTAL, 3640 02:20:15,600 --> 02:20:18,040 SRIRAM CAN YOU GIVE US INSIGHT 3641 02:20:18,040 --> 02:20:18,280 INTO THAT? 3642 02:20:18,280 --> 02:20:20,360 >> I THINK THE QUESTION IS 3643 02:20:20,360 --> 02:20:20,920 BASICALLY THE CORRELATION 3644 02:20:20,920 --> 02:20:22,920 BETWEEN GENE EXPRESSION AND THE 3645 02:20:22,920 --> 02:20:24,720 GLYCAN AND I THINK THIS IS THE 3646 02:20:24,720 --> 02:20:26,920 SORT OF, I THINK IF YOU JUST 3647 02:20:26,920 --> 02:20:27,560 MEASURE THE TRANSCRIPT LEVELS 3648 02:20:27,560 --> 02:20:30,400 AND YOU LOOK AT THE GLYCAN, THE 3649 02:20:30,400 --> 02:20:31,240 RELATIONSHIP IS HIGHLY 3650 02:20:31,240 --> 02:20:32,880 NONLYNNIAN IN TERMS OF HOW IT'S 3651 02:20:32,880 --> 02:20:33,120 TONE. 3652 02:20:33,120 --> 02:20:36,000 AND THAT'S NOT BECAUSE THERE'S 3653 02:20:36,000 --> 02:20:36,480 NO RERELATIONSHIP. 3654 02:20:36,480 --> 02:20:37,320 THE RELATIONSHIP EXISTS IN MY 3655 02:20:37,320 --> 02:20:41,160 OPINION, JUST NOT KNOWN WHAT THE 3656 02:20:41,160 --> 02:20:41,680 RELATIONSHIP EXACTLY IS. 3657 02:20:41,680 --> 02:20:43,320 I THINK YOU NEED TO CONSIDER 3658 02:20:43,320 --> 02:20:44,520 ADDITIONAL FACTORS LIKE 3659 02:20:44,520 --> 02:20:45,880 TRANSCRIPTION FACTOR 3660 02:20:45,880 --> 02:20:47,720 PARTICULARLY AND SORT OF SORT OF 3661 02:20:47,720 --> 02:20:48,600 REGULATION OF THAT PARTICULAR 3662 02:20:48,600 --> 02:20:49,760 GENE AND OTHER FACTORS THAT 3663 02:20:49,760 --> 02:20:51,280 REGULATE HOW DOES THAT GO IN 3664 02:20:51,280 --> 02:20:53,400 THIS THE CONTEXT OF THE PATHWAYS 3665 02:20:53,400 --> 02:20:58,600 THAT ARE THERE AND SO ON? 3666 02:20:58,600 --> 02:21:00,120 SO, YES, SO THE SHORT ANSWER IS 3667 02:21:00,120 --> 02:21:02,080 EVIDENCE THAT WE'VE SEEN IN THE 3668 02:21:02,080 --> 02:21:03,960 GLYCO GENE CHANGES DO RETURN OF 3669 02:21:03,960 --> 02:21:05,360 RESULTSALATE WITH EXPERIMENTAL 3670 02:21:05,360 --> 02:21:06,680 PROVIDED DATA FOR THE DPLI 3671 02:21:06,680 --> 02:21:08,000 KAN--KANA IN MANY, MANY, MANY 3672 02:21:08,000 --> 02:21:10,440 INSTANCES AND THE PEOPLE THAT 3673 02:21:10,440 --> 02:21:12,480 PAPER WE FINALLY WRITE WILL HAVE 3674 02:21:12,480 --> 02:21:13,880 A WHOLE TABLE SHOWING CASE WHERE 3675 02:21:13,880 --> 02:21:16,240 IS THEY HAVE HAD AGREEMENT WITH 3676 02:21:16,240 --> 02:21:18,320 IT BUT THERE'S A LOT MORE TO BE 3677 02:21:18,320 --> 02:21:19,680 DONE IN TERMS OF GENE EXPRESSION 3678 02:21:19,680 --> 02:21:20,600 REGULATION AND HOW IT'S 3679 02:21:20,600 --> 02:21:22,800 REGULATED AND JUST GETTING 3680 02:21:22,800 --> 02:21:24,280 FUNDAMENTAL AND UNDERSTANDING OF 3681 02:21:24,280 --> 02:21:26,800 THAT PROCESS WHICH WE CURRENTLY 3682 02:21:26,800 --> 02:21:28,080 DON'T HAVE BUT WE'RE WORKING 3683 02:21:28,080 --> 02:21:28,480 TOWARDS IT. 3684 02:21:28,480 --> 02:21:30,080 >> CAN I ADD SOMETHING, I'M 3685 02:21:30,080 --> 02:21:32,280 GUILTY OF THIS, MY LAB GENERATED 3686 02:21:32,280 --> 02:21:35,000 ALL KINDS OF GLYCAN PROFILES AND 3687 02:21:35,000 --> 02:21:38,880 YOU CAN SEE AND TRY TO CORRELATE 3688 02:21:38,880 --> 02:21:39,920 THEM IF GENE EXPRESSION PROFILES 3689 02:21:39,920 --> 02:21:41,720 AND YOU CAN MIC PICK OUT THINGS 3690 02:21:41,720 --> 02:21:43,240 THAT MAKE SENSE AND THINGS THAT 3691 02:21:43,240 --> 02:21:44,440 DON'T MAKE SENSE AND I'M 3692 02:21:44,440 --> 02:21:45,280 WONDERING THIS IS A CHALLENGE 3693 02:21:45,280 --> 02:21:47,160 FOR THE FIELD IF THERE'S A WAY 3694 02:21:47,160 --> 02:21:49,560 TO REPRESENT THE GLYCAN PROFILE 3695 02:21:49,560 --> 02:21:55,680 NOT AS A COLLECTION OF AIR BARS 3696 02:21:55,680 --> 02:21:56,680 OF DIFFERENT--THE ASHES 3697 02:21:56,680 --> 02:21:58,360 BUNKEDDANCE OF DIFFERENT GLYCAN 3698 02:21:58,360 --> 02:22:00,080 STRUCTURES BUT SOME KIND OF 3699 02:22:00,080 --> 02:22:02,000 VECTOR THAT SUMMARIZES ALL THE 3700 02:22:02,000 --> 02:22:03,640 RATIVE ABANDANCE OF ALL THE GLUE 3701 02:22:03,640 --> 02:22:04,480 MARIOUS CANS AND I DON'T KNOW 3702 02:22:04,480 --> 02:22:07,440 WHAT THIS IS BUT WE NEED SOME 3703 02:22:07,440 --> 02:22:08,800 UNIFYING QUANTITATIVE MEASURE 3704 02:22:08,800 --> 02:22:13,040 THAT,A LOWS US TO MORE ROBUSTLY 3705 02:22:13,040 --> 02:22:17,480 DO CORRELATIONS I THINK. 3706 02:22:17,480 --> 02:22:18,720 >> I THINK THAT'S MORE OF A 3707 02:22:18,720 --> 02:22:22,280 COMMENT THAN A QUESTION, MIKE, I 3708 02:22:22,280 --> 02:22:23,280 BELIEVE? 3709 02:22:23,280 --> 02:22:23,720 >> [LAUGHTER] 3710 02:22:23,720 --> 02:22:23,920 SORRY. 3711 02:22:23,920 --> 02:22:25,920 >> WELL THERE IS A QUESTION HERE 3712 02:22:25,920 --> 02:22:29,080 THAT'S RELATED AND THAT IS HOW 3713 02:22:29,080 --> 02:22:32,680 WOULD 1 GO ABOUT ACCESSING THE 3714 02:22:32,680 --> 02:22:38,080 GENES AND GENE ANNOTATIONS FROM 3715 02:22:38,080 --> 02:22:41,800 GLYCO ENDS ONCO ISA IT A 3716 02:22:41,800 --> 02:22:42,680 PUBLICLY AVAILABLE RESOURCE? 3717 02:22:42,680 --> 02:22:45,120 >> IF YOU SEND ME AN E-MAIL I 3718 02:22:45,120 --> 02:22:48,080 CAN SEND YOU THE LINK IT'S ON 3719 02:22:48,080 --> 02:22:50,480 THE GITHUB PAGE, IT'S OPEN 3720 02:22:50,480 --> 02:22:53,720 SOURCED SO IT'S NELL-NEB, YOU GO 3721 02:22:53,720 --> 02:22:55,640 TO THE LAB YOU WILL SEE THAT THE 3722 02:22:55,640 --> 02:22:57,280 ONTOLOGY IS ALREADY DEPOSITED, 3723 02:22:57,280 --> 02:22:58,680 IT'S BEEN FORMATTED IN THIS 3724 02:22:58,680 --> 02:23:01,600 MOMENT OF TIME, IT'S IN FINAL 3725 02:23:01,600 --> 02:23:02,680 REFINEMENT BEFORE SUBSITTING IF 3726 02:23:02,680 --> 02:23:04,880 TO OBR ONTOLOGY AND IT'S JUST 3727 02:23:04,880 --> 02:23:07,160 MORE COSMET I CHANGES BEING DONE 3728 02:23:07,160 --> 02:23:09,480 TO MAKE IT LOOK PRETTIER THAN 3729 02:23:09,480 --> 02:23:11,280 FUNCTIONAL INFORMATION THAT'S 3730 02:23:11,280 --> 02:23:12,080 CHANGED BUT IT'S FREELY 3731 02:23:12,080 --> 02:23:14,000 AVAILABLE AND OPEN SOURCED WE DO 3732 02:23:14,000 --> 02:23:16,000 IT ALL ON GITHUB AND YOU CAN SEE 3733 02:23:16,000 --> 02:23:17,280 IT WHEN IT COMES UP. 3734 02:23:17,280 --> 02:23:17,680 >> GREAT. 3735 02:23:17,680 --> 02:23:22,880 AND 1 MORE QUESTION HERE: 3736 02:23:22,880 --> 02:23:24,520 SRIRAM, DO THE GLYCOSYLATION 3737 02:23:24,520 --> 02:23:26,480 PATTERNS WITHIN ORGAN SYSTEMS 3738 02:23:26,480 --> 02:23:28,600 OVERLAP FOR DIFFERENT CANCER 3739 02:23:28,600 --> 02:23:31,200 SUBTYPES, FOR EXAMPLE, 3740 02:23:31,200 --> 02:23:34,240 EPITHELIAL VERSUS MESSENTERY ENK 3741 02:23:34,240 --> 02:23:35,880 MALVERSUS ENDOKRIEN AND CAN YOU 3742 02:23:35,880 --> 02:23:37,680 SHED LIGHT ON OVERLAPS OR 3743 02:23:37,680 --> 02:23:39,480 DEFENSES BETWEEN MALIGNANT AND 3744 02:23:39,480 --> 02:23:42,120 PRECURSOR LESIONS THAT DO EXIST? 3745 02:23:42,120 --> 02:23:44,600 >> YEAH, SO I DON'T THINK I HAVE 3746 02:23:44,600 --> 02:23:47,320 THE--I DON'T THINK I HAVE-- 3747 02:23:47,320 --> 02:23:49,440 >> ANOTHER SEMINAR I GUESS. 3748 02:23:49,440 --> 02:23:50,440 >> WHAT'S THAT? 3749 02:23:50,440 --> 02:23:52,280 >> IT'S ANOTHER SEMINAR. 3750 02:23:52,280 --> 02:23:54,080 >> I GUESS IT'S A REALLY THOUGHT 3751 02:23:54,080 --> 02:23:55,880 PROVOKING PROCESS, I THINK IT'S 3752 02:23:55,880 --> 02:23:56,520 CRITICAL FOR PATIENT CARE, 3753 02:23:56,520 --> 02:23:58,240 PEOPLE WANT TO KNOW ARE 3754 02:23:58,240 --> 02:23:59,160 THEY--WHAT'S THE STATUS WHEN YOU 3755 02:23:59,160 --> 02:24:00,480 GO DOWN AND DO THESE 3756 02:24:00,480 --> 02:24:01,440 MEASUREMENTS ARE THEY GOING TO 3757 02:24:01,440 --> 02:24:02,920 GET SOMETHING THAT'S GOING TO BE 3758 02:24:02,920 --> 02:24:04,920 LIFE THREATENING OR JUST 3759 02:24:04,920 --> 02:24:05,880 SOMETHING REALLY BENIGN OR 3760 02:24:05,880 --> 02:24:07,760 SOMETHING THAT'S NOT REALLY 3761 02:24:07,760 --> 02:24:08,720 CANCEROUS IN NATURE AND I DON'T 3762 02:24:08,720 --> 02:24:10,640 KNOW THAT I HAVE THE EXACT 3763 02:24:10,640 --> 02:24:12,080 ANSWER BUT I CAN GO DOWN TO 3764 02:24:12,080 --> 02:24:13,400 SAYING WE STILL HAVE TO DO THIS 3765 02:24:13,400 --> 02:24:14,840 THING IN TERMS OF WHETHER 3766 02:24:14,840 --> 02:24:17,240 PROGRESSION MAPS CIBOL UP THE 3767 02:24:17,240 --> 02:24:18,360 STAGE SPECIFIC INFORMATION ON 3768 02:24:18,360 --> 02:24:19,680 THEM AND THAT'S SOMETHING WE ARE 3769 02:24:19,680 --> 02:24:22,040 WORKING ON, DO THESE PUBLISHING 3770 02:24:22,040 --> 02:24:23,480 MAPS AND THE GLYCO GENE PICK THE 3771 02:24:23,480 --> 02:24:24,200 SPECIFIC THING UP. 3772 02:24:24,200 --> 02:24:26,200 MANY OF THE CANCERS ARE LOOKING 3773 02:24:26,200 --> 02:24:28,520 AT HERE IN A PARTICULAR NATURE 3774 02:24:28,520 --> 02:24:29,360 PARTICULARLY FOR THE BREAST 3775 02:24:29,360 --> 02:24:31,160 CANCER SO I'M NOT SURE CAN YOU 3776 02:24:31,160 --> 02:24:32,480 ANSWER YOUR QUESTION ON 3777 02:24:32,480 --> 02:24:35,800 ENDOCRINE AND DIFFERENT TYPES 3778 02:24:35,800 --> 02:24:38,080 BUT, I GUESS I'M DOING A BAD JOB 3779 02:24:38,080 --> 02:24:39,000 OF ANSWER THIS QUESTION EXCEPT 3780 02:24:39,000 --> 02:24:41,280 TO SAY THAT I REALLY DON'T KNOW. 3781 02:24:41,280 --> 02:24:43,040 YOU KNOW THERE ARE SOME 3782 02:24:43,040 --> 02:24:44,360 OVERLAPS, THERE ARE SOME 3783 02:24:44,360 --> 02:24:46,280 DISTINCTIONS BUT YOU HAVE TO 3784 02:24:46,280 --> 02:24:48,280 REALLY FOCUS ON FINDING OUT 3785 02:24:48,280 --> 02:24:50,240 WHETHER DIFFERENT CELL TYPES IN 3786 02:24:50,240 --> 02:24:51,760 THE SAME ORGAN GIVE RISE TO 3787 02:24:51,760 --> 02:24:52,800 DIFFERENT SIGNATURES AND WE 3788 02:24:52,800 --> 02:24:54,160 HAVEN'T LOOKEDDA THE IT, THE 3789 02:24:54,160 --> 02:24:56,280 BREAST CANCER WORK WE'VE DONE IS 3790 02:24:56,280 --> 02:24:58,880 BASICALLY HORMONE RELATED IN 3791 02:24:58,880 --> 02:25:03,960 TERMS OF HER 2 AND DIFFERENT EGF 3792 02:25:03,960 --> 02:25:04,480 RECEPTOR FAMILIES. 3793 02:25:04,480 --> 02:25:05,920 THERE ARE NO MEASURE OF SAYING, 3794 02:25:05,920 --> 02:25:07,680 YOU KNOW ARE WE GOING TO BE ABLE 3795 02:25:07,680 --> 02:25:09,960 TO PICK UP EARLY PEOPLE IN THIS 3796 02:25:09,960 --> 02:25:10,880 LATE STAGE OF THE GAME. 3797 02:25:10,880 --> 02:25:15,240 >> I HAVE A QUESTION FOR RADO, I 3798 02:25:15,240 --> 02:25:18,680 REALLY APPRECIATED YOUR COMMENT 3799 02:25:18,680 --> 02:25:20,800 ABOUT HOW GAG STRUCTURE AND 3800 02:25:20,800 --> 02:25:23,080 SULFATION PATTERNS ARE GOING TO 3801 02:25:23,080 --> 02:25:25,080 INFLUENCE A HUGE ARRAY OF 3802 02:25:25,080 --> 02:25:25,880 DIFFERENT SIGNALING PATHWAYS, 3803 02:25:25,880 --> 02:25:29,840 IT'S NOT 1 THING, - IT IS MANY, 3804 02:25:29,840 --> 02:25:30,240 THINGS. 3805 02:25:30,240 --> 02:25:31,640 SO THE QUESTION, I GUESS IS 3806 02:25:31,640 --> 02:25:34,120 THERE I'M ASSUME THRG ARE A LOT 3807 02:25:34,120 --> 02:25:34,840 OF BIOINFORMATIC RESOURCES OUT 3808 02:25:34,840 --> 02:25:36,960 THERE THAT PARSE OUT SIGNALING 3809 02:25:36,960 --> 02:25:38,960 PATHWAYS, HOW WELL DO THEY 3810 02:25:38,960 --> 02:25:42,960 OVERLAY THE INFLUENCE OF 3811 02:25:42,960 --> 02:25:44,000 MODULATORS LIKE GLYCOGRID 3812 02:25:44,000 --> 02:25:45,080 SERVICES KAN--KANAS AFTER 3813 02:25:45,080 --> 02:25:47,280 ACTIVATION OF SIGNALING 3814 02:25:47,280 --> 02:25:47,520 PATHWAYS. 3815 02:25:47,520 --> 02:25:48,880 ARE THERE INFORMATIC TOOLS TO 3816 02:25:48,880 --> 02:25:51,040 HELP MODEL THAT. 3817 02:25:51,040 --> 02:25:51,520 >> I DON'T KNOW. 3818 02:25:51,520 --> 02:25:54,560 SO WHEN WE LOOK AT THAT, WE JUST 3819 02:25:54,560 --> 02:25:56,400 BASICALLY DO SOME KIND OF 3820 02:25:56,400 --> 02:25:57,320 LITERATURE SEARCHES AND TRY TO 3821 02:25:57,320 --> 02:26:01,920 BUILD SOME KIND OF MAPS OF 3822 02:26:01,920 --> 02:26:04,480 INFLUENCE BUT, IT ACTUALLY--THE 3823 02:26:04,480 --> 02:26:05,280 STUDENTS STRUGGLE THROUGH IT AND 3824 02:26:05,280 --> 02:26:07,640 I DON'T KNOW ABOUT RESOURCES 3825 02:26:07,640 --> 02:26:09,720 THAT I WOULD POINT OUT. 3826 02:26:09,720 --> 02:26:16,960 >> SO THEREYA A HOLE THERE. 3827 02:26:16,960 --> 02:26:19,080 >> YEAH. 3828 02:26:19,080 --> 02:26:25,040 >> OKAY, MIKE. 3829 02:26:25,040 --> 02:26:25,560 ANY OTHER QUESTIONS? 3830 02:26:25,560 --> 02:26:29,720 >> ONE LAST QUESTION FOR JOSH. 3831 02:26:29,720 --> 02:26:32,520 SO CAN YOU TELL US HOW WE'RE 3832 02:26:32,520 --> 02:26:34,960 DOING AS A COMMUNITY? 3833 02:26:34,960 --> 02:26:37,680 ARE WE MISSING A LOT OF STUFF? 3834 02:26:37,680 --> 02:26:38,280 ARE WE OVERANALYZING? 3835 02:26:38,280 --> 02:26:39,320 YOU GAVE US NICE CASE STUDIES 3836 02:26:39,320 --> 02:26:41,080 BUT HAVE YOU FELT MORE BROADLY 3837 02:26:41,080 --> 02:26:46,440 TO SEE HOW MUCH WE'RE FOOLING 3838 02:26:46,440 --> 02:26:47,080 OURSELVES? 3839 02:26:47,080 --> 02:26:48,480 >> THERE'S A SIGNIFICANT 3840 02:26:48,480 --> 02:26:50,480 FRACTION OF THE DPLI KAN--KANA 3841 02:26:50,480 --> 02:26:54,880 COMPOSITIONS REPORTED IN DPLI 3842 02:26:54,880 --> 02:26:58,080 KAN--KANA AND I FORGET THE NAME 3843 02:26:58,080 --> 02:27:00,600 OF THE DATABASE MAINTAINED IN 3844 02:27:00,600 --> 02:27:03,040 AUSTRALIA THAT SHOW COMPOSITIONS 3845 02:27:03,040 --> 02:27:04,240 THEY'VE TAKEN FROM PAPERS THAT 3846 02:27:04,240 --> 02:27:09,280 WERE NOT AWARE OF THIS 3847 02:27:09,280 --> 02:27:09,600 PHENOMENON. 3848 02:27:09,600 --> 02:27:11,640 THERE ARE SEVERAL NEW TOOLS THAT 3849 02:27:11,640 --> 02:27:15,160 ARE COMING OUT IN THE LAST 2 OR 3850 02:27:15,160 --> 02:27:19,560 3 YEARS THAT ARE STARTING TO 3851 02:27:19,560 --> 02:27:21,880 INCLUDE OMONIA REDUCTION IN PART 3852 02:27:21,880 --> 02:27:24,080 OF THEIR SEARCH STRATEGY AND THE 3853 02:27:24,080 --> 02:27:25,640 FURTHER GLYCO FEE AND DECIPHER 3854 02:27:25,640 --> 02:27:28,080 TO NAME JUST 3 THAT CAME OUT 3855 02:27:28,080 --> 02:27:29,000 RECENTLY HOWEVER, THESE AREN'T 3856 02:27:29,000 --> 02:27:31,880 REALLY GOOD AT EXPLAINING ALL OF 3857 02:27:31,880 --> 02:27:34,160 THE DIFFERENT TYPES OF 3858 02:27:34,160 --> 02:27:36,360 AMBIGUITIES THAT YOU WOULD 3859 02:27:36,360 --> 02:27:39,280 OBSERVE, ADDITIONALLY, IF YOU 3860 02:27:39,280 --> 02:27:41,800 WERE TO USE AN OFF THE SHELF 3861 02:27:41,800 --> 02:27:43,560 TOOL LIKE BIONIC THAT IS 3862 02:27:43,560 --> 02:27:45,440 DESIGNED FOR THIS TYPE OF WORK, 3863 02:27:45,440 --> 02:27:51,800 YOU WON'T GET ANY SORT OF 3864 02:27:51,800 --> 02:27:53,080 CORRECTIONS FOR THESE. 3865 02:27:53,080 --> 02:27:56,680 THE REAL THREAT OF COURSE IS 3866 02:27:56,680 --> 02:28:01,040 THAT YOUR GLYCO--YOUR GLUE 3867 02:28:01,040 --> 02:28:01,480 GLYCON IS 3868 02:28:01,480 --> 02:28:09,280 TOO SMALL AND YOU'RE MISSING OUT 3869 02:28:09,280 --> 02:28:10,880 ON NICHE CASES BUT WE ONLY 3870 02:28:10,880 --> 02:28:13,560 EXPECT WHAT WE EXPECT TO FIND. 3871 02:28:13,560 --> 02:28:15,360 IN--I HAVE A 3 OR 4 CANCER DATA 3872 02:28:15,360 --> 02:28:17,520 SETS THAT I'VE LOOKED AT, AND IN 3873 02:28:17,520 --> 02:28:24,560 AT LEAST 2 OF THEM, THE ACTUAL 3874 02:28:24,560 --> 02:28:25,240 CLAIMS OF DIFFERENTIAL ABUNDANCE 3875 02:28:25,240 --> 02:28:29,840 OF TBLIEK O FORMS AT A SPECIFIC 3876 02:28:29,840 --> 02:28:33,160 SITE IS CORRUPTED BY THIS TYPE 3877 02:28:33,160 --> 02:28:38,280 OF ERROR WHERE THEY OBSERVED 3878 02:28:38,280 --> 02:28:39,280 THAT AMMONIUM ADDUCTED ISOBERNEA 3879 02:28:39,280 --> 02:28:41,320 DEETIC FORM IS THE THING THAT IS 3880 02:28:41,320 --> 02:28:45,000 DIFFERENTIALLY EXPRESSED WHEN 3881 02:28:45,000 --> 02:28:48,280 IT'S REALLY JUST THE FRACTION OF 3882 02:28:48,280 --> 02:28:50,000 OMANYIA REDUCTION WHICH IS 3883 02:28:50,000 --> 02:28:52,080 INTRODUCED DURING SAMPLE PREP 3884 02:28:52,080 --> 02:28:52,480 THAT'S DIFFERING. 3885 02:28:52,480 --> 02:28:54,280 SO IT'S ACTUALLY A BATCH EFFECT 3886 02:28:54,280 --> 02:28:58,000 MAKING IT VERY DIFFICULT TO GIVE 3887 02:28:58,000 --> 02:29:01,480 YOU A HARD NUMBER ABOUT HOW BAD 3888 02:29:01,480 --> 02:29:01,880 IT IS. 3889 02:29:01,880 --> 02:29:05,680 >> SO MAYBE JUST A FOLLOW UP, SO 3890 02:29:05,680 --> 02:29:08,360 PEOPLE TRY TO ANCHOR THE GLYCO 3891 02:29:08,360 --> 02:29:09,440 PROTEIN COMPLEXEMIC ANALYSIS BY 3892 02:29:09,440 --> 02:29:10,720 DOING GLUE MARIOUS KOAMIC 3893 02:29:10,720 --> 02:29:12,600 ANALYSIS TOO TO DEFINE WHAT'S 3894 02:29:12,600 --> 02:29:16,040 ACTUALLY THERE IN AN ORTHOGONAL 3895 02:29:16,040 --> 02:29:18,920 WAY ARE THOSE BETTER ON MAYBE 3896 02:29:18,920 --> 02:29:19,880 THERE AREN'T ENOUGH DATA SETS 3897 02:29:19,880 --> 02:29:21,840 OUT THERE TO JUDGE IT YET? 3898 02:29:21,840 --> 02:29:23,040 >> THERE AREN'T MANY DATA SETS 3899 02:29:23,040 --> 02:29:23,640 TO DO THAT. 3900 02:29:23,640 --> 02:29:24,960 IT DOES TURN OUT TO BE BETTER 3901 02:29:24,960 --> 02:29:27,040 BECAUSE YOU CAN BE VERY 3902 02:29:27,040 --> 02:29:31,000 PERMISSIVE ON THE GLYCAN SEARCH 3903 02:29:31,000 --> 02:29:33,880 AND USE THAT TO GIVE YOU AN 3904 02:29:33,880 --> 02:29:34,240 UPFRONT PROFILE. 3905 02:29:34,240 --> 02:29:35,880 OBVIOUSLY THERE ARE LIMITS TO 3906 02:29:35,880 --> 02:29:39,600 DEPTH ESPECIALLY IF YOU WANT TO 3907 02:29:39,600 --> 02:29:43,120 THEN DRILL DEEPER WITH MASS 3908 02:29:43,120 --> 02:29:44,160 SPECTROMETRYOT GLYCANS WHICH 3909 02:29:44,160 --> 02:29:49,280 INVOLVES MORE SAMPLE HANDLING. 3910 02:29:49,280 --> 02:29:50,040 GLYCONNECT AND COMPOSER BOTH 3911 02:29:50,040 --> 02:29:57,720 GIVE US A WAY TO--GO GET THOSE 3912 02:29:57,720 --> 02:30:00,120 SAMPLE SPECIFIC GL YKOAMS IF WE 3913 02:30:00,120 --> 02:30:01,440 KNOW THEY'RE AVAILABLE TO US AND 3914 02:30:01,440 --> 02:30:03,320 THE ORGANISM OF INTEREST IS 3915 02:30:03,320 --> 02:30:04,120 INCLUDED THERE, HOWEVER, THOSE 3916 02:30:04,120 --> 02:30:06,480 NET WORKS WILL BE NECESSARY PLEA 3917 02:30:06,480 --> 02:30:07,520 INCOMPLETE. 3918 02:30:07,520 --> 02:30:08,720 AND SO, THESE EXPLORATORY 3919 02:30:08,720 --> 02:30:11,600 EXPANDED SYRUP SPACES WILL STILL 3920 02:30:11,600 --> 02:30:16,000 BE NECESSARY ANCHORING THINGS IN 3921 02:30:16,000 --> 02:30:18,880 EVERYTHING IN THE KNOWN SET 3922 02:30:18,880 --> 02:30:21,080 FIRST AND THEN THE SPECULATIVE 3923 02:30:21,080 --> 02:30:22,240 STUFF FURTHER OUT IS IMPORTANT. 3924 02:30:22,240 --> 02:30:23,680 I WANT TO TALK ABOUT ANOTHER 3925 02:30:23,680 --> 02:30:26,480 TECHNIQUE THAT I DEVELOPED 3926 02:30:26,480 --> 02:30:27,960 CALLED GLYCAN NETWORK SMOOTHING 3927 02:30:27,960 --> 02:30:30,240 WHICH DOES THAT BUT THAT THERE'S 3928 02:30:30,240 --> 02:30:34,200 ONLY TIME FOR 1 TALK. 3929 02:30:34,200 --> 02:30:35,040 >> MICHAEL, DOUG HAS 1 LAST 3930 02:30:35,040 --> 02:30:36,200 QUESTION, MAYBE TO CLOSE OUT THE 3931 02:30:36,200 --> 02:30:36,440 SESSION? 3932 02:30:36,440 --> 02:30:38,320 YOU WANT TO READ IT. 3933 02:30:38,320 --> 02:30:43,000 >> SURE. 3934 02:30:43,000 --> 02:30:43,280 I SEE IT. 3935 02:30:43,280 --> 02:30:45,480 DOUG SAYS HOW WOULD YOU RATE THE 3936 02:30:45,480 --> 02:30:48,000 USABILITY OF THE APPROACH THAT 3937 02:30:48,000 --> 02:30:48,320 YOU DESCRIBE? 3938 02:30:48,320 --> 02:30:50,680 HOW CAN ITS ADOPTION BE 3939 02:30:50,680 --> 02:30:50,920 PROMOTED? 3940 02:30:50,920 --> 02:30:53,400 I'M THINKING ABOUT THE GAP 3941 02:30:53,400 --> 02:30:54,520 BETWEEN SOFTWARE DEVELOPED AS 3942 02:30:54,520 --> 02:30:56,080 PART OF A RESEARCH PROPONENT 3943 02:30:56,080 --> 02:30:58,680 ECTOMYOSIN VERSUS A TOOL THAT BE 3944 02:30:58,680 --> 02:31:02,320 MADE AVAILABLE TO THE BROADER 3945 02:31:02,320 --> 02:31:02,600 COMMUNITY? 3946 02:31:02,600 --> 02:31:05,280 >> IT'S A GOOD QUESTION. 3947 02:31:05,280 --> 02:31:07,760 SO THE APPROACH I DESCRIBED IS 3948 02:31:07,760 --> 02:31:10,680 INTEGRATED TO THAT GLYCOPEPTIDE 3949 02:31:10,680 --> 02:31:11,960 SEARCH ENGINE THAT I WROTE. 3950 02:31:11,960 --> 02:31:13,280 OBVIOUSLY I USE IT AND A SMALL 3951 02:31:13,280 --> 02:31:14,520 MEMBER OF PEOPLE USE IT WHILE 3952 02:31:14,520 --> 02:31:16,960 THE OTHER TOOLS I MENTIONED 3953 02:31:16,960 --> 02:31:18,280 EARLIER HAVE REALLY LARGE REACH 3954 02:31:18,280 --> 02:31:22,040 IN THE COMMUNITY ESPECIALLY 3955 02:31:22,040 --> 02:31:22,280 BIONIC. 3956 02:31:22,280 --> 02:31:24,000 MY METHOD CAN COULD BE APPLIED 3957 02:31:24,000 --> 02:31:25,560 TO THAT SAME TYPE OF DATA I 3958 02:31:25,560 --> 02:31:26,640 DON'T NEED TO HAVE SPECIAL NSKS 3959 02:31:26,640 --> 02:31:31,600 ABOUT HOW THE SEARCH WAS DONE, 3960 02:31:31,600 --> 02:31:33,480 HOWEVER, WE DON'T HAVE A GOOD 3961 02:31:33,480 --> 02:31:37,560 WAY TO GET THE OUTPUT FROM 1 3962 02:31:37,560 --> 02:31:39,280 CLIEK O PROTEOMIC SEARCH TOOL TO 3963 02:31:39,280 --> 02:31:40,880 LOOK THE SAME AS EVERY OTHER 3964 02:31:40,880 --> 02:31:44,080 TOOL BECAUSE WE LACK 3965 02:31:44,080 --> 02:31:46,880 STANDARDIZATION IN HOW WE REPORT 3966 02:31:46,880 --> 02:31:48,640 GLYCO PEPTIDE IDs, IT'S A WORK 3967 02:31:48,640 --> 02:31:49,920 IN PROGRESS GIVEN ALL THE 3968 02:31:49,920 --> 02:31:52,880 DIFFERENT WAYS WE DO IDENTIFY 3969 02:31:52,880 --> 02:31:55,000 GLYCO PEPTIDES. 3970 02:31:55,000 --> 02:31:56,640 AS TO HOW RELIABLE THE TECHNIQUE 3971 02:31:56,640 --> 02:31:58,080 IS, IT IS SENSITIVE TO THE TYPE 3972 02:31:58,080 --> 02:32:01,920 OF DATA THAT YOU GIVE IT IF YOU 3973 02:32:01,920 --> 02:32:06,280 HAVE A VERY LARGE DATA SET AND 3974 02:32:06,280 --> 02:32:07,480 RELAXED FDR CONSTRAINTS, IT CAN 3975 02:32:07,480 --> 02:32:10,960 LEARN THE WRONG THINGS SO THE 3976 02:32:10,960 --> 02:32:13,280 PROCEDURE FOR AUTOMATICALLY 3977 02:32:13,280 --> 02:32:15,920 FITTING SUCH A MODEL, MAY BE 3978 02:32:15,920 --> 02:32:17,120 MORE DELICATE THAN I THINK IT IS 3979 02:32:17,120 --> 02:32:23,040 JUST BECAUSE I HAVE NOT SEEN IT 3980 02:32:23,040 --> 02:32:25,120 IN THE WILD. 3981 02:32:25,120 --> 02:32:25,400 [LAUGHTER] 3982 02:32:25,400 --> 02:32:26,200 >> OKAY. 3983 02:32:26,200 --> 02:32:31,800 THANK YOU FOR THE ANSWER JOSHUA 3984 02:32:31,800 --> 02:32:34,320 AND SRIRAM HAS I QUICK FOLLOW 3985 02:32:34,320 --> 02:32:34,880 UP, JUST BRIEFLY. 3986 02:32:34,880 --> 02:32:36,480 >> LIKE YOU WHAT SAID, MY 3987 02:32:36,480 --> 02:32:37,800 CONCERN IS ADDING MORE ADDUCTS 3988 02:32:37,800 --> 02:32:39,880 INCREASES DAILY BASIS THEA BASE 3989 02:32:39,880 --> 02:32:40,640 SIZE PARTICULARLY FOR LARGE 3990 02:32:40,640 --> 02:32:42,040 SAMPLE SYSTEMS WHERE YOU HAVE 3991 02:32:42,040 --> 02:32:42,680 SAY THE HUMAN PROTEIN COMPLEX I 3992 02:32:42,680 --> 02:32:43,560 DON'T MEAN THAT YOU'RE LOOKING 3993 02:32:43,560 --> 02:32:45,720 AT AND I'M JUST WONDERING 3994 02:32:45,720 --> 02:32:48,560 WHETHER ADDING VARIABLES CAUSES 3995 02:32:48,560 --> 02:32:50,200 MORE FALSE DISCOVERY UNLESS THE 3996 02:32:50,200 --> 02:32:52,680 PROGRAMS BUILT ARE REALLY, 3997 02:32:52,680 --> 02:32:54,640 REALLY, REALLY TIGHT AND I THAT 3998 02:32:54,640 --> 02:32:56,400 I SEE AS A CHALLENGE BECAUSE YOU 3999 02:32:56,400 --> 02:32:58,120 COULD ENTER IT 1 BY 1 AND POINT 4000 02:32:58,120 --> 02:32:59,760 THE DIFFERENCE OUT FROM A LARGER 4001 02:32:59,760 --> 02:33:00,880 SCALE THIS COULD BE A PROBLEM. 4002 02:33:00,880 --> 02:33:07,280 IN, THAT IS TRUE. 4003 02:33:07,280 --> 02:33:10,120 HOWEVER, WITH A COUPLE OF 4004 02:33:10,120 --> 02:33:11,080 CONSTRAINTS CAN YOU GREATLY 4005 02:33:11,080 --> 02:33:11,440 DIMINISH THAT. 4006 02:33:11,440 --> 02:33:14,720 FOR EXAMPLE, IF YOU ARE GOING TO 4007 02:33:14,720 --> 02:33:16,000 BE KEPTICAL OF ADDUKS ISSUES CAN 4008 02:33:16,000 --> 02:33:17,360 YOU LIMIT YOURSELF TO ONLY 4009 02:33:17,360 --> 02:33:20,480 ACCEPTING AN IDEPTICTION THAT IS 4010 02:33:20,480 --> 02:33:22,960 IESHES DENTIFIED BOTH UNADDUCTED 4011 02:33:22,960 --> 02:33:24,440 AND UNSUPPORTED ADDUBBED AND 4012 02:33:24,440 --> 02:33:27,040 THAT IS THE DEFAULT MODE FOR MY 4013 02:33:27,040 --> 02:33:28,200 TOOL THAT WILL LEAD TO 4014 02:33:28,200 --> 02:33:29,280 SITUATIONS WHERE YOU ONLY 4015 02:33:29,280 --> 02:33:30,120 FRAGMENT AND IDENTIFY THE 4016 02:33:30,120 --> 02:33:30,840 PRACTICING MENTORSHIP SKILLED 4017 02:33:30,840 --> 02:33:32,680 FORM YOU GET IT WRONG BUT 4018 02:33:32,680 --> 02:33:34,440 RETENTION TIME MODELING HELPS 4019 02:33:34,440 --> 02:33:40,280 YOU CORRECT THOSE SITUATIONS. 4020 02:33:40,280 --> 02:33:42,760 THERE IN AMMONIA ADDUKS THERE'S 4021 02:33:42,760 --> 02:33:43,960 NO SIGNATURE ION BECAUSE IT 4022 02:33:43,960 --> 02:33:46,320 FALLS APART AND LOOKS LIKE A 4023 02:33:46,320 --> 02:33:47,680 PROTEIN TANDEM INSPECTION BUT 4024 02:33:47,680 --> 02:33:50,240 OTHER TYPES LIKE METALLIC CAT 4025 02:33:50,240 --> 02:33:52,040 ION PRODUCTS ARE REALLY 4026 02:33:52,040 --> 02:33:53,880 DETEBILITYIBLE IN THE PEPTIDE 4027 02:33:53,880 --> 02:33:55,040 POLICE Y-AXONS THEY STRONGLY 4028 02:33:55,040 --> 02:33:56,680 BIND AND SHIFT EVERYTHING. 4029 02:33:56,680 --> 02:34:02,240 SO THOSE SHOULD NOT BE A HUGE 4030 02:34:02,240 --> 02:34:05,760 CONCERN FOR BALLOANING SEARCH 4031 02:34:05,760 --> 02:34:06,240 SPACE. 4032 02:34:06,240 --> 02:34:08,440 OBVIOUSLY, IMPROVEMENTS IN FDR 4033 02:34:08,440 --> 02:34:10,400 ARE ALWAYS NEEDED, GLYCO PEPTIDE 4034 02:34:10,400 --> 02:34:12,680 FDR TOOK A HUGE STEP FORWARD IN 4035 02:34:12,680 --> 02:34:18,160 2017 OR SO, BUT EACH THAT 4036 02:34:18,160 --> 02:34:20,360 TECHNIQUE HAS LIMITS. 4037 02:34:20,360 --> 02:34:21,000 >> OKAY, THANK YOU. 4038 02:34:21,000 --> 02:34:23,560 OKAY, THANK YOU JOSHUA AND ALL 4039 02:34:23,560 --> 02:34:24,640 OF OUR SPEAKERS TODAY WE ARE 4040 02:34:24,640 --> 02:34:26,280 GOING TO HAVE TO END THIS. 4041 02:34:26,280 --> 02:34:29,680 WE HAD A REALLY WONDERFUL 4042 02:34:29,680 --> 02:34:32,480 SESSION, GREAT QUESTIONS, AND 4043 02:34:32,480 --> 02:34:34,080 SO, MIKE, EVERYONE COMES BACK AT 4044 02:34:34,080 --> 02:34:36,480 1:00 O'CLOCK, IS THAT CORRECT? 4045 02:34:36,480 --> 02:34:36,880 >> 1:00 O'CLOCK. 4046 02:34:36,880 --> 02:34:37,080 YES. 4047 02:34:37,080 --> 02:34:39,520 >> OKAY, THANK YOU ALL AGAIN. 4048 02:34:39,520 --> 02:34:58,160 >> THANK EVERYBODY. 4049 02:34:58,160 --> 02:35:04,480 >> HELLO EVERYONE, WE HAVE 6 4050 02:35:04,480 --> 02:35:06,400 SPEAKERS AND THANK YOU TO THEIR 4051 02:35:06,400 --> 02:35:07,320 PARTIC PATHWAY GIVESITION AND AT 4052 02:35:07,320 --> 02:35:08,600 THE END OF THIS AFTERNOON'S 4053 02:35:08,600 --> 02:35:09,720 SESSION, WE WILL HAVE A PANEL 4054 02:35:09,720 --> 02:35:10,560 DISCUSSION WITH THE SPEAKERS 4055 02:35:10,560 --> 02:35:13,560 WILL BE AVAILABLE TO ANSWER THE 4056 02:35:13,560 --> 02:35:13,920 QUESTIONS. 4057 02:35:13,920 --> 02:35:15,520 AND SO I'M HAPPY TO INTRODUCE 4058 02:35:15,520 --> 02:35:19,720 OUR FIRST SPEAKER, HUGO BELLEN 4059 02:35:19,720 --> 02:35:26,920 FROM BAYLOR COLLEGE OF MEDICINE. 4060 02:35:26,920 --> 02:35:30,320 TAKE IT AWAY. 4061 02:35:30,320 --> 02:35:35,320 >> ALL RIGHT, SO I WILL TALK 4062 02:35:35,320 --> 02:35:36,960 ABOUT GLUCOSILL CERAMIDES ARE 4063 02:35:36,960 --> 02:35:38,120 GENERATED BY NEURONAL ACTIVITY 4064 02:35:38,120 --> 02:35:40,440 AND TRANSPORTED TO THE GLUE 4065 02:35:40,440 --> 02:35:42,280 MARIOUSA VIA EXOSTUDIES OF 4066 02:35:42,280 --> 02:35:43,320 MULTIPLE ENDOCRINES FOR 4067 02:35:43,320 --> 02:35:45,840 DEGRADATION UPON RELEASE OF THE 4068 02:35:45,840 --> 02:35:55,720 GLIAL TGF AND BMP FROM NEWT 4069 02:35:55,720 --> 02:35:56,120 FLIES. 4070 02:35:56,120 --> 02:36:02,360 THIS WORK WAS DONE BY A POST DOC 4071 02:36:02,360 --> 02:36:03,800 IN THE LAB. 4072 02:36:03,800 --> 02:36:05,600 SO CERAMIDE IS REALLY IMPORTANT 4073 02:36:05,600 --> 02:36:07,600 IN LIPID METABOLISM AND PLAYS A 4074 02:36:07,600 --> 02:36:10,080 REALLY IMPORTANT ROLE IN MANY 4075 02:36:10,080 --> 02:36:11,240 DISEASES BECAUSE WHEN THERE IS 4076 02:36:11,240 --> 02:36:15,000 LITTLE OR TOO MUCH, THERE ARE 4077 02:36:15,000 --> 02:36:16,160 PROBLEMS AND MANY TIMES THERE 4078 02:36:16,160 --> 02:36:20,240 ARE PROBLEMS WITH ALL KINDS OF 4079 02:36:20,240 --> 02:36:25,160 ISSUES, MEMBRANE FLUIDITY, 4080 02:36:25,160 --> 02:36:26,680 SIGNALING BETWEEN CELLS BUT ANY 4081 02:36:26,680 --> 02:36:30,160 NUMBER OF DISEASES AS SHOWN 4082 02:36:30,160 --> 02:36:32,320 SHEER, CAN YOU SEE IN THE 4083 02:36:32,320 --> 02:36:34,520 CERAMIDE IT'S SHOWN HERE, AND 4084 02:36:34,520 --> 02:36:37,800 WHEN THE PROCESS OF DEGRADATION 4085 02:36:37,800 --> 02:36:40,880 OF THE BACK TO CERAMIDE IS 4086 02:36:40,880 --> 02:36:42,600 IMPAIRED YOU GET GAWSHIER'S 4087 02:36:42,600 --> 02:36:44,800 DISEASE, AND THIS WILL BE THE 4088 02:36:44,800 --> 02:36:46,960 TOPIC OF THE TALK TODAY. 4089 02:36:46,960 --> 02:36:52,640 NOT ONLY FOR A MODIFIED BY SUGAR 4090 02:36:52,640 --> 02:36:58,640 AND [INDISCERNIBLE] AND GAL ACT 4091 02:36:58,640 --> 02:37:01,320 O SILL CERAMIDE PLAYS AN 4092 02:37:01,320 --> 02:37:05,320 IMPORTANT ROLE IN IMPAIRING THE 4093 02:37:05,320 --> 02:37:07,840 DEGRADATION OF [INDISCERNIBLE] 4094 02:37:07,840 --> 02:37:10,840 CAUSES A MORE DEBILITATING 4095 02:37:10,840 --> 02:37:12,040 DISEASE CALLED DEAD WHAT. 4096 02:37:12,040 --> 02:37:14,000 SO YOU CAN SEE THAT CERAMIDE IS 4097 02:37:14,000 --> 02:37:15,560 AT THE CENTER OF REALLY ONSET 4098 02:37:15,560 --> 02:37:18,880 DISEASES THAT ARE QUITE 4099 02:37:18,880 --> 02:37:22,920 SIGNIFICANT, MOST OF THEM IN 4100 02:37:22,920 --> 02:37:26,760 CHILDHOOD, AND WHEN WE LOOK AT 4101 02:37:26,760 --> 02:37:28,360 FINGER LIPID METABOLISM IT'S 4102 02:37:28,360 --> 02:37:30,120 QUITE COMPLICATED BECAUSE THE 4103 02:37:30,120 --> 02:37:31,600 SERIES POINTS MID IS PRODUCED 4104 02:37:31,600 --> 02:37:36,520 FIRST IN THE ER, WHEN SERIES 4105 02:37:36,520 --> 02:37:39,600 POINTSINE ARE BROUGHT TOGETHER 4106 02:37:39,600 --> 02:37:40,720 TO FORM INTERMEDIATES THAT ARE 4107 02:37:40,720 --> 02:37:42,880 EVENTUALLY IN THE ER AND END UP 4108 02:37:42,880 --> 02:37:43,160 IN CERAMIDE. 4109 02:37:43,160 --> 02:37:46,720 AND SERIES POINTS MID IS THEN 4110 02:37:46,720 --> 02:37:49,200 TRANSFERRED TO THE GOLGI AND IN 4111 02:37:49,200 --> 02:37:52,760 THE GOLGI, THERE ARE LOT EVER OF 4112 02:37:52,760 --> 02:37:53,960 CHANGES THAT CAN OCCUR TO 4113 02:37:53,960 --> 02:37:55,600 CERAMIDE AND YOU CAN MAKE 4114 02:37:55,600 --> 02:37:59,160 CERAMIDE AS ALREADY MENTIONED, 4115 02:37:59,160 --> 02:38:00,120 OR GLUE COCERAMIDE TO BUILD UP 4116 02:38:00,120 --> 02:38:01,680 ON THESE TO MAKE ALL OF THESE 4117 02:38:01,680 --> 02:38:04,440 DIFFERENT SERIES POINTS MIDS. 4118 02:38:04,440 --> 02:38:05,840 AND IT'S REALLY NOT WELL 4119 02:38:05,840 --> 02:38:07,880 UNDERSTOOD WHAT THEY'RE ALL 4120 02:38:07,880 --> 02:38:11,440 DOING BUT THEY ALL SEEM TO BE TO 4121 02:38:11,440 --> 02:38:13,120 SOME EXTENT IMPORTANT BECAUSE 4122 02:38:13,120 --> 02:38:14,080 DISRUPTION OF THE ENZYMES THAT 4123 02:38:14,080 --> 02:38:16,680 ARE PLAYING A ROLE IN THIS 4124 02:38:16,680 --> 02:38:21,840 PATHWAY CAN LEAD TO PRETTY 4125 02:38:21,840 --> 02:38:22,240 SEVERE PHENOTYPES. 4126 02:38:22,240 --> 02:38:23,400 SERIES POINTSA MINE IS EMBEDDED 4127 02:38:23,400 --> 02:38:33,400 IN THE PLASMA MEMBRANE AND 4128 02:38:33,400 --> 02:38:38,240 RETURN IN THE SPHLINGOSINE, AND 4129 02:38:38,240 --> 02:38:40,600 THIS CAN BE MODIFIED AS I SAID 4130 02:38:40,600 --> 02:38:42,480 AND THESE MODIFICATIONS ARE ALSO 4131 02:38:42,480 --> 02:38:45,000 TRANSFERRED FROM THE GOLGY TO 4132 02:38:45,000 --> 02:38:45,960 THE PLASMA MEMBRANE AND MAY PLAY 4133 02:38:45,960 --> 02:38:50,320 A ROLE IN THE VARIETY OF 4134 02:38:50,320 --> 02:38:52,640 PROCESSES. 4135 02:38:52,640 --> 02:38:54,920 NOW GBA WHICH IS GAWCHIER'S 4136 02:38:54,920 --> 02:38:56,760 DISEASE, WHICH IS AN ENZYME 4137 02:38:56,760 --> 02:38:58,600 THAT'S INVOLVED IN THE 4138 02:38:58,600 --> 02:38:59,680 HYDROLYSIS OF SUGAR FROM 4139 02:38:59,680 --> 02:39:02,680 CERAMIDE AND WHEN THAT ENZYME IS 4140 02:39:02,680 --> 02:39:03,760 IMPAIRED IT CAN LEAD TO A 4141 02:39:03,760 --> 02:39:05,280 VARIETY OF DISEASES FROM 4142 02:39:05,280 --> 02:39:06,600 CHILDHOOD TO ADULTHOOD IN ALL 4143 02:39:06,600 --> 02:39:10,640 CASES THE DISEASE IS RECESSIVE 4144 02:39:10,640 --> 02:39:15,720 AND I SHOULD NOTE THAT THE 4145 02:39:15,720 --> 02:39:18,240 PATIENTS OF KIDS WHO HAVE THESE 4146 02:39:18,240 --> 02:39:20,600 RECESSIVE DISEASE ARE OFTEN MORE 4147 02:39:20,600 --> 02:39:22,480 LIKELY TO GET PARKINSON'S 4148 02:39:22,480 --> 02:39:24,240 DISEASE, AND A FEW ARE LIKELY IN 4149 02:39:24,240 --> 02:39:28,760 STORAGE DISEASE BECAUSE THIS IS 4150 02:39:28,760 --> 02:39:32,080 A LYSOSOMAL STORAGE DISEASE WILL 4151 02:39:32,080 --> 02:39:34,120 HAVE ASSOCIATIONS WITH 4152 02:39:34,120 --> 02:39:35,760 PARKINSON'S DISEASE AND THE WAY 4153 02:39:35,760 --> 02:39:38,120 I THINK ABOUT IT IS THESE CASES 4154 02:39:38,120 --> 02:39:39,720 ARE VERY SEVERE CASES BECAUSE 4155 02:39:39,720 --> 02:39:43,120 BOTH COPIES OF THE PROTEINS 4156 02:39:43,120 --> 02:39:46,080 ENCODED BY THE GENES ARE 4157 02:39:46,080 --> 02:39:47,160 AFFECTED BUT ONLY 1 COPY IS 4158 02:39:47,160 --> 02:39:49,520 AFFECTED, IT MAY BE A MUCH MORE 4159 02:39:49,520 --> 02:39:53,920 INSIDIOUS AND SLOW PROCESS AND A 4160 02:39:53,920 --> 02:39:55,640 SIGNIFICANT PORTION OF THESE 4161 02:39:55,640 --> 02:39:57,880 PARENTS THAT CARRY THESE DISEASE 4162 02:39:57,880 --> 02:39:59,520 CAN GET PARKINSON'S DISEASE. 4163 02:39:59,520 --> 02:40:01,440 SO WHEN YOU APPROACH THIS, WHEN 4164 02:40:01,440 --> 02:40:03,240 WE START STUDYING DISEASES, 4165 02:40:03,240 --> 02:40:05,240 TYPICALLY TO FIRST TRY TO CREATE 4166 02:40:05,240 --> 02:40:06,320 SEVERE LOSS OF FUNCTION 4167 02:40:06,320 --> 02:40:10,400 MUTATIONS AND WE DEVELOP THIS 4168 02:40:10,400 --> 02:40:12,960 TECHNOLOGY BASED ORIGINALLY ON 4169 02:40:12,960 --> 02:40:14,120 MIMIC INSERTIONS, TRANSPOSABLE 4170 02:40:14,120 --> 02:40:17,880 ELEMENT INSERTIONS THAT WE COULD 4171 02:40:17,880 --> 02:40:20,920 CONVERT THROUGH WHAT IS SHOWN 4172 02:40:20,920 --> 02:40:21,360 HERE. 4173 02:40:21,360 --> 02:40:23,600 WE DO THIS WITH CRISPR 4174 02:40:23,600 --> 02:40:26,880 TECHNOLOGY AND WHAT WE DOE IS WE 4175 02:40:26,880 --> 02:40:29,800 INSERT INTO AN INTRON, HERE IS 4176 02:40:29,800 --> 02:40:33,040 THE GBA 1 B IN FRUIT FLY, AND 4177 02:40:33,040 --> 02:40:40,000 SPLICE IT ON TO GAL4, AND THAT 4178 02:40:40,000 --> 02:40:42,000 TRUNCATES TRANSCRIPTION BECAUSE 4179 02:40:42,000 --> 02:40:43,200 OF THE PRESENCE OF THE 4180 02:40:43,200 --> 02:40:44,640 [INDISCERNIBLE] AND THEN THE 4181 02:40:44,640 --> 02:40:47,600 GAL4 IS PRODUCED BY THIS 4182 02:40:47,600 --> 02:40:49,480 TRUNCATED TRANSCRIPT WHEN 4183 02:40:49,480 --> 02:40:50,680 TRANSLATED AND THE GAL4 CAN BE 4184 02:40:50,680 --> 02:40:55,200 USED FOR A VARIETY OF PURPOSES. 4185 02:40:55,200 --> 02:40:56,920 VERY OFTEN WE USE THIS TO 4186 02:40:56,920 --> 02:41:01,120 HUMANIZE THE FLY AND DRIVE AUAS 4187 02:41:01,120 --> 02:41:03,600 WITH A HUMAN CDNA BUT WE CAN 4188 02:41:03,600 --> 02:41:07,960 ALSO OBVIOUSLY USE THIS TO 4189 02:41:07,960 --> 02:41:09,240 LOCALIZE WHERE THE GENE IS 4190 02:41:09,240 --> 02:41:12,960 EXPRESSED AND WE DID THIS FOR A 4191 02:41:12,960 --> 02:41:15,400 GBA TO OUR SURPRISE, THE GENE 4192 02:41:15,400 --> 02:41:16,440 WAS ONLY EXPRESSED IN GLUE 4193 02:41:16,440 --> 02:41:19,640 MARIOUSA SO IN THE TOP, YOU SEE 4194 02:41:19,640 --> 02:41:22,280 IN GREEN THE NEURONS IN RED THE 4195 02:41:22,280 --> 02:41:23,080 GLIA AND IN THE RIGHT YOU SLEEP 4196 02:41:23,080 --> 02:41:24,200 APNEA AND OBESITYY A BLOW UP AND 4197 02:41:24,200 --> 02:41:26,680 YOU SEE THERE IS ABSOLUTELY NO 4198 02:41:26,680 --> 02:41:29,000 OVERLAP BETWEEN THE GREEN AND 4199 02:41:29,000 --> 02:41:30,240 THE RED. 4200 02:41:30,240 --> 02:41:34,120 BUT WHEN YOU LABEL FOR A GLIALL 4201 02:41:34,120 --> 02:41:36,240 MARKER, THERE IS NEARLY A 4202 02:41:36,240 --> 02:41:40,120 PERFECT OVERLAP BETWEEN THE 2 4203 02:41:40,120 --> 02:41:47,920 AND WE'VE DONE THIS WE'VE TRACED 4204 02:41:47,920 --> 02:41:56,720 THIS ASK WE NEVER SAW THERE WAS 4205 02:41:56,720 --> 02:41:59,200 IN NEURONS SO THIS BEGS THE 4206 02:41:59,200 --> 02:42:00,920 QUESTIONS, WHAT HAPPENS WITH 4207 02:42:00,920 --> 02:42:03,520 NEURONS PRODUCE THE DPLIEWK O 4208 02:42:03,520 --> 02:42:09,280 CERAMIDE AND MOW DID --HOW DOES IT 4209 02:42:09,280 --> 02:42:12,280 END UP IN GLIA AND FIRST WE 4210 02:42:12,280 --> 02:42:13,920 ASSAYED A WHOLE HOST OF 4211 02:42:13,920 --> 02:42:16,720 PHENOTYPES THAT WERE ASSOCIATED 4212 02:42:16,720 --> 02:42:17,680 WITH GBA BECAUSE THIS INSERTION 4213 02:42:17,680 --> 02:42:19,400 ALLOWS TO YOU LOOK AT THE 4214 02:42:19,400 --> 02:42:20,800 EXPRESSION PATTERN THAT IS A 4215 02:42:20,800 --> 02:42:22,200 SEVERE LOSS OF FUNCTION 4216 02:42:22,200 --> 02:42:22,480 MUTATION. 4217 02:42:22,480 --> 02:42:23,920 AND THE TAKE HOME MEASESSAGE 4218 02:42:23,920 --> 02:42:26,120 HERE IS THAT THE SYMPTOMS 4219 02:42:26,120 --> 02:42:28,000 TYPICALLY STORT SHOWING UP AT 4220 02:42:28,000 --> 02:42:31,360 DAY 15, 18, THE FLIES ARE SHORT 4221 02:42:31,360 --> 02:42:32,720 LIVED, THE GENERATEDITTIC SYSTEM 4222 02:42:32,720 --> 02:42:33,920 CLEAN, CAN YOU RESCUE THIS BY 4223 02:42:33,920 --> 02:42:38,120 EXPRESSION OF THE HUMAN CDNA AND 4224 02:42:38,120 --> 02:42:40,280 DIVIDE CDNA OR A GENOMIC RESCUE 4225 02:42:40,280 --> 02:43:00,040 CONTRUCT IN ALL CASES YOU HAVE 4226 02:43:00,040 --> 02:43:00,440 RESCUE. 4227 02:43:00,440 --> 02:43:01,720 THEY DON'T CLIMB VERY WELL BUT 4228 02:43:01,720 --> 02:43:04,080 THE KEY HERE IS TO FOCUS ON THE 4229 02:43:04,080 --> 02:43:05,680 MECHANISM BY WHICH THE CERAMIDE 4230 02:43:05,680 --> 02:43:13,320 IS TRANSFERRED FROM NEURONS TO 4231 02:43:13,320 --> 02:43:14,040 GLIA. 4232 02:43:14,040 --> 02:43:15,280 SO THIS ALLOWS SOME REALLY NICE 4233 02:43:15,280 --> 02:43:27,480 EXPERIMENTS IF YOU LOOK AT THESE 4234 02:43:27,480 --> 02:43:29,720 IN THE I THESE CELLS HERE THAT 4235 02:43:29,720 --> 02:43:31,480 ARE GLIA AND IT TURNS OUT THESE 4236 02:43:31,480 --> 02:43:34,000 CELLS THAT ARE LABELED IN GREEN 4237 02:43:34,000 --> 02:43:35,200 HERE EXPRESS GBA AND THE CELLS 4238 02:43:35,200 --> 02:43:36,880 THAT ARE LABELED IN GRAY DO NOT, 4239 02:43:36,880 --> 02:43:38,600 THOSE ARE THE PHOTO RECEPTORS, 4240 02:43:38,600 --> 02:43:41,640 THE NICE THING TO WORK WITH THE 4241 02:43:41,640 --> 02:43:44,440 EYE IS THAT YOU CAN REDUCE 4242 02:43:44,440 --> 02:43:45,440 ACTIVITY BY REDUCING PHOTO 4243 02:43:45,440 --> 02:43:46,680 RECEPTORS THROUGH LIGHT AND SEE 4244 02:43:46,680 --> 02:43:47,760 WHAT HAPPENS AND WHAT WE'RE 4245 02:43:47,760 --> 02:43:50,920 DOING HERE AND WE'RE MONITOR--WE 4246 02:43:50,920 --> 02:43:54,320 ARE MONITORING THE DPLIEWK O 4247 02:43:54,320 --> 02:43:57,120 CERAMIDE WITH AN ANTIBODY AS CAN 4248 02:43:57,120 --> 02:43:59,720 YOU SEE THE GLUCOCERAMIDE IS 4249 02:43:59,720 --> 02:44:03,520 ACCUMULATED IN THESE GREEN CELLS 4250 02:44:03,520 --> 02:44:03,960 THESE GLIAL CELLS. 4251 02:44:03,960 --> 02:44:05,640 NOW IF THE FLIES ARE RAISED IN 4252 02:44:05,640 --> 02:44:08,760 THE DARK, THERE ARE BARELY ANY 4253 02:44:08,760 --> 02:44:10,440 DPLEEL CERAMIDE THAT SURROUNDS 4254 02:44:10,440 --> 02:44:11,520 THE PHOTO RECEPTORS THAT ARE 4255 02:44:11,520 --> 02:44:25,680 LABELED IN RED HERE, YOU CAN SEE 4256 02:44:25,680 --> 02:44:26,400 THESE IN GREEN. 4257 02:44:26,400 --> 02:44:29,000 IF YOU LOOK AT GBA AND KEEP THE 4258 02:44:29,000 --> 02:44:30,760 GBA MUTANT IN THE DARK, YOU SEE 4259 02:44:30,760 --> 02:44:35,520 THERE IS ESSENT YELLLY NO 4260 02:44:35,520 --> 02:44:36,320 DIFFERENCE BETWEEN THE FLIES IN 4261 02:44:36,320 --> 02:44:38,240 THE DARK THAT ARE WILD TYPE 4262 02:44:38,240 --> 02:44:41,080 VERSUS THE FLIES THAT ARE GBA 4263 02:44:41,080 --> 02:44:41,960 RAISED IN THE DARK. 4264 02:44:41,960 --> 02:44:44,080 HOWEVER, WHEN YOU PUT THEM FOR 4265 02:44:44,080 --> 02:44:45,720 12 HOURS AND EXPOSE THEM TO 4266 02:44:45,720 --> 02:44:47,440 LIGHT, YOU START SEEING THAT 4267 02:44:47,440 --> 02:44:50,480 THERE IS A DPLIEWK O CERAMIDE 4268 02:44:50,480 --> 02:44:51,640 ACCUMULATION IN THE PHOTO 4269 02:44:51,640 --> 02:44:53,480 RECEPTORS AND THE GLUE MARIOUSA 4270 02:44:53,480 --> 02:44:55,320 START REALLY PILING UP HIGH 4271 02:44:55,320 --> 02:44:57,440 LEVELS OF DPLIEWK O CERAMIDE AND 4272 02:44:57,440 --> 02:45:00,400 THE GLUE MARIOUSA CLEARLY BECOME 4273 02:45:00,400 --> 02:45:04,720 SICK, THEY KIND OF BECOME 4274 02:45:04,720 --> 02:45:05,040 VACCULATED. 4275 02:45:05,040 --> 02:45:09,200 AND IF YOU DO THIS FOR AN EXTRA 4276 02:45:09,200 --> 02:45:11,600 DAY, CAN YOU SEE THAT THE PHOTO 4277 02:45:11,600 --> 02:45:18,400 RECEPTORS START REALLY SUFFERING 4278 02:45:18,400 --> 02:45:19,960 AND EVEN THOUGH AFTER YOU KNOW 4279 02:45:19,960 --> 02:45:21,720 THIS EXPOSURE FROM THE ABSENCE 4280 02:45:21,720 --> 02:45:24,640 OF GBA, THE DPLEEL CELLS KEEP ON 4281 02:45:24,640 --> 02:45:26,160 PILING UP THE GLUCOCERAMIDE, 4282 02:45:26,160 --> 02:45:27,480 THEY FAIL TO DEGRADE IT AND 4283 02:45:27,480 --> 02:45:30,400 THERE IS A VERY SEVERE DEMISE OF 4284 02:45:30,400 --> 02:45:34,720 THE PHOTO RECEPTORS AND THE 4285 02:45:34,720 --> 02:45:35,120 GLIAL CELLS. 4286 02:45:35,120 --> 02:45:39,560 AND THIS IS NICELY SHOWN WHEN 4287 02:45:39,560 --> 02:45:42,280 YOU LOOK AT TRANSMISSION 4288 02:45:42,280 --> 02:45:43,160 ELECTROMICROSCOPY, AND WHEN YOU 4289 02:45:43,160 --> 02:45:45,520 SEE THAT WHEN YOU LOOK IN THE 4290 02:45:45,520 --> 02:45:46,920 YELLOW WHITE BACKGROUND IF YOU 4291 02:45:46,920 --> 02:45:48,000 SEE THE BACKGROUND HERE YOU CAN 4292 02:45:48,000 --> 02:45:49,440 SEE THE BLUE CELLS HERE WHICH 4293 02:45:49,440 --> 02:45:55,880 ARE THE GLIAL CELLS AND NOTE O 4294 02:45:55,880 --> 02:45:57,520 RECEPTORS THEY FORM A NICELY 4295 02:45:57,520 --> 02:45:59,720 THIN SLIVER BUT IN THE MUTANTS 4296 02:45:59,720 --> 02:46:03,480 THEY BECOME EXPANDED AND THEY 4297 02:46:03,480 --> 02:46:09,560 BECOME LOADED WITH THESE HOLES, 4298 02:46:09,560 --> 02:46:10,000 THESE VACCULES. 4299 02:46:10,000 --> 02:46:12,880 AND IF WE NOW PRESENT YET 4300 02:46:12,880 --> 02:46:16,320 ANOTHER 12 HOURS OF LIGHT TO THE 4301 02:46:16,320 --> 02:46:19,080 YELLOW WHITE CELLS THAT HAVE TBA 4302 02:46:19,080 --> 02:46:22,720 AND WE LABEL FOR A LYSOSOMA 4303 02:46:22,720 --> 02:46:24,920 MARKER, CTSL, WE SEE THAT THERE 4304 02:46:24,920 --> 02:46:27,120 IS A MILD ACCUMULATION OF CTSL 4305 02:46:27,120 --> 02:46:28,520 AND IF THERE'S AN INCREASE IN 4306 02:46:28,520 --> 02:46:29,120 THE LYSOSTUDIES OF MULTIPLE 4307 02:46:29,120 --> 02:46:30,720 ENDOCRINES BUT WHEN YOU LOOK IN 4308 02:46:30,720 --> 02:46:32,920 THE GBA MUTANTS YOU SEE A 4309 02:46:32,920 --> 02:46:33,880 DRAMATIC INCREASE IN THE 4310 02:46:33,880 --> 02:46:35,320 LYSOSOME AND YOU CAN SEE THAT 4311 02:46:35,320 --> 02:46:37,760 THE CERAMIDE IS NOT CONFINED TO 4312 02:46:37,760 --> 02:46:41,320 THE LYSOSOMES BUT EXPANDS TRUE 4313 02:46:41,320 --> 02:46:43,200 OUT THE CELL, AND THAT THE PHOTO 4314 02:46:43,200 --> 02:46:44,880 RECEPTORS ARE REALLY HAMMERED, 4315 02:46:44,880 --> 02:46:47,080 SO THE LONGER YOU KEEP THEM 4316 02:46:47,080 --> 02:46:48,280 EXPOSED TO LIGHT, THE MORE 4317 02:46:48,280 --> 02:46:49,920 ACTIVE THEY ARE, THE MORE 4318 02:46:49,920 --> 02:46:51,760 DPLIEWK O CERAMIDE THEY FORM, 4319 02:46:51,760 --> 02:46:53,280 THE GLUCOCELL SERIES POINTS MID 4320 02:46:53,280 --> 02:46:54,520 CANNOT BE DEGRADED IN THE GLUE 4321 02:46:54,520 --> 02:46:55,920 MARIOUSA AND JUST PILES UP IN 4322 02:46:55,920 --> 02:46:57,480 THE DPLIA AND EVENTUALLY PILES 4323 02:46:57,480 --> 02:47:01,440 UP IN THE NEURONS. 4324 02:47:01,440 --> 02:47:03,600 IF YOU WAIT A FEW MORE DAYS YOU 4325 02:47:03,600 --> 02:47:05,640 GET A MASSIVE DEMISE OF THE 4326 02:47:05,640 --> 02:47:07,560 PHOTO RECEPTORS AND THE FLEEL 4327 02:47:07,560 --> 02:47:11,320 CELLS AS IS SHOWN HERE AND YOU 4328 02:47:11,320 --> 02:47:15,000 CAN SEE THAT THERE IS A MASSIVE 4329 02:47:15,000 --> 02:47:16,280 NEURY DEGENERATIVE PHENOTYPE IN 4330 02:47:16,280 --> 02:47:17,600 THE PHOTO RECEPTORS THAT ARE 4331 02:47:17,600 --> 02:47:19,880 INDUCED IN AFTER A FEW DAYS. 4332 02:47:19,880 --> 02:47:25,040 SO THE IN ACCIDENT QUESTION THEN 4333 02:47:25,040 --> 02:47:29,120 IS, IS ACTIVITY REALLY AT THE 4334 02:47:29,120 --> 02:47:30,440 ROOT OF THIS PHENOTYPE BECAUSE 4335 02:47:30,440 --> 02:47:32,320 WITH THE PHOTO RECEPTORS YOU 4336 02:47:32,320 --> 02:47:34,640 HAVE AN SAIRKS, WE CAN JUST 4337 02:47:34,640 --> 02:47:35,720 STIMULATE WITH LIGHT AND YOU CAN 4338 02:47:35,720 --> 02:47:37,960 SAY WELL, THAT'S IN THE PHOTO 4339 02:47:37,960 --> 02:47:39,000 RECEPTORS, WHAT ABOUT THE REST 4340 02:47:39,000 --> 02:47:41,520 OF THE BRAIN. 4341 02:47:41,520 --> 02:47:43,840 SO WE CAN EXPRESS WITH IN THE 4342 02:47:43,840 --> 02:47:47,080 NEURONS TRIP A WHICH IS A 4343 02:47:47,080 --> 02:47:47,680 TEMPERATURE SENSITIVE CHANNEL 4344 02:47:47,680 --> 02:47:50,400 THAT WHEN YOU KEEP THE FLIES AT 4345 02:47:50,400 --> 02:47:52,920 18, WILL NOT BE USED AND YOU CAN 4346 02:47:52,920 --> 02:47:54,240 SEE THAT THERE'S VERY LITTLE 4347 02:47:54,240 --> 02:47:57,200 DPLIEWK O CERAMIDE IN THE BRAIN 4348 02:47:57,200 --> 02:48:00,640 THAT IS SHOWN HERE AND WHEN 4349 02:48:00,640 --> 02:48:03,120 YOU--WE USE THE WORD HEAT SHOCK 4350 02:48:03,120 --> 02:48:04,520 BUT IT'S NOT REALLY WE JUST 4351 02:48:04,520 --> 02:48:07,440 TRANSFER THE FLIES FROM 18 TO 29 4352 02:48:07,440 --> 02:48:09,200 AND INDUCE THE ACTIVITY OF THIS 4353 02:48:09,200 --> 02:48:12,320 TRIP A CHANNEL SO THAT IT NOW 4354 02:48:12,320 --> 02:48:14,440 STARTS GAINING IONS AND WHEN YOU 4355 02:48:14,440 --> 02:48:15,560 SEE IS AGAIN, THROUGHOUT THE 4356 02:48:15,560 --> 02:48:17,120 BRAIN YOU CAN NOW SEE THE 4357 02:48:17,120 --> 02:48:18,520 DPLIEWK O CERAMIDE IS 4358 02:48:18,520 --> 02:48:21,760 ACCUMULATING SO IT'S CLEAR THAT 4359 02:48:21,760 --> 02:48:28,400 NEURONAL ACTIVITY PLAYS AN 4360 02:48:28,400 --> 02:48:29,040 IMPORTANT ROLE HERE. 4361 02:48:29,040 --> 02:48:30,680 ALL RIGHT, SO ARE THE NEURONS 4362 02:48:30,680 --> 02:48:33,520 PRODUCING THE GRIEWK O CERAMIDE 4363 02:48:33,520 --> 02:48:39,520 OR WHERE IS THAT GLUCOCERAMIDE 4364 02:48:39,520 --> 02:48:41,280 PRODUCED IF IT'S NOT IN NEURONS 4365 02:48:41,280 --> 02:48:47,720 SO THE FIRST THING THAT THEY DID 4366 02:48:47,720 --> 02:48:52,280 WAS TO KNOCK ON THE ENZYME THAT 4367 02:48:52,280 --> 02:48:53,680 IS IN THE GLUCOSILV TRANSFER ACE 4368 02:48:53,680 --> 02:48:56,840 AND SO THE IDEA IS NOW, LET'S DO 4369 02:48:56,840 --> 02:48:58,800 AN RNAI JUST IN THE PHOTO 4370 02:48:58,800 --> 02:49:01,800 RECEPTORS, THIS IS SHOWN HERE, 4371 02:49:01,800 --> 02:49:05,520 AND CHECK WHAT HAPPENS WITH 4372 02:49:05,520 --> 02:49:06,200 GLUCOCERAMIDE ACCUMULATION AND 4373 02:49:06,200 --> 02:49:08,520 HE OR SHE BOOSTED THE SIGNAL A 4374 02:49:08,520 --> 02:49:10,760 LITTLE BIT AND YOU CAN SEE THAT 4375 02:49:10,760 --> 02:49:12,440 THERE IS SOME GLUCOCERAMIDE IN 4376 02:49:12,440 --> 02:49:13,840 THE PHOTO RECEPTORS, THERE A LOT 4377 02:49:13,840 --> 02:49:16,920 OF DPLIEWK O CERAMIDE IN THE 4378 02:49:16,920 --> 02:49:18,120 CONTROLS BUT WHEN SHE KNOCKS 4379 02:49:18,120 --> 02:49:19,720 DOWN IN THE PHOTO RECEPTORS AND 4380 02:49:19,720 --> 02:49:22,600 THE ENZYME THAT MAKES DPLIEWK O 4381 02:49:22,600 --> 02:49:23,560 CERAMIDE OBVIOUSLY, YOU KNOW 4382 02:49:23,560 --> 02:49:24,920 VERY LITTLE DPLIEWK O CERAMIDE 4383 02:49:24,920 --> 02:49:26,960 IN THE PHOTO RECEPTOR, ALSO VERY 4384 02:49:26,960 --> 02:49:31,440 LITTLE GROUP OF CERAMIDE IN THE 4385 02:49:31,440 --> 02:49:31,760 GLUE MARIOUSA. 4386 02:49:31,760 --> 02:49:33,320 AND IN THE GLUE MARIOUSA THEY 4387 02:49:33,320 --> 02:49:37,880 ARRIVE THERE FROM THESE PHOTO 4388 02:49:37,880 --> 02:49:40,560 RECEPTORS. 4389 02:49:40,560 --> 02:49:43,320 IF SHE KNOCKS DOWN THE DPLIEWK O 4390 02:49:43,320 --> 02:49:46,000 SILL CERAMIDE AND TRANSFERAISE 4391 02:49:46,000 --> 02:49:49,720 IN THE GLIA, THERE IS NO EFFECT, 4392 02:49:49,720 --> 02:49:53,320 SO THAT ARGUES THAT WHATEVER IS 4393 02:49:53,320 --> 02:49:55,560 IN THE GLIA IS DERIVED FROM THE 4394 02:49:55,560 --> 02:49:57,320 PHOTO RECEPTORS AND INDEED 4395 02:49:57,320 --> 02:49:59,800 TRANSFER UP ON NEURONAL 4396 02:49:59,800 --> 02:50:00,920 ACTIVITY, THE GLUCOCERAMIDE TO 4397 02:50:00,920 --> 02:50:03,720 THE GLIA AND THAT THE ENZYME 4398 02:50:03,720 --> 02:50:04,640 THAT IS EXPRESSED SPECIFICALLY 4399 02:50:04,640 --> 02:50:11,560 IN THERE AND ABLE TO DEGRADE 4400 02:50:11,560 --> 02:50:12,960 THESE, GLUCOCERAMIDE BACK TO 4401 02:50:12,960 --> 02:50:15,040 SERUM, SO THIS RAISED THE 4402 02:50:15,040 --> 02:50:17,720 QUESTION AS TO HOW DOES--WHAT IS 4403 02:50:17,720 --> 02:50:20,760 THE MECHANISM BY WHICH GLC CER 4404 02:50:20,760 --> 02:50:22,880 IS TRANSFER FRIDAY NEURON TO 4405 02:50:22,880 --> 02:50:24,040 GLUE MARIOUSA UPON ACTIVITY SO 4406 02:50:24,040 --> 02:50:27,800 FOR THIS WE TURN TO VERTEBRATE 4407 02:50:27,800 --> 02:50:28,960 CELLS AND WHAT [INDISCERNIBLE] 4408 02:50:28,960 --> 02:50:31,400 DID IS SHE COLLECTED VERTEBRATE 4409 02:50:31,400 --> 02:50:35,280 CELLS, NEURONS IN GLIA AND 4410 02:50:35,280 --> 02:50:37,360 LOOKED AT THE EXPRESSION OF GBA 4411 02:50:37,360 --> 02:50:39,840 IN HUMAN CELLS IN THE GLIA AND 4412 02:50:39,840 --> 02:50:41,480 NEURONS AND NOTE THAT 4413 02:50:41,480 --> 02:50:43,920 IMMEDIATELY THAT IN GLIA THE 4414 02:50:43,920 --> 02:50:46,600 HUMAN GBA IS EXPRESSED MUCH MORE 4415 02:50:46,600 --> 02:50:49,440 ABUNDANTLY THAN IN NEURONS. 4416 02:50:49,440 --> 02:50:51,520 SHE THEN TOOK NBD, DPLIEWK O 4417 02:50:51,520 --> 02:50:56,000 CERAMIDE WHICH IS A 4418 02:50:56,000 --> 02:50:57,040 FLUORESCENTLY LABELED CERAMIDE, 4419 02:50:57,040 --> 02:50:59,360 TOOK THE NEURONS AND EXPOSED 4420 02:50:59,360 --> 02:51:02,880 THEM TO THIS MBD CERAMIDE FOR 30 4421 02:51:02,880 --> 02:51:03,720 MINUTES FOR 4-DEGREES CELSIUS 4422 02:51:03,720 --> 02:51:08,280 AND YOU CAN SEE NICELY THIS MBD 4423 02:51:08,280 --> 02:51:10,440 CERAMIDE WILL LABEL THESE 4424 02:51:10,440 --> 02:51:13,560 MEMBRANES AND IF YOU SHIFT THEM 4425 02:51:13,560 --> 02:51:14,720 TO 30-DEGREES CELSIUS FOR 30 4426 02:51:14,720 --> 02:51:16,000 MINUTES SOME OF IT IS 4427 02:51:16,000 --> 02:51:18,280 INTERNALIZED AND THAT IS WHAT IS 4428 02:51:18,280 --> 02:51:18,680 SHOWN HERE. 4429 02:51:18,680 --> 02:51:21,800 SO THIS IS VERY SIMPLE ASSAY. 4430 02:51:21,800 --> 02:51:27,720 NEXT, WHAT SHE DID IS SHE TOOK A 4431 02:51:27,720 --> 02:51:29,120 COVER SLIP, UNDERCOVER SLIP 4432 02:51:29,120 --> 02:51:33,360 CULTURED NEURONS AND SO, LET'S 4433 02:51:33,360 --> 02:51:35,040 MAKE SURE THOO THESE NEURONS ON 4434 02:51:35,040 --> 02:51:36,560 THE TOP CANNOT TOUCH THE NEURONS 4435 02:51:36,560 --> 02:51:37,800 THAT ARE AT THE BOTTOM. 4436 02:51:37,800 --> 02:51:44,640 SO THE NEURONS AT THE BOTTOM ARE 4437 02:51:44,640 --> 02:51:47,840 LABELED WITH GLC NBD AND THEY 4438 02:51:47,840 --> 02:51:50,880 AFTER 30 MINUTES TAKE UP IN GLC 4439 02:51:50,880 --> 02:51:52,720 CERAMIDE, THERE IS NO GLC SERIES 4440 02:51:52,720 --> 02:51:54,360 POINTS MID THAT TRANSFERRED FROM 4441 02:51:54,360 --> 02:51:56,240 THESE NEURONS THAT THE BOTTOM TO 4442 02:51:56,240 --> 02:52:01,240 THE NEURONS AT THE TOP. 4443 02:52:01,240 --> 02:52:03,720 HOWEVER, WHEN YOU CHANGE THAT 4444 02:52:03,720 --> 02:52:05,120 AND INSTEAD OF PUTTING NEURONS 4445 02:52:05,120 --> 02:52:07,840 AT THE TOP, YOU PUT GLIA AT THE 4446 02:52:07,840 --> 02:52:10,160 TOP, YOU SEE AGAIN NO LABEL OF 4447 02:52:10,160 --> 02:52:11,640 THE GLIA BUT YOU SEE A PRETTY 4448 02:52:11,640 --> 02:52:16,920 DIG 95 CANT DECREASE OF THE 4449 02:52:16,920 --> 02:52:18,440 GLUCOCERAMIDE THAT IS PRESENT IN 4450 02:52:18,440 --> 02:52:19,360 THE NEURON. 4451 02:52:19,360 --> 02:52:21,200 SO SOMEHOW, THE GLUCOSERIES 4452 02:52:21,200 --> 02:52:24,720 POINTSA MIDHERE IS RELEASED AND 4453 02:52:24,720 --> 02:52:27,720 IT'S NOT SHOWING UP IN GLIA, 4454 02:52:27,720 --> 02:52:30,080 HOWEVER, TO KNOCK DOWN GBA IN 4455 02:52:30,080 --> 02:52:32,360 GLIA AND WHEN YOU DO THAT YOU 4456 02:52:32,360 --> 02:52:39,520 SEE THAT THE GLIA START LABELING 4457 02:52:39,520 --> 02:52:41,840 PRETTY STRONGLY AS NBD GLC 4458 02:52:41,840 --> 02:52:44,160 CERAMIDE SO THIS ARGUES THAT IN 4459 02:52:44,160 --> 02:52:46,400 CELL CULTURE THE NEURONS WITH 4460 02:52:46,400 --> 02:52:48,320 THE CERAMIDE, THE NEURONS TAKE 4461 02:52:48,320 --> 02:52:52,840 IT UP, AND IF YOU KNOCK DOWN GBA 4462 02:52:52,840 --> 02:52:54,640 IN THE GLIA, THEN THE GLIA TAKE 4463 02:52:54,640 --> 02:52:58,040 IT UP AND IF YOU KNOCK DOWN GBA, 4464 02:52:58,040 --> 02:53:01,400 GLIA COULD BE THE PROCESS THE 4465 02:53:01,400 --> 02:53:03,880 GLUCOCERAMIDE AND THEREFORE PILE 4466 02:53:03,880 --> 02:53:04,400 UP THE GLUCOCERAMIDE. 4467 02:53:04,400 --> 02:53:06,920 THE NEXT QUESTION IS HOW IS THIS 4468 02:53:06,920 --> 02:53:08,040 TRANSFER OCCURRING FROM NEURONS 4469 02:53:08,040 --> 02:53:12,360 TO GLIA, WHAT ARE THE NECKANISMS 4470 02:53:12,360 --> 02:53:17,320 THAT UNDERLIE THIS. 4471 02:53:17,320 --> 02:53:18,720 AND SO, [INDISCERNIBLE] WAS 4472 02:53:18,720 --> 02:53:20,000 USING DIFFERENT MEDIA IS THIS 4473 02:53:20,000 --> 02:53:25,480 WAS A MEDIA THAT JUST CONSISTS 4474 02:53:25,480 --> 02:53:27,320 OF SUGARS AND SALTS. 4475 02:53:27,320 --> 02:53:29,720 ONE DAY WHEN SHE USED TGF BETA 4476 02:53:29,720 --> 02:53:31,960 AND SHE LOOKED AT THESE NEURONS, 4477 02:53:31,960 --> 02:53:35,360 SHE SAW THAT THERE WAS NO LABEL 4478 02:53:35,360 --> 02:53:36,840 AT ALL. 4479 02:53:36,840 --> 02:53:40,280 THAT ALL GLUCOCERAMIDE WAS 4480 02:53:40,280 --> 02:53:40,720 TRANSFERRED. 4481 02:53:40,720 --> 02:53:42,600 SO THIS WAS A SERENDIPITOUS 4482 02:53:42,600 --> 02:53:44,640 DISCOVERY SO SHE CULTURED THE 4483 02:53:44,640 --> 02:53:46,960 NEURONS IN ACSF AND THEN ADDED 4484 02:53:46,960 --> 02:53:49,640 50 NANO MOLARS OF TGF BETA AND 4485 02:53:49,640 --> 02:53:52,520 WHAT YOU THEN DO, IS YOU IMMUNO 4486 02:53:52,520 --> 02:53:55,760 PRECIPITATE WITH AN ANTIBODY 4487 02:53:55,760 --> 02:53:57,280 AGAINST CD63 WHICH RECOGNIZES 4488 02:53:57,280 --> 02:53:58,120 EXOSTUDIES STUDIES OF MULTIPLE 4489 02:53:58,120 --> 02:53:58,720 ENDOCRINES AND THE FIRST THING 4490 02:53:58,720 --> 02:54:01,520 YOU CAN SEE IS THAT WHEN YOU PUT 4491 02:54:01,520 --> 02:54:03,000 IN TGF BETA THERE IS A VERY 4492 02:54:03,000 --> 02:54:04,280 STRONG INDUCTION OF THE 4493 02:54:04,280 --> 02:54:09,400 PRODUCTION OF EXOSTUDIES OF 4494 02:54:09,400 --> 02:54:11,120 MULTIPLE ENDOCRINES AND SHE THEN 4495 02:54:11,120 --> 02:54:11,640 LOOKED THE EXOSTUDIES OF 4496 02:54:11,640 --> 02:54:13,240 MULTIPLE ENDOCRINES IN THE 4497 02:54:13,240 --> 02:54:15,280 ABSENCE OF TGF BETA AT THE MBD 4498 02:54:15,280 --> 02:54:20,720 CERAMIDE AND THERE WAS A VERY 4499 02:54:20,720 --> 02:54:23,400 OBVIOUS SIGNIFICANT INCREASE IN 4500 02:54:23,400 --> 02:54:27,040 THE MBD LEUCOSERUM. 4501 02:54:27,040 --> 02:54:30,320 SO WHAT ABOUT THE ENDOGENOUS 4502 02:54:30,320 --> 02:54:30,920 GLUCOCERAMIDE? 4503 02:54:30,920 --> 02:54:36,600 SO SHE CULTURED THE NEURONS, SHE 4504 02:54:36,600 --> 02:54:38,320 IN ACSF, WHICH DOESN'T CONTAIN 4505 02:54:38,320 --> 02:54:40,280 ANY PROTEIN JUST SALT AND SUGAR, 4506 02:54:40,280 --> 02:54:43,440 AND THEN PUT IN TGF BETA AND 4507 02:54:43,440 --> 02:54:46,880 THEN TOOK THE SUPERINATENT AND 4508 02:54:46,880 --> 02:54:49,520 THE CELLS AND MEASURED THROUGH 4509 02:54:49,520 --> 02:54:51,080 LIPID OMICS, THE LEVELS OF 4510 02:54:51,080 --> 02:54:52,040 CERAMIDE IN THE SUPERINATENT IN 4511 02:54:52,040 --> 02:54:54,360 THE LEVEL OF FLUKE O CERAMIDE IN 4512 02:54:54,360 --> 02:54:55,760 THE SUPERINATENT, AND YOU CAN 4513 02:54:55,760 --> 02:54:58,720 SEE THAT THE SUPERINATENT, IS 4514 02:54:58,720 --> 02:55:03,720 NOT MUCH ENRICHED IN CERAMIDE IN 4515 02:55:03,720 --> 02:55:04,160 GLUCOCERAMIDE. 4516 02:55:04,160 --> 02:55:06,680 THE IT HAS A MINOR DECREASE IN 4517 02:55:06,680 --> 02:55:08,320 THE CERAMIDE BUT IT'S NOT 4518 02:55:08,320 --> 02:55:10,200 STATISTIC LOAMACYY SIGNIFICANT 4519 02:55:10,200 --> 02:55:12,520 BUT IT CLEARLY ARGUES THAT THE 4520 02:55:12,520 --> 02:55:16,880 CELLS SECRETE THESE CERAMIDES IN 4521 02:55:16,880 --> 02:55:18,600 GLUCOCERAMIDE UP UPON EXPOSURE 4522 02:55:18,600 --> 02:55:22,520 OF THE TGF BETA SO I WOULD LIKE 4523 02:55:22,520 --> 02:55:24,080 TO END WITH THE MODEL HERE AND 4524 02:55:24,080 --> 02:55:28,960 SAY THAT UPON NEURONAL ACTIVITY 4525 02:55:28,960 --> 02:55:31,480 NEURONS PRODUCE GLIEWRK O 4526 02:55:31,480 --> 02:55:37,720 CERAMIDE IS VERY TOXIC IF IT 4527 02:55:37,720 --> 02:55:38,840 PILES UP. 4528 02:55:38,840 --> 02:55:41,800 THE GLIAL CELLS SECRETE SIGNAL 4529 02:55:41,800 --> 02:55:43,520 WHICH IS TGFBETTA AND IN FLY 4530 02:55:43,520 --> 02:55:47,200 THIS IS IS BPPAND ALL OF THIS TO 4531 02:55:47,200 --> 02:55:49,720 HOM O LOLLINGS TO TGF BETA AND 4532 02:55:49,720 --> 02:55:51,280 THAT IS RECEIVED BY THE NEURONS 4533 02:55:51,280 --> 02:55:52,480 THAT INDUCES THE FORMATION OF 4534 02:55:52,480 --> 02:55:54,160 THESE EXOSTUDIES OF MULTIPLE 4535 02:55:54,160 --> 02:55:54,840 ENDOCRINES, AND THESE EXOSTUDIES 4536 02:55:54,840 --> 02:55:56,880 OF MULTIPLE ENDOCRINES ARE 4537 02:55:56,880 --> 02:55:58,400 PRODUCED BY MULTICANNED WHAT 4538 02:55:58,400 --> 02:56:00,600 BODIES SO THE CERAMIDE FROM THE 4539 02:56:00,600 --> 02:56:02,320 MEMBRANE OF THE NEURONS TRAVELS 4540 02:56:02,320 --> 02:56:04,280 TO LYSOSOME BUT AT AN 4541 02:56:04,280 --> 02:56:09,880 INTERMEDIATE STEP AT THE 4542 02:56:09,880 --> 02:56:11,720 MULTI[INDISCERNIBLE] BODY STEP, 4543 02:56:11,720 --> 02:56:13,960 THE CERAMIDE, THE 4544 02:56:13,960 --> 02:56:14,640 MULTI[INDISCERNIBLE] BODIES 4545 02:56:14,640 --> 02:56:15,800 REDUCE THE MEMBRANE UNDER THE 4546 02:56:15,800 --> 02:56:16,880 FORM OF EXOSTUDIES OF MULTIPLE 4547 02:56:16,880 --> 02:56:17,520 ENDOCRINES, THESE EXOSTUDIES OF 4548 02:56:17,520 --> 02:56:18,320 MULTIPLE ENDOCRINES ARE THEN 4549 02:56:18,320 --> 02:56:21,360 TAKEN UP BY THE LYSOSOMES AND 4550 02:56:21,360 --> 02:56:23,880 THE LYSOSOMES--BY THE GLIAL 4551 02:56:23,880 --> 02:56:26,200 CELLS AND TRAFFIC IN A VERY 4552 02:56:26,200 --> 02:56:29,280 PRECISE WAY THAT WE HAVEN'T 4553 02:56:29,280 --> 02:56:30,720 REALLY FIGURED OUT IN ENOUGH 4554 02:56:30,720 --> 02:56:33,240 DETAIL TO TALK ABOUT RIGHT NOW, 4555 02:56:33,240 --> 02:56:36,320 BUT THEY END UP IN THE LYSOSOME 4556 02:56:36,320 --> 02:56:40,080 AND IN THE LYSOSOME THE SERIES 4557 02:56:40,080 --> 02:56:41,720 POINTS MID IT'S DEGRADED BA 4558 02:56:41,720 --> 02:56:42,440 BEING TO CERAMIDE. 4559 02:56:42,440 --> 02:56:44,960 AND IF THIS PROCESS DOES NOT 4560 02:56:44,960 --> 02:56:47,480 OCCUR IN GIA, THE IT PILES UP IN 4561 02:56:47,480 --> 02:56:49,480 GLUE MARIOUSA, THIS PILES UP IN 4562 02:56:49,480 --> 02:56:52,360 NEURON, AND EVENTUALLY LEADS TO 4563 02:56:52,360 --> 02:56:52,800 THE NEURONAL DEMISE. 4564 02:56:52,800 --> 02:56:58,520 AND SO I WILL END UP HERE AND 4565 02:56:58,520 --> 02:56:59,560 GIVE CREDIT, [INDISCERNIBLE] WAS 4566 02:56:59,560 --> 02:57:05,840 80% OF THE WORK AND WE HAVE 4567 02:57:05,840 --> 02:57:07,640 ELECTRON MICROSUPONY AND WE GOT 4568 02:57:07,640 --> 02:57:10,680 HELP FROM THE MAYO CLINIC FOR 4569 02:57:10,680 --> 02:57:11,000 METABOLOMICS. 4570 02:57:11,000 --> 02:57:11,320 THANK YOU. 4571 02:57:11,320 --> 02:57:13,000 >> GREAT. 4572 02:57:13,000 --> 02:57:15,320 THANK YOU SO MUCH HUGO, THAT WAS 4573 02:57:15,320 --> 02:57:17,280 A FASCINATING STORY AND AGAIN 4574 02:57:17,280 --> 02:57:19,200 FOR THE AUDIENCE, PLEASE CLICK 4575 02:57:19,200 --> 02:57:21,560 ON SEND LIVE FEEDBACK ICON TO 4576 02:57:21,560 --> 02:57:22,920 SUBMIT YOUR QUESTIONS AND THEN 4577 02:57:22,920 --> 02:57:24,960 AT THE END OF THIS AFTERNOON'S 4578 02:57:24,960 --> 02:57:26,600 SESSION, THE SPEAKERS WILL BE 4579 02:57:26,600 --> 02:57:30,920 AVAILABLE TO ANSWER THE 4580 02:57:30,920 --> 02:57:31,440 QUESTIONS. 4581 02:57:31,440 --> 02:57:31,640 OKAY? 4582 02:57:31,640 --> 02:57:35,520 SO MOVING ON OUR NEXT SPEAKER IS 4583 02:57:35,520 --> 02:57:36,640 LYNN SCHRIML, WHY THE UNIVERSITY 4584 02:57:36,640 --> 02:57:38,320 OF MARYLAND SCHOOL OF MEDICINE. 4585 02:57:38,320 --> 02:57:40,880 AND THE SHE WILL BE TELLING US 4586 02:57:40,880 --> 02:57:42,760 ABOUT MODELING AND INTEGRATING 4587 02:57:42,760 --> 02:57:46,360 RARE DISEASE DATA WITH THE HUMAN 4588 02:57:46,360 --> 02:57:46,760 DISEASE ONTOLOGY. 4589 02:57:46,760 --> 02:57:53,040 TAKE IT AWAY LYNN. 4590 02:57:53,040 --> 02:57:55,320 >> THANK YOU FOR INVITING ME TO 4591 02:57:55,320 --> 02:57:56,120 THIS MEETING, LOOKING FORWARD TO 4592 02:57:56,120 --> 02:57:58,440 TALKING TO BUT THE HUMAN DISEASE 4593 02:57:58,440 --> 02:57:59,400 ONTOLOGY AND SPECIFICALLY ABOUT 4594 02:57:59,400 --> 02:58:02,120 HOW WE MODEL AND INTEGRATE RARE 4595 02:58:02,120 --> 02:58:04,160 DISEASE DATA WITHIN THE THIS 4596 02:58:04,160 --> 02:58:04,920 ONTOLOGY. 4597 02:58:04,920 --> 02:58:06,880 IT'S QUITE A PROCESS AS YOU CAN 4598 02:58:06,880 --> 02:58:09,240 IMAGINE EXTENDING OVER SEVERAL 4599 02:58:09,240 --> 02:58:10,720 YEARS BUT BUT I'M GOING TO GIVE 4600 02:58:10,720 --> 02:58:12,560 YOU INSIGHTS IN HOW WE MAKE 4601 02:58:12,560 --> 02:58:13,520 THESE DECISIONS ABOUT MODELING 4602 02:58:13,520 --> 02:58:19,520 AND HOW WE INTEGRATE THIS DATA. 4603 02:58:19,520 --> 02:58:21,080 I WANT TO START OFF WITH LOOKING 4604 02:58:21,080 --> 02:58:23,520 AT HOW WE DEVELOP STANDARD AND 4605 02:58:23,520 --> 02:58:25,600 REALLY WALK YOU THROUGH THIS 4606 02:58:25,600 --> 02:58:27,160 KIND OF TIMELINE THAT ALL THE 4607 02:58:27,160 --> 02:58:28,360 VARIOUS STANDARDS OF PRODUCTS 4608 02:58:28,360 --> 02:58:29,560 I'VE BEEN INVOLVED WITH FOR THE 4609 02:58:29,560 --> 02:58:32,480 LAST 20 YEARS WITH THE 4610 02:58:32,480 --> 02:58:33,880 BIOMEDICAL ONTOLOGYS AND 4611 02:58:33,880 --> 02:58:34,600 METAGENOMIC STANDARDS REALLY GO 4612 02:58:34,600 --> 02:58:36,720 THROUGH THE SAME SORT OF STEPS. 4613 02:58:36,720 --> 02:58:38,920 AS CAN YOU SEE FROM THIS FIGURE, 4614 02:58:38,920 --> 02:58:40,560 A LONG PROCESS, NOT JUST A YEAR 4615 02:58:40,560 --> 02:58:44,120 FOR A SINGLE PROJECT OR A GRANT 4616 02:58:44,120 --> 02:58:46,440 CYCLE BUT CAN INVOLVE SEVERAL 4617 02:58:46,440 --> 02:58:47,160 DECADES OF WORK. 4618 02:58:47,160 --> 02:58:48,600 THE 4 KEY THINGS I WANT TO TALK 4619 02:58:48,600 --> 02:58:51,120 ABOUT ARE IN THE CIRCLES HERE, 4620 02:58:51,120 --> 02:58:53,160 SO IDENTIFYING A COMMON NEED. 4621 02:58:53,160 --> 02:58:54,920 WHEN YOU'RE WORKING ON THESE 4622 02:58:54,920 --> 02:58:55,920 TYPES OF PROJECTS REALLY 4623 02:58:55,920 --> 02:58:57,840 BRINGING A COMMUNITY TOGETHER TO 4624 02:58:57,840 --> 02:58:59,480 ADDRESS A COMMON NEED, 4625 02:58:59,480 --> 02:59:00,400 IDENTIFYING WHO IN THAT 4626 02:59:00,400 --> 02:59:03,160 COMMUNITY CAN WORK AS PARTNERS, 4627 02:59:03,160 --> 02:59:05,160 LOOKING AT HOW YOU CAN ORGANIZE 4628 02:59:05,160 --> 02:59:06,200 THAT INFORMATION, BUT NOT JUST 4629 02:59:06,200 --> 02:59:07,520 FOR YOUR PROJECT BUT HOW DO YOU 4630 02:59:07,520 --> 02:59:10,320 CONNECT IT TO OTHER DATA THAT'S 4631 02:59:10,320 --> 02:59:12,480 OUT THERE, HOW DO YOU MAKE IT 4632 02:59:12,480 --> 02:59:12,960 INTEROPERABLE. 4633 02:59:12,960 --> 02:59:14,880 AND THEN AGAIN, HOW YOU EVOLVE 4634 02:59:14,880 --> 02:59:18,560 THAT PROJECT OVER TIME TO HAVE 4635 02:59:18,560 --> 02:59:20,200 NEW IMPLEMENTATIONS, HOW TO 4636 02:59:20,200 --> 02:59:21,120 IDENTIFY NEEDS IN THE COMMUNITY 4637 02:59:21,120 --> 02:59:22,880 AND HOW TO BRING THOSE BACK 4638 02:59:22,880 --> 02:59:26,720 WITHIN OUR SYSTEM HERE SO YOU'RE 4639 02:59:26,720 --> 02:59:29,160 ALWAYS CONTINUALLY EVOLVING, 4640 02:59:29,160 --> 02:59:30,400 WORKING WITH THE COMMUNITY TO 4641 02:59:30,400 --> 02:59:31,480 BRING THAT INFORMATION TOGETHER 4642 02:59:31,480 --> 02:59:33,120 AND REALLY THE END GOAL ON THE 4643 02:59:33,120 --> 02:59:35,720 FAR RIGHT IS INTEROPERABLE 4644 02:59:35,720 --> 02:59:36,160 KNOWLEDGE RESOURCES. 4645 02:59:36,160 --> 02:59:37,120 THIS IS FOR NOT JUST THE 4646 02:59:37,120 --> 02:59:40,440 ONTOLOGY BUT FOR THE PARPTENERS 4647 02:59:40,440 --> 02:59:43,120 YOU WORK WITH AND FOR THE 4648 02:59:43,120 --> 02:59:43,560 COMMUNITY AT LARGE. 4649 02:59:43,560 --> 02:59:46,320 AS YOU CAN SEE ON THE SLIDE, THE 4650 02:59:46,320 --> 02:59:48,440 DISEASE ONTOLOGY OR THE DOH AS 4651 02:59:48,440 --> 02:59:51,960 WE LIKE TO CALL IT STARTED 4652 02:59:51,960 --> 02:59:54,600 HUMBLY WITH JUST A SMALL NUMBER 4653 02:59:54,600 --> 02:59:55,440 OF CLINICALLY AUTHORITATIVE 4654 02:59:55,440 --> 02:59:56,840 RESOURCES AND THEN WE'VE GROWN 4655 02:59:56,840 --> 02:59:58,400 FROM THERE AND THAT'S WHEY WILL 4656 02:59:58,400 --> 02:59:59,520 TAKEN--THEYUC ABOUT TODAY. 4657 02:59:59,520 --> 03:00:02,920 I WANTED TO TOUCH BASE AGAIN 4658 03:00:02,920 --> 03:00:06,120 ABOUT THESE INTERROPERABILITY 4659 03:00:06,120 --> 03:00:06,600 KNOWLEDGE RESOURCES. 4660 03:00:06,600 --> 03:00:07,640 THIS SLIDE IS SHOWING THE 4661 03:00:07,640 --> 03:00:09,720 DISEASE ONTOLOGY AND HOW WE 4662 03:00:09,720 --> 03:00:10,760 CONNECT THROUGH LENS OF DISEASE 4663 03:00:10,760 --> 03:00:12,080 TO ALL THESE DIFFERENT TYPES OF 4664 03:00:12,080 --> 03:00:13,760 DATA AND THEN THERE'S SOME 4665 03:00:13,760 --> 03:00:15,560 EXAMPLES AROUND THE OUTSIDE OF 4666 03:00:15,560 --> 03:00:18,520 THE SLIDE OF RESOURCES THAT ARE 4667 03:00:18,520 --> 03:00:20,080 PARTICULARLY I THINK IMPORTANT 4668 03:00:20,080 --> 03:00:25,520 FOR A GLYCO BIOLOGY AND YOU SEE 4669 03:00:25,520 --> 03:00:27,480 GLYGEN AND UNIPROBE AND MANY 4670 03:00:27,480 --> 03:00:29,400 OTHERS WE THROIRCHG OVER 300 4671 03:00:29,400 --> 03:00:31,200 SUCH RESOURCES BUT I REALLY WANT 4672 03:00:31,200 --> 03:00:32,920 TO CONTRAIT ON THE BLUE BOXES ON 4673 03:00:32,920 --> 03:00:35,120 THIS SLIDE, LOOKINGA THE 4674 03:00:35,120 --> 03:00:36,320 DIFFERENT TYPES OF DATA AND THE 4675 03:00:36,320 --> 03:00:37,720 REASON THESE TYPES OF DATA ARE 4676 03:00:37,720 --> 03:00:38,840 HIGHLIGHTED AND I THINK IT'S 4677 03:00:38,840 --> 03:00:40,680 IMPORTANT TO CONSIDER HOW TO 4678 03:00:40,680 --> 03:00:42,120 CONNECT INFORMATION ACROSS THESE 4679 03:00:42,120 --> 03:00:42,320 SYSTEMS. 4680 03:00:42,320 --> 03:00:46,000 WE DON'T WORK EVER IN JUST 1 4681 03:00:46,000 --> 03:00:47,320 SYSTEM, AND REALLY THINKING 4682 03:00:47,320 --> 03:00:48,240 ABOUT HOW ONTOLOGY CAN HAVE THAT 4683 03:00:48,240 --> 03:00:51,400 ROLE TO WORK WITH THE DIFFERENT 4684 03:00:51,400 --> 03:00:52,480 RESOURCES TO ENABLE THEM TO KNOW 4685 03:00:52,480 --> 03:00:54,320 WHEN THEY'RE TALKING ABOUT 1 4686 03:00:54,320 --> 03:00:55,280 PARTICULAR DISEASE, THEY ARE 4687 03:00:55,280 --> 03:00:56,440 REALLY TALKING ABOUT THE SAME 4688 03:00:56,440 --> 03:00:57,960 DISEASE, NOT A NAME VARIATION 4689 03:00:57,960 --> 03:00:59,680 NOT AN OLDER NAME, BUT TO THE 4690 03:00:59,680 --> 03:01:05,400 CONNECT THAT DATA AND THEN THEY 4691 03:01:05,400 --> 03:01:07,120 CAN EXCHANGE DATA OF THIS 4692 03:01:07,120 --> 03:01:08,400 INTEROPERABILITY THAT EXAMPLE IS 4693 03:01:08,400 --> 03:01:09,840 THE COMMON FUNDED EQUO SYSTEM OR 4694 03:01:09,840 --> 03:01:11,920 GENOME RESOURCES BUT THERE ARE 4695 03:01:11,920 --> 03:01:14,080 MANY, WHERE PLAY WORK TOGETHER 4696 03:01:14,080 --> 03:01:14,800 TO INTEGRATE MANY DIFFERENT DATA 4697 03:01:14,800 --> 03:01:16,120 TYPES AND THEN DISEASE IS JUST 1 4698 03:01:16,120 --> 03:01:23,720 OF THOSE ASPECTS THAT WE GET TO 4699 03:01:23,720 --> 03:01:24,040 WORK WITH. 4700 03:01:24,040 --> 03:01:28,320 ALLOCATES ITS HEART THE HUMAN 4701 03:01:28,320 --> 03:01:29,760 ONTOLOGY IS THE BASES OF DISEASE 4702 03:01:29,760 --> 03:01:32,200 AND WE WANT TO LOOK AT THE CAUSE 4703 03:01:32,200 --> 03:01:32,520 OF DISEASE. 4704 03:01:32,520 --> 03:01:33,960 SO WE STARTED ON THIS IN 2003 4705 03:01:33,960 --> 03:01:35,520 AND AS WE MOVE FORWARD WE WANT 4706 03:01:35,520 --> 03:01:37,320 TO UNDERSTAND THE DEEPER ASPECT 4707 03:01:37,320 --> 03:01:37,640 OF DISEASE. 4708 03:01:37,640 --> 03:01:39,320 HOW COULD WE TAKE THESE LONG 4709 03:01:39,320 --> 03:01:41,440 LISTS OF DISEASES, YOU KNOW THE 4710 03:01:41,440 --> 03:01:42,880 ICDs, THE MESHES, THE NCI 4711 03:01:42,880 --> 03:01:44,320 SOURCES WHICH ARE FANTASTIC 4712 03:01:44,320 --> 03:01:46,960 RESOURCES BUT HOW COULD WE 4713 03:01:46,960 --> 03:01:48,720 REORGANIZE THEM SO WE'RE LOOK AT 4714 03:01:48,720 --> 03:01:50,160 THEM AS A CLINICAL POINT OF VIEW 4715 03:01:50,160 --> 03:01:51,200 AND THAT'S THE IMAGE OF THE 4716 03:01:51,200 --> 03:01:56,160 MIDDLE OF THE SLIDE I AM SHOWING 4717 03:01:56,160 --> 03:02:00,000 YOU, THIS IS OUR OBO SLIDE, THIS 4718 03:02:00,000 --> 03:02:01,360 CLASSIFIES DISEASES INTO THEIR 4719 03:02:01,360 --> 03:02:02,880 MOST APPROPRIATE CATEGORY SO WE 4720 03:02:02,880 --> 03:02:03,920 CAN HAVE FURTHER INFORMATION 4721 03:02:03,920 --> 03:02:05,560 ABOUT THEM BUT ALSO BRING 4722 03:02:05,560 --> 03:02:06,960 RELATED DISEASES TOGETHER, WE 4723 03:02:06,960 --> 03:02:08,000 LOOK AT CLINICS SIGNIFICANT 4724 03:02:08,000 --> 03:02:09,920 FEATURES AND I LISTED THOSE ON 4725 03:02:09,920 --> 03:02:11,800 THE SIDE OF THE SLIDE, AND 4726 03:02:11,800 --> 03:02:14,960 THAT'S HOW IT REALLY STARTED, 4727 03:02:14,960 --> 03:02:16,600 HOW DO WE BEND THIS INFORMATION, 4728 03:02:16,600 --> 03:02:17,880 HOW DO WE GET FURTHER KNOWLEDGE 4729 03:02:17,880 --> 03:02:21,040 ABOUT IT BUT ON THE OTHER SIDE 4730 03:02:21,040 --> 03:02:22,440 I'LL SHOWING YOU OUR OWL TREE, 4731 03:02:22,440 --> 03:02:24,280 SO THIS IS OUR PROGRESSION OVER 4732 03:02:24,280 --> 03:02:29,800 TIME AND THIS IS INCLUDING 4733 03:02:29,800 --> 03:02:31,320 ONTOLOGYS THAT LOOK THEA OTHER 4734 03:02:31,320 --> 03:02:32,040 FEATURES AND MECHANISMS OF 4735 03:02:32,040 --> 03:02:33,920 DISEASE TO GIVE US FURTHER MORE 4736 03:02:33,920 --> 03:02:36,080 TAILED INFORMATION ABOUT THE 4737 03:02:36,080 --> 03:02:36,920 DISEASES THEMSELVES AND THEIR 4738 03:02:36,920 --> 03:02:37,760 MECHANISMS AND IF YOU WANT TO 4739 03:02:37,760 --> 03:02:39,680 LEARN MORE ABOUT THE PROJECT OR 4740 03:02:39,680 --> 03:02:41,160 OUR LATEST PAPER, I PUT A LINK 4741 03:02:41,160 --> 03:02:43,640 HERE IS IN THE NUCLEIC DATABASES 4742 03:02:43,640 --> 03:02:45,040 RESEARCH ISSUE THAT CAME OUT 4743 03:02:45,040 --> 03:02:45,360 LAST JANUARY. 4744 03:02:45,360 --> 03:02:46,600 CAN YOU ALSO GO TO OUR WEBSITE 4745 03:02:46,600 --> 03:02:48,600 WHERE WE DO GIVE YOU LINKS TO 4746 03:02:48,600 --> 03:02:50,400 ALL THE CITATIONS WE'VE 4747 03:02:50,400 --> 03:02:52,200 IDENTIFIED, A LINKING TO THE 4748 03:02:52,200 --> 03:02:53,760 DISEASE ONTOLOGY AND WE'RE AT A 4749 03:02:53,760 --> 03:02:55,280 LITTLE OVER 1500 AT THIS POINT. 4750 03:02:55,280 --> 03:02:56,680 SO PLEASE TAKE A LOOK AND YOU 4751 03:02:56,680 --> 03:02:59,480 CAN SEE ALL THESE VARIOUS USE 4752 03:02:59,480 --> 03:03:00,640 CASES AND MAYBE IDENTIFY OTHER 4753 03:03:00,640 --> 03:03:04,480 WAYS THAT WOULD BE ALIGNED TO 4754 03:03:04,480 --> 03:03:04,920 YOUR WORK. 4755 03:03:04,920 --> 03:03:07,040 BEFORE I MOVE ON I WANT TO TALK 4756 03:03:07,040 --> 03:03:08,320 ABOUT RARE DISEASE DATA 4757 03:03:08,320 --> 03:03:09,960 INTEGRATION ITSELF, JUST TO 4758 03:03:09,960 --> 03:03:10,720 REALLY HIGHLIGHT THESE STEPS, AS 4759 03:03:10,720 --> 03:03:12,280 CAN YOU IMAGINE THERE'S A LOST 4760 03:03:12,280 --> 03:03:14,000 RESOURCES OUT THERE FOR ANY TYPE 4761 03:03:14,000 --> 03:03:18,880 OF DISEASE, BUT FOR RARE 4762 03:03:18,880 --> 03:03:20,520 DISEASE, WE DATA FROM ALL THESE 4763 03:03:20,520 --> 03:03:21,360 RESOURCES BUT WHAT'S IMPORTANT 4764 03:03:21,360 --> 03:03:24,160 ABOUT THEM ARE THEY ARE 4765 03:03:24,160 --> 03:03:25,400 AUTHORITATIVE RESOURCES, WE'RE 4766 03:03:25,400 --> 03:03:26,640 CAREFUL WHERE WE JAR OR DATA 4767 03:03:26,640 --> 03:03:27,720 FROM AND HOW WE BRING IT 4768 03:03:27,720 --> 03:03:28,920 TOGETHER BECAUSE A BIG ASPECT OF 4769 03:03:28,920 --> 03:03:30,920 WHAT WE'RE DOING IS LOOKING AT 4770 03:03:30,920 --> 03:03:31,960 THIS VARIOUS DISEASE 4771 03:03:31,960 --> 03:03:33,840 REPRESENTATIONS AND AS YOU CAN 4772 03:03:33,840 --> 03:03:34,920 IMAGINE, ANY DATABASE HAS UPDATE 4773 03:03:34,920 --> 03:03:36,360 AS THE DEFINITE TIMES, DIFFERENT 4774 03:03:36,360 --> 03:03:38,080 CYCLES AND WE LOOK AT THAT 4775 03:03:38,080 --> 03:03:39,280 INFORMATION AND WE COMPILE IT 4776 03:03:39,280 --> 03:03:40,920 WITH THE CURRENT LITERATURE AND 4777 03:03:40,920 --> 03:03:43,960 WE REALLY BRING THE INFORMATION 4778 03:03:43,960 --> 03:03:45,040 TOGETHER IN OUR SYSTEM BUT WE 4779 03:03:45,040 --> 03:03:47,920 ALSO WANT TO LOOK AT HOW WE 4780 03:03:47,920 --> 03:03:49,400 CONNECT THAT DATA TO OTHER 4781 03:03:49,400 --> 03:03:51,360 VOCABULARIES SO THERE ARE A 4782 03:03:51,360 --> 03:03:52,760 NUMBER OF CLINICAL VOCABULARIES 4783 03:03:52,760 --> 03:03:54,400 OUT THERE OVER TIME, 1 THING WE 4784 03:03:54,400 --> 03:03:56,920 DO SPECIFICALLY IS WE DO MAP TO 4785 03:03:56,920 --> 03:03:58,520 EACH OF THEM AND THIS IS A 4786 03:03:58,520 --> 03:04:00,160 CURATED TASK AND A CONTINUAL 4787 03:04:00,160 --> 03:04:03,560 BASIS, WE ARE ABLE TO THEN 4788 03:04:03,560 --> 03:04:05,200 DISTINCTLY IDENTIFY THESE 1 TO 1 4789 03:04:05,200 --> 03:04:08,760 MAPPINGS AND THESE 2 TERMS ARE 4790 03:04:08,760 --> 03:04:10,920 EXACTLY RIGHT IN THESE CASES ARE 4791 03:04:10,920 --> 03:04:11,960 CONNECTED AND 1 RESOURCE SPLITS 4792 03:04:11,960 --> 03:04:14,680 OR ANOTHER PUTS THEM TOGETHER, 4793 03:04:14,680 --> 03:04:16,320 AS LIKE ALL THE SUBTEXT GOES 4794 03:04:16,320 --> 03:04:17,120 INTO 1. 4795 03:04:17,120 --> 03:04:18,840 THESE ARE CALLED SCOS MAPPINGS 4796 03:04:18,840 --> 03:04:22,120 AND WE'RE ABLE TO DISTINCTLY 4797 03:04:22,120 --> 03:04:25,600 DEFINE THESE 1 TO 1 WHEN THERE'S 4798 03:04:25,600 --> 03:04:26,920 BROADER OR NARROWER MATCHES SO 4799 03:04:26,920 --> 03:04:29,040 THAT ALLOWS TO DO A LOT OF 4800 03:04:29,040 --> 03:04:30,200 INTERESTING CONNECTIONS WITH THE 4801 03:04:30,200 --> 03:04:30,480 DISEASES. 4802 03:04:30,480 --> 03:04:31,640 THE LAST THING ON THE SLIDE I 4803 03:04:31,640 --> 03:04:41,480 WANT TO POINT OUT IS THAT NOW 4804 03:04:41,480 --> 03:04:43,080 THE CURRENT COULD YOU WANT IN 4805 03:04:43,080 --> 03:04:45,520 THE SLIDE, IN IS JUST UNDER 4806 03:04:45,520 --> 03:04:46,840 11,000, SO IT'S HYMN HALF OF 4807 03:04:46,840 --> 03:04:48,480 WHAT WE REPRESENT ARE CLASSIFIED 4808 03:04:48,480 --> 03:04:50,040 AS RARE DISEASES IN 1 OF THESE 4809 03:04:50,040 --> 03:04:51,080 SYSTEMS, SO AS I'M GOING 4810 03:04:51,080 --> 03:04:52,640 FORWARD, YOU WILL SEE THAT THE 4811 03:04:52,640 --> 03:04:54,920 THINGS WE'RE DOING FOR ALL OF 4812 03:04:54,920 --> 03:04:56,120 THE DISEASES IS SOMETHING VERY 4813 03:04:56,120 --> 03:04:57,760 MUCH DOING FOR RARE DISEASES. 4814 03:04:57,760 --> 03:04:59,880 WE REALLY HAVE MORE OF A 4815 03:04:59,880 --> 03:05:01,280 WHOLISTIC APPROACH FOR DECS AND 4816 03:05:01,280 --> 03:05:03,680 WE DO RECORD THAT THEY'RE RARE, 4817 03:05:03,680 --> 03:05:05,200 AND WHAT THE ASSPEBTS OF THEM 4818 03:05:05,200 --> 03:05:08,960 ARE RARE, BUT ALL OF THIS IS 4819 03:05:08,960 --> 03:05:11,000 BRINGING YOU TO SHOW US OUR 4820 03:05:11,000 --> 03:05:12,400 COMPLEX DISEASE MODELING WORK 4821 03:05:12,400 --> 03:05:13,720 THAT WE'VE BEEN WORKING ON FOR 4822 03:05:13,720 --> 03:05:14,600 THE NEXT 5 YEARS ACTUALLY. 4823 03:05:14,600 --> 03:05:15,520 SO WE HAVE A CLINICIAN TEAM AND 4824 03:05:15,520 --> 03:05:18,160 I WILL SHOW YOU AT THE VERY END 4825 03:05:18,160 --> 03:05:19,280 OF THE PRESENTATION. 4826 03:05:19,280 --> 03:05:20,920 BUT THEY'VE BEEN ASSESSING HOW 4827 03:05:20,920 --> 03:05:25,600 WE USE THE WORDS, WE USE TO 4828 03:05:25,600 --> 03:05:27,200 DESCRIBE DISEASES AND THIS SLIDE 4829 03:05:27,200 --> 03:05:29,240 IS MEANT TO SHOW YOU HOW WE 4830 03:05:29,240 --> 03:05:30,320 RECOGNIZE THE VERY FUZZINESS IN 4831 03:05:30,320 --> 03:05:39,320 THE WORK THAT WE'RE DOING SO IN 4832 03:05:39,320 --> 03:05:41,400 SOME TYPES OF RESOURCES HERE WE 4833 03:05:41,400 --> 03:05:43,960 LOOK AT THE HUMAN PHENOTYPE 4834 03:05:43,960 --> 03:05:46,360 ONTOLOGY, IN OTHERS WE LOOK AT 4835 03:05:46,360 --> 03:05:48,240 THE CLEFT LIP PAL MEAT MIGHT BE 4836 03:05:48,240 --> 03:05:49,640 A FEATURE OF A DISEASE WHEREAS 4837 03:05:49,640 --> 03:05:51,360 IN THE HUMAN DISEASE AND 4838 03:05:51,360 --> 03:05:53,400 ONTOLOGY WE HAVE DISTINCT 4839 03:05:53,400 --> 03:05:56,920 DISEASES REPRESENTED. 4840 03:05:56,920 --> 03:05:58,000 I THINK UNDERSTANDING WHAT TYPE 4841 03:05:58,000 --> 03:05:59,720 OF DATA YOU'RE WORKING WITH 4842 03:05:59,720 --> 03:06:01,000 APPROXIMATE ANY RESOURCE WHETHER 4843 03:06:01,000 --> 03:06:02,800 THEY'RE DESCRIBING A PHENOTYPE 4844 03:06:02,800 --> 03:06:03,920 OR PHENOTYPIC FEATURES OF A 4845 03:06:03,920 --> 03:06:05,360 DISEASE OR A DISEASE ITSELF IS 4846 03:06:05,360 --> 03:06:07,200 IMPORTANT AND THAT I THINK IS 4847 03:06:07,200 --> 03:06:08,320 THE COMMUNITIES MOVE IT A LOT IN 4848 03:06:08,320 --> 03:06:09,520 THE LAST NUMBER OF YEARS TO 4849 03:06:09,520 --> 03:06:11,400 REALLY DO THIS AND WE WORK WITH 4850 03:06:11,400 --> 03:06:12,800 HPO AGAIN AND OTHER GROUPS TO 4851 03:06:12,800 --> 03:06:14,840 MAKE SURE, YOU KNOW HOW WE'RE 4852 03:06:14,840 --> 03:06:16,360 DOING THIS AND THAT WE'RE 4853 03:06:16,360 --> 03:06:22,680 UNDERSTANDING EACH OTHER'S 4854 03:06:22,680 --> 03:06:23,040 REPRESENTATIONS. 4855 03:06:23,040 --> 03:06:24,200 AND I WANT TO GIVE YOU AN 4856 03:06:24,200 --> 03:06:25,400 EXAMPLE HERE OF DISEASE 4857 03:06:25,400 --> 03:06:27,240 NOMENCLATURE AND WHY IT'S 4858 03:06:27,240 --> 03:06:27,520 IMPORTANT. 4859 03:06:27,520 --> 03:06:28,200 DISEASES NAME CHANGE QUITE A BIT 4860 03:06:28,200 --> 03:06:29,520 OVER TIME AND YOU MAY HAVE 4861 03:06:29,520 --> 03:06:30,720 NOTICED THIS YOURS, I'M SHOWING 4862 03:06:30,720 --> 03:06:32,520 YOU AN EXAMPLE HERE OF JUST SOME 4863 03:06:32,520 --> 03:06:34,440 DISEASES THAT ARE PERINENT TO 4864 03:06:34,440 --> 03:06:36,320 OUR CONVERSATION TODAY, BUT THE 4865 03:06:36,320 --> 03:06:38,800 IMPORTANT PART HERE IS THAT AS 4866 03:06:38,800 --> 03:06:39,920 THESE TERM NAMES CHANGE, THERE 4867 03:06:39,920 --> 03:06:41,200 NEEDS TO BE A WAY TO KEEP TRACK 4868 03:06:41,200 --> 03:06:42,720 OF THEM AND THAT 1 OF THE ROLES 4869 03:06:42,720 --> 03:06:44,920 THAT WE PLAY WITHIN THE DOH. 4870 03:06:44,920 --> 03:06:47,520 SO AGAIN, THIS IS IMPORTANT 4871 03:06:47,520 --> 03:06:50,120 BECAUSE PEOPLE USE DIFFERENT 4872 03:06:50,120 --> 03:06:50,520 NAMES FOR DISEASES. 4873 03:06:50,520 --> 03:06:51,840 AT TIMES YOU WILL SEE IN THE 4874 03:06:51,840 --> 03:06:54,280 MIDDLE OF THE SLIDE, I THINK 4875 03:06:54,280 --> 03:06:56,720 YEAH, PGM 1 AS WE REFER TO AS A 4876 03:06:56,720 --> 03:07:01,520 DISEASE NAME IN THIS CASE, BUT 4877 03:07:01,520 --> 03:07:04,520 ACTUALLY THE PROPER DEC NAME IS 4878 03:07:04,520 --> 03:07:07,320 GENERAL DISORDER GLYCOSYLATION 1 4879 03:07:07,320 --> 03:07:07,560 T. 4880 03:07:07,560 --> 03:07:08,720 SO IT'S GOOD TO RECOGNIZE THAT 4881 03:07:08,720 --> 03:07:10,520 WE HAVE THESE NAMES AND TO 4882 03:07:10,520 --> 03:07:11,920 INTEGRATE THESE SYNONYMS WITH 4883 03:07:11,920 --> 03:07:12,760 THE PROPER NOMENCLATURE AND 4884 03:07:12,760 --> 03:07:13,360 UPDISTRICT ATTORNEY THESE AND 4885 03:07:13,360 --> 03:07:14,760 THIS IS SOMETHING WE DO A 4886 03:07:14,760 --> 03:07:16,720 REGULAR BASIS, WE GO THROUGH 4887 03:07:16,720 --> 03:07:19,080 DRNT AREAS OF THE ONTOLOGY AND 4888 03:07:19,080 --> 03:07:20,120 UPDATE THEM, REVIEW THEM WITH 4889 03:07:20,120 --> 03:07:21,640 WHAT THE COMMUNITY IS DOING SO 4890 03:07:21,640 --> 03:07:24,240 THAT WHEN DAT IS ASSOCIATED, 1 4891 03:07:24,240 --> 03:07:26,720 DATABASE WITH 1 NAME, BUT THE 4892 03:07:26,720 --> 03:07:27,960 NOMENCLATURE HAS CHANGED, WE CAN 4893 03:07:27,960 --> 03:07:29,000 STILL CONTINUALLY TRACK THAT AND 4894 03:07:29,000 --> 03:07:35,880 THEN ALL OF OUR USERS CAN AS 4895 03:07:35,880 --> 03:07:36,720 WELL. 4896 03:07:36,720 --> 03:07:43,800 NOW TALKING ABOUT THE DISEASE, 4897 03:07:43,800 --> 03:07:45,880 HOW WE MODEL THE DATEDDA IS WITH 4898 03:07:45,880 --> 03:07:48,280 THE ONTOLOGY AND THEN OUR 4899 03:07:48,280 --> 03:07:49,400 RESOURCES CAN ANNOTATE SO THAT'S 4900 03:07:49,400 --> 03:07:51,240 STEPS OF WHAT WE WANT TO YOU 4901 03:07:51,240 --> 03:07:53,360 THINK ABOUT MOVING FORWARD, SO 4902 03:07:53,360 --> 03:07:56,720 I'M SHOWING YOU ON THE LEFT A 4903 03:07:56,720 --> 03:07:59,360 NUMBER OF CLINICAL VOCABULARIES, 4904 03:07:59,360 --> 03:08:02,400 ACTUALLY THE ONTOLOGY FROM THE 4905 03:08:02,400 --> 03:08:03,440 BOUNDARY THAT ENCODE THESE 4906 03:08:03,440 --> 03:08:04,120 DIFFERENT TYPES OF INFORMATION 4907 03:08:04,120 --> 03:08:05,600 THAT WE WANT TO INCLUDE. 4908 03:08:05,600 --> 03:08:09,440 I AM HIGHLIGHTING ON THE ORANGE 4909 03:08:09,440 --> 03:08:10,880 ARROWS, THAT RECENTLY BEEN 4910 03:08:10,880 --> 03:08:11,720 ADDING, WHAT THESE ALLOW US TO 4911 03:08:11,720 --> 03:08:17,520 DO IS TO HAVE A VERY STRUCTURED 4912 03:08:17,520 --> 03:08:19,720 DESCRIPTION OF WHAT THESE 4913 03:08:19,720 --> 03:08:21,280 DISEASE TO DISEASE RELATIONSHIPS 4914 03:08:21,280 --> 03:08:23,120 ARE, USING ONTOLOGYS, WE USE 4915 03:08:23,120 --> 03:08:26,000 THEIR TERMS AND IDs SO IT'S 4916 03:08:26,000 --> 03:08:27,320 INTEROPERABLE METHOD FOR 4917 03:08:27,320 --> 03:08:28,480 CONTINUING TO EXPAND OUR 4918 03:08:28,480 --> 03:08:32,360 DESCRIPTION OF DISEASES 4919 03:08:32,360 --> 03:08:32,680 THEMSELVES. 4920 03:08:32,680 --> 03:08:34,080 HERE I'M SHOWING YOU AN EXAMPLE 4921 03:08:34,080 --> 03:08:35,600 OF THE VARIOUS MODELING FEATURES 4922 03:08:35,600 --> 03:08:38,040 AND MECHANISMS AND I'M 4923 03:08:38,040 --> 03:08:45,440 HIGHLIGHTING CHILDHOOD ONSET SO 4924 03:08:45,440 --> 03:08:48,760 WORKING WITH CLINGEN AND CIVIC, 4925 03:08:48,760 --> 03:08:49,720 WE DIFFERENTIATE THE DIFFERENT 4926 03:08:49,720 --> 03:08:52,600 AGES OF ONSET FOR THESE 4927 03:08:52,600 --> 03:08:55,240 CONDITIONS AS PEOPLE ARE AND OUR 4928 03:08:55,240 --> 03:08:56,320 GROUP IS ANNOTATING THE CLINICAL 4929 03:08:56,320 --> 03:09:00,120 DPROWPS IN CIVIC AND THAT IS 4930 03:09:00,120 --> 03:09:01,440 GOING INTO CLINGEN AS WELL, SO 4931 03:09:01,440 --> 03:09:02,720 WE WORKED WITH THE HUMAN 4932 03:09:02,720 --> 03:09:03,960 ONTOLOGY TO DO THIS, THIS IS 4933 03:09:03,960 --> 03:09:05,360 SHOWING THE PROCESS OF DOING 4934 03:09:05,360 --> 03:09:06,680 THAT WHERE WE IDENTIFY THE 4935 03:09:06,680 --> 03:09:09,440 TOMORROWS AND BRING IN THE ONSET 4936 03:09:09,440 --> 03:09:13,080 ONTOLOGY AS PART OF THE HPO AND 4937 03:09:13,080 --> 03:09:14,000 THEN WE ANNOTATE THAT 4938 03:09:14,000 --> 03:09:15,280 INFORMATION ACROSS ALL THE 4939 03:09:15,280 --> 03:09:16,680 DISEASES WHERE WE DO 4940 03:09:16,680 --> 03:09:18,560 DEFINITIVELY KNOW THE AGE OF 4941 03:09:18,560 --> 03:09:20,680 ONSET OF A DISEASE AND I'M 4942 03:09:20,680 --> 03:09:22,720 SHOWING YOU ON THE RIGHT SIDE AN 4943 03:09:22,720 --> 03:09:23,840 EXAMPLE OF A DISEASE ONTOLOGY 4944 03:09:23,840 --> 03:09:25,240 PAGE WHERE WE HAVE THE 4945 03:09:25,240 --> 03:09:27,560 DEFINITIONS THAT ARE DEFINED BY 4946 03:09:27,560 --> 03:09:29,320 OUR CURATORS AND THEY FOLLOW 4947 03:09:29,320 --> 03:09:39,240 VERY SPECIFIC GUIDELINES TO DO 4948 03:09:39,240 --> 03:09:40,920 THIS, SO THE BOTTOM RIGHT I'M 4949 03:09:40,920 --> 03:09:42,560 SHOWING YOU IS HOW WE DEFINE 4950 03:09:42,560 --> 03:09:43,640 THIS ONSET RELATIONSHIP, NOW IS 4951 03:09:43,640 --> 03:09:44,720 PART OF ONTOLOGY WORK WHERE WE 4952 03:09:44,720 --> 03:09:47,800 DEFINE WHAT ARE COWLED SUBCLASS 4953 03:09:47,800 --> 03:09:49,480 LOGICAL AXIOMS AND IN THIS CASE, 4954 03:09:49,480 --> 03:09:51,000 WE USE A RELATIONSHIP TERM 4955 03:09:51,000 --> 03:09:52,320 CALLED EXISTENCE STARTS DURING, 4956 03:09:52,320 --> 03:09:54,920 THAT'S 1 PHRASE AND THEN IN 4957 03:09:54,920 --> 03:09:57,120 CHILDHOOD ONSET IS THE HPO TERM, 4958 03:09:57,120 --> 03:09:59,160 THIS ALLOWS US TO HAVE THIS 4959 03:09:59,160 --> 03:10:00,560 PHRASE ASSOCIATED WITH WITH 4960 03:10:00,560 --> 03:10:02,600 CHILDHOOD ONSET AND THEN TO 4961 03:10:02,600 --> 03:10:03,520 INTEGRATE THAT INTO OTHER 4962 03:10:03,520 --> 03:10:05,200 DISEASE TERMS SO THEN WE CAN 4963 03:10:05,200 --> 03:10:07,400 SAY, AH, THIS TERM IS ALSO A 4964 03:10:07,400 --> 03:10:08,680 CHILDHOOD ONSET DISEASE AND WE 4965 03:10:08,680 --> 03:10:10,480 DO THIS THROUGHOUT ALL OF THE 4966 03:10:10,480 --> 03:10:13,760 DATA TYPES I WAS SHOWING ON THE 4967 03:10:13,760 --> 03:10:15,440 LAST SLIDE, ASHES NAT ME, CELL 4968 03:10:15,440 --> 03:10:20,720 TYPES WE STARTED WITH THOSE 4969 03:10:20,720 --> 03:10:22,840 ANDONATOLOGYS SO WE HAVE A MORE 4970 03:10:22,840 --> 03:10:26,160 ROBUST DESCRIPTION OF DISEASE. 4971 03:10:26,160 --> 03:10:27,720 NOW I WANT TO GIVE YOU ANOTHER 4972 03:10:27,720 --> 03:10:28,920 EXAMPLE HOW BRINGING THIS 4973 03:10:28,920 --> 03:10:30,440 INFORMATION TOGETHER GIVES YOU A 4974 03:10:30,440 --> 03:10:31,320 MORE EXTENDED VIEW OF DISEASE. 4975 03:10:31,320 --> 03:10:33,640 THIS IS WORK WE DID WITH THE 4976 03:10:33,640 --> 03:10:35,280 DATABASE, THE LAST NUMBER OF 4977 03:10:35,280 --> 03:10:37,000 YEARS, IS TO REALLY DESCRIBE FOR 4978 03:10:37,000 --> 03:10:39,760 ANY DISEASE THAT HAS AN IMMUNE 4979 03:10:39,760 --> 03:10:42,520 ASPECT TO IT TO BRING THAT 4980 03:10:42,520 --> 03:10:43,160 INFORMATION TOGETHER, SO THAT 4981 03:10:43,160 --> 03:10:45,760 YOU SEE ON THE LEFT SIDE OF YOUR 4982 03:10:45,760 --> 03:10:47,320 SLIDE, WHERE ALL THESE DIFFERENT 4983 03:10:47,320 --> 03:10:49,080 TYPES OF IMMUNE SYSTEM RELATED 4984 03:10:49,080 --> 03:10:51,320 DISEASES ARE THEN BROUGHT UNDER 4985 03:10:51,320 --> 03:10:52,440 THE AUTOIMMUNE DEC BRANCH AND 4986 03:10:52,440 --> 03:10:54,200 THEN AGAIN WE LOOK AT COMMON 4987 03:10:54,200 --> 03:10:56,680 MECHANISM BY DOING THIS. 4988 03:10:56,680 --> 03:10:57,560 OVERALL THOSE ONTOLOGYS I'VE 4989 03:10:57,560 --> 03:10:59,000 BEEN TALKING ABOUT THAT WE'VE 4990 03:10:59,000 --> 03:11:01,880 BEEN INCLUDING IN THIS, WE HAVE 4991 03:11:01,880 --> 03:11:03,320 ALMOST LENCH THOUSAND OF THESE 4992 03:11:03,320 --> 03:11:06,400 ASSOCIATIONS BEEN CURATED BY OUR 4993 03:11:06,400 --> 03:11:06,720 TEAM. 4994 03:11:06,720 --> 03:11:08,280 AND THAT WILL BRING--AND THEY 4995 03:11:08,280 --> 03:11:10,080 ALLOWS US TO HAVE AN ENRICHED 4996 03:11:10,080 --> 03:11:11,120 EXPLANATION OF DISEASES BUT 4997 03:11:11,120 --> 03:11:16,120 AGAIN TO HAVE DIFFERENT LENSES 4998 03:11:16,120 --> 03:11:17,880 LOOKING AT ANATOMY LENS AND 4999 03:11:17,880 --> 03:11:19,080 THESE LENSES TO GIVE DIFFERENT 5000 03:11:19,080 --> 03:11:20,840 VIEWS OF ONTOLOGY AND THE DATA. 5001 03:11:20,840 --> 03:11:22,280 NOW THIS SLIDE IS REALLY JUST 5002 03:11:22,280 --> 03:11:23,520 GOING INTO THE MODELING, A 5003 03:11:23,520 --> 03:11:24,680 LITTLE BUILT MORE, SO AS WE WERE 5004 03:11:24,680 --> 03:11:26,360 DOING ALL THIS WORK OVER THE 5005 03:11:26,360 --> 03:11:36,600 LAST 5 YEARS WE WANT TO THINK 5006 03:11:36,600 --> 03:11:38,560 ABOUT--SO THIS AN EARLY MODEL WE 5007 03:11:38,560 --> 03:11:40,520 PUT TOGETHER LOOKING AT BREAST 5008 03:11:40,520 --> 03:11:42,920 CARCINOMA SO WE HAVE A VIEW IN 5009 03:11:42,920 --> 03:11:44,320 OUR MIND OR EVEN WRITING IT UP 5010 03:11:44,320 --> 03:11:46,440 ON THE BOARD AS WE'RE WORKING ON 5011 03:11:46,440 --> 03:11:48,000 IT, HOW DO WE HAVE THESE 5012 03:11:48,000 --> 03:11:48,920 DIFFERENT DESCRIPTIONS WHAT HAVE 5013 03:11:48,920 --> 03:11:50,160 A DISEASE COULD BE AND HOW BEING 5014 03:11:50,160 --> 03:11:52,440 WE PUT THAT INTO THE ONTOLOGY. 5015 03:11:52,440 --> 03:11:53,440 YOU KNOW FIRST YOU HAVE THE 5016 03:11:53,440 --> 03:11:55,200 IDEA, AND THEN THE ONTOLOGY 5017 03:11:55,200 --> 03:11:56,520 MODELING HAS TO OCCUR AND SO 5018 03:11:56,520 --> 03:12:00,160 THIS IS REALLY WHAT'S THAT'S 5019 03:12:00,160 --> 03:12:00,520 DESCRIBING. 5020 03:12:00,520 --> 03:12:02,440 OUR CLINICAL GROUP, WE ALSO WENT 5021 03:12:02,440 --> 03:12:04,480 THROUGH A NUMBER OF EXERCISES, 5022 03:12:04,480 --> 03:12:07,880 MANY, MANY MONTHS OF THINKING 5023 03:12:07,880 --> 03:12:10,240 ABOUT WHAT ARE ALL THE ODORSITS 5024 03:12:10,240 --> 03:12:11,480 OF DISEASE, DISEASE IS NOT 5025 03:12:11,480 --> 03:12:13,800 CLEAN, IT'S A MESSY SYSTEM, 5026 03:12:13,800 --> 03:12:14,920 THERE'S LOTS OF EXPRESSIONS TO 5027 03:12:14,920 --> 03:12:16,320 THE RULES, SO WHAT I'M SHOWING 5028 03:12:16,320 --> 03:12:17,880 YOU HERE TO THE VARIOUS 5029 03:12:17,880 --> 03:12:19,520 EXCEPTIONS TO THE RULE OR 5030 03:12:19,520 --> 03:12:20,600 ODORSITS THAT WE HAVE TO DEAL 5031 03:12:20,600 --> 03:12:22,760 WITH SO WE HAVE THE SAME DISEASE 5032 03:12:22,760 --> 03:12:23,520 BUT DIFFERENT FACTORS INVOLVED 5033 03:12:23,520 --> 03:12:24,920 AND HOW DO YOU INCLUDE THAT, HOW 5034 03:12:24,920 --> 03:12:26,920 DO YOU MODEL IT, THEN ON THE 5035 03:12:26,920 --> 03:12:28,000 OPPOSITE SIDE, YOU HAVE 5036 03:12:28,000 --> 03:12:29,320 DIFFERENT DISEASES, THAT GD HAVE 5037 03:12:29,320 --> 03:12:32,320 THE SAME OR OVERLAPPING FACTORS, 5038 03:12:32,320 --> 03:12:33,880 SO AGAIN, VARIOUS TYPES OF 5039 03:12:33,880 --> 03:12:35,360 SITUATIONS AND THESE ARE THE 5040 03:12:35,360 --> 03:12:36,320 VARIOUS SITUATIONS WE WORKED ON 5041 03:12:36,320 --> 03:12:38,440 TO DEVELOP OUR MODEL TO BE ABLE 5042 03:12:38,440 --> 03:12:42,600 TO CHARACTERIZE DATA ABOUT 5043 03:12:42,600 --> 03:12:43,560 DISEASES. 5044 03:12:43,560 --> 03:12:45,400 AS YOU CAN WELL IMAGINE AND GIVE 5045 03:12:45,400 --> 03:12:46,680 OUT DISEASES, THERE'S ALWAYS 5046 03:12:46,680 --> 03:12:47,440 DIFFERENT ASPECTS INVOLVE WIDE 5047 03:12:47,440 --> 03:12:48,400 DISEASE AND WHAT WE'RE SHOWING 5048 03:12:48,400 --> 03:12:50,640 YOU HERE IS THIS IS REALLY A 5049 03:12:50,640 --> 03:12:51,520 SPECTRUM. 5050 03:12:51,520 --> 03:12:54,120 VERY FEW DISEASES FALL ON THE 2 5051 03:12:54,120 --> 03:12:54,320 ENDS. 5052 03:12:54,320 --> 03:12:56,280 MANY THINGS FALL IN THE MIDDLE 5053 03:12:56,280 --> 03:12:56,920 OF THIS SPECTRUM. 5054 03:12:56,920 --> 03:13:00,000 IT MAKE ITS VERY COMPLICATED TO 5055 03:13:00,000 --> 03:13:01,000 CHARACTERIZE BUT VERY 5056 03:13:01,000 --> 03:13:01,920 CHALLENGING AND ACTUALLY REALLY 5057 03:13:01,920 --> 03:13:05,280 INTRIGUING TO WORK ON IT, THESE 5058 03:13:05,280 --> 03:13:05,920 VERY MULTIFACTORIAL ASPECTS OF 5059 03:13:05,920 --> 03:13:07,440 HUMAN DISEASE AND THAT'S WHERE 5060 03:13:07,440 --> 03:13:08,360 YOU HAVE BEEN WORKING FOR THE 5061 03:13:08,360 --> 03:13:09,920 LAST NUMBER OF YEARS TO GET THE 5062 03:13:09,920 --> 03:13:11,240 ONTOLOGY SO WE COULD ENCODE ALL 5063 03:13:11,240 --> 03:13:12,680 THIS INFORMATION WITH ALL THOSE 5064 03:13:12,680 --> 03:13:15,920 LISTS OF ONTOLOGYS I SHOWED YOU. 5065 03:13:15,920 --> 03:13:17,440 ONE OF THE LISTS WE PUT TOGETHER 5066 03:13:17,440 --> 03:13:20,440 TO START TO THINK ABOUT WHAT IS 5067 03:13:20,440 --> 03:13:21,920 THAT CONTINUUM, THINGS LIKE WIDE 5068 03:13:21,920 --> 03:13:23,480 WHAT DOESN'T HAVE ENVIRONMENTAL 5069 03:13:23,480 --> 03:13:25,520 TRIGGERS BUT MANY GENES OR MANY 5070 03:13:25,520 --> 03:13:26,280 GENETIC COMPONENTS TO THE VERY 5071 03:13:26,280 --> 03:13:37,520 BOTTOM OF THE SLIDE, SOMETHING 5072 03:13:37,520 --> 03:13:39,160 LIKE RISIN POISONING AND SO 5073 03:13:39,160 --> 03:13:40,680 AGAIN, THIS IS THE HELPED US 5074 03:13:40,680 --> 03:13:41,920 DEVELOP THE MODEL. THIS IS THE 5075 03:13:41,920 --> 03:13:42,840 MODEL WE ARE PUTTING TOGETHER 5076 03:13:42,840 --> 03:13:45,120 AND WE ARE PUTTING IN FOR A 5077 03:13:45,120 --> 03:13:45,720 PUBLITIONICATION THIS MONTH. 5078 03:13:45,720 --> 03:13:47,440 WHAT I WANT YOU TO WALK AROUND 5079 03:13:47,440 --> 03:13:48,520 IN A CIRCLE AND YOU'RE LOOKING 5080 03:13:48,520 --> 03:13:51,560 AT A LITTLE BIT, THINK ABOUT ALL 5081 03:13:51,560 --> 03:13:52,720 THE VARIOUS THINGS THAT CAN COME 5082 03:13:52,720 --> 03:13:55,120 INTO PLAY FOR A HUMAN DEC TO 5083 03:13:55,120 --> 03:13:55,760 OCCUR. 5084 03:13:55,760 --> 03:13:58,880 WHAT AFFECTS IT, WHAT IMPACTS 5085 03:13:58,880 --> 03:13:59,120 IT. 5086 03:13:59,120 --> 03:14:03,320 SO THAT WAS OUR TASK, REALLY TO 5087 03:14:03,320 --> 03:14:05,560 THINK ABOUT AND TO DO DEEP, DEEP 5088 03:14:05,560 --> 03:14:06,520 DIVING AND LITERATURE, AND WHAT 5089 03:14:06,520 --> 03:14:08,040 WAS GOING TO IMPACT THESE, HOW 5090 03:14:08,040 --> 03:14:10,520 CAN WE MODEL AND THEN IF WE 5091 03:14:10,520 --> 03:14:13,360 DEVISE THE MODEL COULD WE THEN 5092 03:14:13,360 --> 03:14:14,880 IMPROVE THE ONTOLOGY, COULD WE 5093 03:14:14,880 --> 03:14:16,760 THEN TEST IT AND ASSESS HOW WELL 5094 03:14:16,760 --> 03:14:19,600 THE MODEL DID, BUT ALSO THE GOAL 5095 03:14:19,600 --> 03:14:23,320 OF ALL THIS ALSO IS TO HAVE A 5096 03:14:23,320 --> 03:14:25,920 MORE ENRICHED UNDERSTANDING OF 5097 03:14:25,920 --> 03:14:26,160 DISEASE. 5098 03:14:26,160 --> 03:14:29,040 ONE OR SLIDE ABOUT THE MODELING; 5099 03:14:29,040 --> 03:14:29,960 WELL, ACTUALLY 2 MORE. 5100 03:14:29,960 --> 03:14:30,640 I THINK. 5101 03:14:30,640 --> 03:14:32,880 SO 1 ASPECT OF THIS IS LOOKING 5102 03:14:32,880 --> 03:14:34,520 AT DISEASE DRIVERS BECAUSE 5103 03:14:34,520 --> 03:14:35,520 THAT'S THE CURRENT FOCUSES OF 5104 03:14:35,520 --> 03:14:37,240 OUR WORK AND WE WORKED WITH A 5105 03:14:37,240 --> 03:14:39,120 NUMBER OF OTHER FOUNDRY GROUPS 5106 03:14:39,120 --> 03:14:41,640 TO REALLY COME UP WITH THE BEST 5107 03:14:41,640 --> 03:14:43,880 WAY TO WHAT THESE DRIVERS ARE SO 5108 03:14:43,880 --> 03:14:45,520 WE COULD CATEGORIZE THEM, 5109 03:14:45,520 --> 03:14:47,320 CONNECT THEM TO OTHER ANATOLOGYS 5110 03:14:47,320 --> 03:14:49,320 BUT ALSO REALLY TO JUST BE ABLE 5111 03:14:49,320 --> 03:14:51,080 TO UNDERSTAND HOW THESE 5112 03:14:51,080 --> 03:14:52,280 MECHANISMS WORKING AND DESCRIBE 5113 03:14:52,280 --> 03:14:53,680 THEM IN THE ONTOLOGY. 5114 03:14:53,680 --> 03:14:56,120 THIS IS OUR DESCRIPTION OF HOW 5115 03:14:56,120 --> 03:14:57,880 THIS PROCESS WORKS SO WE HAVE 5116 03:14:57,880 --> 03:14:59,320 THIS MODEL, WE WANT TO TEST THE 5117 03:14:59,320 --> 03:15:00,840 MODEL SO WE HAVE DISEASES IN THE 5118 03:15:00,840 --> 03:15:02,800 ONTOLOGY, WE LOOK AT THE 5119 03:15:02,800 --> 03:15:03,960 ENVIRONMENT AMILLIO FACTORS, WE 5120 03:15:03,960 --> 03:15:05,920 HAVE THIS ENVIRONMENTAL FACTOR 5121 03:15:05,920 --> 03:15:07,320 ONTOLOGY, AND THEN IF THERE ARE 5122 03:15:07,320 --> 03:15:08,920 NEW TERMS THAT NEED TO BE ADDED 5123 03:15:08,920 --> 03:15:11,360 WE DO AND THEN WE'RE ABLE TO 5124 03:15:11,360 --> 03:15:12,320 ANNOTATEOT LEFT SIDE, THE 5125 03:15:12,320 --> 03:15:16,920 CLASSIFICATION OF THE DISEASES 5126 03:15:16,920 --> 03:15:17,320 THEMSELVES. 5127 03:15:17,320 --> 03:15:18,400 FETAL ALCOHOL SYNDROME IS A GOOD 5128 03:15:18,400 --> 03:15:19,680 EXAMPLE OF THE FIRST 1 WE PUT IN 5129 03:15:19,680 --> 03:15:20,920 TO REALLY LOOK AT ALL THE 5130 03:15:20,920 --> 03:15:23,320 VARIOUS FACTORS AND BUT AGAIN 5131 03:15:23,320 --> 03:15:24,520 WE'RE USING THIS PAST DISEASE 5132 03:15:24,520 --> 03:15:27,520 DRIVER AND ALCOHOL IS THE DRIVER 5133 03:15:27,520 --> 03:15:28,000 FOR THE DISEASE. 5134 03:15:28,000 --> 03:15:30,320 BUT WE HAVE A MODEL THAT'S 5135 03:15:30,320 --> 03:15:31,920 GREAT, WE HAVE NEED TO TEST IT 5136 03:15:31,920 --> 03:15:33,440 TO MAKE SURE OUR KNOWLEDGE OF 5137 03:15:33,440 --> 03:15:35,200 CURRENT DISEASES AND THE 5138 03:15:35,200 --> 03:15:36,160 CONDITIONS DIDN'T BREAK IT OR 5139 03:15:36,160 --> 03:15:38,080 DID IT BREAK IT AND WHAT DO WE 5140 03:15:38,080 --> 03:15:38,440 NEED TO CHANGE. 5141 03:15:38,440 --> 03:15:41,640 SO I WILL SHOW YOU 2 SLIDES OF 5142 03:15:41,640 --> 03:15:42,840 DISEASES THAT WERE THE RESULT OF 5143 03:15:42,840 --> 03:15:43,760 THIS. 5144 03:15:43,760 --> 03:15:46,760 SO WE WORKED FIRST ON DIABETES 5145 03:15:46,760 --> 03:15:53,200 COLLITEIS AND PART --MELLITUS AND THIS 5146 03:15:53,200 --> 03:15:56,120 IS THE TEAM BRINGING IN THEIR 5147 03:15:56,120 --> 03:15:57,000 KNOWLEDGE ABOUT HOW DIABETES 5148 03:15:57,000 --> 03:15:58,080 SHOULD BE DESCRIBED IN THE 5149 03:15:58,080 --> 03:15:58,920 CLINICAL SETTING AS WELL AS 5150 03:15:58,920 --> 03:16:00,560 LITERATE AND YOU ARE THIS 5151 03:16:00,560 --> 03:16:03,040 RESULTED IN A CHANGE OF OUR TREE 5152 03:16:03,040 --> 03:16:04,880 ITSELF, AN UPDATED VERSION OF IT 5153 03:16:04,880 --> 03:16:06,360 AND THEN ALSO BECAUSE DIABETES, 5154 03:16:06,360 --> 03:16:11,120 THE WORD IS OFTEN USED FOR 5155 03:16:11,120 --> 03:16:12,560 DIABETES MELLITUS AS WELL, SO WE 5156 03:16:12,560 --> 03:16:14,200 REVIEWED THAT AREA OF ONTOLOGY 5157 03:16:14,200 --> 03:16:15,640 AND UPDATED AND INTEGRATE ALL 5158 03:16:15,640 --> 03:16:16,040 THIS INFORMATION. 5159 03:16:16,040 --> 03:16:16,840 SO THIS IS SOMETHING WE PUT A 5160 03:16:16,840 --> 03:16:18,480 LOT OF TIME IN, LOTS OF DISEASES 5161 03:16:18,480 --> 03:16:20,320 WE DO THIS WORK WITH, SO THAT WE 5162 03:16:20,320 --> 03:16:22,360 CAN IMPROVE THOSE 5163 03:16:22,360 --> 03:16:22,960 CLASSIFICATIONS. 5164 03:16:22,960 --> 03:16:25,680 NOW THE LAST SLIDE HERE, IS 5165 03:16:25,680 --> 03:16:27,080 TALKING ABOUT ASTHMA, THIS IS 5166 03:16:27,080 --> 03:16:28,120 DEFINITELY A MORE COMPLEX ASPECT 5167 03:16:28,120 --> 03:16:29,800 OF WHAT WE ARE DOING AND YOU CAN 5168 03:16:29,800 --> 03:16:31,040 SEE THE TREE AS CHANGED 82IT A 5169 03:16:31,040 --> 03:16:32,480 LOT BUT THIS IS THE FIRST 5170 03:16:32,480 --> 03:16:34,920 INSTANCE WE LOOKED AT ENDOTYPES 5171 03:16:34,920 --> 03:16:37,440 AND THESE ARE IN REPORT QUITE A 5172 03:16:37,440 --> 03:16:40,760 LOT IN LITERATURE FOR COMPLEX 5173 03:16:40,760 --> 03:16:41,800 DISEASES, THESE PATHOPHYSIOLOGY, 5174 03:16:41,800 --> 03:16:44,520 TYPE COMBINATIONS AND I CLICKED 5175 03:16:44,520 --> 03:16:45,840 THE DEFINITION OF T-2 ASTHMA 5176 03:16:45,840 --> 03:16:47,200 THEA THE BOTTOM TO GIVE YOU 5177 03:16:47,200 --> 03:16:49,280 REFERENCE BUT THERE ARE A NEW 5178 03:16:49,280 --> 03:16:54,200 WAY TO LOOK AT GROUPS OF 5179 03:16:54,200 --> 03:16:55,680 PATIENTS AND WHAT ARE THE 5180 03:16:55,680 --> 03:16:56,720 ASSPEBTS OF THERE DISEASE AND 5181 03:16:56,720 --> 03:16:58,520 THIS IS ALL REVISED IN THE 5182 03:16:58,520 --> 03:16:59,960 ONTOLOGY BUT THIS IS A 5183 03:16:59,960 --> 03:17:01,120 CLINICALLY RELEVANT WAY OF 5184 03:17:01,120 --> 03:17:02,040 LOOKING AT COMPLEX DISEASE BUT 5185 03:17:02,040 --> 03:17:04,880 IT BRINGS IN A LOT OF NEW 5186 03:17:04,880 --> 03:17:05,920 ASPECTS WE THEN--WE THEN ARE 5187 03:17:05,920 --> 03:17:11,920 ABLE TO IMPROVE OUR DATA 5188 03:17:11,920 --> 03:17:12,240 CONNECTIONS. 5189 03:17:12,240 --> 03:17:13,880 AND LASTLY I WANT TO SHOW YOU MY 5190 03:17:13,880 --> 03:17:15,040 TEAM, THERE'S A CLINICAL TEAM UP 5191 03:17:15,040 --> 03:17:17,680 AT THE TOP AT THE CANNED WHAT 5192 03:17:17,680 --> 03:17:19,680 SCHOOL OF MEDICINE AND WE HAVE A 5193 03:17:19,680 --> 03:17:21,840 NUMBER OF CURATORS AND 5194 03:17:21,840 --> 03:17:22,600 INFORMATICS AVAILABLE AS WELL IN 5195 03:17:22,600 --> 03:17:24,040 THE TEAM AND BRINGING THIS DATA 5196 03:17:24,040 --> 03:17:24,320 TOGETHER. 5197 03:17:24,320 --> 03:17:25,680 THANK YOU AND IT WILL CLICK INTO 5198 03:17:25,680 --> 03:17:27,920 THE LAST COUPLE SLIDES, THIS IS 5199 03:17:27,920 --> 03:17:29,320 JUST ALL THE GROUPS WE WORK WITH 5200 03:17:29,320 --> 03:17:30,840 AND IT'S TOO MUCH FOR 1 SLIDE, 5201 03:17:30,840 --> 03:17:32,920 BUT JUST WANT TO MAKE SURE IT 5202 03:17:32,920 --> 03:17:39,120 GOT MENTIONED, THANK YOU IF ARE 5203 03:17:39,120 --> 03:17:39,920 YOUR TIME. 5204 03:17:39,920 --> 03:17:40,200 >> GREAT. 5205 03:17:40,200 --> 03:17:43,400 THANK YOU LYNN FOR A FANTASTIC 5206 03:17:43,400 --> 03:17:44,160 PRESENTATION, AGAIN EVERYONE 5207 03:17:44,160 --> 03:17:46,360 PLEASE USE THE SEND LIVE 5208 03:17:46,360 --> 03:17:48,440 FEEDBACK LINK TO SUBDMIT YOUR 5209 03:17:48,440 --> 03:17:49,600 QUESTIONS, WE WILL ASSEMBLE ALL 5210 03:17:49,600 --> 03:17:52,120 THOSE QUESTIONS IN THE CHAT AND 5211 03:17:52,120 --> 03:17:54,320 THEN THE END OF THE SESSION THIS 5212 03:17:54,320 --> 03:17:55,200 AFTERNOON, THE SPEAKERS WILL BE 5213 03:17:55,200 --> 03:17:56,680 AVAILABLE TO ANSWER THE 5214 03:17:56,680 --> 03:17:57,920 QUESTIONS, OKAY? 5215 03:17:57,920 --> 03:18:00,920 SO MOVING ON TO OUR NEXT SPEAKER 5216 03:18:00,920 --> 03:18:06,000 OUR NEXT SPEAKER IS EVGENIA, 5217 03:18:06,000 --> 03:18:07,960 SHISHKO VA WHY THE UNIVERSITY OF 5218 03:18:07,960 --> 03:18:10,080 WISCONSIN AND THE TIELTS OF HER 5219 03:18:10,080 --> 03:18:12,040 TALK IS DEFINING MITOCHONDRIAL 5220 03:18:12,040 --> 03:18:14,480 PROTEIN FUNCTION AND DISEASE 5221 03:18:14,480 --> 03:18:17,320 PATHOLOGY THROUGH MULTI-OMIC 5222 03:18:17,320 --> 03:18:19,000 PROFILING. 5223 03:18:19,000 --> 03:18:21,320 OKAY,A TAKE IT AWAY EVGENIA. 5224 03:18:21,320 --> 03:18:23,120 >> THANK YOU TO THE ORGANIZERS 5225 03:18:23,120 --> 03:18:24,440 AND THANKS VERY HAVING ME. 5226 03:18:24,440 --> 03:18:33,760 CAN YOU SEE MY--WE CAN SEE YOUR 5227 03:18:33,760 --> 03:18:33,960 SLIDE. 5228 03:18:33,960 --> 03:18:35,840 [INDISCERNIBLE] MOUSE? 5229 03:18:35,840 --> 03:18:40,680 LET ME--I SEE YOUR POINTER. 5230 03:18:40,680 --> 03:18:42,200 OKAY, SO VERY EXCITED TO TALK TO 5231 03:18:42,200 --> 03:18:43,680 YOU ABOUT THIS PROJECT THAT I'VE 5232 03:18:43,680 --> 03:18:45,040 BEEN WORKING ON FOR WIGHT A 5233 03:18:45,040 --> 03:18:46,920 WHILE IN THE NEXT 20 MINUTES I 5234 03:18:46,920 --> 03:18:50,120 WILL TALK A LOT ABOUT PROTEOMICS 5235 03:18:50,120 --> 03:18:51,720 AND BIO-INFORMATICS AND REAR 5236 03:18:51,720 --> 03:18:53,520 DISEASES I WON'T TALK ABOUT ANY 5237 03:18:53,520 --> 03:18:54,160 ASSPEBTS OF GLYCO BIOLOGY 5238 03:18:54,160 --> 03:18:56,480 HOWEVER, WHICH MAY BE A BIT OF A 5239 03:18:56,480 --> 03:18:57,760 CHANGE OF BASE [INDISCERNIBLE] 5240 03:18:57,760 --> 03:19:00,960 FOR OTHER PRESENTATIONS TODAY. 5241 03:19:00,960 --> 03:19:02,480 SO, BEFORE WE DIVE INTO SCIENCE, 5242 03:19:02,480 --> 03:19:03,880 I WOULD LIKE TO POINT OUT THAT 5243 03:19:03,880 --> 03:19:05,840 THIS PROJECT HAS BEEN VERY LONG 5244 03:19:05,840 --> 03:19:07,360 IN MAKING, THE INITIAL FUNDING 5245 03:19:07,360 --> 03:19:12,120 FOR IT WAS OBTAINED IN 20 FEIGN 5246 03:19:12,120 --> 03:19:16,680 BY MY BOSS JOSH COON AND THE 5247 03:19:16,680 --> 03:19:21,480 DAVE P A GLIARINI, THEY SPENT 5248 03:19:21,480 --> 03:19:22,520 SEVERAL YEARS COLLECTING CELLS 5249 03:19:22,520 --> 03:19:25,320 AND DATA COLLECTION AND THEN WE 5250 03:19:25,320 --> 03:19:28,440 SPENT YEARS COLLECTING DATA 5251 03:19:28,440 --> 03:19:28,920 SHARINGA, AND DRAFTING 5252 03:19:28,920 --> 03:19:31,080 MANUSCRIPT AND THEN WITH THE 5253 03:19:31,080 --> 03:19:32,960 LAST YEAR THE MANUSCRIPT IS IN 5254 03:19:32,960 --> 03:19:35,680 REVIEW AND RECENTLY ACCEPTED FOR 5255 03:19:35,680 --> 03:19:37,200 US AND SHOULD APPEAR IN PRINT 5256 03:19:37,200 --> 03:19:37,400 SOON. 5257 03:19:37,400 --> 03:19:38,920 ALONG WITH THE COURSE OF THE 5258 03:19:38,920 --> 03:19:41,480 PROJECT NEARLY 30 PEOPLE HAVE 5259 03:19:41,480 --> 03:19:42,640 CONTRIBUTED TO IT. 5260 03:19:42,640 --> 03:19:46,640 TOO MANY TO NAME RIGHT NOW, BUT 5261 03:19:46,640 --> 03:19:48,960 WE ALSO PICKED UP SEVERAL 5262 03:19:48,960 --> 03:19:50,520 COLLABORATORS FROM ALL OVER THE 5263 03:19:50,520 --> 03:19:52,440 WORLD INCLUDING THE UK AND 5264 03:19:52,440 --> 03:19:52,840 TURKEY. 5265 03:19:52,840 --> 03:19:56,240 SO IT'S JUST REALLY BEEN QUITE A 5266 03:19:56,240 --> 03:20:07,280 GLOBAL EFFORT FOR THIS PROJECT. 5267 03:20:07,280 --> 03:20:14,520 MORE OFTEN THAN NOT, IT IS QUITE 5268 03:20:14,520 --> 03:20:18,120 TYPICAL THAT THE LAB MAY LOOK AT 5269 03:20:18,120 --> 03:20:27,160 RNA OR RNASEQ OR PERHAPS 5270 03:20:27,160 --> 03:20:31,840 PROTEINS USING SPECIFICALLY 5271 03:20:31,840 --> 03:20:33,640 PROTEOMICS AND THAL TENDENCY TO 5272 03:20:33,640 --> 03:20:35,840 LOOK AT BIOMOLECULES TO LOOK IN 5273 03:20:35,840 --> 03:20:37,120 SPECIFIC SUBSECTION SYSTEM 5274 03:20:37,120 --> 03:20:39,440 ACTUALLY SOMEWHAT LIMITING 5275 03:20:39,440 --> 03:20:41,520 BECAUSE THE TRUTH IS THAT INSIDE 5276 03:20:41,520 --> 03:20:43,280 THE CELLS THEY DON'T EXIST IF 5277 03:20:43,280 --> 03:20:44,360 ISOLATION AND THEY TEND TO 5278 03:20:44,360 --> 03:20:45,520 INTERACT WITH EACH OTHER AND 5279 03:20:45,520 --> 03:20:46,680 WORK TOGETHER QUITE A BITE. 5280 03:20:46,680 --> 03:20:48,920 THE EXAMPLE SHOWN HERE IS THE 5281 03:20:48,920 --> 03:20:50,240 DEPICTION OF LIPID SYNTHESIS 5282 03:20:50,240 --> 03:20:52,080 PATHWAYS AND AS YOU CAN SEE HERE 5283 03:20:52,080 --> 03:20:55,400 IT HERE AND LIPIDS PROTEINS AND 5284 03:20:55,400 --> 03:20:56,440 METABOLITES AND SHOWN IN COLORS 5285 03:20:56,440 --> 03:20:59,360 REALLY WORK TOGETHER TO CARRY 5286 03:20:59,360 --> 03:21:01,760 OUT THIS VARIOUS PROCESSES, AND 5287 03:21:01,760 --> 03:21:03,600 IF WE WERE TO MEASURE PROTEINS 5288 03:21:03,600 --> 03:21:07,320 ALONE, IT WOULD GET A VERY 5289 03:21:07,320 --> 03:21:10,840 DIFFERENT AND MOST LIKELY 5290 03:21:10,840 --> 03:21:12,320 INCOMPLETE FUNCTION OF THIS 5291 03:21:12,320 --> 03:21:12,840 [INDISCERNIBLE] PATHWAYS. 5292 03:21:12,840 --> 03:21:16,720 AND THE NEED FOR THIS PULTY OMIC 5293 03:21:16,720 --> 03:21:17,920 STUDY THAT INTERROGATE SEVERAL 5294 03:21:17,920 --> 03:21:20,160 KINDS OF BI MOLECULES IS REALLY 5295 03:21:20,160 --> 03:21:24,240 APPEARANCE IN STUDIES OF 5296 03:21:24,240 --> 03:21:27,280 METABOLISM AND KIND OF OVERALL 5297 03:21:27,280 --> 03:21:29,520 METABOLOMICS BASIS FOR MANY 5298 03:21:29,520 --> 03:21:41,840 INTERROGATIONS OF MANY 5299 03:21:41,840 --> 03:21:45,160 BIOLOGICAL SYSTEMS. 5300 03:21:45,160 --> 03:21:46,000 THESE ORGANLES ARE PARTICULARLY 5301 03:21:46,000 --> 03:21:47,320 IMPORTANT TO THE STUDIES BECAUSE 5302 03:21:47,320 --> 03:21:49,080 OF THE METABOLIC PATHWAYS THAT 5303 03:21:49,080 --> 03:21:49,680 OCCUR IN THEM. 5304 03:21:49,680 --> 03:21:51,040 THERE ARE SOME BI CHEMICAL 5305 03:21:51,040 --> 03:21:52,520 PROCESSES THAT TAKE PLACE IN 5306 03:21:52,520 --> 03:21:55,320 MITOCHONDRIA THAT ARE TEXTBOOK 5307 03:21:55,320 --> 03:21:56,880 MATERIALS SUCH ASOXIDATIVE 5308 03:21:56,880 --> 03:21:59,240 PHOSPHORYLATION OR OTCA CYCLE 5309 03:21:59,240 --> 03:22:01,240 AND THERE ARE SOME LESS THAN 5310 03:22:01,240 --> 03:22:05,400 WELL KNOWN PROCESSES LIKE STRESS 5311 03:22:05,400 --> 03:22:08,200 SIGNALING, OR LIPID 5312 03:22:08,200 --> 03:22:08,560 MODIFICATION. 5313 03:22:08,560 --> 03:22:12,880 GIVEN HOW MANY PROCESSES OCCUR, 5314 03:22:12,880 --> 03:22:14,200 IT COMES AS NO SURPRISE THAT 5315 03:22:14,200 --> 03:22:15,920 THERE ARE VARIOUS HUMAN DISEASES 5316 03:22:15,920 --> 03:22:19,800 THAT ARE ASSOCIATED WITH 5317 03:22:19,800 --> 03:22:20,400 MITOCHONDRIAL DYSFUNCTION AND 5318 03:22:20,400 --> 03:22:24,880 THIS ORDER IS IN THE INDIVIDUAL 5319 03:22:24,880 --> 03:22:26,520 EFFECT AND THIS IS ASSOCIATED 5320 03:22:26,520 --> 03:22:29,040 WITH SINGLE MUTATIONS IN THE 5321 03:22:29,040 --> 03:22:32,840 SINGY GENE, AND SOME OF THEM 5322 03:22:32,840 --> 03:22:34,680 QUITE PROMINENT IS 5323 03:22:34,680 --> 03:22:40,680 CARDIOMYOPATHY OF PARKINSON'S 5324 03:22:40,680 --> 03:22:43,560 DISEASE, IT'S VERY SIGNIFICANT 5325 03:22:43,560 --> 03:22:44,160 IMPORTANT ORGANLES OF PROTEIN 5326 03:22:44,160 --> 03:22:46,120 COMPLEX I DON'T MEAN OF 5327 03:22:46,120 --> 03:22:51,120 MITOCHONDRIA IS NOT SUPERWELL 5328 03:22:51,120 --> 03:22:52,680 ANNOTATED, [INDISCERNIBLE] IS 5329 03:22:52,680 --> 03:22:55,520 THE PROTEINS TO LOCALIZE IN 2 5330 03:22:55,520 --> 03:22:58,680 MITOCHONDRIA IN HUMAN CELLS AND 5331 03:22:58,680 --> 03:23:02,800 ABOUT 25% OF THESE PROTEINS ARE 5332 03:23:02,800 --> 03:23:07,040 ACTUALLY LACKING FUNCTIONAL 5333 03:23:07,040 --> 03:23:07,320 MUTATION. 5334 03:23:07,320 --> 03:23:08,320 SO THE GOAL OF OUR PROJECT HERE 5335 03:23:08,320 --> 03:23:10,680 WAS TO TRY TO PROVIDE THESE 5336 03:23:10,680 --> 03:23:13,720 PROTEINS WITH SOME KIND OF 5337 03:23:13,720 --> 03:23:14,600 FUNCTIONAL DESCRIPTION THROUGH 5338 03:23:14,600 --> 03:23:15,840 GENERATING A LARGE COLLECTION OF 5339 03:23:15,840 --> 03:23:19,840 KNOCK OUT CELL LINES. 5340 03:23:19,840 --> 03:23:22,240 SO WE BEGIN BY INSTRUCTING THE 5341 03:23:22,240 --> 03:23:23,640 LIST OF PROTEINS FROM 5342 03:23:23,640 --> 03:23:24,720 [INDISCERNIBLE] WHERE WE THEN 5343 03:23:24,720 --> 03:23:26,680 FILTERED THAT LIST AGAINST A 5344 03:23:26,680 --> 03:23:29,280 LIST OF PROTEINS THAT ARE 5345 03:23:29,280 --> 03:23:37,880 NONESSENTIAL EXPRESS INDEED CELL 5346 03:23:37,880 --> 03:23:39,320 LINE AND IF MADE THE KNOCK OUT 5347 03:23:39,320 --> 03:23:44,560 CELL LINES FOR US SO IF WE LOOK 5348 03:23:44,560 --> 03:23:45,920 AT THE LIST OF CHARACTERIZED 5349 03:23:45,920 --> 03:23:48,240 PROTEINS WE WANT TO FOCUS ON THE 5350 03:23:48,240 --> 03:23:50,640 1S THAT LACKED ESTABLISHED 5351 03:23:50,640 --> 03:23:51,960 FUNCTIONAL LIMITATIONS SO WE 5352 03:23:51,960 --> 03:23:55,600 REALLY WANTED TO LOOK AT THOSE 5353 03:23:55,600 --> 03:23:57,680 THAT ARE JUST--WE REALLY DON'T 5354 03:23:57,680 --> 03:24:02,040 KNOW ANYTHING ABOUT THEM, 5355 03:24:02,040 --> 03:24:02,600 CHROMOSOME 5 [INDISCERNIBLE] 5356 03:24:02,600 --> 03:24:05,280 THIS TYPE OF PROTEINS ALSO 5357 03:24:05,280 --> 03:24:08,040 WANTED TO FOCUS ON THE 1S THAT 5358 03:24:08,040 --> 03:24:10,680 HAD NO HOMOLOGY WITH YEAST 5359 03:24:10,680 --> 03:24:11,320 BECAUSE OTHERWISE YOU SHOULD 5360 03:24:11,320 --> 03:24:14,720 DISCOVER THOSE IN YEAST, FOR THE 5361 03:24:14,720 --> 03:24:15,800 CHARACTERIZED PROTEINS, WE TRY 5362 03:24:15,800 --> 03:24:17,120 TO COMPOSE THE LIST IN SUCH A 5363 03:24:17,120 --> 03:24:19,080 WAY THAT IT WOULD INCLUDE 5364 03:24:19,080 --> 03:24:24,000 SEVERAL MEMBERS OF EACH CORE 5365 03:24:24,000 --> 03:24:24,640 METAON CHONDRIAL PATHWAY, AND 5366 03:24:24,640 --> 03:24:26,520 SORT OF THE PATH THAT I SHOWED 5367 03:24:26,520 --> 03:24:30,920 YOU EARLIER, THE TCGA CYCLE 5368 03:24:30,920 --> 03:24:31,640 SIGNALING MITOCHONDRIAL DNA 5369 03:24:31,640 --> 03:24:33,200 STABILITY MAKING ALL OF THOSE 5370 03:24:33,200 --> 03:24:35,800 PATHWAYS ARE COVERED BY OUR LIST 5371 03:24:35,800 --> 03:24:36,760 OF CHARACTERIZED ON PROTEINS 5372 03:24:36,760 --> 03:24:41,600 MOST ARE FOCUSED ON THE 1S IN 5373 03:24:41,600 --> 03:24:43,080 PRIORITIZED PROTEINS THAT 5374 03:24:43,080 --> 03:24:47,120 ENCLOUDED THAT CONTAIN THE KNOWN 5375 03:24:47,120 --> 03:24:47,560 DISEASE ASSOCIATIONS. 5376 03:24:47,560 --> 03:24:50,320 AS DOCUMENTED ON THE DATABASE. 5377 03:24:50,320 --> 03:24:53,120 ONCE WE WENT THROUGH STEPS OR 5378 03:24:53,120 --> 03:24:54,920 FILTERING WE END UP WITH A LIST 5379 03:24:54,920 --> 03:24:56,760 OF GENE TARGETS, 6 OF WHICH WERE 5380 03:24:56,760 --> 03:24:59,480 THE SENTINAL TARGETS SO THAT THE 5381 03:24:59,480 --> 03:25:01,000 PROTEINS AND 50 WERE THE 5382 03:25:01,000 --> 03:25:02,640 UNCHARACTERRIZED 1S THAT WE WERE 5383 03:25:02,640 --> 03:25:04,960 HOPING TO ANNOTATE IN THE 5384 03:25:04,960 --> 03:25:05,400 PROCESS OF STUDY. 5385 03:25:05,400 --> 03:25:10,160 WE PASS THIS ON TO HORIZON WHERE 5386 03:25:10,160 --> 03:25:11,360 THE USE CRISPR CAS TECHNOLOGY TO 5387 03:25:11,360 --> 03:25:14,800 GENERATE THE KNOCK OUTS FOR US. 5388 03:25:14,800 --> 03:25:16,120 ONCE IN POSSESSION OF THE KNOCK 5389 03:25:16,120 --> 03:25:18,360 OUT WE GREW THE CELL LINES IN 3 5390 03:25:18,360 --> 03:25:20,800 TO 4 REPLICATES AND I ALSO NEED 5391 03:25:20,800 --> 03:25:22,880 TO MENTION THAT FOR THE CELL 5392 03:25:22,880 --> 03:25:24,840 LINES WOULD HAVE DUPLICATE 5393 03:25:24,840 --> 03:25:26,600 CLONES MEANING THE SAME KNOCK 5394 03:25:26,600 --> 03:25:28,920 OUT WAS CREATED USING 2 5395 03:25:28,920 --> 03:25:30,520 DIFFERENT GUIDE RNAs SO IT WAS 5396 03:25:30,520 --> 03:25:32,040 200 DIFFERENT KNOCK OUT CELL 5397 03:25:32,040 --> 03:25:36,320 LINES THAT WERE THEN--THEN 5398 03:25:36,320 --> 03:25:38,120 ANALYZED USING 3 DIFFERENT 5399 03:25:38,120 --> 03:25:39,920 DISCOVERY MASS SPEC ROMETRY 5400 03:25:39,920 --> 03:25:42,920 PLATFORMS SO IF WE ANALYZE THE 5401 03:25:42,920 --> 03:25:45,920 PROTEINS USING SINGLE SHOT 5402 03:25:45,920 --> 03:25:47,320 PROTEOMICS AND LABELED 5403 03:25:47,320 --> 03:25:48,000 PREQUANTITATION, WE ALSO 5404 03:25:48,000 --> 03:25:51,600 PERFORMS A DISCOVERY LIPID OMICS 5405 03:25:51,600 --> 03:25:58,680 ASSAY USING CMS, AND TARGETED 5406 03:25:58,680 --> 03:26:00,560 METABOLOMICS USING UGCMS, AND WE 5407 03:26:00,560 --> 03:26:02,400 ALSO HAD MITOCHONDRIAL 5408 03:26:02,400 --> 03:26:06,520 DNSEQUENCING AND CELL GROWTH 5409 03:26:06,520 --> 03:26:06,840 PHENOTYPING. 5410 03:26:06,840 --> 03:26:08,120 AS A RESULT OF THIS EFFORT WE 5411 03:26:08,120 --> 03:26:10,200 ENDED UP WITH OVER 1000 5412 03:26:10,200 --> 03:26:10,920 MOLECULAR MEASUREMENTS PER EACH 5413 03:26:10,920 --> 03:26:15,360 CELL LINE THAT WE PROFILED. 5414 03:26:15,360 --> 03:26:16,680 AND MAJORITY OF THOSE 5415 03:26:16,680 --> 03:26:17,840 MEASUREMENTS WERE PROTEIN 5416 03:26:17,840 --> 03:26:20,360 MEASUREMENTS, IN FACT WE MEASURE 5417 03:26:20,360 --> 03:26:22,160 IT NEARLY 1000 MITOCHONDRIA 5418 03:26:22,160 --> 03:26:23,120 PROTEINS WHICH KOYOKO SPONDY 5419 03:26:23,120 --> 03:26:24,200 LIGHTISSED TO 81% OF THE 5420 03:26:24,200 --> 03:26:33,000 PROTEINS REPORTED TO BE IN 5421 03:26:33,000 --> 03:26:34,120 [INDISCERNIBLE]. 5422 03:26:34,120 --> 03:26:37,680 WE ALSO HAD OVER 50 DIFFERENT 5423 03:26:37,680 --> 03:26:40,520 CLASSES AND METABOLITES 5424 03:26:40,520 --> 03:26:41,320 REPRESENTING SEVERAL SMALL 5425 03:26:41,320 --> 03:26:42,040 MOLECULE CLASSES. 5426 03:26:42,040 --> 03:26:44,360 AS YOU MENTIONED ONCE YOU WORK 5427 03:26:44,360 --> 03:26:46,760 WITH SUCH AMOUNT OF DATAY SO 5428 03:26:46,760 --> 03:26:48,520 IT'S 4000 MEASUREMENTS TIMES THE 5429 03:26:48,520 --> 03:26:51,120 NUMBER OF CELL LINES THAT WE 5430 03:26:51,120 --> 03:26:53,480 GREW, YOU END WITH ABSURDLY 5431 03:26:53,480 --> 03:26:54,040 LARGE DATA SET. 5432 03:26:54,040 --> 03:26:56,600 SO WE HAD OVER 8 MILLION 5433 03:26:56,600 --> 03:26:58,120 MOLECULAR MEASUREMENTS THAT WE 5434 03:26:58,120 --> 03:26:58,920 GENERATED IN THE COURSE OF THE 5435 03:26:58,920 --> 03:27:03,800 STUDY AND BY THE WAY WE PULLED 5436 03:27:03,800 --> 03:27:07,360 THIS STUDY MITOMICS WHICH STANDS 5437 03:27:07,360 --> 03:27:11,280 FOR MITOCHONDRIAL ORPHAN PROTEIN 5438 03:27:11,280 --> 03:27:12,000 MULTIOMIC CRISPR SCREEN SO IT'S 5439 03:27:12,000 --> 03:27:13,880 THE NAME OF THE APPROACH AS WELL 5440 03:27:13,880 --> 03:27:15,320 AS THE NAME OF THE DATA SET WE 5441 03:27:15,320 --> 03:27:16,960 GENERATED OPERATED AND AS YOU 5442 03:27:16,960 --> 03:27:18,600 MENTIONED, SHARING A DATA SET 5443 03:27:18,600 --> 03:27:20,560 THAT LARGE AND EXPLORING THAT 5444 03:27:20,560 --> 03:27:22,480 DATA BECOMES VERY CHALLENGING 5445 03:27:22,480 --> 03:27:23,880 QUICKLY SO THROUGHOUT THE COURSE 5446 03:27:23,880 --> 03:27:26,520 OF THE STUDY, WE USE THE CUSTOM 5447 03:27:26,520 --> 03:27:29,480 WEBSITE APPROACH TO SHARE THE 5448 03:27:29,480 --> 03:27:31,320 DATA AMONGST DIFFERENT 5449 03:27:31,320 --> 03:27:33,880 COLLABORATING GROUPS AND NOW, 5450 03:27:33,880 --> 03:27:38,160 THIS WEBSITE COULD BE FOUND OUT 5451 03:27:38,160 --> 03:27:40,520 UNDER THE MAIN MITOMICS APP. 5452 03:27:40,520 --> 03:27:44,080 AND IT WAS USED IN THE LAB 5453 03:27:44,080 --> 03:27:45,120 PREVIOUSLY CALLED AGER NOT, I 5454 03:27:45,120 --> 03:27:48,040 WILL NOT GO INTO TOO MUCH DETAIL 5455 03:27:48,040 --> 03:27:49,320 ABOUT THIS TOOL, AND YOU CAN 5456 03:27:49,320 --> 03:28:02,800 READ ALL ABOUT IT IN THIS 5457 03:28:02,800 --> 03:28:07,920 APPLICATION FROM 2020. 5458 03:28:07,920 --> 03:28:08,840 BUT BRIEFLY, THEY WILL USE THIS 5459 03:28:08,840 --> 03:28:10,400 WITH THE CONTROLS AND THE 5460 03:28:10,400 --> 03:28:11,080 GENERATE A DATABASE TAKEN--THEY 5461 03:28:11,080 --> 03:28:14,760 CAN BE USED TO CREATE THIS 5462 03:28:14,760 --> 03:28:16,120 CUSTOM WEBSITE AND WHILE WE USE 5463 03:28:16,120 --> 03:28:18,760 THIS INTERACT WITH THE WEBSITE, 5464 03:28:18,760 --> 03:28:20,120 THEY CAN GENERATE ONDEMAND 5465 03:28:20,120 --> 03:28:21,120 VISUALIZATIONS AND EXPLORE THE 5466 03:28:21,120 --> 03:28:25,560 DATA THROUGH THE VARIETY OF 5467 03:28:25,560 --> 03:28:26,800 COMMONLY USED [INDISCERNIBLE], 5468 03:28:26,800 --> 03:28:29,360 RELATION ANALYSIS AND SUCH. 5469 03:28:29,360 --> 03:28:31,920 AND SINSZ THIS EXISTS AS A 5470 03:28:31,920 --> 03:28:34,120 WEBSITE, IT'S VERY EASY TO SHARE 5471 03:28:34,120 --> 03:28:35,080 THIS DATA TO CURATE THE DAILY 5472 03:28:35,080 --> 03:28:38,320 BASIS AT AND IT'S ALSO PASSWORD 5473 03:28:38,320 --> 03:28:39,120 PROTECTED SO SPECIFIC 5474 03:28:39,120 --> 03:28:40,440 INDIVIDUALS NEED TO BE INVITED 5475 03:28:40,440 --> 03:28:48,960 TO VIEW THE DATA SO IT'S QUITE 5476 03:28:48,960 --> 03:28:49,200 SAFE. 5477 03:28:49,200 --> 03:28:51,080 SORRY, I'M HAVING AN ISSUE 5478 03:28:51,080 --> 03:29:05,640 CLICKING THE SLIDES. 5479 03:29:05,640 --> 03:29:06,040 ONE SECOND. 5480 03:29:06,040 --> 03:29:07,920 HERE WE GO SO WHEN YOU FIRST 5481 03:29:07,920 --> 03:29:10,600 GENERATE A LARGE DATA SET LIKE 5482 03:29:10,600 --> 03:29:12,320 THAT, YOU TYPICALLY WOULD DO 5483 03:29:12,320 --> 03:29:13,520 SOME KIND OF SPOT CHECKING OF 5484 03:29:13,520 --> 03:29:14,680 THE DAILY BASIS THEA AND THAT'S 5485 03:29:14,680 --> 03:29:17,040 WHAT WE DID, AS YOU KNOW WE HAD 5486 03:29:17,040 --> 03:29:17,960 MANY PROTEINS OF NEW FUNCTION, 5487 03:29:17,960 --> 03:29:19,920 SO WE LOOK TO SEE HOW THE LOSS 5488 03:29:19,920 --> 03:29:21,680 OF THOSE PROTEINS AFFECTS THE 5489 03:29:21,680 --> 03:29:24,160 PHENOTYPES OF THE CELLS. 5490 03:29:24,160 --> 03:29:25,840 ONE OF THE CELL LINES WORK WITH 5491 03:29:25,840 --> 03:29:29,920 THE CONTAIN THE DELETION OF THE 5492 03:29:29,920 --> 03:29:31,800 ENZYME CALLED [INDISCERNIBLE], 5493 03:29:31,800 --> 03:29:37,320 PULSATIVITY 2 AND THIS ENZYME 5494 03:29:37,320 --> 03:29:39,480 TURNS INTO KARNITTINE AND IN THE 5495 03:29:39,480 --> 03:29:41,920 LIPID OMICS DATA FOR THE CELL 5496 03:29:41,920 --> 03:29:44,040 LINE VERY QUICKLY IDENTIFIED 5497 03:29:44,040 --> 03:29:48,320 THAT THERE WAS AN ACCUMULATION 5498 03:29:48,320 --> 03:29:49,520 OF THE THE KARNITTINE SPECIES 5499 03:29:49,520 --> 03:29:52,040 THERE WAS A SPECIFIC LOSS OF 5500 03:29:52,040 --> 03:29:56,320 FUNCTION WITH THIS PROTEIN. 5501 03:29:56,320 --> 03:29:59,000 SIMILARLY, WE OBSERVED CHANGES 5502 03:29:59,000 --> 03:29:59,840 IN METABOLOMICS DATA FOR 5503 03:29:59,840 --> 03:30:01,360 EXAMPLE, IN THE CELL LINE THAT 5504 03:30:01,360 --> 03:30:04,200 LACKED THE PROTEIN CALLED SLC 25 5505 03:30:04,200 --> 03:30:08,280 A 1, WE NOTICED THAT THERE WAS A 5506 03:30:08,280 --> 03:30:10,280 PRONOUNCED ACCUMULATION OF 5507 03:30:10,280 --> 03:30:12,480 METABOLITE OF 2 HYDROXIC ACID 5508 03:30:12,480 --> 03:30:14,480 AND THIS IS CONSISTENT WITH THE 5509 03:30:14,480 --> 03:30:17,200 FUNCTIONAL PROTEIN BECAUSE AS OF 5510 03:30:17,200 --> 03:30:19,680 CTLA21 WAS A TRANSPORTER IN IT'S 5511 03:30:19,680 --> 03:30:25,200 ABSENCE IT ACCUMULATES AND GETS 5512 03:30:25,200 --> 03:30:26,680 CONVERTED INTO THE 5513 03:30:26,680 --> 03:30:27,720 [INDISCERNIBLE] ACID WHICH IS 5514 03:30:27,720 --> 03:30:30,520 WHAT WE'RE OBSERVE IN THE 5515 03:30:30,520 --> 03:30:31,920 METABOLOMICS DATA AND THIS IS 5516 03:30:31,920 --> 03:30:40,720 THE HALLMARK OF THE DISEASE 5517 03:30:40,720 --> 03:30:43,200 CALLED [INDISCERNIBLE] AND IT 5518 03:30:43,200 --> 03:31:28,480 AND CAPITULATE AND THOSE TYPES. 5519 03:31:28,480 --> 03:31:34,520 --AND THERE'S KIND OF GLOBS OF 5520 03:31:34,520 --> 03:31:35,120 METABOLITES THROUGHOUT THIS. 5521 03:31:35,120 --> 03:31:36,440 PLOT IT'S HARD TO TELL WHAT THIS 5522 03:31:36,440 --> 03:31:39,320 IS FOR THE BEHAVIOR, WE'RE 5523 03:31:39,320 --> 03:31:41,720 OBSERVING BOTH, YOU KNOW THERE 5524 03:31:41,720 --> 03:31:42,800 COULD BE TECHNICAL EXPLANATIONS 5525 03:31:42,800 --> 03:31:44,560 BAZ IF YOU REMEMBER WE USE THE 5526 03:31:44,560 --> 03:31:46,640 DIFFERENT PLATFORMS AND USE 5527 03:31:46,640 --> 03:31:48,600 SEPARATE PAL ATS IF ARE THIS 5528 03:31:48,600 --> 03:31:50,000 ANALYSIS, THIS COULD BE A 5529 03:31:50,000 --> 03:31:52,120 REFLECTION OF THE DATABASE 5530 03:31:52,120 --> 03:31:53,040 ITSELF AND PERHAPS FUNCTIONAL 5531 03:31:53,040 --> 03:31:54,680 CONNECTION IF THE LIPIDS AMONGST 5532 03:31:54,680 --> 03:31:56,480 TRITE TO TYPE IT IN AND 5533 03:31:56,480 --> 03:32:00,440 CONNECTION BETWEEN LIPIDS AND 5534 03:32:00,440 --> 03:32:01,960 THE VARIOUS PROTEINS. 5535 03:32:01,960 --> 03:32:03,760 MANY ASPECTS OF [INDISCERNIBLE] 5536 03:32:03,760 --> 03:32:05,920 RANDOM BUT NO MATTER HOW WE 5537 03:32:05,920 --> 03:32:07,400 CHANGE THE PARAMETERS AND WE 5538 03:32:07,400 --> 03:32:09,680 ALWAYS END UP WITH THIS CLUSTER 5539 03:32:09,680 --> 03:32:14,280 HERE AND THIS VERY TIGHT CLUSTER 5540 03:32:14,280 --> 03:32:16,480 ACTUALLY, IS ZOOMED IN HERE AND 5541 03:32:16,480 --> 03:32:18,920 YOU COULD ACTUALLY SEE IT 5542 03:32:18,920 --> 03:32:24,120 CONSISTS WITH A LOT OF AND 5543 03:32:24,120 --> 03:32:25,400 CORRELATION AND MICRO STUDIES OF 5544 03:32:25,400 --> 03:32:26,400 MULTIPLE ENDOCRINAL PROTEINS SO 5545 03:32:26,400 --> 03:32:29,040 IT WAS ENCOURAGING TO SEE SUCH 5546 03:32:29,040 --> 03:32:30,840 TYPE CONNECTIONS AND WE ALSO 5547 03:32:30,840 --> 03:32:34,280 NOTICE THAT THERE'S SEVERAL 5548 03:32:34,280 --> 03:32:35,440 SMALL METABOLITES SUCH AS 5549 03:32:35,440 --> 03:32:38,400 [INDISCERNIBLE] ACID AND SID 5550 03:32:38,400 --> 03:32:42,320 RICK ACID AND 5551 03:32:42,320 --> 03:32:42,920 PROPIONYLKARNITTINEITINE AND 5552 03:32:42,920 --> 03:32:45,520 THEY'VE BEEN KNOWN TO HAVE VERY 5553 03:32:45,520 --> 03:32:50,640 SIGNIFICANT FUNCTIONS IN MIGHT 5554 03:32:50,640 --> 03:32:51,040 MITOCHONDRIA. 5555 03:32:51,040 --> 03:32:54,040 SO ALL IN ALL THIS IS 5556 03:32:54,040 --> 03:32:56,120 ENCOURAGING BUT THE DATA 5557 03:32:56,120 --> 03:32:57,120 MAINTAINS RELATIONSHIPS AND 5558 03:32:57,120 --> 03:32:58,760 PERHAPS AGAIN LOOKING FOR NOVEL 5559 03:32:58,760 --> 03:33:00,680 RELATIONSHIPS, AND USING THIS 5560 03:33:00,680 --> 03:33:02,200 DATA SET. 5561 03:33:02,200 --> 03:33:09,600 SO 1 OF THE MOLECULAR PATHWAYS 5562 03:33:09,600 --> 03:33:15,040 WAS BY SYNTHESIS OF CO 5563 03:33:15,040 --> 03:33:16,640 FACTOR--COQ10 IT'S A MOLECULE 5564 03:33:16,640 --> 03:33:32,880 THAT PLAYS A ROLE IN OXIDATIVE 5565 03:33:32,880 --> 03:33:33,280 MOLECULARRIZATION. 5566 03:33:33,280 --> 03:33:35,000 SO WE SAW THE DEPLETES OF THE 5567 03:33:35,000 --> 03:33:38,840 FINAL LEVELS OF THIS MODEL AND 5568 03:33:38,840 --> 03:33:40,360 THIS WAS SUPER HAPPY TO SEE THAT 5569 03:33:40,360 --> 03:33:42,240 ONCE WE LOOKED ACROSS VARIOUS 5570 03:33:42,240 --> 03:33:45,000 CELL LINES OF THE PROFILE, IN 5571 03:33:45,000 --> 03:33:47,120 OUR STUDY, WE NOTICED THERE WAS 5572 03:33:47,120 --> 03:33:48,800 A KNOCK OUT APPEARED THAT HAD 5573 03:33:48,800 --> 03:33:54,400 THE PHENOTYPE VERY SIMILAR TO 5574 03:33:54,400 --> 03:33:57,720 THE 1S THAT AND PROTEINS MISSING 5575 03:33:57,720 --> 03:33:59,520 OBSERVED IN THE CELL LINES THAT 5576 03:33:59,520 --> 03:34:02,880 WERE MISS NOTHING VARIOUS 5577 03:34:02,880 --> 03:34:05,680 ENZYMES THIS IS QUITE CURIOUS 5578 03:34:05,680 --> 03:34:07,320 AND WE HAVE MORE INFORMATION 5579 03:34:07,320 --> 03:34:14,320 ABOUT THE POSSIBLE FUNCTION 5580 03:34:14,320 --> 03:34:14,520 HERE. 5581 03:34:14,520 --> 03:34:15,720 SO THIS IS A CHANGE OF VARIOUS 5582 03:34:15,720 --> 03:34:18,720 PROTEINS IN THE CELL LINES HERE, 5583 03:34:18,720 --> 03:34:20,400 AND YOU CAN SEE THE PEER ITSELF 5584 03:34:20,400 --> 03:34:22,480 IS INCREASING THE METHOD BUT 5585 03:34:22,480 --> 03:34:23,680 ALSO OBSERVE THERE ARE SEVERAL 5586 03:34:23,680 --> 03:34:27,560 MEMBERS OF THE THIS PATHWAY 5587 03:34:27,560 --> 03:34:31,080 DEPICTED HERE AND INTERESTINGLY, 5588 03:34:31,080 --> 03:34:33,640 WE ARE ALSO SEVERAL COMPONENTS 5589 03:34:33,640 --> 03:34:35,400 OF A COMPLEX MODULE AS WELL AS 5590 03:34:35,400 --> 03:34:36,840 FACTORS SHOWN HERE IN GREEN AND 5591 03:34:36,840 --> 03:34:47,600 BLUE, THAT WERE ALSO DECREASED 5592 03:34:47,600 --> 03:34:50,600 AND YOU CAN SEE THAT THE COMPLEX 5593 03:34:50,600 --> 03:34:52,560 1 OR COQ ARE RELATED TO EACH 5594 03:34:52,560 --> 03:34:54,600 OTHER SO THERE NEEDS TO BE SOME 5595 03:34:54,600 --> 03:34:55,640 SORT OF COORDINATION BETWEEN THE 5596 03:34:55,640 --> 03:34:57,400 2 BUT THE MOMENT UPON WHEN WE 5597 03:34:57,400 --> 03:34:58,680 MADE IN OBSERVATION HAS BEEN 5598 03:34:58,680 --> 03:35:00,680 NOTHING KNOWN ABOUT HOW THOSE 2 5599 03:35:00,680 --> 03:35:02,320 MAY BE TALKING TO EACH OTHER AND 5600 03:35:02,320 --> 03:35:08,560 HOW THOSE LEVELS MIGHT BE 5601 03:35:08,560 --> 03:35:09,640 COORDINATED AND AN INTERESTING 5602 03:35:09,640 --> 03:35:12,520 PIECE CAME FROM NEW CASTLE 5603 03:35:12,520 --> 03:35:16,120 UNIVERSITY IN HIS LAB AND IN 5604 03:35:16,120 --> 03:35:17,960 FACT, THE COLLABORATORS CLINICAL 5605 03:35:17,960 --> 03:35:22,080 GENETICIST AND THEY HAVE COME 5606 03:35:22,080 --> 03:35:24,280 ACROSS A FAMILY WHERE APPEARANCE 5607 03:35:24,280 --> 03:35:27,040 HARVARD MUTATION IN APPEARED 5608 03:35:27,040 --> 03:35:30,320 GENE IN 1 OF THE CHILDREN HAPPEN 5609 03:35:30,320 --> 03:35:35,400 TO BE HOMOZYGOUS FOR THIS 5610 03:35:35,400 --> 03:35:38,920 MUTATION, WHICH CAUSE FATAL 5611 03:35:38,920 --> 03:35:42,720 SYNDROME THAT INVOLVED COMPLEX 5612 03:35:42,720 --> 03:35:44,920 LIST OF SYMPTOMS SHOWN OVER HERE 5613 03:35:44,920 --> 03:35:47,320 AND INTERESTINGLY THESE SYMPTOMS 5614 03:35:47,320 --> 03:35:49,320 ARE QUITE CONSISTENT WITH THE 5615 03:35:49,320 --> 03:35:51,600 LOSS OF POINTS AND CUE 5616 03:35:51,600 --> 03:35:58,520 FUNCTIONALITIES AS WELLs 1, SO 5617 03:35:58,520 --> 03:35:59,560 THIS WAS ANOTHER POINTING THAT 5618 03:35:59,560 --> 03:36:00,680 HOW IT WAS INVOLVED SO IN THE 5619 03:36:00,680 --> 03:36:02,320 INTEREST OF TIME I WILL SKIP THE 5620 03:36:02,320 --> 03:36:04,240 DESCRIPTIONS OF SOME OF THIS 5621 03:36:04,240 --> 03:36:06,160 OTHER BIOCHEMICAL DATA, BUT 5622 03:36:06,160 --> 03:36:08,440 BASICALLY FOR EVER A SERIES OF 5623 03:36:08,440 --> 03:36:10,840 RISKS WE DEMONSTRATED HERE CAN 5624 03:36:10,840 --> 03:36:15,000 INTERACT WITH VARIOUS ASSEMBLY 5625 03:36:15,000 --> 03:36:17,240 FACTORS OF COMPLEX 1 AND IT'S 5626 03:36:17,240 --> 03:36:20,920 FACT OF THE LOSS OF THOSE ON 5627 03:36:20,920 --> 03:36:21,920 CELLULAROXIDATIVE COMSUMPTION 5628 03:36:21,920 --> 03:36:23,920 RATE IS ALSO CONSISTENT WITH 5629 03:36:23,920 --> 03:36:28,720 THIS ROLE IN COQ AS WELL AS 5630 03:36:28,720 --> 03:36:29,320 FUNCTIONALITY COMPLEX 1. 5631 03:36:29,320 --> 03:36:30,760 BASED ON THE INITIAL MASS SPEC 5632 03:36:30,760 --> 03:36:33,760 DAILY BASIS IT ISA AND FURTHER 5633 03:36:33,760 --> 03:36:34,960 BIOCHEMICAL EXPERIMENTS, SORT OF 5634 03:36:34,960 --> 03:36:40,480 PROPOSED THIS MODEL OF THE PEER 5635 03:36:40,480 --> 03:36:42,040 OF FUNCTION WHERE IT SLIDES ON 5636 03:36:42,040 --> 03:36:47,280 THE INTERPHASE OF COMPLEX 1 AND 5637 03:36:47,280 --> 03:36:50,760 BIOSYNTHESIS, SORT OF ACHIEVING 5638 03:36:50,760 --> 03:36:51,640 EXPRESSION OF [INDISCERNIBLE] 5639 03:36:51,640 --> 03:36:53,920 AND TYING THE 2 PATHWAYS 5640 03:36:53,920 --> 03:36:54,200 TOGETHER. 5641 03:36:54,200 --> 03:36:59,440 AND ACTUALLY WE NAMED PYURF, 5642 03:36:59,440 --> 03:37:04,040 NDUFAFQ, WHICH IS INVOLVE WIDE 5643 03:37:04,040 --> 03:37:06,080 THIS PROCESS. 5644 03:37:06,080 --> 03:37:07,880 ANOTHER STORY WE HAD ABOUT KNOCK 5645 03:37:07,880 --> 03:37:13,320 OUT OF THE PROTEIN CALLED 5646 03:37:13,320 --> 03:37:16,360 RABIF5, IT'S ALSO KNOWN AS C20 5647 03:37:16,360 --> 03:37:19,240 ORF24, AND NOW COLLABORATING IN 5648 03:37:19,240 --> 03:37:23,440 THE LAB, [INDISCERNIBLE] MADE AN 5649 03:37:23,440 --> 03:37:25,000 OBSERVATION SHOWING THAT THE 5650 03:37:25,000 --> 03:37:30,640 DOES HE LESION WAS A VERY 5651 03:37:30,640 --> 03:37:32,040 SPECIFIC LOSS AND DECREASE IN 5652 03:37:32,040 --> 03:37:33,800 ABUNDANCE OF THE PROTEIN OF CO1 5653 03:37:33,800 --> 03:37:36,800 AND AS YOU CAN SEE WE HAVE 2 5654 03:37:36,800 --> 03:37:43,120 CELL LINES WITH THE LACKING OF 5655 03:37:43,120 --> 03:37:52,280 RABIF5, SO IT WAS A VERY STRONG 5656 03:37:52,280 --> 03:37:52,680 OBSERVATION. 5657 03:37:52,680 --> 03:37:57,800 AND THIS WAS VERY INTERESTING 5658 03:37:57,800 --> 03:37:59,920 BECAUSE TMCO1 IS A VERY 5659 03:37:59,920 --> 03:38:02,680 IMPORTANT POINT ITSELF, IT'S A 5660 03:38:02,680 --> 03:38:04,800 PROTEIN THAT'S ENDOPLAZ MIDSIC 5661 03:38:04,800 --> 03:38:06,760 RETIC LUMRELATED TO PROTEIN, AND 5662 03:38:06,760 --> 03:38:11,840 IT MAY HAVE A FUNCTION IN 5663 03:38:11,840 --> 03:38:12,320 CALCIUM TRANSFERAISE. 5664 03:38:12,320 --> 03:38:13,960 SO THIS WAS CURIOUS TO US 5665 03:38:13,960 --> 03:38:18,680 BECAUSE AS YOU KNOW RABIF5 IS A 5666 03:38:18,680 --> 03:38:19,680 MITOCHONDRIA PROTEIN AND WE 5667 03:38:19,680 --> 03:38:21,120 WONDERED IF THE 2 TYPES WERE 5668 03:38:21,120 --> 03:38:22,400 TOGETHER AND MAYBE INVOLVED IN 5669 03:38:22,400 --> 03:38:25,640 THE CROSS TALK WITHIN THESE 2 5670 03:38:25,640 --> 03:38:27,240 TYPES OF ORGANLES. 5671 03:38:27,240 --> 03:38:28,680 SO WE VALIDATED THIS OBSERVATION 5672 03:38:28,680 --> 03:38:30,120 THROUGH WESTERN BLOT AND THIS IS 5673 03:38:30,120 --> 03:38:31,680 ALSO WHICH IS SHOWN OVER HERE 5674 03:38:31,680 --> 03:38:34,720 AND WE ALSO SHOWED USING SMALL 5675 03:38:34,720 --> 03:38:37,800 INTERFERON RNAs THAT THE LOSS 5676 03:38:37,800 --> 03:38:39,400 OF RABIF5 IS THE LOSS OF 1 AND 5677 03:38:39,400 --> 03:38:43,320 THE OTHER WAY AROUND DELETION OF 5678 03:38:43,320 --> 03:38:47,120 TEAM CO1 WITH THE LOSS OF RABIF5 5679 03:38:47,120 --> 03:38:52,920 SO THIS IS ACTUALLY NEUTRAL. 5680 03:38:52,920 --> 03:38:54,440 WE ALSO GOT A VERY INTERESTING 5681 03:38:54,440 --> 03:38:58,520 PIECE OF INFORMATION FROM OUR 5682 03:38:58,520 --> 03:39:03,680 COLLABORATORS AND THE LAB AT THE 5683 03:39:03,680 --> 03:39:05,680 UNIVERSITY IN TURKEY AND HAD IS 5684 03:39:05,680 --> 03:39:06,840 ALL GENETICIST AND THEY'VE BEEN 5685 03:39:06,840 --> 03:39:08,920 WORKING WITH SEVERAL FAMILIES 5686 03:39:08,920 --> 03:39:14,840 IMPACTED BY A RARE DISEASE OLD 5687 03:39:14,840 --> 03:39:16,120 SUPERFICIAL THORACIC DISPLASSIA, 5688 03:39:16,120 --> 03:39:17,440 CFTD, AND MOST KNOWN CASES OF 5689 03:39:17,440 --> 03:39:22,080 THE DISEASE ARE RELATED TO 5690 03:39:22,080 --> 03:39:22,880 MUTATIONS IN GENE 1501 HOWEVER, 5691 03:39:22,880 --> 03:39:25,000 THERE ARE SOME CASES OF THE 5692 03:39:25,000 --> 03:39:27,920 DISEASE THAT HAVE NOT BEEN 5693 03:39:27,920 --> 03:39:39,520 EXPLAINED BY ANY MUTATIONS IN 5694 03:39:39,520 --> 03:39:39,960 TMC01. 5695 03:39:39,960 --> 03:39:41,400 THE LAB WAS ACTUALLY ABLE TO 5696 03:39:41,400 --> 03:39:45,560 FIND A MUTATION IN THE GENE 5697 03:39:45,560 --> 03:39:47,000 ENCODING IN RABIF5 THAT CAUSED A 5698 03:39:47,000 --> 03:39:50,520 LOSS OF PROTEIN THAT'S A SINGLE 5699 03:39:50,520 --> 03:39:54,280 ACID 5700 03:39:54,280 --> 03:39:55,400 ACID LIMITATION THAT DOESN'T 5701 03:39:55,400 --> 03:39:57,120 APPEAR IN THE SICKNESS OF THE 5702 03:39:57,120 --> 03:39:58,920 GENE AND THERE WAS THIS FAMILY 5703 03:39:58,920 --> 03:40:01,120 SHOWN OVER HERE, THE GENO GRAM 5704 03:40:01,120 --> 03:40:04,640 OF THIS HERE, THAT ACTUALLY HAD 5705 03:40:04,640 --> 03:40:06,360 SEVERAL INDIVIDUALS AIVETTED BY 5706 03:40:06,360 --> 03:40:08,240 THIS DISEASE, SO HERE AT THE 5707 03:40:08,240 --> 03:40:13,280 SPECIFIC MUTATION AND RAPIDLY 5. 5708 03:40:13,280 --> 03:40:14,920 WE WERE ACTUALLY ABLE TO OBTAIN 5709 03:40:14,920 --> 03:40:16,520 THE FIBRO PLAOF THES FROM AN 5710 03:40:16,520 --> 03:40:17,920 EFFECTIVE INDIVIDUAL SHOWN HERE 5711 03:40:17,920 --> 03:40:19,920 AND BY SOME MIRACLE THE CELLS 5712 03:40:19,920 --> 03:40:21,120 WERE SHIPPED FROM THIS AND CAME 5713 03:40:21,120 --> 03:40:22,880 FROM THIS INDIVIDUAL AND SHIPPED 5714 03:40:22,880 --> 03:40:24,680 FROM TURKEY ARRIVED TO ST. LOUIS 5715 03:40:24,680 --> 03:40:27,320 AND THERE OUR COLLABORATOR WAS 5716 03:40:27,320 --> 03:40:32,040 ABLE TO INSPECT THEM AND NOT 5717 03:40:32,040 --> 03:40:37,320 WILD TYPE SEQUENCE OF RAB5 IF 5718 03:40:37,320 --> 03:40:40,520 AND CAUSED INCREASE OF THE TMCO1 5719 03:40:40,520 --> 03:40:45,520 AND THIS LED TO THE 5720 03:40:45,520 --> 03:40:45,880 [INDISCERNIBLE]. 5721 03:40:45,880 --> 03:40:47,680 IN THE INTEREST OF TIME WE WILL 5722 03:40:47,680 --> 03:40:49,680 HAVE TO SKIP THE OTHER STORIES 5723 03:40:49,680 --> 03:40:51,200 WE OBSERVED BUT THERE WAS 5724 03:40:51,200 --> 03:40:58,600 ANOTHER PUBLICATION THAT 5725 03:40:58,600 --> 03:41:00,680 DESCRIBES THE PATHOLOGY THAT WAS 5726 03:41:00,680 --> 03:41:03,840 LINKED TO A RARE FATAL 5727 03:41:03,840 --> 03:41:06,360 AUTOINFLAMMATORY SYNDROME THAT 5728 03:41:06,360 --> 03:41:09,400 IS DEMONSTRATED AND WITH STORAGE 5729 03:41:09,400 --> 03:41:13,440 ISSUES WITH THE LOSS OF C2 5730 03:41:13,440 --> 03:41:14,880 ORFSCAIN AND THE RESULT OF THIS 5731 03:41:14,880 --> 03:41:18,520 PROJECT WE MANAGED TO PROPOSE 5732 03:41:18,520 --> 03:41:19,560 SOME POSSIBLE FUNCTIONAL 5733 03:41:19,560 --> 03:41:25,920 LIMITATIONS FOR ANOTHER FEIGN OR 5734 03:41:25,920 --> 03:41:27,120 CHARACTERIZE PROTEINS AND ALL OF 5735 03:41:27,120 --> 03:41:28,320 THESE OBSERVATIONS APPEAR IN THE 5736 03:41:28,320 --> 03:41:32,200 MANUSCRIPT AND THEY'RE READY 5737 03:41:32,200 --> 03:41:33,400 APPROXIMATE FOR FUTURE 5738 03:41:33,400 --> 03:41:34,040 BIOLOGICAL STUDIES. 5739 03:41:34,040 --> 03:41:35,320 SO IN CONCLUSION, I WOULD LIKE 5740 03:41:35,320 --> 03:41:37,120 TO REMIND YOU WE WORKED ON THE 5741 03:41:37,120 --> 03:41:38,160 PROJECT CALLED MIRROR IMAGE 5742 03:41:38,160 --> 03:41:40,160 TOPICS WHICH IS A LARGE 5743 03:41:40,160 --> 03:41:42,160 MULTIOMIC RESOURCE FOR THE 5744 03:41:42,160 --> 03:41:43,520 MITOCHONDRIA HAL BIOLOGIC 5745 03:41:43,520 --> 03:41:45,400 IMMUNITY THAT CHARACTERIZES OVER 5746 03:41:45,400 --> 03:41:49,080 200 VARIOUS IMK OUT CELL LINES 5747 03:41:49,080 --> 03:41:52,800 IN LOOKING TO ESTABLISH 5748 03:41:52,800 --> 03:41:53,560 CONNECTION MITOCHONDRIA PROTEINS 5749 03:41:53,560 --> 03:41:55,000 OF KNOWN AND KNOWN FUNCTIONS AND 5750 03:41:55,000 --> 03:41:56,680 DM THE COURSE OF THE PROJECT WE 5751 03:41:56,680 --> 03:41:58,120 WERE ABLE TO PROVIDE FUNCTIONAL 5752 03:41:58,120 --> 03:42:00,520 MUTATIONS FOR SEVERAL PROTEINS 5753 03:42:00,520 --> 03:42:03,960 AND PINPOINT THEIR ROLES IN 5754 03:42:03,960 --> 03:42:07,480 VARIOUS RARE DISEASES AND IN 5755 03:42:07,480 --> 03:42:09,680 GENERAL THE MOST IMPORTANTLY 5756 03:42:09,680 --> 03:42:11,320 MITOTIC SYSTEM HYPOTHESIS 5757 03:42:11,320 --> 03:42:15,040 GENERATING RESOURCE, WE'RE 5758 03:42:15,040 --> 03:42:16,680 HOPING THAT IT WILL REALLY JUMP 5759 03:42:16,680 --> 03:42:19,480 IN IT AND FOLLOW UP ON THE LEADS 5760 03:42:19,480 --> 03:42:24,120 FOR THE RIGHT DISCOVERY IN THIS 5761 03:42:24,120 --> 03:42:24,360 RESOURCE. 5762 03:42:24,360 --> 03:42:25,680 I'D LIKE TO THANK NUMEROUS 5763 03:42:25,680 --> 03:42:26,960 MEMBERS OF THE LAB THAT WORKED 5764 03:42:26,960 --> 03:42:31,040 ON THIS PROJECT OVER THE YEARS 5765 03:42:31,040 --> 03:42:33,040 ALSO OUR COLLABORATORS IN LABS 5766 03:42:33,040 --> 03:42:34,680 FROM ALL AROUND THE WORLD AND 5767 03:42:34,680 --> 03:42:36,320 OUR FUNDING RESOURCES AND OF 5768 03:42:36,320 --> 03:42:40,800 COURSE ALL OF YOU, THANKS A LOT. 5769 03:42:40,800 --> 03:42:46,680 >> GREAT, THANK YOU SO MUCH, 5770 03:42:46,680 --> 03:42:47,680 EVGENIA, GREAT TALK. 5771 03:42:47,680 --> 03:42:51,400 AS A REMINDER PLEASE USE THE 5772 03:42:51,400 --> 03:42:53,360 LINK: SEND LIVE FEEDBACK, TO 5773 03:42:53,360 --> 03:42:54,080 SUBCOMMIT YOUR QUESTIONS AND 5774 03:42:54,080 --> 03:42:55,920 AGAIN AT THE END OF OUR 5775 03:42:55,920 --> 03:42:56,680 AFTERNOON SESSION IN ABOUT AN 5776 03:42:56,680 --> 03:42:58,200 HOUR AND ALL THE SPEAKERS WILL 5777 03:42:58,200 --> 03:42:59,600 AVAILABLE TO ANSWER THOSE 5778 03:42:59,600 --> 03:42:59,880 QUESTIONS. 5779 03:42:59,880 --> 03:43:03,200 SO NOW TO MOVE ON, OUR NEXT 5780 03:43:03,200 --> 03:43:07,720 SPEAKER IS DANIEL GRAHAM AT THE 5781 03:43:07,720 --> 03:43:09,040 BROAD INTUITY AND THE TIELT OF 5782 03:43:09,040 --> 03:43:12,440 HIS TALK IS CLUES FROM HUMAN 5783 03:43:12,440 --> 03:43:14,560 GENETICS IMPLICATE GLYCO BIOLOGY 5784 03:43:14,560 --> 03:43:16,760 AND INTESTINAL BARRIER INTEGRITY 5785 03:43:16,760 --> 03:43:17,200 AND INFLAMMATION. 5786 03:43:17,200 --> 03:43:23,400 OKAY, CAN YOU TAKE IT AWAY, 5787 03:43:23,400 --> 03:43:23,640 DANIEL? 5788 03:43:23,640 --> 03:43:24,120 >> OKAY, THANKS. 5789 03:43:24,120 --> 03:43:25,400 IT'S REALLY NICE TO BE WITH YOU 5790 03:43:25,400 --> 03:43:26,640 THIS AFTERNOON AND I'VE REALLY 5791 03:43:26,640 --> 03:43:29,400 ENJOYED ALL THE TALKS SO FAR. 5792 03:43:29,400 --> 03:43:30,360 AND IT'S A PLEASURE TO BE ABLE 5793 03:43:30,360 --> 03:43:34,760 TO TELL YOU A BIT ABOUT OUR WORK 5794 03:43:34,760 --> 03:43:39,520 IN HUMAN GENETICS AND AND OUR 5795 03:43:39,520 --> 03:43:41,360 JOURNEY FROM GOING FROM LEADS 5796 03:43:41,360 --> 03:43:44,200 FROM HUMAN GENETICS TO DISEASE 5797 03:43:44,200 --> 03:43:46,440 MECHANISMS THAT LED US TO FLIEK 5798 03:43:46,440 --> 03:43:50,520 O BIOLOGY AND THEN UNEXPECTED 5799 03:43:50,520 --> 03:43:53,760 WAY TAUGHT US A LOT ABOUT THE 5800 03:43:53,760 --> 03:43:57,680 MECHANISTIC BASIS OF HUMAN 5801 03:43:57,680 --> 03:43:59,120 DISEASE AND OUR STRATEGIC PLAN 5802 03:43:59,120 --> 03:44:00,960 EDGE CEREALLY FOCUSED ON THIS 5803 03:44:00,960 --> 03:44:05,080 IDEA THAT THERE'S TREMENDOUS 5804 03:44:05,080 --> 03:44:05,680 GENETIC DIVERSITY AROUND THE 5805 03:44:05,680 --> 03:44:07,320 GLOBE AND IN POPULATIONS AND 5806 03:44:07,320 --> 03:44:11,440 THIS HAS BEEN ENRICHED OVER THE 5807 03:44:11,440 --> 03:44:13,840 YEARS THROUGH EVOLUTION AND THE 5808 03:44:13,840 --> 03:44:15,960 TASK OF EVOLUTION HAS REALLY 5809 03:44:15,960 --> 03:44:17,560 BEEN IN THE'MUNE SYSTEM TO 5810 03:44:17,560 --> 03:44:20,240 BALANCE THE RISK OF AUTOIMMUNITY 5811 03:44:20,240 --> 03:44:21,520 WITH PROTECTIVE DEFENSE AGAINST 5812 03:44:21,520 --> 03:44:23,680 PATHOGENS AND IN THAT CONTEXT, 5813 03:44:23,680 --> 03:44:27,200 PATHOGENS ARE REALLY STRONG 5814 03:44:27,200 --> 03:44:28,120 SELECTIVE PRESSURE FOR 5815 03:44:28,120 --> 03:44:28,600 EVOLUTION. 5816 03:44:28,600 --> 03:44:32,760 SO, AS A RESULT OF THAT, THERE 5817 03:44:32,760 --> 03:44:34,320 ARE GENES THAT ARE GENETIC 5818 03:44:34,320 --> 03:44:36,760 VARIANTS THAT ARE ASSOCIATE WIDE 5819 03:44:36,760 --> 03:44:37,520 ROBUST PROTECTION AGAINST 5820 03:44:37,520 --> 03:44:39,680 PATHOGENS BUT THEY COME AT THE 5821 03:44:39,680 --> 03:44:40,880 RISK OF AUTOIMMUNITY. 5822 03:44:40,880 --> 03:44:42,440 AND THE REVERSE IS TRUE AS WELL, 5823 03:44:42,440 --> 03:44:44,520 THERE ARE VARIANTS THAT ARE 5824 03:44:44,520 --> 03:44:49,400 ASSOCIATED WITH PROTECTION FROM 5825 03:44:49,400 --> 03:44:51,400 IMMUNO DEFICIENT PATHOGENS OR 5826 03:44:51,400 --> 03:44:53,560 AUTOIMMUNITY BUT SUSCEPTIBILITY 5827 03:44:53,560 --> 03:44:56,400 TO INFECTION THROUGH THE COURSE 5828 03:44:56,400 --> 03:44:57,120 OF IMMUNO DEFICIENCY. 5829 03:44:57,120 --> 03:45:02,560 AND THIS RICH SOURCE OF GENETIC 5830 03:45:02,560 --> 03:45:04,160 DIVERSITY HAS BEEN KIND OF AN 5831 03:45:04,160 --> 03:45:05,800 ENGINEER OF DISCOVERY FOR 5832 03:45:05,800 --> 03:45:07,640 UNDERSTANDING HOW THE IMMUNE 5833 03:45:07,640 --> 03:45:11,680 SYSTEM WORKS AND HOW AUTOIMMUNE 5834 03:45:11,680 --> 03:45:11,920 IMMUNE 5835 03:45:11,920 --> 03:45:12,760 DISEASES PROGRESS IN GENERAL AND 5836 03:45:12,760 --> 03:45:14,920 THERE ARE A COUPLE OF DIFFERENT 5837 03:45:14,920 --> 03:45:16,320 GENETIC STRATEGIES THAT HAVE 5838 03:45:16,320 --> 03:45:18,640 BEEN REALLY FRUITFUL IN THIS 5839 03:45:18,640 --> 03:45:20,280 REGARD SO GWAS STUDY VS BEEN 5840 03:45:20,280 --> 03:45:23,600 GOOD AT FINDING COMMON VARIANTS 5841 03:45:23,600 --> 03:45:25,120 THAT ARE ASSOCIATED WITH DISEASE 5842 03:45:25,120 --> 03:45:27,480 OUTCOMES AND THEY TEND TO HAVE A 5843 03:45:27,480 --> 03:45:30,440 SMALL EFFECT SIZE BECAUSE THEY 5844 03:45:30,440 --> 03:45:31,720 AFFECT--THEY FALL IN NONCODING 5845 03:45:31,720 --> 03:45:35,040 REGIONS OF THE GENOME, AND THEY 5846 03:45:35,040 --> 03:45:36,320 AFFECT GENE EXPRESSION AND 5847 03:45:36,320 --> 03:45:38,160 SUBTLE WAYS BUT NEVERTHELESS, 5848 03:45:38,160 --> 03:45:42,600 THEY POINT TO IMPORTANT GENES 5849 03:45:42,600 --> 03:45:43,800 THAT HAVE STATISTICAL 5850 03:45:43,800 --> 03:45:44,480 ASSOCIATIONS WITH DISEASE 5851 03:45:44,480 --> 03:45:45,480 PHENOTYPES AND MORE RECENTLY AS 5852 03:45:45,480 --> 03:45:47,080 THE COST OF THE SEQUENCING HAS 5853 03:45:47,080 --> 03:45:48,800 GONE DOWN, WE'VE SEEN MORE AND 5854 03:45:48,800 --> 03:45:52,280 MORE EXOME SEQUENCING STUDIES 5855 03:45:52,280 --> 03:45:53,800 THAT ARE REALLY VERY WELL 5856 03:45:53,800 --> 03:45:55,600 POWERED TO FIND CODING VARIANTS 5857 03:45:55,600 --> 03:45:57,520 IN GENES THAT ARE MORE RARE BUT 5858 03:45:57,520 --> 03:45:58,760 HAVE A LARGER EFFECT SIZE 5859 03:45:58,760 --> 03:46:00,000 BECAUSE THEY AFFECT PROTEIN 5860 03:46:00,000 --> 03:46:01,560 FUNCTION AND IF YOU CAN FIGURE 5861 03:46:01,560 --> 03:46:03,920 OUT HOW THEY AFFECT PROTEIN 5862 03:46:03,920 --> 03:46:05,240 FUNCTION, IT LEADS YOU DIRECTLY 5863 03:46:05,240 --> 03:46:09,320 TO MECHANISMS IN SOME CASES. 5864 03:46:09,320 --> 03:46:12,520 SO OUR STRATEGY HAS BEEN TO 5865 03:46:12,520 --> 03:46:16,160 LEVERAGE ADVANCES FROM GWAS AND 5866 03:46:16,160 --> 03:46:20,240 EXOME SEQUENCING TO MAP RISK 5867 03:46:20,240 --> 03:46:22,560 GENES AND VARIANTS TO CELLULAR 5868 03:46:22,560 --> 03:46:24,320 FUNCTION AND TO DO THAT WE'VE 5869 03:46:24,320 --> 03:46:27,400 EMPLOYED A NUMBER OF CRISPR 5870 03:46:27,400 --> 03:46:28,560 SCREENS USING MANY DIFFERENT 5871 03:46:28,560 --> 03:46:31,240 READ OUTS AND IMMUNE PATHWAYS 5872 03:46:31,240 --> 03:46:34,920 AND FROM THERE FOLLOW UP WITH 5873 03:46:34,920 --> 03:46:36,920 MULTIOMICS STRATEGIES TO TRY TO 5874 03:46:36,920 --> 03:46:38,880 FIND MOLECULAR MECHANISMS FOR 5875 03:46:38,880 --> 03:46:40,360 THESE GENESS AND VARIANTS AND 5876 03:46:40,360 --> 03:46:43,400 THEN BUILDING OUT TOWARDS THE 5877 03:46:43,400 --> 03:46:44,320 MORE PHYSIOLOGICAL UNDERSTANDING 5878 03:46:44,320 --> 03:46:46,880 OF HOW THESE VARIANTS WORK IN 5879 03:46:46,880 --> 03:46:48,720 ANIMAL MODELS AND BY STUDYING 5880 03:46:48,720 --> 03:46:49,120 PATIENT SAMPLES. 5881 03:46:49,120 --> 03:46:54,000 AND THE GOAL OF ALL OF THIS IS 5882 03:46:54,000 --> 03:46:55,520 TO AGAINERATE NEW INSIGHTS 5883 03:46:55,520 --> 03:46:56,440 SPECIFIC DETAILS ON DISEASE THAT 5884 03:46:56,440 --> 03:46:59,600 ARE SUFFICIENTLY DEEP TO FORMUTE 5885 03:46:59,600 --> 03:47:00,360 NEW THERAPEUTIC HYPOTHESIS. 5886 03:47:00,360 --> 03:47:05,120 AND IF YOU TURN THE CRANE, CAN 5887 03:47:05,120 --> 03:47:06,200 YOU DO THIS PROCESS OVER AND 5888 03:47:06,200 --> 03:47:08,800 OVER AND CAN YOU MAP GENES TO 5889 03:47:08,800 --> 03:47:10,480 PATHWAYS AND FIND NOW 5890 03:47:10,480 --> 03:47:11,760 CONNECTIONS BETWEEN GENETIC 5891 03:47:11,760 --> 03:47:13,160 VARIANCE AND BIOLOGICAL 5892 03:47:13,160 --> 03:47:13,480 PROCESSES. 5893 03:47:13,480 --> 03:47:17,920 WE'VE DONE A LOT OF WORK IN 5894 03:47:17,920 --> 03:47:20,640 INFLAMMATORY BOWEL DISEASE, 5895 03:47:20,640 --> 03:47:22,600 CHRONS AND ULCRATIVE COLITIS AND 5896 03:47:22,600 --> 03:47:27,640 MAP WAYS TO ADAPTIVE IMMUNITY 5897 03:47:27,640 --> 03:47:28,720 AND HANDLING MICROBIAL PATHOGENS 5898 03:47:28,720 --> 03:47:32,920 AS WELL AS MICROBIOME ENTITIES 5899 03:47:32,920 --> 03:47:39,040 BUT WHAT IS PERHAPS MORE 5900 03:47:39,040 --> 03:47:41,360 SURPRISING IS THE CONNECTION THE 5901 03:47:41,360 --> 03:47:43,240 GENETIC CONNECTION BETWEEN IBD 5902 03:47:43,240 --> 03:47:45,960 AND EPITHELIAL BARRIER FUNCTION 5903 03:47:45,960 --> 03:47:48,920 AND IN THIS CONTEXT, THE BARRIER 5904 03:47:48,920 --> 03:47:53,080 ACTIVITY IN THE COLON IS 5905 03:47:53,080 --> 03:47:54,680 CONFERRED BY 3 DIFFERENT LAYERS, 5906 03:47:54,680 --> 03:47:58,200 SO THE FIRST LAYER IS THE 5907 03:47:58,200 --> 03:47:59,640 EPITHELIAL CELL LAYER AND THIS 5908 03:47:59,640 --> 03:48:01,800 FORMS A BARRIER THROUGH THE 5909 03:48:01,800 --> 03:48:02,760 FORMATION OF JUNCTIONAL 5910 03:48:02,760 --> 03:48:05,520 COMPLEXES THAT FUSE THE CELLS 5911 03:48:05,520 --> 03:48:08,680 TOGETHER AND IT'S--IT'S 5912 03:48:08,680 --> 03:48:11,280 ESSENTIALLY IMPERMEABLE TO 5913 03:48:11,280 --> 03:48:11,520 MICROBES. 5914 03:48:11,520 --> 03:48:14,280 AND THEN AT THE VERY SURFACE OF 5915 03:48:14,280 --> 03:48:17,680 THE EPITHELIAL CELLS AND THE 5916 03:48:17,680 --> 03:48:19,000 GLYCOICAL EXPECTATIONS LAYER, 5917 03:48:19,000 --> 03:48:21,520 THESE DENSE GLYCO PROTEINS THAT 5918 03:48:21,520 --> 03:48:22,920 AGAIN PERFORMANCE AN IMPORTANT 5919 03:48:22,920 --> 03:48:24,520 BARRIER FUNCTION AND THEN BEYOND 5920 03:48:24,520 --> 03:48:28,640 THAT, IS THE MUCUS, AND THE 5921 03:48:28,640 --> 03:48:30,520 MUCUS IS OBVIOUSLY THE WELL 5922 03:48:30,520 --> 03:48:32,800 CHARACTERIZED BLIEK O PROTEIN 5923 03:48:32,800 --> 03:48:35,400 THAT HAS UNIQUE VISITINGICAL 5924 03:48:35,400 --> 03:48:36,920 ELASTIC PROPERTIES THAT FORM A 5925 03:48:36,920 --> 03:48:40,320 BEAR WRER TO PENETRATION THROUGH 5926 03:48:40,320 --> 03:48:41,960 MIKE ROBES IN THE MICROBIOME AND 5927 03:48:41,960 --> 03:48:44,120 TOGETHER THESE 3 ELEMENTS REALLY 5928 03:48:44,120 --> 03:48:46,000 PROTECT THE IMMUNE SYSTEM FROM 5929 03:48:46,000 --> 03:48:49,800 INVASION OF FOREIGN ENTITIES, 5930 03:48:49,800 --> 03:48:54,040 AND ALSO LIMIT INFLAMMATION, AND 5931 03:48:54,040 --> 03:48:58,880 SO, THIS IS THE MAJOR LINK TO 5932 03:48:58,880 --> 03:49:03,920 FLIEK O BIOLOGIES IN THIS 5933 03:49:03,920 --> 03:49:04,640 BARRIER INTEGRITY FUNCTION. 5934 03:49:04,640 --> 03:49:06,920 SO THE MUCUS IS SECRETED BY 5935 03:49:06,920 --> 03:49:09,560 GOBLET CELLS IN THE MUCOSA. 5936 03:49:09,560 --> 03:49:11,320 AND SECRETING THAT LARGE VOLUME 5937 03:49:11,320 --> 03:49:14,120 OF MUCUS PUTS QUITE A BURDEN ON 5938 03:49:14,120 --> 03:49:31,080 THE ENDOPLASMIC RETIC LUMOF 5939 03:49:31,080 --> 03:49:32,200 THESE CELLS. 5940 03:49:32,200 --> 03:49:35,080 --CAN BE OBSERVED AT THE SINGLE 5941 03:49:35,080 --> 03:49:36,320 CELL LEVEL IN TRANSCREPT OHMICS 5942 03:49:36,320 --> 03:49:38,960 AND IN HEALTHY SUBJECTS YOU SEE 5943 03:49:38,960 --> 03:49:40,320 STRONG STRESS SIGNATURE AND 5944 03:49:40,320 --> 03:49:41,600 CELLS, AND THAT'S REAL LE A 5945 03:49:41,600 --> 03:49:44,680 FUNCTION OF THE FACT THAT THEY 5946 03:49:44,680 --> 03:49:51,560 HAVE TO MAKE SO MUCH LIKE O 5947 03:49:51,560 --> 03:49:52,840 PROTEIN MUCINs, AND DURING THE 5948 03:49:52,840 --> 03:49:55,280 COURSE OF PROTEIN TRANSLATION 5949 03:49:55,280 --> 03:49:59,680 AND GLYCOSYLATION IN THE ER, IT 5950 03:49:59,680 --> 03:50:00,920 WAS GLYCOSYLATION SIGNALS SERVE 5951 03:50:00,920 --> 03:50:07,080 AS SORTING SIGNALS TO TRAFFIC, 5952 03:50:07,080 --> 03:50:09,120 PROTEINS THROUGH ER TO THE GOLGI 5953 03:50:09,120 --> 03:50:10,920 AND SECRETED INTO THE LUMEN OF 5954 03:50:10,920 --> 03:50:13,400 THE GUT AND UNDER STRESS OR 5955 03:50:13,400 --> 03:50:16,480 UNDER DURESS, CAN YOU SEE AN 5956 03:50:16,480 --> 03:50:17,520 ACCUMULATION OF UNFOLDED 5957 03:50:17,520 --> 03:50:21,280 PROTEINS IN THE ER, AND CELLS 5958 03:50:21,280 --> 03:50:23,160 HAVE DEVELOPED MANY SENSOR ARMS 5959 03:50:23,160 --> 03:50:25,160 THAT CAN DETECT UNFOLDED 5960 03:50:25,160 --> 03:50:27,680 PROTEINS AND THEN ILLICIT AN 5961 03:50:27,680 --> 03:50:29,240 ADAPTIVE RESPONSE TO THE 5962 03:50:29,240 --> 03:50:30,520 UNFOLDED PROTEIN RESPONSE TO 5963 03:50:30,520 --> 03:50:34,720 UPREGULATE ALL OF THE SECRETION 5964 03:50:34,720 --> 03:50:35,160 MACHINERY INCLUDING 5965 03:50:35,160 --> 03:50:36,120 GLYCOSYLATION MACHINERY TO TRY 5966 03:50:36,120 --> 03:50:37,720 TO RESOLVE THE STRESS OF THE 5967 03:50:37,720 --> 03:50:40,320 CELLS CAN DO THEIR JOB AND MAKE 5968 03:50:40,320 --> 03:50:41,400 THE MUCIN BARRIER. 5969 03:50:41,400 --> 03:50:44,680 SO THERE ARE 3 SENSOR PATHWAYS 5970 03:50:44,680 --> 03:50:47,800 THAT DETECT ER STRESS AND THEY 5971 03:50:47,800 --> 03:50:51,040 CONVERGE ON 3 TRANSCRIPTION 5972 03:50:51,040 --> 03:50:53,960 FACTORS XBP1 ATF6 AND ATF4, AND 5973 03:50:53,960 --> 03:50:56,280 SO WE DEVELOPED CRISPR SCREENING 5974 03:50:56,280 --> 03:50:59,320 STRATEGY TO TRY TO IDENTIFY NEW 5975 03:50:59,320 --> 03:51:03,720 IBD RISK GENES THAT AFFECT ER 5976 03:51:03,720 --> 03:51:04,120 STRESS RESPONSES. 5977 03:51:04,120 --> 03:51:07,240 SO WE SET UP 3 REPORTER SYSTEMS, 5978 03:51:07,240 --> 03:51:10,160 THE FIRST IS AN ER STRESS TEST 5979 03:51:10,160 --> 03:51:14,040 WHERE WE BLOCK GLYCOSYLATION 5980 03:51:14,040 --> 03:51:15,320 WITH [INDISCERNIBLE] AND MEASURE 5981 03:51:15,320 --> 03:51:17,080 LIFE OR DEATH OUTCOME OF THE 5982 03:51:17,080 --> 03:51:17,320 CELLS. 5983 03:51:17,320 --> 03:51:22,200 THE XEKD SCREENING IS LOOKING AT 5984 03:51:22,200 --> 03:51:23,920 ACTIVATION OF XBP1 THROUGH A 5985 03:51:23,920 --> 03:51:26,160 SPLICING EVENT THAT TURNS ON 5986 03:51:26,160 --> 03:51:27,200 UNFOLDED PROTEIN RESPONSE AND 5987 03:51:27,200 --> 03:51:29,640 THE THIRD SCREENING SYSTEM IS 5988 03:51:29,640 --> 03:51:35,120 LOOKING AT ER HOMEOSTASIS 5989 03:51:35,120 --> 03:51:38,280 ESSENTIALLY MEASURING THE RATIO 5990 03:51:38,280 --> 03:51:43,720 OF SECRETORY OUTPUT TO CHAPERON 5991 03:51:43,720 --> 03:51:47,960 OCCUPANCY. 5992 03:51:47,960 --> 03:51:54,120 AND IN 1 OF IN THE XBP SLICING 5993 03:51:54,120 --> 03:51:57,680 AND WHEN WE KNOCK IT OUT, IT'S 5994 03:51:57,680 --> 03:52:02,080 THE XBP1 REPORTER IT TURNS OUT 5995 03:52:02,080 --> 03:52:05,480 TMEM258 IS LOCATED IN A RISK 5996 03:52:05,480 --> 03:52:06,920 LOCATED FOR CHRONS DISEASE AND 5997 03:52:06,920 --> 03:52:08,480 THIS GENE IS NOT VERY WELL 5998 03:52:08,480 --> 03:52:10,280 CHARACTERIZED AND IT HAS 2 5999 03:52:10,280 --> 03:52:11,680 TRANSMEMBRANE DOMAINS AND THAT'S 6000 03:52:11,680 --> 03:52:17,840 IT, THERE'S REALLY NOTHING 6001 03:52:17,840 --> 03:52:20,520 RECOGNIZABLE OUT IN THAT GENE IS 6002 03:52:20,520 --> 03:52:22,360 HENCE IT WAS OVERLOOKED IN THE 6003 03:52:22,360 --> 03:52:24,120 GWAS STUDIES BECAUSE THERE'S NO 6004 03:52:24,120 --> 03:52:25,320 KNOWN FUNCTION AND THERE'S 6005 03:52:25,320 --> 03:52:26,880 OTHERS IN THE NEIGHBORHOOD SO WE 6006 03:52:26,880 --> 03:52:28,160 EMBAKERRED ON A SERIES OF 6007 03:52:28,160 --> 03:52:31,840 STUDIES TO FIGURE OUT WHAT 6008 03:52:31,840 --> 03:52:33,280 TMEM258 DOES, IT LOCALIZED 6009 03:52:33,280 --> 03:52:38,680 EXCLUSIVE TO THE ER WITH CHAPPER 6010 03:52:38,680 --> 03:52:40,640 OWNS LIKE KALNECKSIN AND WE YOU 6011 03:52:40,640 --> 03:52:51,000 KNOCK IT OUT IT BLOCKS PATHWAYS 6012 03:52:51,000 --> 03:52:51,480 WITH [INDISCERNIBLE]. 6013 03:52:51,480 --> 03:52:56,480 AND AND THEN WE DID PROTEOMIC 6014 03:52:56,480 --> 03:52:57,400 EXPERIMENTS THAT OPENED THE 6015 03:52:57,400 --> 03:52:59,640 DOORS FOR US IN GLYCO BIOLOGY. 6016 03:52:59,640 --> 03:53:02,840 IT TURNS OUT TMEM 258 WAS AN 6017 03:53:02,840 --> 03:53:04,520 UNKNOWN SUBUNIT OF THE OST 6018 03:53:04,520 --> 03:53:09,360 COMPLEX, SO THIS IS THE 6019 03:53:09,360 --> 03:53:10,520 OLIGOSACCHARIDE TRANSFERAISE 6020 03:53:10,520 --> 03:53:11,360 COMPLEX, HIGHLY CONSERVED ACROSS 6021 03:53:11,360 --> 03:53:15,000 THE TREE OF LIFE AND PERFORMS 6022 03:53:15,000 --> 03:53:16,520 THE FIRST STEP IN TPHREU RACING 6023 03:53:16,520 --> 03:53:20,320 COSALATION OF MASON PROTEINS. 6024 03:53:20,320 --> 03:53:21,840 AND A COUPLE YEARS AFTER WE MADE 6025 03:53:21,840 --> 03:53:24,400 THIS DISCOVERY THERE'S A 6026 03:53:24,400 --> 03:53:25,440 BEAUTIFUL CRYOEM STRUCTURE 6027 03:53:25,440 --> 03:53:27,240 PUBLISHED OF THE OST COMPLEX AND 6028 03:53:27,240 --> 03:53:31,840 YOU CAN SEE TMEM258 NESTLED INTO 6029 03:53:31,840 --> 03:53:33,680 THE TRANSMEMBRANE REGION HERE. 6030 03:53:33,680 --> 03:53:36,840 SO IT WAS EASY TO MISS BUT 6031 03:53:36,840 --> 03:53:39,120 NEVERTHELESS IT IS A REQUIRED 6032 03:53:39,120 --> 03:53:41,400 COMPONENT OF THIS COMPLEX. 6033 03:53:41,400 --> 03:53:46,480 SO WE MADE A XOK OUT MOUSE AND 6034 03:53:46,480 --> 03:53:50,200 IT'S EMBRYONIC LETHAL BUT THE 6035 03:53:50,200 --> 03:53:53,120 HEXES SURVIVE AND WE'RE ABLE TO 6036 03:53:53,120 --> 03:53:54,040 TAKE HETEROZYGOUS COLONIC STEM 6037 03:53:54,040 --> 03:53:57,720 CELLS AND MAKE ORGANOID CULTURES 6038 03:53:57,720 --> 03:54:00,680 AND YOU CAN SEE THESE SPHEROID 6039 03:54:00,680 --> 03:54:02,160 ORGANLES WE WERE ABLE TO 6040 03:54:02,160 --> 03:54:05,520 GENERATE AND USE CRISPR TO KNOCK 6041 03:54:05,520 --> 03:54:07,280 OUT THE OTHER 258 AND WHEN WE DO 6042 03:54:07,280 --> 03:54:09,760 SO THE CELLS UNDER GO ER STRESS 6043 03:54:09,760 --> 03:54:12,080 AND THE BARRIER DISSOLVES SO 6044 03:54:12,080 --> 03:54:14,880 THIS REALLY HIGHLIGHTS THE 6045 03:54:14,880 --> 03:54:17,120 IMPORTANCE OF GLYCOSYLATION AND 6046 03:54:17,120 --> 03:54:17,880 MAINTAINING ER HOMEIO STASE AND 6047 03:54:17,880 --> 03:54:21,240 I SAY HOW IMPORTANT THAT IS FOR 6048 03:54:21,240 --> 03:54:24,200 CELLS IN EPITHELIAL LAYER TO 6049 03:54:24,200 --> 03:54:28,160 FORM THE BARRIER AND TO CRETE 6050 03:54:28,160 --> 03:54:32,480 MUSEINS AND HOST SYSTEM FROM 6051 03:54:32,480 --> 03:54:33,320 INVASION BY MICROBES. 6052 03:54:33,320 --> 03:54:35,280 SO THIS A SCHEMATIC THAT I'M 6053 03:54:35,280 --> 03:54:36,720 SURE IS VERY FAMILIAR TO MOST OF 6054 03:54:36,720 --> 03:54:42,040 THE AUDIENCE HERE, LOOKING AT 6055 03:54:42,040 --> 03:54:43,920 NGLYCOSYLATION IN THE EM TR AND 6056 03:54:43,920 --> 03:54:48,680 THE 258 IS THE OST ACTS HERE 6057 03:54:48,680 --> 03:54:50,200 EARLY, AND AND STEP OF 6058 03:54:50,200 --> 03:54:52,040 GLYCOSYLATION BUT OUR SCREENING 6059 03:54:52,040 --> 03:54:56,640 CAMPAIGN IDENTIFIED A WHOLE LOT 6060 03:54:56,640 --> 03:54:58,400 OF OTHER IBD RISK GENES THAT ARE 6061 03:54:58,400 --> 03:55:00,360 ACTING WITH THE SAME PATHWAY 6062 03:55:00,360 --> 03:55:02,640 WHICH IS SOMEWHAT SURPRISING 6063 03:55:02,640 --> 03:55:03,840 INCLUDING RFT 1 AND ANOTHER GENE 6064 03:55:03,840 --> 03:55:07,720 I WILL TALK ABOUT A BIT, 6065 03:55:07,720 --> 03:55:10,920 SLCTHREEN 8A, THIS TRANSPORTER 6066 03:55:10,920 --> 03:55:11,880 GENE TRANSPORTS MAN GANNA EASE 6067 03:55:11,880 --> 03:55:14,880 AND ZINC AND IT'S AN IMPORTANT 6068 03:55:14,880 --> 03:55:17,160 FACTOR FOR THESE TRANSFER ACE 6069 03:55:17,160 --> 03:55:22,160 INSWROAMS THAT ELABORATE TPHREU 6070 03:55:22,160 --> 03:55:31,320 RACING KAN--KANAS LOOK THE GOLGY 6071 03:55:31,320 --> 03:55:32,280 SECRETATTORY PATHWAY. 6072 03:55:32,280 --> 03:55:35,280 THESE HAD BEEN IN DISORDS OF 6073 03:55:35,280 --> 03:55:36,920 GLYCOSYLATION SO THERE WERE 6074 03:55:36,920 --> 03:55:37,600 HYPER FOREVERRIC MUTATIONS THAT 6075 03:55:37,600 --> 03:55:40,200 LEAD TO NULL PROTEIN AND HAVE 6076 03:55:40,200 --> 03:55:42,600 VERY SEVERE OUTCOMES ASSOCIATE 6077 03:55:42,600 --> 03:55:47,080 TD WITH DEVELOPMENTAL DEFECTS 6078 03:55:47,080 --> 03:55:47,520 AND SO FORTH. 6079 03:55:47,520 --> 03:55:48,680 SO THESE ARE VERY SEVERE 6080 03:55:48,680 --> 03:55:50,520 MUTATIONS AND THE MUTATIONS WE 6081 03:55:50,520 --> 03:55:53,880 SEE IN IBD ARE MORE SUBTLE, SO, 6082 03:55:53,880 --> 03:56:00,080 THEY'RE MORE COMMON AND THEY 6083 03:56:00,080 --> 03:56:02,880 HAVE EFFECTS THAT ARE NOT QUITE 6084 03:56:02,880 --> 03:56:06,040 AS PENETRANT OF DISORDERS OF 6085 03:56:06,040 --> 03:56:07,040 GLYCOSYLATION BUT NEVERTHELESS, 6086 03:56:07,040 --> 03:56:08,520 ASSOCIATED 39 A IS A POSTER 6087 03:56:08,520 --> 03:56:10,000 CHILD OF A MRI O TROAPIC VARIANT 6088 03:56:10,000 --> 03:56:14,200 AND THE REASON IS THAT THIS ALLY 6089 03:56:14,200 --> 03:56:15,840 91 T SUBSIDIARY CONSTITUTION IS 6090 03:56:15,840 --> 03:56:20,520 ASSOCIATED WITH RISK OF IBD, BUT 6091 03:56:20,520 --> 03:56:24,320 ALSO BLOOD LIPID LEVELS, 6092 03:56:24,320 --> 03:56:25,520 CARDIOVASCULAR DISEASE, 6093 03:56:25,520 --> 03:56:27,240 SCHIZOPHRENIA, PARKINSONS, AND 6094 03:56:27,240 --> 03:56:28,120 MANY OTHER PHENOTYPES. 6095 03:56:28,120 --> 03:56:30,080 AND THAT'S PROBABLY A REFLECTION 6096 03:56:30,080 --> 03:56:32,120 OF HOW IMPORTANT MAN GANNA EASE 6097 03:56:32,120 --> 03:56:34,920 IS IN FOR MANY BIOLOGICAL 6098 03:56:34,920 --> 03:56:37,520 SYSTEMS BUT ALSO THE IMPORTANCE 6099 03:56:37,520 --> 03:56:38,680 OF GLYCOSYLATION IN MANY 6100 03:56:38,680 --> 03:56:39,680 DIFFERENT ORGAN SYSTEMS AND 6101 03:56:39,680 --> 03:56:40,040 DISEASES. 6102 03:56:40,040 --> 03:56:43,720 SO WE MADE A KNOCK-IN MOUSE 6103 03:56:43,720 --> 03:56:46,520 WHERE WE INTRODUCED THIS RISK 6104 03:56:46,520 --> 03:56:51,080 VARIANT A391 T TO THE ENDOGENOUS 6105 03:56:51,080 --> 03:56:53,680 39 A 8 LOCUST AND WE MEASURED IF 6106 03:56:53,680 --> 03:56:58,680 THE BLOOD MAN GANNAIES AND WE 6107 03:56:58,680 --> 03:57:00,720 SEE REDUCED MANGANESE IN THESE 6108 03:57:00,720 --> 03:57:01,960 MICE IN THE BLOOD, LIVER AND 6109 03:57:01,960 --> 03:57:11,960 COAL AN AND LEVELS OF ZINC WERE 6110 03:57:11,960 --> 03:57:13,040 NORMAL AND WE HYPOTHESIZED THAT 6111 03:57:13,040 --> 03:57:16,680 THE VARIANT AND THE LACK OF 6112 03:57:16,680 --> 03:57:17,320 MANGANESE WOULD AFFECT THESE 6113 03:57:17,320 --> 03:57:18,760 STRUCTURALLY ARES AND I'M 6114 03:57:18,760 --> 03:57:19,320 SHOWING CERTAINLY--CERTAINLY 6115 03:57:19,320 --> 03:57:20,680 LECTURE ROUGH ATOM MICROGRAPH OF 6116 03:57:20,680 --> 03:57:22,440 A SINGLE EPITHELIAL CELL AND AT 6117 03:57:22,440 --> 03:57:24,320 THE TIP OF THE EPITHELIAL CELL, 6118 03:57:24,320 --> 03:57:27,200 YOU SEE THESE FINGER LIKE 6119 03:57:27,200 --> 03:57:28,520 PROJECTIONS OF MICROVILLI AND AT 6120 03:57:28,520 --> 03:57:30,800 THE VERY END OF THE THE VILLI, 6121 03:57:30,800 --> 03:57:33,880 SEE THE SHADOWY LAYER, THAT'S 6122 03:57:33,880 --> 03:57:39,200 THE GLYCO KALYX AND THE A3192, 6123 03:57:39,200 --> 03:57:41,520 THE FLIEK O FELIX HAS BEEN IN 6124 03:57:41,520 --> 03:57:43,920 PATCH, SUGGESTING THAT THE 6125 03:57:43,920 --> 03:57:45,280 DEFECT RESULTS IN VARIED DEFECTS 6126 03:57:45,280 --> 03:57:49,840 AND ANOTHER WAY TO LOOK AT THIS 6127 03:57:49,840 --> 03:57:51,680 ABOVE THE GLYCO CALYX, AND YOU 6128 03:57:51,680 --> 03:57:54,280 CAN STAIN THE MUCUS LAYER WITH P 6129 03:57:54,280 --> 03:57:58,560 A S AND WILD TYPE YOU SEE NICE 6130 03:57:58,560 --> 03:58:00,520 PALE PLURIBU DENSE MUCUS LAYER 6131 03:58:00,520 --> 03:58:02,160 ABOVE THE EPITHELIUM AND IN THE 6132 03:58:02,160 --> 03:58:07,760 VARIANT MICE THIS MUCUS LAYER IS 6133 03:58:07,760 --> 03:58:08,360 THINNER. 6134 03:58:08,360 --> 03:58:10,320 AND MORE VISCUS. 6135 03:58:10,320 --> 03:58:16,160 THIS MUCUS LAYER PREVENTS A 6136 03:58:16,160 --> 03:58:17,320 BARRIER BY MICROBES WHICH YOU 6137 03:58:17,320 --> 03:58:18,880 CAN DEFECT IN FISH ON THE GREEN 6138 03:58:18,880 --> 03:58:19,760 PROBE ON THE RIGHT HERE AND YOU 6139 03:58:19,760 --> 03:58:21,200 CAN SEE IN THE VALID AND 6140 03:58:21,200 --> 03:58:24,080 RELIABLE YABT THERE'S MORE 6141 03:58:24,080 --> 03:58:25,640 BACTERIA CLOSER TO THE 6142 03:58:25,640 --> 03:58:26,480 EPITHELIAL LAYER APPROXIMATE AND 6143 03:58:26,480 --> 03:58:29,440 IN FACT, SOME CASES PENETRATING 6144 03:58:29,440 --> 03:58:30,280 SUGGESTING THAT THERE'S EXPOSURE 6145 03:58:30,280 --> 03:58:40,200 TO THE IMMUNE SYSTEM AND CHRONIC 6146 03:58:40,200 --> 03:58:40,920 LOW GRADE INFLAMMATION. 6147 03:58:40,920 --> 03:58:42,680 SO AS A RESULT OF THESE COMPLEX 6148 03:58:42,680 --> 03:58:44,400 BARRIER, WE SEE IN THESE MICE A 6149 03:58:44,400 --> 03:58:48,440 LEAKY GUT SO WHEN WE FEED THEM A 6150 03:58:48,440 --> 03:58:50,760 DYE ORALLY, YOU CAN SEE IT 6151 03:58:50,760 --> 03:58:51,840 TRANSLATEICATES INTO THE BLOOD 6152 03:58:51,840 --> 03:58:53,800 MUCH MORE RAPID LOAMACYY THAN 6153 03:58:53,800 --> 03:58:55,360 THE VARIANT AND THIS LEAKY 6154 03:58:55,360 --> 03:58:57,480 BARRIER SENSITIZES MICE TO CO 6155 03:58:57,480 --> 03:58:59,520 LITIS, AND SO WHEN WE TRIGGER BY 6156 03:58:59,520 --> 03:59:02,280 DSS, WHICH IS THE EPITHELIAL 6157 03:59:02,280 --> 03:59:04,080 IRRITANT, THE VARIANT MICE DROP 6158 03:59:04,080 --> 03:59:06,720 WEIGHT VERY RAPID LOAMACYY AND 6159 03:59:06,720 --> 03:59:08,400 DEVELOP 69S SIGNS OF 6160 03:59:08,400 --> 03:59:08,920 INFLAMMATION, SEVERE 6161 03:59:08,920 --> 03:59:10,200 INFLAMMATION IN THE COLON THAT 6162 03:59:10,200 --> 03:59:15,320 CAN BE VISUALIZED HERE. 6163 03:59:15,320 --> 03:59:17,240 THIS IS I THINK A REALLY 6164 03:59:17,240 --> 03:59:22,320 INTERESTING EXAMPLE OF A GENETIC 6165 03:59:22,320 --> 03:59:24,440 VARIANT THAT AFFECTS 6166 03:59:24,440 --> 03:59:26,480 GLYCOSYLATION AND THE OUTCOME IS 6167 03:59:26,480 --> 03:59:30,720 VERY DIVERSE ACROSS DECEASES. 6168 03:59:30,720 --> 03:59:33,760 SO EVEN THIS COMMON A391 T 6169 03:59:33,760 --> 03:59:36,520 VARIANT IS ASSOCIATED WITH MANY 6170 03:59:36,520 --> 03:59:37,520 DECEASES INCLUDING IBD BUT NOT 6171 03:59:37,520 --> 03:59:39,640 EVERYBODY WHO CARRY THIS IS 6172 03:59:39,640 --> 03:59:41,160 VARIANT GETS ANY DISEASE AND 6173 03:59:41,160 --> 03:59:43,800 SOME PEOPLE GET IBD, SOME PEOPLE 6174 03:59:43,800 --> 03:59:45,120 GET SCHIZOPHRENIA AND OTHER 6175 03:59:45,120 --> 03:59:51,640 DISEASES WHICH SUGGEST THERE ARE 6176 03:59:51,640 --> 03:59:52,960 MANY OTHER ADDITIONAL EXTRANSIC 6177 03:59:52,960 --> 03:59:54,560 VARIABLES THAT INTERACT WITH THE 6178 03:59:54,560 --> 03:59:55,840 VARIANT TO CAUSE DISEASE SO THAT 6179 03:59:55,840 --> 04:00:00,920 COULD BE OTHER GENERATEDITTIC 6180 04:00:00,920 --> 04:00:02,320 VARIABLES THAT THAT PUSH THE 6181 04:00:02,320 --> 04:00:04,120 PATHWAY TOWARDS 1 DISEASE OR THE 6182 04:00:04,120 --> 04:00:07,520 OTHER BUT ALSO VIERNLTAL 6183 04:00:07,520 --> 04:00:08,720 VARIABLES FOR EXAMPLE, MANGANESE 6184 04:00:08,720 --> 04:00:14,160 IN THE DIET OR INSULT TO THE 6185 04:00:14,160 --> 04:00:15,280 MICROBIOME THAT MIGHT RESULT 6186 04:00:15,280 --> 04:00:17,800 FROM INFECTION BUT THE FACT THAT 6187 04:00:17,800 --> 04:00:24,760 THE OUTCOME OF A GENERATED 6188 04:00:24,760 --> 04:00:26,680 THETIC SUGGESTS THAT THERAPEUTIC 6189 04:00:26,680 --> 04:00:27,680 INTERVENTIONS CAN TIP THE 6190 04:00:27,680 --> 04:00:28,360 DALLASCOWBOYS.COM BANS AND THERE 6191 04:00:28,360 --> 04:00:30,440 MAY BE OPPORTUNITIES TO RESTORE 6192 04:00:30,440 --> 04:00:33,120 MAIN GANNA EASE OR EFFICIENT OF 6193 04:00:33,120 --> 04:00:36,480 A GLYCOSYLATION TO TREAT MANY OF 6194 04:00:36,480 --> 04:00:39,760 THESE COMMON AUTOIMMUNE 6195 04:00:39,760 --> 04:00:40,040 DISEASES. 6196 04:00:40,040 --> 04:00:41,120 SO I'LL PAUSE HERE BECAUSE WE'RE 6197 04:00:41,120 --> 04:00:42,200 A LITTLE SHORT ON TIME. 6198 04:00:42,200 --> 04:00:49,520 I WANT TO ACKNOWLEDGE MY LONG 6199 04:00:49,520 --> 04:00:51,800 TIME COLLABORATORS WHOSE BUYER 6200 04:00:51,800 --> 04:00:53,360 CHAMPIONS OF GENETICS AND 6201 04:00:53,360 --> 04:00:54,960 FUNCTIONAL GENOMICS, I ALSO WANT 6202 04:00:54,960 --> 04:01:00,120 TO ACKNOWLEDGE 2 POST DOCS WHO 6203 04:01:00,120 --> 04:01:04,480 WORKED ON THIS, AND FUNDING BEST 6204 04:01:04,480 --> 04:01:06,080 WORK AND AND I'LL PAUSE HERE, 6205 04:01:06,080 --> 04:01:06,480 THANK YOU. 6206 04:01:06,480 --> 04:01:09,360 THANK YOU SO MUCH DANIEL, THAT'S 6207 04:01:09,360 --> 04:01:13,680 A FASCINATING STORY. 6208 04:01:13,680 --> 04:01:14,960 AND AGAIN, FOR EVERYONE IF HAVE 6209 04:01:14,960 --> 04:01:16,400 YOU QUESTIONS FOR DANIEL OR 6210 04:01:16,400 --> 04:01:18,800 OTHER SPEAKERS PLEASE US THE 6211 04:01:18,800 --> 04:01:21,000 SEND LIKE LIVE FEEDBACK LINK TO 6212 04:01:21,000 --> 04:01:23,480 SUBMIT IME ANDS AGAIN AT THE END 6213 04:01:23,480 --> 04:01:24,920 OF OUR AFTERNOON EGZ ISS IN 6214 04:01:24,920 --> 04:01:29,160 ABOUT 40 MINUTES WE GALLON 6215 04:01:29,160 --> 04:01:29,920 THROUGH THOSE QUESTIONS. 6216 04:01:29,920 --> 04:01:36,920 SO OUR NEXT SPEAKER IS CHIARA 6217 04:01:36,920 --> 04:01:39,640 MANCIN- I FROM 6218 04:01:39,640 --> 04:01:40,240 RUTGERIATRICKIZATIONS ROBERT 6219 04:01:40,240 --> 04:01:42,200 WOODS JOHNSON MEDICAL SCHOOL AND 6220 04:01:42,200 --> 04:01:48,760 HER TALK IS DEVELOPING ZEBRA 6221 04:01:48,760 --> 04:01:50,760 FISH MODELS OF DISTROGLY 6222 04:01:50,760 --> 04:01:51,520 KAN--KANA OPEN MEETINGATHY. 6223 04:01:51,520 --> 04:01:52,720 SO THANK YOU VERY MUCH FOR 6224 04:01:52,720 --> 04:01:54,160 HAVING ME, AND TO BE ABLE TO 6225 04:01:54,160 --> 04:01:59,360 TELL YOU SOME OF THE LATEST 6226 04:01:59,360 --> 04:02:02,360 RESEARCH WE'VE BEEN DOING IN MY 6227 04:02:02,360 --> 04:02:04,880 LABORATORY AT RUTGERS AND THE 6228 04:02:04,880 --> 04:02:06,400 CHILD HEALTH INTUITY SO I'VE 6229 04:02:06,400 --> 04:02:14,480 BEEN INTERESTED IN THE KINETICS 6230 04:02:14,480 --> 04:02:16,520 OF DYSTROGLYCANOP A THY FOR A 6231 04:02:16,520 --> 04:02:18,120 NUMBER OF YEARS SO THIS IS 6232 04:02:18,120 --> 04:02:20,680 BITTER IN THE MUSCLE IN THE EYES 6233 04:02:20,680 --> 04:02:21,320 AND IN THE BRAIN. 6234 04:02:21,320 --> 04:02:28,760 THESE KIDS WILL HAVE VERY SEVERE 6235 04:02:28,760 --> 04:02:30,040 AND MULTITELETYPES OF OCULAR 6236 04:02:30,040 --> 04:02:32,360 DEFECTS BOTH IN THE RETINA, 6237 04:02:32,360 --> 04:02:34,600 RETINA DISPLACIA BUT ALSO IN THE 6238 04:02:34,600 --> 04:02:35,680 ANTERIOR CHAMBER SO THAT WOULD 6239 04:02:35,680 --> 04:02:56,480 BE YOUR LENS OR YOUR CORN RA. 6240 04:02:56,480 --> 04:02:58,440 THIS IS DISREPRESENTED IN THE 6241 04:02:58,440 --> 04:03:00,240 CEREBELLUM AND BRAIN STEM ARE 6242 04:03:00,240 --> 04:03:04,200 SEVERELY DISRUPTED THIS IS THE 6243 04:03:04,200 --> 04:03:08,080 MOST SEVERE FORM THAT'S AND THIS 6244 04:03:08,080 --> 04:03:10,400 IS WWS AND THESE CHILDREN IN 6245 04:03:10,400 --> 04:03:32,160 GENERAL WILL SURVIVE 3 TO 6 6246 04:03:32,160 --> 04:03:32,960 YEARS OF LIFE. 6247 04:03:32,960 --> 04:03:36,840 AND YOU MIGHT HAVE HEARD OF THIS 6248 04:03:36,840 --> 04:03:46,120 GENE THAT'S IN DUCHENNEAND THIS 6249 04:03:46,120 --> 04:03:53,320 THE GLYCANS CAUSES SOME TYPE OF 6250 04:03:53,320 --> 04:03:55,440 MUSCLE DISEASE THESE ARE COMPOSE 6251 04:03:55,440 --> 04:03:57,400 OF OF 2 SUBUNITS FROM THE SAME 6252 04:03:57,400 --> 04:03:58,600 GENE THAT JUST CLEAVED TO HAVE 6253 04:03:58,600 --> 04:04:04,320 DATA IN THE MEMBRANE AND ALPHA 6254 04:04:04,320 --> 04:04:06,760 GLYCAN OUTSIDE OF THE CELLULAR 6255 04:04:06,760 --> 04:04:08,400 SPACE IN THE INTRA CELLULAR MATE 6256 04:04:08,400 --> 04:04:11,360 EXCITATORY HERE IT SHOWS 1 OF 6257 04:04:11,360 --> 04:04:13,240 THE INTERACTORS WHICH IS LAM NIN 6258 04:04:13,240 --> 04:04:17,520 2 ALSO MUTATIONS IN LAM NIN 6259 04:04:17,520 --> 04:04:24,280 MUSCULAR DISORDER, THIS 6260 04:04:24,280 --> 04:04:35,520 INTERACTION IS MEDIATED THROUGH 6261 04:04:35,520 --> 04:04:39,560 1 OF THESE DISORDERS IS THAT 6262 04:04:39,560 --> 04:04:43,320 THEY'RE CLINICALLY AND SOWED YOU 6263 04:04:43,320 --> 04:04:46,120 THIS HERE THE FLUID IN THE BRAIN 6264 04:04:46,120 --> 04:04:47,400 WHITE INSTEAD OF BEING BLACK, 6265 04:04:47,400 --> 04:04:50,120 IT'S A DIFFERENT MRI BUT YOU CAN 6266 04:04:50,120 --> 04:04:50,920 APPRECIATE HOW DISRUPTIVE THIS 6267 04:04:50,920 --> 04:05:07,560 BRAIN IS AND IF YOU GO DOWN THE 6268 04:05:07,560 --> 04:05:09,120 SPECTRUM THERE ARE 18 GENES THAT 6269 04:05:09,120 --> 04:05:10,400 HAVE BEEN IDENTIFIED THIS FAR 6270 04:05:10,400 --> 04:05:12,720 THAT CAN EXPLAIN UP TO 70% OF 6271 04:05:12,720 --> 04:05:14,600 CASES OF THIS, DEPENDING ON THE 6272 04:05:14,600 --> 04:05:18,560 COHORT THAT YOU WORK WITH AND 6273 04:05:18,560 --> 04:05:20,320 MUTATIONS IN THE SAME CAN CAUSE 6274 04:05:20,320 --> 04:05:26,520 A RANGE OF PHENOTYPES FROM THE 6275 04:05:26,520 --> 04:05:29,160 VERY AND SLIGHTLY LESS FEVER TO 6276 04:05:29,160 --> 04:05:30,680 PATIENTS HAVING NO BRAIN 6277 04:05:30,680 --> 04:05:33,320 PHENOTYPE AND ONLY MUSCULAR 6278 04:05:33,320 --> 04:05:34,880 DYSTROPHY WITH VARYING SEVERITY 6279 04:05:34,880 --> 04:05:36,520 AND SOMETIMES SHOWING UP LATER 6280 04:05:36,520 --> 04:05:41,960 IN LIFE OR IN SOME LIMITED CASES 6281 04:05:41,960 --> 04:05:43,240 AUTISM AND INTELLECTUAL 6282 04:05:43,240 --> 04:05:46,280 DISABILITY, THERE IS NO CLEAR 6283 04:05:46,280 --> 04:05:47,120 GENO TYPE CORRELATION EVEN 6284 04:05:47,120 --> 04:05:49,320 THOUGH THERE ARE CLASSES OF THIS 6285 04:05:49,320 --> 04:05:59,240 THAT WE WILL DISCUSS. 6286 04:05:59,240 --> 04:06:00,440 IN A SECOND. 6287 04:06:00,440 --> 04:06:01,600 THIS HAS HAPPENED THROUGH 6288 04:06:01,600 --> 04:06:03,160 DECADES NOW STARTING FROM LARGE 6289 04:06:03,160 --> 04:06:04,600 FAMILIES WITH TRADITIONAL 6290 04:06:04,600 --> 04:06:05,360 LINKAGE ANALYSIS APPROXIMATE 6291 04:06:05,360 --> 04:06:10,880 WITH THE ADVENT OF SEQUENCING 6292 04:06:10,880 --> 04:06:13,240 NOW 32 WITH THE GENES AND 6293 04:06:13,240 --> 04:06:15,000 SPORADIC CASES AND IT WAS REALLY 6294 04:06:15,000 --> 04:06:16,080 MAIRKSZING WHEN THE SEQUENCING 6295 04:06:16,080 --> 04:06:19,520 CAME INTO LINE BECAUSE IT TOOK 6296 04:06:19,520 --> 04:06:22,040 10 YEARS TO TO IDENTIFY THE 6297 04:06:22,040 --> 04:06:23,600 FIRST GROUP OF GENES WITH THIS 6298 04:06:23,600 --> 04:06:30,840 LARGE FAMILY STUDIES AND THEN IN 6299 04:06:30,840 --> 04:06:48,920 THE NEXT 3 YEARS AND TRY TO GIVE 6300 04:06:48,920 --> 04:06:52,880 INFORMATION ON GENETIC DIAGNOSIS 6301 04:06:52,880 --> 04:06:54,520 AND THESE GENESS ARE IESHES 6302 04:06:54,520 --> 04:06:55,400 DEBTIFIED APPROXIMATE WE GAME 6303 04:06:55,400 --> 04:06:57,480 INVESTED IN THE DEVELOPING ZEBRA 6304 04:06:57,480 --> 04:07:01,320 FISH MODEL THAT COULD HELP VERY 6305 04:07:01,320 --> 04:07:02,720 QUICKLY FIGURE OUT WHETHER THE 6306 04:07:02,720 --> 04:07:04,920 GENE FTION OBTAINED THROUGH THE 6307 04:07:04,920 --> 04:07:05,520 SEQUENCING THE CAUSATIVE GENE 6308 04:07:05,520 --> 04:07:09,160 AND FIGURE OUT WHAT THE 6309 04:07:09,160 --> 04:07:10,200 PHENOTYPE OF THIS RETINAL 6310 04:07:10,200 --> 04:07:11,360 LOCATIONIN OPEN MEETINGATHY WAS 6311 04:07:11,360 --> 04:07:15,400 IN THE ZEB WRA FISH. 6312 04:07:15,400 --> 04:07:17,760 SINCE I'M NOT PROSEPTORSING ANY 6313 04:07:17,760 --> 04:07:18,480 BIOINFORMATIC, MY CONTRIBUTION 6314 04:07:18,480 --> 04:07:19,520 TO THE SYMPOSIUM IS TO LET YOU 6315 04:07:19,520 --> 04:07:24,480 KNOW ABOUT SOME OF THE SHARING 6316 04:07:24,480 --> 04:07:28,400 SITES THAT ARE AVAILABLE FOR 6317 04:07:28,400 --> 04:07:45,360 GENETICS, MATCH MAKER EXCHANGE 6318 04:07:45,360 --> 04:07:47,080 AND GENE MATCHER INTO THESE 6319 04:07:47,080 --> 04:07:48,800 SYSTEMS AND I ALWAYS WANT TO 6320 04:07:48,800 --> 04:07:50,320 MAKE SURE THAT IT'S NOT JUST 6321 04:07:50,320 --> 04:07:51,720 NECESSARILY FOR THE GENETICIST, 6322 04:07:51,720 --> 04:07:52,680 IF THERE'S A GENE OF INTEREST 6323 04:07:52,680 --> 04:07:58,600 AND YOU WOULD LIKE TO STUDY 6324 04:07:58,600 --> 04:07:59,240 SPECIFIC VARIANTS THAT MAY 6325 04:07:59,240 --> 04:08:00,520 CHARGE THE FUNCTION OFIOURE 6326 04:08:00,520 --> 04:08:01,880 PROACTIVE TEEN YOU CAN PUT THE 6327 04:08:01,880 --> 04:08:03,120 GENE OF INTEREST INTO THE 6328 04:08:03,120 --> 04:08:04,120 DATABASES WHICH IS SOMETHING 6329 04:08:04,120 --> 04:08:06,520 THAT WE'RE DOING IN PARTICULAR 6330 04:08:06,520 --> 04:08:10,640 FOR SOME OTHER PROJECT IN THE 6331 04:08:10,640 --> 04:08:13,000 LAB TO TRY TO IDENTIFY SPECIFIC 6332 04:08:13,000 --> 04:08:19,880 DOMAINS THAT HAVE CLINICAL 6333 04:08:19,880 --> 04:08:20,120 RELEVANCE. 6334 04:08:20,120 --> 04:08:23,200 SO THIS HAS REALLY INFORMED ALSO 6335 04:08:23,200 --> 04:08:24,920 THE GLYCO BIOLOGY BECAUSE AS 6336 04:08:24,920 --> 04:08:26,920 THESE GENES WERE IDENTIFIED 6337 04:08:26,920 --> 04:08:28,440 THERE HAS BEEN WORK FROM 6338 04:08:28,440 --> 04:08:29,840 MULTIPLE LABS TO TRY TO FIGURE 6339 04:08:29,840 --> 04:08:35,080 OUT WHAT YOU WERE DOING AND THIS 6340 04:08:35,080 --> 04:08:38,560 HAS AX ALLOWED TO US TO IDENTIFY 6341 04:08:38,560 --> 04:08:40,000 ALL OF COMPOSITION--SORRY, THE 6342 04:08:40,000 --> 04:08:44,720 COMPOSITION OF THE GLYKAN--KANAS 6343 04:08:44,720 --> 04:08:47,240 THAT ARE BOUND TO AND THAT ARE 6344 04:08:47,240 --> 04:08:51,640 DISRUPTED IN THESE DISORDERS. 6345 04:08:51,640 --> 04:08:53,440 THIS HAS BEEN REALLY COMPLICATED 6346 04:08:53,440 --> 04:08:55,200 EFFORT, FOR EXAMPLE, I WAS 6347 04:08:55,200 --> 04:08:59,040 INVOLVED IN THE IESHES 6348 04:08:59,040 --> 04:09:00,680 DENTIFICATION THAT WAS WITH AND 6349 04:09:00,680 --> 04:09:02,160 THEN WE FINALLY FIGURED OUT THAT 6350 04:09:02,160 --> 04:09:06,400 IT'S NECESSARY TO ADD THE 6351 04:09:06,400 --> 04:09:09,520 [INDISCERNIBLE] TO THESE MAN OS 6352 04:09:09,520 --> 04:09:14,920 THESE ARE ALL GLYCANS, SO IT'S 6353 04:09:14,920 --> 04:09:15,560 DIFFERENT FROM END. 6354 04:09:15,560 --> 04:09:18,120 AND WE FIGURED OUT WHAT ALL 6355 04:09:18,120 --> 04:09:18,800 THESE TRANSFERAISES DO WHICH 6356 04:09:18,800 --> 04:09:20,520 TOOK A LONG TIME AND THIS ALSO 6357 04:09:20,520 --> 04:09:25,320 HELPED CHANGE A CLASSIFICATION 6358 04:09:25,320 --> 04:09:35,920 OF THE DISEASE SO AS THEY WERE 6359 04:09:35,920 --> 04:09:37,120 SAYING BEFORE, SOMETIMES THAT 6360 04:09:37,120 --> 04:09:38,320 HAVE MUTATIONS IN THESE WHICH 6361 04:09:38,320 --> 04:09:42,040 ARE VERY, VERY RARE AND 6362 04:09:42,040 --> 04:09:43,520 SECONDARY THESE THAT HAVE 6363 04:09:43,520 --> 04:09:45,640 MUTATIONS IN THE TRANSFER ACES 6364 04:09:45,640 --> 04:09:46,680 THAT GLUE MARIOUS COSALATE FOR 6365 04:09:46,680 --> 04:09:56,520 THE GLYCAN AND THEN THERE IS A 6366 04:09:56,520 --> 04:09:57,760 GROUP OF THAT AIVET THE 6367 04:09:57,760 --> 04:09:59,760 GENERATION OF THE DONEARS FOR 6368 04:09:59,760 --> 04:10:02,640 THE MANO AND THE RIBITOL THAT 6369 04:10:02,640 --> 04:10:06,520 WILL THEN BE FED TO THE TRANSFER 6370 04:10:06,520 --> 04:10:10,920 ACES TO GENERATE THESE GLYCANS. 6371 04:10:10,920 --> 04:10:13,640 WE STILL HAVE 30% OF CASES THAT 6372 04:10:13,640 --> 04:10:16,760 DO NOT HAVE A GENETIC DIAGNOSIS 6373 04:10:16,760 --> 04:10:17,120 AT THIS TIME. 6374 04:10:17,120 --> 04:10:28,080 AND I WOULD LIKE TO REMIND YOU 6375 04:10:28,080 --> 04:10:28,880 THAT SOPHISTICATED RIGHT NOW 6376 04:10:28,880 --> 04:10:31,400 WELL IS A BIG EFFORT TO IDENTIFY 6377 04:10:31,400 --> 04:10:33,160 NONCODING OF REGULATORY 6378 04:10:33,160 --> 04:10:39,640 MUTATIONS WITH THE IDEA THAT 6379 04:10:39,640 --> 04:10:41,720 SOME OF THESE MAY BE IN THE 6380 04:10:41,720 --> 04:10:43,920 KNOWN GENES BECAUSE THEY'VE BEEN 6381 04:10:43,920 --> 04:10:46,120 DISCOVERED FOR A WHILE NOW AND 6382 04:10:46,120 --> 04:10:48,120 WE CAN IESHES DENTIFY ALL THESE 6383 04:10:48,120 --> 04:10:50,800 MUTATIONS IN GROUPS TO IDENTIFY 6384 04:10:50,800 --> 04:10:51,320 THERAPEUTIC INTERVENTION. 6385 04:10:51,320 --> 04:10:53,320 AND HERE I WANT TO TELL YOU 6386 04:10:53,320 --> 04:10:54,320 ABOUT OUR OWN CONTRIBUTION IN 6387 04:10:54,320 --> 04:10:56,280 TRYING TO DO THIS WHICH IS 6388 04:10:56,280 --> 04:11:01,120 TRYING TO DEVELOP ZEBRA FISH 6389 04:11:01,120 --> 04:11:07,200 MODELS OF THE DJSTROGLYCACIN, OP 6390 04:11:07,200 --> 04:11:10,120 A THIES, AND SO MOST OF THE 6391 04:11:10,120 --> 04:11:13,640 MOUSE MODEL ARES WHERE THE JEEPS 6392 04:11:13,640 --> 04:11:15,440 ARE REMOVED IN SPECIFIC TISSUES 6393 04:11:15,440 --> 04:11:17,320 AT DIFFERENT TYPES BUT THERE 6394 04:11:17,320 --> 04:11:19,160 ISN'T A GENETIC MODEL WHERE YOU 6395 04:11:19,160 --> 04:11:21,840 MODEL THE ENTIRE DEVELOPMENT, 6396 04:11:21,840 --> 04:11:23,840 THE ENTIRE DEVELOPMENT AND 6397 04:11:23,840 --> 04:11:25,520 DISRUPTION OF THE ENTIRE IN THE 6398 04:11:25,520 --> 04:11:26,800 WHOLE BODY, THE ZEBRA FISH IS A 6399 04:11:26,800 --> 04:11:27,840 GREAT MODAND HE WILL I CAME TO 6400 04:11:27,840 --> 04:11:30,640 IT AS I STARTED DOING EXOME 6401 04:11:30,640 --> 04:11:34,000 SEQUENCING BECAUSE IT'S FAST, 6402 04:11:34,000 --> 04:11:36,080 YOU CAN ACTUALLY LOOK AT AN 6403 04:11:36,080 --> 04:11:37,400 EMBRYO IS SEE THE DEVELOPMENT OF 6404 04:11:37,400 --> 04:11:39,320 THE EYES OF THE BRAIN AND OF THE 6405 04:11:39,320 --> 04:11:43,520 MUSCLE WITHIN 24 HOURS, OF 6406 04:11:43,520 --> 04:11:45,040 FERTILIZATION, AND THE MOM WILL 6407 04:11:45,040 --> 04:11:47,160 HAVE HUNDREDS OF BABIES THAT ARE 6408 04:11:47,160 --> 04:11:48,120 EXTERNALLY FERTILIZED WHICH ALSO 6409 04:11:48,120 --> 04:11:51,240 GIVES YOU ACCESS TO THE VERY 6410 04:11:51,240 --> 04:11:53,240 FIRST FERTILIZED CELL AND YOU 6411 04:11:53,240 --> 04:11:54,880 CAN PERFORM GENETIC 6412 04:11:54,880 --> 04:11:55,880 MODIFICATIONS AND INTERVENTION 6413 04:11:55,880 --> 04:11:59,320 IN THE 1 CELL EMBRYO. 6414 04:11:59,320 --> 04:12:00,680 HERE SHOWING [INDISCERNIBLE] AND 6415 04:12:00,680 --> 04:12:03,920 NUCLEOTIDE BUT NOW WE CAN ALSO 6416 04:12:03,920 --> 04:12:04,760 DO CRISPR CAS 9 WHICH I WILL 6417 04:12:04,760 --> 04:12:08,200 TELL YOU ABOUT IN A SECOND. 6418 04:12:08,200 --> 04:12:10,680 THIS IS AN OLD EXAMPLE BUT I 6419 04:12:10,680 --> 04:12:12,560 REALLY LIKE THIS PARTICULAR FISH 6420 04:12:12,560 --> 04:12:15,800 MODEL BECAUSE MULTIPLE FISH 6421 04:12:15,800 --> 04:12:17,560 MODELS ENDED UP SHOWING EXACTLY 6422 04:12:17,560 --> 04:12:24,400 THE SAME PHENOTYPE, THIS WAS THE 6423 04:12:24,400 --> 04:12:26,120 POMGNT2 FISH FOR 3 DAYS THEY 6424 04:12:26,120 --> 04:12:28,360 LARGE AND SHORT AND THEY HAVE 6425 04:12:28,360 --> 04:12:29,320 THE CHARACTERISTIC BENT TAIL. 6426 04:12:29,320 --> 04:12:31,760 SO THE BABY FISH IS IN A SHELL 6427 04:12:31,760 --> 04:12:34,080 AND USUALLY STARTS MOVING AROUND 6428 04:12:34,080 --> 04:12:36,400 16, 17, HOURS AND IF IT CANNOT 6429 04:12:36,400 --> 04:12:40,040 MOVE, THE TAIL WILL REMAIN STUCK 6430 04:12:40,040 --> 04:12:41,480 IN THIS BENT POSITION WHICH IS 6431 04:12:41,480 --> 04:12:45,120 ACTUALLY SIMILAR TO THE 6432 04:12:45,120 --> 04:12:46,760 CONTRACTURES THAT THE BEASHS 6433 04:12:46,760 --> 04:12:49,400 HAVE WITH THESE DISORDERS 6434 04:12:49,400 --> 04:12:51,520 BECAUSE THEY WEAK AND THEY 6435 04:12:51,520 --> 04:12:52,760 CANNOT MOVE WELL IN THE WOMB. 6436 04:12:52,760 --> 04:12:57,480 THESE FISH WILL HAVE IMPAIRED 6437 04:12:57,480 --> 04:12:58,560 MOBILITY THEY DISPLAY SIMILAR 6438 04:12:58,560 --> 04:12:59,840 FORMATIONS IN THE 1S IN THE 6439 04:12:59,840 --> 04:13:02,360 PATIENT WITH THE DISRUPTION OF 6440 04:13:02,360 --> 04:13:04,000 THE RETINALLIZATION AND ALSO IN 6441 04:13:04,000 --> 04:13:05,680 THE LENS OF AN END THEY WILL 6442 04:13:05,680 --> 04:13:08,920 HAVE THE DISRUPTIONS IN BRAIN IN 6443 04:13:08,920 --> 04:13:09,760 BRAIN DEVELOPMENT WHICH ARE 6444 04:13:09,760 --> 04:13:14,040 SIMILAR TO THE 1S IN THE 6445 04:13:14,040 --> 04:13:14,320 PATIENTS. 6446 04:13:14,320 --> 04:13:15,280 THE MOST IMPORTANT THING IS THAT 6447 04:13:15,280 --> 04:13:16,600 THE SAME ANTIBODIES THAT WERE 6448 04:13:16,600 --> 04:13:18,120 USED FOR DIAGNOSIS IN THE HUMAN 6449 04:13:18,120 --> 04:13:26,520 SAMPLES CAN BE USED IN THE ZEBRA 6450 04:13:26,520 --> 04:13:26,760 FISH. 6451 04:13:26,760 --> 04:13:28,080 THESE WERE ORIGE NAWILLLY 6452 04:13:28,080 --> 04:13:30,840 DIAGNOSED ON THE ANTIBODY ON 6453 04:13:30,840 --> 04:13:31,800 MUSCLE BIOPSIES, MUSCLE BIOPSIES 6454 04:13:31,800 --> 04:13:32,960 ARE NOT DONE THAT MUCH ANYMORE 6455 04:13:32,960 --> 04:13:34,880 BECAUSE WE HAVE ALL OF THE 6456 04:13:34,880 --> 04:13:37,200 GENETICS AND MAKES NO SENSE TO 6457 04:13:37,200 --> 04:13:41,560 DO AN INVASIVE PROCEDURE IN A 6458 04:13:41,560 --> 04:13:43,360 CHILD AT THIS TIME BUT THE DATA 6459 04:13:43,360 --> 04:13:44,320 FROM SEVERAL YEARS AGO SHOWS 6460 04:13:44,320 --> 04:13:46,080 THAT IN THE MUSCLE, AND THIS IS 6461 04:13:46,080 --> 04:13:48,520 JUST A MUSCLE SECTION, AND YOU 6462 04:13:48,520 --> 04:13:50,680 SEE THE EXTRA CELLULAR MATE 6463 04:13:50,680 --> 04:13:53,320 EXCITATORY AND THE GLYCOSYLATED 6464 04:13:53,320 --> 04:13:56,440 GLYCAN AROUND THE MY O FIBER AND 6465 04:13:56,440 --> 04:13:58,360 THE LOSS OF GLYCOSYLATION WITH 6466 04:13:58,360 --> 04:14:00,440 THE SAMPLE WITH ALSO DISRUPTION 6467 04:14:00,440 --> 04:14:02,160 IN THE LAM INTERFERON. 6468 04:14:02,160 --> 04:14:05,800 THIS MEMBRANE IS LOCALIZED INTO 6469 04:14:05,800 --> 04:14:07,280 THE STRUCTURES THAT ARE CALLED 6470 04:14:07,280 --> 04:14:10,920 MY O RECEPTORS AND THEY WILL RUN 6471 04:14:10,920 --> 04:14:14,320 LONGITUDINALLY AND WHEN YOU 6472 04:14:14,320 --> 04:14:15,840 REMOVE [INDISCERNIBLE] YOU LOSE 6473 04:14:15,840 --> 04:14:16,440 DPLI COSALATION OF THIS GRID 6474 04:14:16,440 --> 04:14:17,240 SERVICES KAN--KANA AND THIS 6475 04:14:17,240 --> 04:14:17,880 PARTICULAR STRUCTURE AND YOU 6476 04:14:17,880 --> 04:14:25,240 WILL HAVE A HIGHLY DISRUPTED 6477 04:14:25,240 --> 04:14:25,800 MUSCLE STRUCTURE. 6478 04:14:25,800 --> 04:14:27,120 THE OTHER THING YOU CAN DO IN 6479 04:14:27,120 --> 04:14:28,640 THE ZEBRA FISH TO RESCUE 6480 04:14:28,640 --> 04:14:30,480 PHENOTYPES TO ACTUALLY SHOW THE 6481 04:14:30,480 --> 04:14:31,720 PHENOTYPE THAT THE FUNCTION OF 6482 04:14:31,720 --> 04:14:34,800 THE PROTEIN IS CONSERVED AND 6483 04:14:34,800 --> 04:14:36,360 THAT THE PHENOTYPE IS SPECIFIC 6484 04:14:36,360 --> 04:14:38,840 AND WE'VE DONE A LOT OF WORK 6485 04:14:38,840 --> 04:14:40,120 WITH THE ANALYSIS OF MISSENSED 6486 04:14:40,120 --> 04:14:41,400 MUTATIONS BECAUSE THEN IF YOU 6487 04:14:41,400 --> 04:14:43,080 WANT TO VALIDATE YOUR MISSENSED 6488 04:14:43,080 --> 04:14:44,360 MUTATION YOU FIND IN THE PATIENT 6489 04:14:44,360 --> 04:14:46,120 YOU CAN INTRODUCE IN THE HUMAN 6490 04:14:46,120 --> 04:14:47,840 MRNA AND TRY TO PUT IN THE ZEBRA 6491 04:14:47,840 --> 04:14:50,480 FISH AND SEE WHETHER THE PROTEIN 6492 04:14:50,480 --> 04:14:51,400 FUNCTIONS PRESERVED IN IN 6493 04:14:51,400 --> 04:14:54,280 PARTICULAR CASE, THIS WAS A LOSS 6494 04:14:54,280 --> 04:14:56,240 OF FUNCTION MUTATION BECAUSE YOU 6495 04:14:56,240 --> 04:14:58,120 CANNOT RESCUE THE EFFECT OF THE 6496 04:14:58,120 --> 04:14:58,480 MORPHOLIN O. 6497 04:14:58,480 --> 04:15:02,120 SO THIS WAS A PRESENTATION OF 6498 04:15:02,120 --> 04:15:04,120 THE WHAT IS CALLED THE MORPHIN 6499 04:15:04,120 --> 04:15:06,680 WHICH IS THE MORPHOLIN O 6500 04:15:06,680 --> 04:15:08,120 INJECTED FISH, BUT 1 OF THE 6501 04:15:08,120 --> 04:15:10,000 ISSUES THERE'S BEEN A LOT OF 6502 04:15:10,000 --> 04:15:10,680 DISCUSSION IN THE ZEBRA FISH 6503 04:15:10,680 --> 04:15:13,040 FIELD TO THE LEVEL OF 6504 04:15:13,040 --> 04:15:15,200 NONSPECIFIC EFFECTS CAUSED BY 6505 04:15:15,200 --> 04:15:21,280 MORPHOLIN OS AND IN GENERAL 6506 04:15:21,280 --> 04:15:23,600 EVOLVED TO CRISPRs AND OTHER 6507 04:15:23,600 --> 04:15:25,280 GENETIC MUTANTS ALSO THE MORPH O 6508 04:15:25,280 --> 04:15:26,480 LINE O KNOCK DOWN IS TEMPORARY 6509 04:15:26,480 --> 04:15:29,560 AND SO IF YOU WANT TO DO MORE 6510 04:15:29,560 --> 04:15:32,400 LONG-TERM TREATMENTS STUDIES OR 6511 04:15:32,400 --> 04:15:33,000 STUDY DIFFERENT DEVELOPMENTAL 6512 04:15:33,000 --> 04:15:34,480 ASPECTS OF THE DISEASE, YOU 6513 04:15:34,480 --> 04:15:36,560 CANNOT REALLY DO IT IN THIS 6514 04:15:36,560 --> 04:15:37,120 EARLY MODELS. 6515 04:15:37,120 --> 04:15:38,920 AND SO WHAT WE'VE BEEN DOING FOR 6516 04:15:38,920 --> 04:15:41,240 THE PAST COUPLE OF YEARS IN MY 6517 04:15:41,240 --> 04:15:46,680 LAB, IS TO START DEVELOPING AN 6518 04:15:46,680 --> 04:15:48,240 ARRAY OF MUTANTS SO THAT WE CAN 6519 04:15:48,240 --> 04:15:50,000 THEN SEE WHAT HAPPENS IN THESE 6520 04:15:50,000 --> 04:15:51,520 GENETIC MUTANTS AND IN THE ZEBRA 6521 04:15:51,520 --> 04:15:55,160 FISH AND WHETHER WE CAN USE IT 6522 04:15:55,160 --> 04:15:57,400 FOR DRUG SCREENING AND FOR 6523 04:15:57,400 --> 04:15:58,000 TESTING DIFFERENT THERAPEUTIC 6524 04:15:58,000 --> 04:15:59,120 INTERVENTIONS AND SO WHAT I 6525 04:15:59,120 --> 04:16:02,200 WANTED TO DO TODAY WAS SHARE 6526 04:16:02,200 --> 04:16:03,920 SOME UNPUBLISHED DATA ON THE 6527 04:16:03,920 --> 04:16:05,760 BEGINNING OF THIS PROJECT AND ON 6528 04:16:05,760 --> 04:16:08,120 SOME OF THE MODELS THAT WE'VE 6529 04:16:08,120 --> 04:16:09,960 MADE AND SO 1 OF THE FIRST 6530 04:16:09,960 --> 04:16:13,680 MODELS THAT WE'VE BEEN STUDYING 6531 04:16:13,680 --> 04:16:17,080 IS POMT1, AND IF FORMS A COMPLEX 6532 04:16:17,080 --> 04:16:18,480 WITH POMT2, AND ATTACHES THESE 6533 04:16:18,480 --> 04:16:26,760 TO THE DPLI KAN--KANA PROTEIN. 6534 04:16:26,760 --> 04:16:31,680 AND THIS WAS LED BY CHRIS AND 6535 04:16:31,680 --> 04:16:33,400 BRITTANY IN THE LAB. 6536 04:16:33,400 --> 04:16:35,080 SO IT WAS DIFFICULT TO STUDY THE 6537 04:16:35,080 --> 04:16:37,120 FISH, THE MORPHIN HAD BEEN MADE 6538 04:16:37,120 --> 04:16:38,120 ISSUES THE PHENOTYPE WAS 6539 04:16:38,120 --> 04:16:40,720 REQUIRED AND THEY REARED HIGH 6540 04:16:40,720 --> 04:16:41,520 CONCENTRATIONS OF MORPH O LINE O 6541 04:16:41,520 --> 04:16:43,640 AND THEN IT BECOMES REALLY 6542 04:16:43,640 --> 04:16:45,320 DIFFICULT TO TELL WHETHER THAT'S 6543 04:16:45,320 --> 04:16:53,000 REAL PHENOTYPE OR NOT. 6544 04:16:53,000 --> 04:16:56,400 ONE THING THAT EMERGED IS IN THE 6545 04:16:56,400 --> 04:17:00,080 MRNA BY THE MOTHER, THE FEMALE 6546 04:17:00,080 --> 04:17:01,920 RELEASE HUNDREDS OF EGGS, SHE IS 6547 04:17:01,920 --> 04:17:03,680 NOT A GOOD MOM BECAUSE SHE LETS 6548 04:17:03,680 --> 04:17:05,800 THEM COMPETE WITH EACH OTHER 6549 04:17:05,800 --> 04:17:07,120 BECAUSE WHOEVER SURVIVES 6550 04:17:07,120 --> 04:17:10,840 SURVIVES BUT SHE WILL PROVIDE 6551 04:17:10,840 --> 04:17:12,880 MRNA OF SEVERAL GENES IN THE 6552 04:17:12,880 --> 04:17:17,320 YOLK THAT WILL SUPPORT EARLY 6553 04:17:17,320 --> 04:17:18,280 DEVELOPMENT BECAUSE OTHERWISE, 6554 04:17:18,280 --> 04:17:20,080 THEY WOULDN'T REALLY HAVE 6555 04:17:20,080 --> 04:17:23,960 INITIAL MRNAs TO START THE 6556 04:17:23,960 --> 04:17:28,760 DIVISION AND DIFFERENTIATION. 6557 04:17:28,760 --> 04:17:31,240 SO WE OBTAINED THESE FISH AT THE 6558 04:17:31,240 --> 04:17:32,680 BEGINNING OF THE PANDEMIC WOO 6559 04:17:32,680 --> 04:17:34,000 BECAUSE WE HAD THE MUSEUM STANTS 6560 04:17:34,000 --> 04:17:36,240 FROM THE ZEBRA FISH PROJECT THAT 6561 04:17:36,240 --> 04:17:37,680 A WERE NOT ANALYZING AND THE 6562 04:17:37,680 --> 04:17:39,120 MUTATION PLOT IS AT THE SANGER 6563 04:17:39,120 --> 04:17:40,760 CENTER, THAT I MUTATED THROUGH 6564 04:17:40,760 --> 04:17:42,440 THE IMMUNE SCREENS AND DOUBLE 6565 04:17:42,440 --> 04:17:43,880 CHECKED EVERY SINGLE GENE IN THE 6566 04:17:43,880 --> 04:17:46,640 ZEBRA FISH AND THE 6567 04:17:46,640 --> 04:17:47,480 CHARACTERIZATION THAT THEY HAVE 6568 04:17:47,480 --> 04:17:50,080 DONE IS ONLY UP TO 5 DAYS POST 6569 04:17:50,080 --> 04:17:52,680 FERTILIZATION SO THERE WAS NO 6570 04:17:52,680 --> 04:17:53,920 PHENOTYPE RESPORTED BUT WE 6571 04:17:53,920 --> 04:17:56,400 THOUGHT, WELL, LET'S JUST START 6572 04:17:56,400 --> 04:17:57,240 LOOKING AT THIS FISH. 6573 04:17:57,240 --> 04:18:00,080 IT HAD A VERY LATE TRUNCATING 6574 04:18:00,080 --> 04:18:02,240 STOP CO DON, BUT THERE ARE 6575 04:18:02,240 --> 04:18:04,640 SIMILAR MUTANT MUTATIONS IN THE 6576 04:18:04,640 --> 04:18:06,520 HUMANS THAT CAUSE NONSENSE 6577 04:18:06,520 --> 04:18:07,400 MEDIATED DECAY. 6578 04:18:07,400 --> 04:18:08,480 THAT HAPPEN AROUND THE SAME 6579 04:18:08,480 --> 04:18:12,640 AREA, SO I THOUGHT LET'S TRY 6580 04:18:12,640 --> 04:18:12,920 ANYWAYS. 6581 04:18:12,920 --> 04:18:14,160 AND IDEA IS THAT WHEN HAVE YOU 6582 04:18:14,160 --> 04:18:15,400 GENES THAT ARE SO HIGHLY 6583 04:18:15,400 --> 04:18:16,360 PROVIDED BY THE MOTHER, 6584 04:18:16,360 --> 04:18:18,120 SOMETIMES WHAT YOU HAVE TO DO, 6585 04:18:18,120 --> 04:18:21,360 YOU HAVE TO MAKE A KNOCK OUT MOM 6586 04:18:21,360 --> 04:18:23,640 TO REMOVE THE MATERNAL MRNA AND 6587 04:18:23,640 --> 04:18:24,920 THEN YOU'RE PHENOTYPE WILL 6588 04:18:24,920 --> 04:18:27,840 EMERGE IN THE EMBRYOS FROM THE 6589 04:18:27,840 --> 04:18:28,680 SEDENTARY GENERATION SO WE GAVE 6590 04:18:28,680 --> 04:18:32,440 THIS A TRY AND 1 THING THAT WAS 6591 04:18:32,440 --> 04:18:33,960 LEGALLY INTERESTING IS ACTUALLY 6592 04:18:33,960 --> 04:18:35,720 WE WERE NOT ABLE TO GET KNOCK 6593 04:18:35,720 --> 04:18:37,120 OUT MOMS BECAUSE THE KNOCK OUT 6594 04:18:37,120 --> 04:18:40,520 FISH START TO DIE AFTER 30 DAYS 6595 04:18:40,520 --> 04:18:41,480 POST FERTILIZATION AND MOST OF 6596 04:18:41,480 --> 04:18:43,960 THEM ARE GONE BY 60 DAYS WHICH 6597 04:18:43,960 --> 04:18:51,480 IS BEFORE THE TIME OF ZEBRA FISH 6598 04:18:51,480 --> 04:18:51,880 ARE FERTILIZEDILE. 6599 04:18:51,880 --> 04:18:53,320 SO THIS WAS VERY EXCITING 6600 04:18:53,320 --> 04:18:55,080 BECAUSE IT WAS EARLY PHENOTYPE 6601 04:18:55,080 --> 04:18:55,800 IN THESE FISH. 6602 04:18:55,800 --> 04:18:57,280 AWLINGS AT 30 DAYS WHEN THERAPY 6603 04:18:57,280 --> 04:19:02,000 AND STILL ALIVE THE KNOCK OUTS 6604 04:19:02,000 --> 04:19:03,120 ARE SIGNIFICANTLY SMALLER THAN 6605 04:19:03,120 --> 04:19:05,120 THE WILD TYPES AND THE HEADS AND 6606 04:19:05,120 --> 04:19:06,520 WHAT'S INTERESTING IS THAT THE 6607 04:19:06,520 --> 04:19:08,320 FEW ARE REMAINING AT 40 DAYS 6608 04:19:08,320 --> 04:19:09,640 THEY'RE STARTING TO RECOVER BUT 6609 04:19:09,640 --> 04:19:11,400 THIS IS BECAUSE THE FISH ARE 6610 04:19:11,400 --> 04:19:13,920 DYING IN TANK THAT FEWER FISH 6611 04:19:13,920 --> 04:19:15,160 COMPETE FOR FOOD THAT THEY CAN 6612 04:19:15,160 --> 04:19:17,240 STILL HAVE ACCESS TO FOOD. 6613 04:19:17,240 --> 04:19:18,560 EVEN IF THEY CAN'T SWIM QUITE AS 6614 04:19:18,560 --> 04:19:22,800 WELL AND I WILL SHOW YOU LATER 6615 04:19:22,800 --> 04:19:23,560 WHAT THAT MEANS. 6616 04:19:23,560 --> 04:19:24,560 SO WE CHECKED WHETHER IT WAS 6617 04:19:24,560 --> 04:19:27,920 TRUE THAT THERE COULD BE 6618 04:19:27,920 --> 04:19:29,040 MEDIATED DECAY AND WE SAW A 6619 04:19:29,040 --> 04:19:32,200 DECREASE IN THE KNOCK OUT IN THE 6620 04:19:32,200 --> 04:19:33,920 MRNA PER POMT1 AND IN ADDITION 6621 04:19:33,920 --> 04:19:37,320 WE SAW THAT AT 30 DAYS THE 6622 04:19:37,320 --> 04:19:38,600 PROTEIN WAS COMPLETELY BLOCKED 6623 04:19:38,600 --> 04:19:40,440 BY WESTERN BLOT AND WE HAVE A GO 6624 04:19:40,440 --> 04:19:41,640 ANTIBODY, I WANT TO MAKE A POINT 6625 04:19:41,640 --> 04:19:43,520 THAT WE HAD A LOT OF TROUBLE 6626 04:19:43,520 --> 04:19:44,680 FINDING THE RIGHT HOUSEKEEPING 6627 04:19:44,680 --> 04:19:45,920 GENE BECAUSE WHEN YOU ARE 6628 04:19:45,920 --> 04:19:47,880 LOOKING AT THE MUSCLE, YOU CAN'T 6629 04:19:47,880 --> 04:19:49,680 REALLY USE ACTIN BECAUSE ACTIN 6630 04:19:49,680 --> 04:19:51,600 IS DISRUPTED, AND GAB DH IS ALSO 6631 04:19:51,600 --> 04:19:53,680 DISRUPTED SO WE ENDED UP WITH 6632 04:19:53,680 --> 04:19:56,520 THE TOTAL PROTEIN SPACE TO MAKE 6633 04:19:56,520 --> 04:19:59,280 SURE THAT ALL OF OUR GELS WERE 6634 04:19:59,280 --> 04:20:00,000 EQUALLY LOADED. 6635 04:20:00,000 --> 04:20:01,800 SIMILAR ISSUES ALSO HAPPEN WITH 6636 04:20:01,800 --> 04:20:05,400 QPC R WHERE WE HAVE IT GO TO 6637 04:20:05,400 --> 04:20:07,760 LIKE 3 OUR 4 DIFFERENT 6638 04:20:07,760 --> 04:20:08,880 HOUSEKEEPING GENES THAT FIND 1 6639 04:20:08,880 --> 04:20:10,600 THAT WAS REFLECTIVE OF THE 6640 04:20:10,600 --> 04:20:11,160 AMOUNT OF MRNA. 6641 04:20:11,160 --> 04:20:12,800 THE OTHER THING THAT WE NOTED, 6642 04:20:12,800 --> 04:20:15,560 SO AS I TOLD YOU THERE'S FLIEK O 6643 04:20:15,560 --> 04:20:21,200 ASPECT BODY THAT SHOWS THE 6644 04:20:21,200 --> 04:20:22,520 PRESENCE OF THAT DPLI KAN--KANA 6645 04:20:22,520 --> 04:20:24,720 THAT WE'RE LOOKINGA THE THAT 6646 04:20:24,720 --> 04:20:27,640 CAUSED ASSEMBLED BAY THOSE 6647 04:20:27,640 --> 04:20:29,440 TRANSFER ACES, SARKS SEMBLE 6648 04:20:29,440 --> 04:20:30,680 TAXER TACHS THE FIRST 1 SO THE 6649 04:20:30,680 --> 04:20:31,760 DPLI KAN--KANA SHOULD BE GONE 6650 04:20:31,760 --> 04:20:34,120 AND IN FACT WHEN WE DID THAT 6651 04:20:34,120 --> 04:20:36,520 ENRICHMENT, WE SHOWED THAT AT 30 6652 04:20:36,520 --> 04:20:43,440 DAYS, THIS WAS COMPLETELY LOST 6653 04:20:43,440 --> 04:20:44,680 WHILE THE BATTA GLYCOSYLATED WAS 6654 04:20:44,680 --> 04:20:46,960 PRESENT IN THE ENRICHED FRACTION 6655 04:20:46,960 --> 04:20:48,520 SO BY 30 DAYS THE GLOI 6656 04:20:48,520 --> 04:20:48,960 COSALATION IS GONE. 6657 04:20:48,960 --> 04:20:51,680 SO IF WE LOOK AT THE MUSCLE, WE 6658 04:20:51,680 --> 04:20:56,240 STARTED TO SEE, WE SEE A SIGN OF 6659 04:20:56,240 --> 04:20:57,040 MUSCLE DISEASE SO I THINK WHAT 6660 04:20:57,040 --> 04:21:00,480 YOU CAN APPRECIATE IN THIS 6661 04:21:00,480 --> 04:21:01,760 HIGHER MAG NI5ICATION PICTURE IS 6662 04:21:01,760 --> 04:21:03,640 HOW THE FIBERS ARE ACTUALLY 6663 04:21:03,640 --> 04:21:04,280 SEPARATE FRIDAY EACH OTHER 6664 04:21:04,280 --> 04:21:06,000 BECAUSE THIS IS SOMETIMES WHAT 6665 04:21:06,000 --> 04:21:09,520 HAPPENS WHEN THERE IS LOSS OF 6666 04:21:09,520 --> 04:21:10,480 THE EPICELLULAR MATRIX THAT 6667 04:21:10,480 --> 04:21:11,240 KEEPS THEM TOGETHER AND ANOTHER 6668 04:21:11,240 --> 04:21:13,720 FEET THAT YOU ARE IS PRESENT IN 6669 04:21:13,720 --> 04:21:14,560 THE DPLI KAN--KANA FISH KNOCK 6670 04:21:14,560 --> 04:21:18,520 OUT IS THE FACT THAT THE MY O 6671 04:21:18,520 --> 04:21:20,760 SET ARE BASICALLY OPEN AND THAT 6672 04:21:20,760 --> 04:21:21,960 DISEASE CONTINUES AT SEVERAL 6673 04:21:21,960 --> 04:21:25,040 PLACES INSTEAD OF LIKE BEING 6674 04:21:25,040 --> 04:21:29,680 NICELY ORGANIZED. 6675 04:21:29,680 --> 04:21:30,920 THIS HISTOLOGICAL PICTURE WAS 6676 04:21:30,920 --> 04:21:31,960 INCREDIBLY DIFFICULT TO OBTAIN 6677 04:21:31,960 --> 04:21:33,800 BECAUSE IN FACT THE MUSCLE FROM 6678 04:21:33,800 --> 04:21:37,480 THESE FISH KIND OF LIKE JUST 6679 04:21:37,480 --> 04:21:38,120 FALLS APART. 6680 04:21:38,120 --> 04:21:45,840 AFTER FIXATION SO IT'S REALLY 6681 04:21:45,840 --> 04:21:46,400 SEVERELY AFFECTED. 6682 04:21:46,400 --> 04:21:47,880 WE THEN OBTAIN A SYSTEM THAT 6683 04:21:47,880 --> 04:21:50,960 ALLOWS TO YOU ANALYZE UP TO LIKE 6684 04:21:50,960 --> 04:21:53,120 96 FISH AT A TIME AND THIS IS 6685 04:21:53,120 --> 04:21:54,600 WHAT 1 EXAMPLE OF WHAT MY LAB 6686 04:21:54,600 --> 04:21:57,120 DID SO THESE ARE ALL DONE THE 6687 04:21:57,120 --> 04:22:02,000 SAME DAY AS 200 REQUEST 88 FISH 6688 04:22:02,000 --> 04:22:03,520 FROM 3 DIFFERENT MATINGS TO BE 6689 04:22:03,520 --> 04:22:07,800 ABLE TO RUN BEHAVIOR AND 6690 04:22:07,800 --> 04:22:08,920 MOBILITY ANALYSIS ON A LARGE 6691 04:22:08,920 --> 04:22:10,480 NUMBER OF SAMPLES AND THIS WILL 6692 04:22:10,480 --> 04:22:12,000 BECOME IMPORTANT IN THE FUTURE 6693 04:22:12,000 --> 04:22:12,880 BECAUSE WE'RE PLANNING TO USE 6694 04:22:12,880 --> 04:22:17,120 THE SYSTEM TO BE ABLE TO DO DRUG 6695 04:22:17,120 --> 04:22:18,680 SCREENINGS AS YOU CAN ADD 6696 04:22:18,680 --> 04:22:19,920 DIFFERENT DRUGS TO EACH 1 OF 6697 04:22:19,920 --> 04:22:21,320 THESE, TO EACH 1 OF THESE WELLS, 6698 04:22:21,320 --> 04:22:24,400 AND SO THE ANALYSIS THAT TOOK 5 6699 04:22:24,400 --> 04:22:28,720 DAYS, DIDN'T REALLY SHOW MUCH 6700 04:22:28,720 --> 04:22:31,400 CHANGE IN MOBILITY BUT WHAT WE 6701 04:22:31,400 --> 04:22:33,320 FOUND THAT ALREADY AT 15 DAYS 6702 04:22:33,320 --> 04:22:35,320 EVEN BEFORE ABOUT ANY OF THE 6703 04:22:35,320 --> 04:22:37,880 OTHER DEFICITS ARE OBSERVED WE 6704 04:22:37,880 --> 04:22:39,600 ALREADY START SEEING SIGNIFICANT 6705 04:22:39,600 --> 04:22:40,920 DIFFERENCES AT LEAST IN THE 6706 04:22:40,920 --> 04:22:42,120 VELOCITY AND IN THIS PARTICULAR 6707 04:22:42,120 --> 04:22:43,680 1 WAS NOT THAT MANY FISH AND SO 6708 04:22:43,680 --> 04:22:45,680 WE'RE GOING TO ADD, WE'RE GOING 6709 04:22:45,680 --> 04:22:47,880 TO ADD MORE SAMPLES BUT WE WERE 6710 04:22:47,880 --> 04:22:49,480 VERY EXCITED THAT THEY SEEM TO 6711 04:22:49,480 --> 04:22:51,800 HAVE THIS EARLY MOBILITY 6712 04:22:51,800 --> 04:22:52,960 PROBLEMS, BUT THEN WE WILL GET 6713 04:22:52,960 --> 04:22:54,520 WORSE AND WORSE AND OF COURSE 6714 04:22:54,520 --> 04:22:55,600 WILL LEAD TO LETHALITY BECAUSE 6715 04:22:55,600 --> 04:22:58,040 THEY HAVE NO ACCESS TO FOOD. 6716 04:22:58,040 --> 04:22:58,880 ANOTHER THING THAT WAS 6717 04:22:58,880 --> 04:23:03,920 INTERESTING WAS THE FACT THAT 6718 04:23:03,920 --> 04:23:07,240 POMT1 HAS TO ACT IN COMBINATION 6719 04:23:07,240 --> 04:23:09,080 OF POMT2 AND THIS WAS 6720 04:23:09,080 --> 04:23:09,920 CRYSTALLIZED A FEW YEARS AGO AND 6721 04:23:09,920 --> 04:23:12,440 WE'RE SEEING THAT EARLY IN 6722 04:23:12,440 --> 04:23:13,480 DEVELOPMENT POMT2, THE FISH IS 6723 04:23:13,480 --> 04:23:16,000 TRYING TO COMPENSATE AND 6724 04:23:16,000 --> 04:23:18,520 OVEREXPRESS POMT2 BUT OF COURSE, 6725 04:23:18,520 --> 04:23:20,120 THERE'S STILL NO GLYCOSYLATION 6726 04:23:20,120 --> 04:23:21,840 BECAUSE THE 2 PROTEINS NEED TO 6727 04:23:21,840 --> 04:23:24,560 BE TOGETHER AND THESE SEEM TO BE 6728 04:23:24,560 --> 04:23:28,160 VERY CLOSELY CO REGULATED. 6729 04:23:28,160 --> 04:23:31,640 SO, WHAT I TOLD YOU SO FAR IS 6730 04:23:31,640 --> 04:23:34,320 THAT POMT1 MUTANTS ARE PROMISING 6731 04:23:34,320 --> 04:23:36,680 NEW MODELS FOR THESE AND THEY 6732 04:23:36,680 --> 04:23:39,680 SHOW COMPLETE LOSS OF THE 6733 04:23:39,680 --> 04:23:41,320 PROTEIN, AND EARLY LETHALITY BUT 6734 04:23:41,320 --> 04:23:48,720 NOT AS EARLY AS THE DAG 1 6735 04:23:48,720 --> 04:23:48,960 MUTANTS. 6736 04:23:48,960 --> 04:23:50,520 THE MUSCLE DISEASE AND THE FISH 6737 04:23:50,520 --> 04:23:53,320 DIE, WE SEE MOBILITY DEFINITES 6738 04:23:53,320 --> 04:23:55,520 MUCH EARLIER, WE ACTUALLY ARE 6739 04:23:55,520 --> 04:23:56,760 STARTING TO SLEE ALSO OCULAR 6740 04:23:56,760 --> 04:23:58,280 PHENOTYPES AND SO WE'RE HOPING 6741 04:23:58,280 --> 04:24:00,320 TO USE THIS ABILITY TO VISION 6742 04:24:00,320 --> 04:24:02,120 AND END POINTS FOR DRUG 6743 04:24:02,120 --> 04:24:03,360 SCREENING AND TRYING TO 6744 04:24:03,360 --> 04:24:06,840 UNDERSTAND THE FUNCTION OF THE 6745 04:24:06,840 --> 04:24:08,480 POMT1 AND 2 COMPLEX DURING 6746 04:24:08,480 --> 04:24:10,800 DEVELOPMENT IN DIFFERENT 6747 04:24:10,800 --> 04:24:11,040 TISSUES. 6748 04:24:11,040 --> 04:24:14,400 I THINK I'M GETTING TO THE END 6749 04:24:14,400 --> 04:24:16,520 OF MY TIME, BUT HOW--I WAS GOING 6750 04:24:16,520 --> 04:24:19,280 TO TELL YOU LIKE VERY, VERY 6751 04:24:19,280 --> 04:24:21,920 QUICKLY, ALSO HOW WE'RE USING 6752 04:24:21,920 --> 04:24:23,560 CRISPR TO GENERATE ADDITIONAL 6753 04:24:23,560 --> 04:24:24,800 MUTANTS IN THE ZEBRA FISH, CAN 6754 04:24:24,800 --> 04:24:29,320 YOU USE THIS REALLY COOL 6755 04:24:29,320 --> 04:24:33,360 APPROACH WHERE CAN YOU DO WHAT'S 6756 04:24:33,360 --> 04:24:35,120 CALLED A CRISPINT AND IT 6757 04:24:35,120 --> 04:24:38,160 GENERATESSA I HIGHLY EMBRYONIC 6758 04:24:38,160 --> 04:24:40,280 EMRIO TO DO ANALYSIS OR YOU CAN 6759 04:24:40,280 --> 04:24:41,560 RAISE THESE FISH AND CROSS THEM 6760 04:24:41,560 --> 04:24:45,320 WITH WILD TYPE TO GENERATE A 6761 04:24:45,320 --> 04:24:45,760 STABLE LINE. 6762 04:24:45,760 --> 04:24:49,520 AND SO I'LL JUST SKIP VERY 6763 04:24:49,520 --> 04:24:57,600 QUICKLY, SO WE'VE STARTED DOING 6764 04:24:57,600 --> 04:25:01,000 THIS, GENERATING POMT2 CHRIS 6765 04:25:01,000 --> 04:25:02,480 PINTS AND DISRUPTING THE GLYCAN 6766 04:25:02,480 --> 04:25:04,080 AND WE DID IT WITH 2 MULTIPLE 6767 04:25:04,080 --> 04:25:05,560 GUIDES AND I WILL SHOW THE 6768 04:25:05,560 --> 04:25:08,640 RESULTS OF THE EARLY ANALYSIS OF 6769 04:25:08,640 --> 04:25:10,240 CRISPENT AND STOP THERE, WE 6770 04:25:10,240 --> 04:25:11,560 DIDN'T SEE SURVIVAL TO AFFECTED 6771 04:25:11,560 --> 04:25:12,800 BUT THE PHENOTYPES THAT WE RVE 6772 04:25:12,800 --> 04:25:14,160 ABOUTED WERE VERY SIMILAR TO 6773 04:25:14,160 --> 04:25:19,280 THOSE THAT WE HAD SEEN IN THE 6774 04:25:19,280 --> 04:25:19,520 MORPHINS. 6775 04:25:19,520 --> 04:25:20,840 AND WHAT I'M SHOWING HERE IS THE 6776 04:25:20,840 --> 04:25:22,680 CONTROL THAT WE USE TO CHECK FOR 6777 04:25:22,680 --> 04:25:24,880 CAS 9 AND THE CAS9 FUNCTION AND 6778 04:25:24,880 --> 04:25:27,520 WE SAW A COMBINATION OF SEVERE 6779 04:25:27,520 --> 04:25:29,360 AND MERE MILDLY AFFECTED FISH 6780 04:25:29,360 --> 04:25:30,240 THAT WAS REMINISCENT OF WHAT WE 6781 04:25:30,240 --> 04:25:33,640 SAW IN THE MORPHINS. 6782 04:25:33,640 --> 04:25:34,800 AND WITH THIS I WILL SKIP 6783 04:25:34,800 --> 04:25:38,440 THROUGH THE VERY LAST SLIDE. 6784 04:25:38,440 --> 04:25:39,960 WHAT I TOLD YOU TODAY THE ZEBRA 6785 04:25:39,960 --> 04:25:43,520 FISH CAN BE USE TOTD STUDY MUSK 6786 04:25:43,520 --> 04:25:45,160 LO DYSTROPHY IN THE MOUSE, AND 6787 04:25:45,160 --> 04:25:48,920 MAY BE THE PERFECT MODEL BUT 6788 04:25:48,920 --> 04:25:49,640 GIVES THE OPPORTUNITY TO STUDY 6789 04:25:49,640 --> 04:25:50,720 THE PROGRESSION IN THE BODY, WE 6790 04:25:50,720 --> 04:25:53,760 CAN USE IT TO MULTIPLEX DRUG 6791 04:25:53,760 --> 04:25:55,120 SCREENING FOR SPECIFIC 6792 04:25:55,120 --> 04:25:56,000 PHENOTYPES AND WHAT I'M 6793 04:25:56,000 --> 04:25:57,360 INTERESTED IN IS ALSO THE 6794 04:25:57,360 --> 04:26:00,600 POSSIBILITY TO USE IT TO STUDY 6795 04:26:00,600 --> 04:26:01,800 DISEASE MODIFIERS SINCE ZEBRA 6796 04:26:01,800 --> 04:26:03,320 FISH TEND TO BE LESS SEVERELY 6797 04:26:03,320 --> 04:26:04,880 AFFECTED AND WITH THAT, I WILL 6798 04:26:04,880 --> 04:26:06,840 THANK EVERYBODY IN MY LAB THAT 6799 04:26:06,840 --> 04:26:11,360 I'VE THANKED ALONG THE WAY AND 6800 04:26:11,360 --> 04:26:12,680 OUR FUNDING SOURCES AND SO YOU A 6801 04:26:12,680 --> 04:26:14,840 PICTURE AND TAKE QUESTIONS AT 6802 04:26:14,840 --> 04:26:16,960 THE END AFTER EVERYBODY'S DONE. 6803 04:26:16,960 --> 04:26:17,960 >> OKAY, GREAT. 6804 04:26:17,960 --> 04:26:21,960 THANK YOU SO MUCH CHIARA, GREAT 6805 04:26:21,960 --> 04:26:22,800 PRESENTATION AND WONDERFUL MODEL 6806 04:26:22,800 --> 04:26:24,560 AND AGAIN, EVERYONE AS A 6807 04:26:24,560 --> 04:26:26,400 REMINDER PLEASE SUBMIT YOUR 6808 04:26:26,400 --> 04:26:29,320 QUESTIONS VIA THE SEND LIVE 6809 04:26:29,320 --> 04:26:30,680 FEEDBACK LINK AND AGAIN I WILL 6810 04:26:30,680 --> 04:26:32,320 ANSWER THOSE QUESTIONS AT THE 6811 04:26:32,320 --> 04:26:32,920 END. 6812 04:26:32,920 --> 04:26:35,720 SO AGAIN, I'M HAPPY TO INTRODUCE 6813 04:26:35,720 --> 04:26:39,120 OUR FINAL SPIKER VERY FITTING 6814 04:26:39,120 --> 04:26:43,040 IT'S MICHAEL TIEMEWHY, ER FROM 6815 04:26:43,040 --> 04:26:43,720 COMPLEX CARBOHYDRATE RESEARCH 6816 04:26:43,720 --> 04:26:45,000 CENTER AT THE UNIVERSITY OF 6817 04:26:45,000 --> 04:26:49,720 GEORGIA EXPW ME WILL TELEUS 6818 04:26:49,720 --> 04:26:52,680 ABOUT GLYGEN: A RESOURCE FOR 6819 04:26:52,680 --> 04:26:54,000 INTEGRATING GLYCO SCIENCE 6820 04:26:54,000 --> 04:27:28,200 KNOWLEDGE. 6821 04:27:28,200 --> 04:27:28,520 OKAY, MIKE. 6822 04:27:28,520 --> 04:27:30,560 >> SO OVER THE LAST COUPLE DAYS 6823 04:27:30,560 --> 04:27:33,560 WE'VE HEARD A LOT OF PLACES 6824 04:27:33,560 --> 04:27:39,200 WHERE GLYCOSCIENCE MY INTERFACE 6825 04:27:39,200 --> 04:27:40,320 WITH MODELING AND I WANT TO TALK 6826 04:27:40,320 --> 04:27:44,320 ABOUT A RESOURCE THAT'S MATURING 6827 04:27:44,320 --> 04:27:45,600 THAT MAY HELP PEOPLE PULL 6828 04:27:45,600 --> 04:27:46,880 TOGETHER KNOWLEDGE IN THE FLIEK 6829 04:27:46,880 --> 04:27:48,720 O SCIENCE DOMAIN TO HELP 6830 04:27:48,720 --> 04:27:51,040 GENERATE HYPOTHESIS RELATED TO 6831 04:27:51,040 --> 04:27:54,480 THEIR WORK, AND LET ME JUST TALK 6832 04:27:54,480 --> 04:27:57,840 INITIALLY ABOUT JUSTIFICATION 6833 04:27:57,840 --> 04:28:00,720 FOR THIS SORT OF EFFORT. 6834 04:28:00,720 --> 04:28:06,000 SO THIS IS A NICE FIGURE FROM A 6835 04:28:06,000 --> 04:28:07,760 REVIEW THAT JAMIE MARTH THAT 6836 04:28:07,760 --> 04:28:08,960 LAYS OUT THE 4 DOMAINS OF 6837 04:28:08,960 --> 04:28:11,520 MOLECULES THAT ARE ESSENTIAL FOR 6838 04:28:11,520 --> 04:28:12,160 LIFE. 6839 04:28:12,160 --> 04:28:15,680 NUCLEIC ACIDS PROTEINS LIPIDS 6840 04:28:15,680 --> 04:28:17,760 AND AS JAMIE EMPHASIZED GLYCANS 6841 04:28:17,760 --> 04:28:27,840 AND FOR EACH OF THESE DOMAINS OF 6842 04:28:27,840 --> 04:28:29,480 LIFE AND FOR 3 OF THESE, THEY 6843 04:28:29,480 --> 04:28:31,480 ARE SUBJECT TO WELL CURATION, 6844 04:28:31,480 --> 04:28:38,720 WELL FUNDED SO GENBANK, 6845 04:28:38,720 --> 04:28:40,280 REFSEQGENE AND LIPIDS BUT WHAT'S 6846 04:28:40,280 --> 04:28:43,480 MISSING IS OR HAS BEEN MISSING 6847 04:28:43,480 --> 04:28:46,040 IN THE PAST IS THE SAME SORT OF 6848 04:28:46,040 --> 04:28:47,880 RESOURCE FOR GLYCANS SO WHERE 6849 04:28:47,880 --> 04:28:50,120 ARE THE GLYCAN DATABASES AND 6850 04:28:50,120 --> 04:28:50,960 WHAT'S HINDERED THEIR 6851 04:28:50,960 --> 04:28:51,800 DEVELOPMENT OVER THE DECADES 6852 04:28:51,800 --> 04:28:53,520 WELL IN MANY WAYS IT HAS TO DO 6853 04:28:53,520 --> 04:28:55,240 WITH THE INTRINSIC NATURE OF 6854 04:28:55,240 --> 04:28:57,160 THESE MOLECULES, THE GLYCANS 6855 04:28:57,160 --> 04:29:00,120 THAT ARE--TEND TO BE BRANCHED, 6856 04:29:00,120 --> 04:29:01,960 AND CAN EXIST IN THE MONOMERS 6857 04:29:01,960 --> 04:29:04,040 THAT BUILD THESE CAN BE LISTENED 6858 04:29:04,040 --> 04:29:07,440 TOGETHER IN VARIOUS SORTS OF 6859 04:29:07,440 --> 04:29:08,640 CHEMISTRY AND COMPLEXITIES AND 6860 04:29:08,640 --> 04:29:13,120 THAT'S HARD TO REPRESENT IPT 6861 04:29:13,120 --> 04:29:14,720 GREATER FORMATICALLY COMPARED TO 6862 04:29:14,720 --> 04:29:40,320 LINEAR POLYMERS LIKE PROTEINS OR 6863 04:29:40,320 --> 04:29:41,360 GENE SEQUENCES. 6864 04:29:41,360 --> 04:29:43,120 --TALK ABOUT GLYCANS AND TALK 6865 04:29:43,120 --> 04:29:44,240 ABOUT POST TRANSLATIONAL MODISHS 6866 04:29:44,240 --> 04:29:47,360 TO PROVIDE A RESOURCE THAT KLOW 6867 04:29:47,360 --> 04:29:48,960 PEOPLE TO INTERROGATE 6868 04:29:48,960 --> 04:29:50,720 GLYCOSCIENCE DATA SO GLYGEN JUST 6869 04:29:50,720 --> 04:29:54,440 A BIT OF BACKGROUND IS FUNDED BY 6870 04:29:54,440 --> 04:29:58,640 THE COMMON FUND, UO1 THAT 6871 04:29:58,640 --> 04:29:59,000 STARTED IN 2017. 6872 04:29:59,000 --> 04:29:59,720 AFRICAN AMERICAN YEAR OF 6873 04:29:59,720 --> 04:30:01,400 PLANNING AND WE THINK THAT'S 6874 04:30:01,400 --> 04:30:02,520 REALLY IMPORTANT, DURING THAT 6875 04:30:02,520 --> 04:30:05,200 YEAR OF PLANNING THE PROCESS WAS 6876 04:30:05,200 --> 04:30:06,600 TO ENGAGE STAKEHOLDERS AND THE 6877 04:30:06,600 --> 04:30:08,120 PEOPLE WE PRESUMED WOULD USE 6878 04:30:08,120 --> 04:30:10,480 THIS RESOURCE TO ASK THEM HOW 6879 04:30:10,480 --> 04:30:11,880 THEY WOULD--WHAT THEY WOULD 6880 04:30:11,880 --> 04:30:14,640 WANT, HOW THEY WOULD USE GLYGEN 6881 04:30:14,640 --> 04:30:16,160 AND WE TRIED TO BUILD THE 6882 04:30:16,160 --> 04:30:17,560 RESOURCE OFFER THE LAST 5 YEARS 6883 04:30:17,560 --> 04:30:19,920 TO ADDRESS THOSE NEEDS AND THOSE 6884 04:30:19,920 --> 04:30:21,240 DESIRES AS WELL AS WE COULD, WE 6885 04:30:21,240 --> 04:30:23,200 ARE IN OUR FINAL YEAR OF COMMON 6886 04:30:23,200 --> 04:30:24,520 FUND SUPPORT HOPING TO BRIDGE TO 6887 04:30:24,520 --> 04:30:26,760 OTHER SORTS OF SUPPORT IN THE 6888 04:30:26,760 --> 04:30:27,000 FUTURE. 6889 04:30:27,000 --> 04:30:30,880 AND WE CONTINUE TO ENGAGE INPUT 6890 04:30:30,880 --> 04:30:32,640 FROM USERS INSIDE AND OUTSIDE 6891 04:30:32,640 --> 04:30:35,280 THE GLYCOSCIENCE COMMUNITY TO 6892 04:30:35,280 --> 04:30:37,000 TRY AND IMPROVE OUR RESOURCE AND 6893 04:30:37,000 --> 04:30:38,680 MOST IMPORTANTLY I THINK FOR OUR 6894 04:30:38,680 --> 04:30:40,400 FUTURE, WE ARE REALLY NOW TRYING 6895 04:30:40,400 --> 04:30:42,200 TO CROSS LINK AS MUCH AS WE CAN 6896 04:30:42,200 --> 04:30:45,520 WITH OTHER DATA TYPES TO TRY AND 6897 04:30:45,520 --> 04:30:47,480 ESSENTIALLY BUILD A BROADER 6898 04:30:47,480 --> 04:31:02,760 KNOWLEDGE IN THE IMPORTANCE OF 6899 04:31:02,760 --> 04:31:03,080 GLYCANS. 6900 04:31:03,080 --> 04:31:04,800 I WANTED TO GO OVER THE FEATURES 6901 04:31:04,800 --> 04:31:05,960 AND STRUCTURE AND I WILL TURN IN 6902 04:31:05,960 --> 04:31:08,960 THE LAST PART OF MY BRIEF 6903 04:31:08,960 --> 04:31:10,000 PRESENTATION IT TALK ABOUT WHAT 6904 04:31:10,000 --> 04:31:11,640 WE CONSIDER SORT OF A FIRST KIND 6905 04:31:11,640 --> 04:31:13,840 OF KNOWLEDGE GRAPH IN THE 6906 04:31:13,840 --> 04:31:15,600 GLYCOSCIENCE DOMAIN FEATURE WE 6907 04:31:15,600 --> 04:31:16,400 CALL THE SUPERSEARCH, SHOW YOU 6908 04:31:16,400 --> 04:31:18,080 HOW WE HOPE THAT IT WILL ALLOW 6909 04:31:18,080 --> 04:31:19,600 PEOPLE TO ENTER INTO GLYCO 6910 04:31:19,600 --> 04:31:21,200 SCIENCE KNOWLEDGE EVEN IF THEY 6911 04:31:21,200 --> 04:31:23,400 KNOW VERY LITTLE ABOUT WHAT 6912 04:31:23,400 --> 04:31:23,720 GLYCANS ARE. 6913 04:31:23,720 --> 04:31:27,080 SO I JUST WANT TO START WITH THE 6914 04:31:27,080 --> 04:31:32,080 LITTLE BIT OF AN ENDORSEMENT OR 6915 04:31:32,080 --> 04:31:34,720 A PERSPECTIVE ABOUT HOW IT FIT 6916 04:31:34,720 --> 04:31:37,360 INTOS A LARGER WORLD OF EFFORTS 6917 04:31:37,360 --> 04:31:38,800 TO UNDERSTAND AND GENERATE 6918 04:31:38,800 --> 04:31:41,240 DATABASES AND KNOWLEDGE BASES IN 6919 04:31:41,240 --> 04:31:42,480 THE GLYCOSCIENCE. 6920 04:31:42,480 --> 04:31:43,680 THIS IS 1 OF THE FOUNDING 6921 04:31:43,680 --> 04:31:48,800 MEMBERS OF THE GLYSPACE ALLIANCE 6922 04:31:48,800 --> 04:31:52,360 THAT INCLUDES GROUPS IN THIS 6923 04:31:52,360 --> 04:31:54,000 JAPAN AND AUSTRALIA AND 6924 04:31:54,000 --> 04:31:56,760 SWITZERLAND, AND A LOT OF THIS 6925 04:31:56,760 --> 04:31:59,120 ALLIANCE AND THIS COOPERATIVITY 6926 04:31:59,120 --> 04:31:59,800 BETWEEN THESE EFFORTINGS REALLY 6927 04:31:59,800 --> 04:32:03,920 ROSE OUT OF EFFORTS THAT THE 6928 04:32:03,920 --> 04:32:05,320 COMMUNITY INITIATED TO BUILD A 6929 04:32:05,320 --> 04:32:11,440 REPOSITORY IN A WAY TO TO HAVE 6930 04:32:11,440 --> 04:32:14,120 EXCEPTIONS FOR GLYCAN STRUCTURES 6931 04:32:14,120 --> 04:32:15,080 SO THAT'SENTIOUS SENTIAL FOR 6932 04:32:15,080 --> 04:32:16,520 DEALING WITH THESE IN AN 6933 04:32:16,520 --> 04:32:17,240 INFORMATIC WAY IN SOMETHING YOU 6934 04:32:17,240 --> 04:32:19,320 CAN REFER TO THE STRUCTURE AS 6935 04:32:19,320 --> 04:32:22,880 CORRELATED POSED TO A CARTOON OR 6936 04:32:22,880 --> 04:32:27,840 A LONG HAND DESCRIBE OF THE 6937 04:32:27,840 --> 04:32:28,760 CHEMICAL IN NATURE. 6938 04:32:28,760 --> 04:32:31,720 SO GLUE MARIOUS TOUCAN TAKES 6939 04:32:31,720 --> 04:32:32,760 THESE EXPRESSIONS TO HARMONIZE 6940 04:32:32,760 --> 04:32:33,880 RECORDS AND WE SHARE THAT 6941 04:32:33,880 --> 04:32:36,120 FEATURE WITH OTHER EFFORTS 6942 04:32:36,120 --> 04:32:36,880 ACROSS THE WORLD. 6943 04:32:36,880 --> 04:32:38,160 AND SOME OF THOSE AS I MENTIONED 6944 04:32:38,160 --> 04:32:47,840 SOME OF THOSE EFFORTS ARE IN 6945 04:32:47,840 --> 04:32:50,720 GRAP AN GLUE MARIOUS CONNECT AND 6946 04:32:50,720 --> 04:32:53,240 WE FORMED THE GLYSPACE ALLIANCE 6947 04:32:53,240 --> 04:32:54,560 AND WE BACK EACH OTHER UP AND 6948 04:32:54,560 --> 04:33:04,800 MOVE FORWARD TOGETHER AND NOT IN 6949 04:33:04,800 --> 04:33:06,520 DIFFERENT DIRECTIONS. 6950 04:33:06,520 --> 04:33:07,920 SO GLYGEN IS BUILT AROUND THIS 6951 04:33:07,920 --> 04:33:12,960 AND IT'S IN A CENTRAL TRIAD OF 6952 04:33:12,960 --> 04:33:17,560 PROTEINS, GLYCANS AND HOW THESE 6953 04:33:17,560 --> 04:33:19,760 GL YCANS MAY BE LINKED TO THE 6954 04:33:19,760 --> 04:33:20,480 MODIIVES OF PROTEINS. 6955 04:33:20,480 --> 04:33:22,000 WOOER ALSO INTERESTED IN GLYCANS 6956 04:33:22,000 --> 04:33:23,320 BY THEMSELVES AND PROTEINS BY 6957 04:33:23,320 --> 04:33:24,640 THEMSELVES BUT THE UNIQUENESS IS 6958 04:33:24,640 --> 04:33:27,320 THAT WE TRY TO TIE IT TOGETHER, 6959 04:33:27,320 --> 04:33:31,560 GLYCOSYLATION IS A CONCEPT AND 6960 04:33:31,560 --> 04:33:32,600 OUR--THE DATA WE DERIVED COMES 6961 04:33:32,600 --> 04:33:35,040 FROM A LARGE NUMBER OF SOURCES 6962 04:33:35,040 --> 04:33:37,720 FROM PROTEINS CAN YOU SEE 6963 04:33:37,720 --> 04:33:39,000 SOME--HERE THAT YOU RECOGNIZE 6964 04:33:39,000 --> 04:33:39,960 FOR DPLI KAN--KANAS WE 6965 04:33:39,960 --> 04:33:44,840 CHARACTERIZE AND BRING IN DATA 6966 04:33:44,840 --> 04:33:46,120 OF DIFFERENT TYPES OF FROM 6967 04:33:46,120 --> 04:33:50,280 VARIOUS SOURCES AND THEN OUR 6968 04:33:50,280 --> 04:33:52,120 PARTNERS AND DATA PROVIDERS 6969 04:33:52,120 --> 04:33:55,640 ALLOW US TO INCORPORATE DPLI 6970 04:33:55,640 --> 04:33:56,200 COSALATION SITE INFORMATION 6971 04:33:56,200 --> 04:34:00,120 ALONG WITH THE PROTEIN IN GLYCAN 6972 04:34:00,120 --> 04:34:01,280 DATA. 6973 04:34:01,280 --> 04:34:03,120 SO WE CURRENTLY COVER A 6974 04:34:03,120 --> 04:34:04,520 RELATIVELY SMALL BUT GROWING 6975 04:34:04,520 --> 04:34:05,920 NUMBER OF SPECIES, WE'VE BEEN 6976 04:34:05,920 --> 04:34:07,920 FOCUSED FROM THE BEGINNING ON 6977 04:34:07,920 --> 04:34:09,240 HUMAN GLYCOSYLATION DATA AS WELL 6978 04:34:09,240 --> 04:34:11,200 AS EXPANDING THAT TO MOUSE AND 6979 04:34:11,200 --> 04:34:13,320 RAT. 6980 04:34:13,320 --> 04:34:14,520 WE'VE ALSO INCLUDED 6981 04:34:14,520 --> 04:34:15,720 INSIGNETHETIC DPLI KAN--KANAS 6982 04:34:15,720 --> 04:34:19,120 WITHIN OUR DATABASE AND VIRAL 6983 04:34:19,120 --> 04:34:21,320 CONSTRUCTS AS WELL AS DISTINCT 6984 04:34:21,320 --> 04:34:24,120 SPECIES AND WE'VE BEGUN TO 6985 04:34:24,120 --> 04:34:25,080 INCORPORATE DROSOPHILA DATA IN 6986 04:34:25,080 --> 04:34:27,080 OUR FINAL YEAR OF FUNDING AND 6987 04:34:27,080 --> 04:34:29,480 THEN EFFORT IS ONGOING. 6988 04:34:29,480 --> 04:34:33,400 AT A GLANCE WHAT WE HAVE IN 6989 04:34:33,400 --> 04:34:36,680 GLYCAN, WELL, OVER 30,000 6990 04:34:36,680 --> 04:34:40,720 GLYCANS OVER 12,000 GLYCO 6991 04:34:40,720 --> 04:34:44,560 PROTEINS, OVER 57,000 SITES 6992 04:34:44,560 --> 04:34:46,520 ACROSS ALL SPECIES 64,000 6993 04:34:46,520 --> 04:34:53,040 PROTEINS ARE ACCESSIBLE THROUGH 6994 04:34:53,040 --> 04:34:54,480 IN GLYCANS DATA. 6995 04:34:54,480 --> 04:34:57,280 BE YOU CAN GET TO THIS DATA IN 1 6996 04:34:57,280 --> 04:34:57,680 OF 2 WAYS. 6997 04:34:57,680 --> 04:34:59,160 YOU CAN GET THROUGH IT THROUGH 6998 04:34:59,160 --> 04:35:01,800 THE DATA PORTAL, ALL THE DATA WE 6999 04:35:01,800 --> 04:35:02,640 INCORPORATED IS FREELY 7000 04:35:02,640 --> 04:35:02,920 AVAILABLE. 7001 04:35:02,920 --> 04:35:03,840 YOU NEED TO ACKNOWLEDGE THAT YOU 7002 04:35:03,840 --> 04:35:05,440 GOT IT FROM US. 7003 04:35:05,440 --> 04:35:08,880 AND THESE ARE AVAILABLE AS FILES 7004 04:35:08,880 --> 04:35:10,520 AND THERE'S A END POINT THAT 7005 04:35:10,520 --> 04:35:15,120 ALLOWS YOU TO DEVELOP YOUR OWN 7006 04:35:15,120 --> 04:35:16,600 QUEERS AND TAKE THE DATA AND DO 7007 04:35:16,600 --> 04:35:18,120 WHATEVER YOU WANT SO IT'S 7008 04:35:18,120 --> 04:35:19,080 FREELYY AVAILABLE SO THERE'S 7009 04:35:19,080 --> 04:35:22,400 ACCESS TO THE DATA DIRECTLY FROM 7010 04:35:22,400 --> 04:35:24,440 THE DATA PORTAL THERE'S ALSO 7011 04:35:24,440 --> 04:35:25,560 ACCESS THROUGH THE WEB INTERFACE 7012 04:35:25,560 --> 04:35:27,760 AND I WILL QUICKLY SHOW YOU THE 7013 04:35:27,760 --> 04:35:28,720 FEATURES OF THAT INTERFACE, THIS 7014 04:35:28,720 --> 04:35:33,960 IS THE HOME PAGE, THIS S&P THE 7015 04:35:33,960 --> 04:35:37,880 GLYGENHOME PLACE AND 7016 04:35:37,880 --> 04:35:39,120 WWW.GLYGEN.ORGWE ENCOURAGE TO 7017 04:35:39,120 --> 04:35:40,800 YOU EXPLORE IT ON YOUR OWN. 7018 04:35:40,800 --> 04:35:42,360 THERE ARE SURFACES THAT 1 CAN 7019 04:35:42,360 --> 04:35:44,960 PERFORM SO THEREYA A SEARCH, 7020 04:35:44,960 --> 04:35:45,800 PROTEIN SEARCH, SITE SEARCH 7021 04:35:45,800 --> 04:35:48,120 AGAIN, THESE ARE THE SORT OF 7022 04:35:48,120 --> 04:35:50,480 CENTRAL TRIAD OF WHAT IT OFFERS, 7023 04:35:50,480 --> 04:35:53,760 AND WE OFFER A SORT OF QUICK 7024 04:35:53,760 --> 04:35:58,000 SEARCHES WHERE YOU CAN PUT IN 7025 04:35:58,000 --> 04:35:59,640 INQUIRIES AND QUICKLY SEE, 7026 04:35:59,640 --> 04:36:02,640 HOPEFULLY GET AN ANSWER, WE 7027 04:36:02,640 --> 04:36:04,960 PROVIDE SOME BACKGROUND, SOME 7028 04:36:04,960 --> 04:36:05,520 INSTRUCTIONAL INFORMATION, 7029 04:36:05,520 --> 04:36:08,320 VIDEOS THAT DESCRIBE HOW TO USE 7030 04:36:08,320 --> 04:36:09,920 ASPECTS OF GLYGEN BUT WE ALSO 7031 04:36:09,920 --> 04:36:10,960 LINKED OTHER RESOURCES BUT ALL 7032 04:36:10,960 --> 04:36:12,160 OF THESE SEARCHES ARE AVAILABLE 7033 04:36:12,160 --> 04:36:15,120 FROM PULL DOWN MENUS OR OF 7034 04:36:15,120 --> 04:36:16,320 COURSE FROM THESE CARDSAs WELL 7035 04:36:16,320 --> 04:36:17,880 SO THIS IS PART OF THE FRONT 7036 04:36:17,880 --> 04:36:21,320 PAGE, IF YOU SCROLL DOWN YOU SEE 7037 04:36:21,320 --> 04:36:22,920 ANOTHER PART OF FRONT PAGE WHERE 7038 04:36:22,920 --> 04:36:24,080 WE HAVE CURATED TPHREU RACING 7039 04:36:24,080 --> 04:36:25,160 KAN--KANA PROTEEF LISTS WHICH 7040 04:36:25,160 --> 04:36:26,400 ARE VERY IMPORTANT FOR THINKING 7041 04:36:26,400 --> 04:36:27,440 ABOUT FUNCTION AND WE WILL TALK 7042 04:36:27,440 --> 04:36:28,680 ABOUT THAT AGAIN IN A LITTLE 7043 04:36:28,680 --> 04:36:29,440 BIT. 7044 04:36:29,440 --> 04:36:32,800 WE HAVE WAYS TO BROWSE THROUGH 7045 04:36:32,800 --> 04:36:33,840 GLYKAN--KANA STRUCTURES EITHER 7046 04:36:33,840 --> 04:36:35,720 AS COMPOSITIONS OR AS ACTUAL 7047 04:36:35,720 --> 04:36:38,320 STRUCTURES THAT ARE INTERRELATED 7048 04:36:38,320 --> 04:36:39,520 BASED ON ISOMERIC 7049 04:36:39,520 --> 04:36:40,360 CONFIGURURATIONS, AGAIN, A DATA 7050 04:36:40,360 --> 04:36:42,920 PORTAL TO GET TO ALL THE DATA, 7051 04:36:42,920 --> 04:36:45,120 WAYS TO INTERACT WITH THE DATA, 7052 04:36:45,120 --> 04:36:46,960 STATISTICS OF OUR DATABASE, AND 7053 04:36:46,960 --> 04:36:50,520 IF WE SCROLL DOWN TO THE BOTTOM, 7054 04:36:50,520 --> 04:36:53,880 THERE'S A UNIQUE SET OF WAYS TO 7055 04:36:53,880 --> 04:36:56,520 UNDERSTAND WHAT GLYGEN DOES BY 7056 04:36:56,520 --> 04:36:58,040 TRY ME QUESTIONS THAT ARE 7057 04:36:58,040 --> 04:37:03,040 PRECANNED THAT,A LOW --ALLOW YOU 7058 04:37:03,040 --> 04:37:04,720 TO SEE WHAT GLYGEN CAN OFFER. 7059 04:37:04,720 --> 04:37:07,680 WE ALSO HAVE A PLAYGROUND WE 7060 04:37:07,680 --> 04:37:09,200 CALL THE SAND BOX WHERE WE TRY 7061 04:37:09,200 --> 04:37:11,840 NEW THINGS AND GENERATE NEW 7062 04:37:11,840 --> 04:37:13,960 TOOLS THAT ENRICH EXPERIENCE OF 7063 04:37:13,960 --> 04:37:15,040 GLYGEN, I WON'T TALK ABOUT THE 7064 04:37:15,040 --> 04:37:16,680 SAND BOX TODAY BUT IT'S AN 7065 04:37:16,680 --> 04:37:18,160 INTERESTING FEATURE THAT WE 7066 04:37:18,160 --> 04:37:19,920 CONTINUE TO DEVELOP AND MOVE 7067 04:37:19,920 --> 04:37:25,000 THINGS THAT FROM THE SAND BOX 7068 04:37:25,000 --> 04:37:25,440 INTO GLYGEN PROPER. 7069 04:37:25,440 --> 04:37:29,200 SO THE REST OF THE TIME I WANT 7070 04:37:29,200 --> 04:37:32,240 TO TALK ABOUT HOW PEOPLE MIGHT 7071 04:37:32,240 --> 04:37:33,640 ACCESS GLYGEN IF I THEY DIDN'T 7072 04:37:33,640 --> 04:37:36,080 KNOW ANYTHING ABOUT THE BIOLOGY, 7073 04:37:36,080 --> 04:37:37,160 MAYBE THEY READ A PAPER AND 7074 04:37:37,160 --> 04:37:38,040 SOMETHING POPS UP IN THE PAPER 7075 04:37:38,040 --> 04:37:40,240 AND YOU WOULD LIKE TO KNOW MORE 7076 04:37:40,240 --> 04:37:40,640 ABOUT THAT RIGHT? 7077 04:37:40,640 --> 04:37:42,040 SO MAYBE A PAPER LIKE THIS, YOU 7078 04:37:42,040 --> 04:37:45,320 ARE INTERESTED IN NOTCH, YOU'RE 7079 04:37:45,320 --> 04:37:46,560 INTERESTED IN NEURAL STEM CELL 7080 04:37:46,560 --> 04:37:47,160 DIFFERENTIATION AND YOU SLEEP 7081 04:37:47,160 --> 04:37:51,040 APNEA AND OBESITYY THIS PAPER 7082 04:37:51,040 --> 04:37:56,520 THAT LOOKS INCREEINGING, LOUIS 7083 04:37:56,520 --> 04:37:57,720 X-CARRYING N-GLYCANS REGULATE 7084 04:37:57,720 --> 04:37:59,720 THE PROLIFERATION OF MOUSE 7085 04:37:59,720 --> 04:38:01,440 EMBRYONIC NEURAL STEM CELLS VIA 7086 04:38:01,440 --> 04:38:02,840 THE NOTCH SIGNALING PATHWAY, AND 7087 04:38:02,840 --> 04:38:04,520 THEY SHOW THAT YOU HAVE A MUCH 7088 04:38:04,520 --> 04:38:05,720 HIGHER ABUNDANCE OF PROTEINS 7089 04:38:05,720 --> 04:38:08,040 THAT ARE MODIFIED WITH LOUIS X 7090 04:38:08,040 --> 04:38:10,720 AND ANTIBODIES TO LEWIS X SO THE 7091 04:38:10,720 --> 04:38:12,160 UNDIFFERENTIATED CELLS A LOT 7092 04:38:12,160 --> 04:38:13,760 MORE STANDING THAN 7093 04:38:13,760 --> 04:38:14,360 DIFFERENTIATED CELLS, RIGHT? 7094 04:38:14,360 --> 04:38:18,600 SO THAT LOOKS LIKE IT MIGHT BE 7095 04:38:18,600 --> 04:38:19,880 AN INTERESTING THING TO LOOK AT 7096 04:38:19,880 --> 04:38:22,440 BUT WHAT IS LEWIS X, WHAT 7097 04:38:22,440 --> 04:38:24,080 PROTEINS ARE MODIFIED WITH THIS 7098 04:38:24,080 --> 04:38:26,320 LEWIS X, DO YOU FIND LEWIS X ON 7099 04:38:26,320 --> 04:38:27,880 A LOT OF PROTEINS OR ANY OF 7100 04:38:27,880 --> 04:38:28,840 THOSE PROTEINS ASSOCIATE WIDE 7101 04:38:28,840 --> 04:38:29,600 DISEASE. 7102 04:38:29,600 --> 04:38:30,920 WHERE WOULD YOU GO TO FIND THAT 7103 04:38:30,920 --> 04:38:31,360 INFORMATION? 7104 04:38:31,360 --> 04:38:32,480 YOU COULD GO BACK TO THE 7105 04:38:32,480 --> 04:38:34,920 LITERATURE AND DO VARIOUS 7106 04:38:34,920 --> 04:38:36,160 LITERATURE SEARCHES, OR YOU 7107 04:38:36,160 --> 04:38:37,960 COULD COME TO GLYGEN AND USE 7108 04:38:37,960 --> 04:38:40,720 LAWN MOWER WE CALL A SUPER 7109 04:38:40,720 --> 04:38:40,920 SEARCH. 7110 04:38:40,920 --> 04:38:44,240 I WILL SHOW YOU HOW THIS ALLOWS 7111 04:38:44,240 --> 04:38:47,360 1 TO INVESTIGATE SORT OF 7112 04:38:47,360 --> 04:38:49,400 MULTIFACTORIAL CONCEPTS OF GLYCO 7113 04:38:49,400 --> 04:38:49,640 SCIENCE. 7114 04:38:49,640 --> 04:38:49,880 RIGHT? 7115 04:38:49,880 --> 04:38:51,920 SO THIS IS A SUPER SEARCH IRPT 7116 04:38:51,920 --> 04:38:53,120 FACE AND CAN YOU SEE THAT WE 7117 04:38:53,120 --> 04:38:54,320 COLLECTED HERE IN THESE BOXES 7118 04:38:54,320 --> 04:38:58,120 THE TYPE OF DATA THAT WE 7119 04:38:58,120 --> 04:39:00,000 ACTUALLY HAVE AT GLYGEN AND FOR 7120 04:39:00,000 --> 04:39:02,240 EACH OF THESE BOXES CAN YOU SEE 7121 04:39:02,240 --> 04:39:04,200 THE NUMBER OF INDIVIDUAL RECORDS 7122 04:39:04,200 --> 04:39:07,640 WE HAVE FOR THAT KIND OF DATA SO 7123 04:39:07,640 --> 04:39:08,280 434,000 SITES. 7124 04:39:08,280 --> 04:39:10,720 THIS IS ACTUALLY A BIT OLD 7125 04:39:10,720 --> 04:39:12,440 EMPLOY I DIDN'T REDO THE DEMO 7126 04:39:12,440 --> 04:39:13,880 LAST NIGHT BUT THE NUMBERS ARE 7127 04:39:13,880 --> 04:39:15,120 ACTUALLY A LITTLE BIT HIGHER 7128 04:39:15,120 --> 04:39:15,280 NOW. 7129 04:39:15,280 --> 04:39:17,360 SO CAN YOU SEE WHAT WE HAVE IN 7130 04:39:17,360 --> 04:39:19,720 THOSE BINS, AND IF YOU CLICK ON 7131 04:39:19,720 --> 04:39:21,120 THE ADVANCED VIEW HERE, IT WILL 7132 04:39:21,120 --> 04:39:24,520 ALSO TELL YOU THEN WHAT WE HAVE 7133 04:39:24,520 --> 04:39:27,400 ON THE EDGES. 7134 04:39:27,400 --> 04:39:30,840 SO, GLYGEN HAS 64,219 PROTEINS. 7135 04:39:30,840 --> 04:39:35,680 53,291 OF THOSE PROTEINS 7136 04:39:35,680 --> 04:39:37,360 TOGETHER HAVE 433,990 SITES 7137 04:39:37,360 --> 04:39:37,960 ASSOCIATED WITH THEM. 7138 04:39:37,960 --> 04:39:43,440 SO 1 CAN BEGIN TO EXPLORE WITHIN 7139 04:39:43,440 --> 04:39:45,400 THAT DATA SET OF CONCEPTS THAT 7140 04:39:45,400 --> 04:39:46,480 MAY LINK THEM TOGETHER SO WE 7141 04:39:46,480 --> 04:39:48,000 WILL START HERE WITH THIS NOTION 7142 04:39:48,000 --> 04:39:50,200 OF DOING A MOTIF, SUPERSEARCH, 7143 04:39:50,200 --> 04:39:52,320 SO CLICK ON THAT MOTIF BOX AND 7144 04:39:52,320 --> 04:39:53,800 THEN CAN YOU ENTER THE 7145 04:39:53,800 --> 04:39:54,920 PARAMETERS THAT YOU MIGHT BE 7146 04:39:54,920 --> 04:39:57,160 INTERESTED IN SEARCHING, WE'RE 7147 04:39:57,160 --> 04:39:58,720 INTERESTED IN INCLUDING A NAME, 7148 04:39:58,720 --> 04:40:01,120 AND THAT NAME IS LEWIS X SO WE 7149 04:40:01,120 --> 04:40:02,720 WILL ASK QUESTIONS ABOUT WHAT 7150 04:40:02,720 --> 04:40:04,920 PROTEINS HAVE LEWIS X ON THEM. 7151 04:40:04,920 --> 04:40:10,520 WHAT GLYCANS CARRY LEWIS X 7152 04:40:10,520 --> 04:40:11,640 EPIEPITOAPPROXIMATE E, SO THIS 7153 04:40:11,640 --> 04:40:13,160 IS OUR INTEREST, WE HIT SYRUP 7154 04:40:13,160 --> 04:40:14,280 AND THE SEARCH RESULTS SHOWS 7155 04:40:14,280 --> 04:40:21,120 THAT IN THE GLYGEN DATABASE 7156 04:40:21,120 --> 04:40:22,840 THERE ARE 86 PROTEINS ASSOCIATED 7157 04:40:22,840 --> 04:40:25,840 WITH LEWIS X BUT THEY MAY 7158 04:40:25,840 --> 04:40:27,760 INCLUDE ENZYMES THAT ARE IN THE 7159 04:40:27,760 --> 04:40:30,920 LEWIS X BUT THERE ARE 7 PROTEINS 7160 04:40:30,920 --> 04:40:35,840 THAT HAVE SIGHTS MODIFIED WITH 7161 04:40:35,840 --> 04:40:38,760 THE WEATHER 1 AND ON THOSE 7 7162 04:40:38,760 --> 04:40:40,160 PROTEINS THERE ARE 12 SITES THAT 7163 04:40:40,160 --> 04:40:41,160 MODIFIED SO WE CAN ASK QUESTIONS 7164 04:40:41,160 --> 04:40:43,040 ABOUT WHAT THE PROTEINS ARE AND 7165 04:40:43,040 --> 04:40:44,200 WHAT THE SITES ARE SO LET'S 7166 04:40:44,200 --> 04:40:46,840 START WITH THE SITES, SO THE 7167 04:40:46,840 --> 04:40:47,520 RESULT LIST FROM THAT SITE 7168 04:40:47,520 --> 04:40:49,720 SEARCH THAT CAME FROM THE SUPER 7169 04:40:49,720 --> 04:40:52,800 SEARCH LISTS PROTEINS BY THE 7170 04:40:52,800 --> 04:40:54,760 UNIPRODUCT SESSIONS AND LISTS 7171 04:40:54,760 --> 04:40:56,120 SITES THAT ARE MODIFIED AND WE 7172 04:40:56,120 --> 04:41:00,120 JUST TAKE THE TOP PROTEIN HERE 7173 04:41:00,120 --> 04:41:02,600 THAT'S MODIFIED AT AMINO ACID 95 7174 04:41:02,600 --> 04:41:06,600 AND THIS PROTEIN IS 7175 04:41:06,600 --> 04:41:07,240 INTER--INTERFERON ALPHA 14 AND 7176 04:41:07,240 --> 04:41:10,600 YOU CAN SEE THAT IN AN 7177 04:41:10,600 --> 04:41:11,640 ASPARRAGING 95, 1 OF THE GLYCO 7178 04:41:11,640 --> 04:41:17,680 FORMS OF THIS PROTEIN HAS THIS 7179 04:41:17,680 --> 04:41:22,720 LEWIS EPITOPE THAT INCLUDES 7180 04:41:22,720 --> 04:41:23,280 [INDISCERNIBLE] SO THIS AS A 7181 04:41:23,280 --> 04:41:24,800 LEWIS X IN THE 1 OF THE GLYCO 7182 04:41:24,800 --> 04:41:27,320 FORMS CAN YOU SEE GO THE TO 7183 04:41:27,320 --> 04:41:27,920 SEQUENCE REPRESENTATION THAT 7184 04:41:27,920 --> 04:41:36,040 SHOW SHOWN HERE AND I'VE PRELIE 7185 04:41:36,040 --> 04:41:39,160 HEIGHTED IT IS SEQUENCE WITH 7186 04:41:39,160 --> 04:41:40,560 FEATURES INCLUDING END LINK 7187 04:41:40,560 --> 04:41:42,640 SEATS SO THE RED UNDERLINE IS 7188 04:41:42,640 --> 04:41:43,840 THE DPLI COSALATION SITE AND 7189 04:41:43,840 --> 04:41:45,360 IT'S HIGHLIGHTED HERE IN GREEN, 7190 04:41:45,360 --> 04:41:46,920 BECAUSE THERE'S A VARIATION 7191 04:41:46,920 --> 04:41:50,520 KNOWN TO BE ASSOCIATED WITH THAT 7192 04:41:50,520 --> 04:41:53,320 ASPARRAGING AND IN FACT THAT 7193 04:41:53,320 --> 04:41:55,680 GLYCOSYLATION SITE, 95, THIS IS 7194 04:41:55,680 --> 04:41:57,680 A VERYIATION IN WHICH THAT 7195 04:41:57,680 --> 04:41:58,320 ASPARRAGING IS CONVERT EXPTD 7196 04:41:58,320 --> 04:42:01,120 THEN OF COURSE IS NO LONGER 7197 04:42:01,120 --> 04:42:02,120 SUBSTRATE FOR DPLI COSALATION 7198 04:42:02,120 --> 04:42:05,240 AND THAT'S ASSOCIATED 7199 04:42:05,240 --> 04:42:06,400 WITH--ASSOCIATED WITH COLORECTAL 7200 04:42:06,400 --> 04:42:06,640 CANCER. 7201 04:42:06,640 --> 04:42:11,200 SO WE'VE GONE FROM THE MOTIF 7202 04:42:11,200 --> 04:42:12,480 IDEA, LEWIS X TO A SPECIFIC 7203 04:42:12,480 --> 04:42:16,600 PROTEIN THAT AS I SPECIFIC SITE 7204 04:42:16,600 --> 04:42:17,760 MODIFIED BY THIS AND VARIATIONS 7205 04:42:17,760 --> 04:42:21,440 OF THATVIATE ARE ASSOCIATE WIDE 7206 04:42:21,440 --> 04:42:22,400 THE DISEASE. 7207 04:42:22,400 --> 04:42:24,720 SO 1 CAN GO IN AND EXPLORE WHAT 7208 04:42:24,720 --> 04:42:25,920 PROACTIVE TEENS WITH WITHIN OUR 7209 04:42:25,920 --> 04:42:27,720 DATA SET THAT CARRY THE 1 AND 7210 04:42:27,720 --> 04:42:29,080 HAVE A LIST OF THOSE PROTEINS, 7211 04:42:29,080 --> 04:42:31,800 AND THIS IS THE PROTEIN THAT WE 7212 04:42:31,800 --> 04:42:33,680 WERE PLEKS PLERRING ALREADY IN 7213 04:42:33,680 --> 04:42:35,080 THE IRPT FERON ALPHA 14 BUT 7214 04:42:35,080 --> 04:42:36,520 THERE ARE OTHERS YOU COULD GO IN 7215 04:42:36,520 --> 04:42:41,560 AND ASK WHAT SITES ARE MODIFIED 7216 04:42:41,560 --> 04:42:43,560 WITH THE LEWIS EPITOPE AS WELL 7217 04:42:43,560 --> 04:42:44,920 AND THIS BECOMES HYPOTHESIS AS 7218 04:42:44,920 --> 04:42:48,280 GENERATED TO SAY, IF I'M ABOUTED 7219 04:42:48,280 --> 04:42:50,560 IN LEWIS X WHAT MIGHT BE 7220 04:42:50,560 --> 04:42:53,680 IMPORTANT TO INVESTIGATOR THIS 7221 04:42:53,680 --> 04:42:54,840 POTENTIAL CARRIER OF LEWIS X SO 7222 04:42:54,840 --> 04:42:57,960 THAT'S IF 1 CAME TO GLYGEN WITH 7223 04:42:57,960 --> 04:42:59,640 NO KNOWLEDGE OF WHAT GLYCANS ARE 7224 04:42:59,640 --> 04:43:01,080 BUT YOU WERE INTERESTED IN A 7225 04:43:01,080 --> 04:43:02,240 FUNCTIONAL MOTIF YOU COULD GET 7226 04:43:02,240 --> 04:43:03,280 INFORMATION UPON I WANT TO 7227 04:43:03,280 --> 04:43:05,040 FINISH UP JUST SHOWING AWAY THRA 7228 04:43:05,040 --> 04:43:07,000 YOU CAN ACQUIRE SORT OF NOVEL 7229 04:43:07,000 --> 04:43:09,000 ANSWERS THAT PROBABLY AREN'T 7230 04:43:09,000 --> 04:43:10,480 AVAILABLE ANYWHERE ELSE TO WHAT 7231 04:43:10,480 --> 04:43:11,880 MANY GRIEK O SCOF THES WOULD 7232 04:43:11,880 --> 04:43:12,840 THINK ARE IMPORTANT QUESTIONS SO 7233 04:43:12,840 --> 04:43:14,720 WE WILL KK BACK TO THE SUPER 7234 04:43:14,720 --> 04:43:16,640 SEARCH AGAIN AND NOW WE'RE GOING 7235 04:43:16,640 --> 04:43:20,560 TO DO A SITE SEARCH SO WE'RE 7236 04:43:20,560 --> 04:43:22,640 GOING TO ASK--WE ARE GOING TO 7237 04:43:22,640 --> 04:43:25,160 QUERY THE DATA FOR SITE AND IN 7238 04:43:25,160 --> 04:43:25,920 PARTICULAR A SITE SEQUENCE AND 7239 04:43:25,920 --> 04:43:30,120 WE WANT TO LOOK AT ASPARRAGE 7240 04:43:30,120 --> 04:43:32,200 GENES THAT BE GO GLUE MARIOUS 7241 04:43:32,200 --> 04:43:35,080 COSALATED AND THOSE APSAR GENES 7242 04:43:35,080 --> 04:43:37,080 THAT WHERE THERE'S A SINGLE 7243 04:43:37,080 --> 04:43:38,920 NUCLEOTIDE SO WE'RE ASKING THE 7244 04:43:38,920 --> 04:43:41,360 QUESTION, SHOW ME ALL IN-LINK 7245 04:43:41,360 --> 04:43:44,720 SITES THAT ARE IMPACTED BY A 7246 04:43:44,720 --> 04:43:50,600 CHANGE IN THE RESIDUE WITHIN THE 7247 04:43:50,600 --> 04:43:58,000 NSX ST OR C SE81. 7248 04:43:58,000 --> 04:44:02,920 SO YOU CAN SEE THAT IS 331 7249 04:44:02,920 --> 04:44:05,120 PROTEINS THAT HAVE 9681 SITES 7250 04:44:05,120 --> 04:44:06,920 THAT HAVE ASPARRAGES THAT MAY BE 7251 04:44:06,920 --> 04:44:08,480 IMPACTED BY VARIATIONS, RIGHT? 7252 04:44:08,480 --> 04:44:10,280 SO WE CAN INVESTIGATE THESE 7253 04:44:10,280 --> 04:44:15,440 SITES AND WE'LL JUST TAKE A TOP 7254 04:44:15,440 --> 04:44:15,960 HIT HERE. 7255 04:44:15,960 --> 04:44:21,400 OF PROTEIN IN THIS CASE, IT'S 7256 04:44:21,400 --> 04:44:21,920 [INDISCERNIBLE] 4. 7257 04:44:21,920 --> 04:44:23,720 AND IF WE LOOK AT DECKNOLOGY, 7258 04:44:23,720 --> 04:44:25,840 AND LOOK AT THE SEQUENCE, AND 7259 04:44:25,840 --> 04:44:29,080 WE'RE LOOKING AT DISPARAGING 7260 04:44:29,080 --> 04:44:35,000 281, WHICH IT IS AS END LINK 7261 04:44:35,000 --> 04:44:37,440 CONSENSUS, AS PARAGING XT AND 7262 04:44:37,440 --> 04:44:39,720 THAT IS MODIFIED TO ASERIES 7263 04:44:39,720 --> 04:44:40,560 POINTSINE IN THIS PARTICULAR 7264 04:44:40,560 --> 04:44:41,960 MUTATION AND IN THIS CASE, IT'S 7265 04:44:41,960 --> 04:44:43,720 NOT DISEASE ASSOCIATED WITH YOU 7266 04:44:43,720 --> 04:44:47,480 ABOUT'S A WHOLE LIST OF SITES 7267 04:44:47,480 --> 04:44:50,280 THAT 1 CAN EXPLORE IN WHICH THE 7268 04:44:50,280 --> 04:44:52,400 CONSENSUS FRIENDLY GLYCOSYLATION 7269 04:44:52,400 --> 04:44:55,920 HAS BEEN MODIFIED AWAY FROM 7270 04:44:55,920 --> 04:44:57,320 GLYCOSYLATED SO I WILL FINISH UP 7271 04:44:57,320 --> 04:45:00,840 WITH SOME OF OUR FUTURE GOALS 7272 04:45:00,840 --> 04:45:02,760 FOR GLYGEN AS WE MOVE OUT OF 7273 04:45:02,760 --> 04:45:06,080 COMMON FUND FUNDING AND HOPE FOR 7274 04:45:06,080 --> 04:45:08,520 FUTURE SUCCESS, AND THAT IS THAT 7275 04:45:08,520 --> 04:45:10,280 OUR--1 OF OUR GUIDING LIGHT 7276 04:45:10,280 --> 04:45:12,040 SYSTEM ALWAYS TO ENHANCE DATA 7277 04:45:12,040 --> 04:45:14,320 ACCESSIBILITY TO FIND WAYS TO 7278 04:45:14,320 --> 04:45:16,640 BRING PEOPLE INTO GLYCO SCIENCE 7279 04:45:16,640 --> 04:45:18,720 DATA THAT DON'T NECESSARILY HAVE 7280 04:45:18,720 --> 04:45:19,760 A BACKGROUND IN GLYCOSCIENCE AND 7281 04:45:19,760 --> 04:45:24,000 WE HOPE TO DO THIS BY BUILDING 7282 04:45:24,000 --> 04:45:25,320 SORT OF DOMAIN SPECIFIC PORTALS 7283 04:45:25,320 --> 04:45:29,720 THAT PEOPLE CAN COME TO GLYGEN 7284 04:45:29,720 --> 04:45:31,560 DATA WITH THEIR OWN EXPERTISE. 7285 04:45:31,560 --> 04:45:33,320 ALWAYS WORKING TO EXPAND THE 7286 04:45:33,320 --> 04:45:36,480 AMOUNT OF VOLUME WE HAVE BEEN 7287 04:45:36,480 --> 04:45:37,640 GLYGEN WHICH IS ALWAYS A MAJOR 7288 04:45:37,640 --> 04:45:40,720 PART OF OUR WORK IS TO FIND AND 7289 04:45:40,720 --> 04:45:42,760 CURATE NEW DATA SETS, WE WANT TO 7290 04:45:42,760 --> 04:45:44,520 BEGIN TO INTEGRATE GLYCO 7291 04:45:44,520 --> 04:45:47,400 CONJUGATE FUNCTIONS IF YOU WILL 7292 04:45:47,400 --> 04:45:50,080 DEFINE IN GO TERMS TO GLYCANS 7293 04:45:50,080 --> 04:45:53,440 AND IT WILL BE DONE BY THE 7294 04:45:53,440 --> 04:45:56,240 MOTIFS THAT OUR GROUP HAS--MOTIF 7295 04:45:56,240 --> 04:45:57,520 LISTS THAT OUR GROUP HAS BUILT 7296 04:45:57,520 --> 04:46:01,520 AND YOU CAN LINK THOSE TO 7297 04:46:01,520 --> 04:46:02,000 FUNCTIONAL PROPERTIES. 7298 04:46:02,000 --> 04:46:04,320 BUT WE ALSO ARE CONTINUING TO 7299 04:46:04,320 --> 04:46:06,360 COLLABORATE WITH VARIOUS 7300 04:46:06,360 --> 04:46:08,720 RESOURCES TO EXPLORE HOW GLYCAN 7301 04:46:08,720 --> 04:46:10,000 DATA CAN INTEGRATE WITH LARGER 7302 04:46:10,000 --> 04:46:11,200 DATA SETS AND IN PARTICULAR OVER 7303 04:46:11,200 --> 04:46:12,600 THE LAST YEAR, WE'VE BEEN 7304 04:46:12,600 --> 04:46:14,920 COLLABORATING WITH THE COMMON 7305 04:46:14,920 --> 04:46:15,960 FUND DATA ECOSYSTEM, TO FIGURE 7306 04:46:15,960 --> 04:46:21,040 OUT WHAT THE BEST WAYS ARE TO 7307 04:46:21,040 --> 04:46:22,120 INTEGRATE VARIOUS GLYGEN DATA 7308 04:46:22,120 --> 04:46:23,520 FORM ATS AND WE'RE ALWAYS TRYING 7309 04:46:23,520 --> 04:46:25,360 AND LOOKING FOR OPPORTUNITIES TO 7310 04:46:25,360 --> 04:46:27,320 TALK WITH NONFLIEK O SCIENTISTS 7311 04:46:27,320 --> 04:46:29,960 AND GLYCO SCIENTISTS TO FIGURE 7312 04:46:29,960 --> 04:46:32,680 OUT HOW BEST GLYGEN CAN SERVE 7313 04:46:32,680 --> 04:46:33,960 THEIR NEEDS AND JUST TO FINISH 7314 04:46:33,960 --> 04:46:35,320 UP THIS WAS THE LAST TIME WE 7315 04:46:35,320 --> 04:46:37,720 WERE ABLE ABLE TO BE TOGETHER, 7316 04:46:37,720 --> 04:46:40,720 NOW SEVERAL YEARS AGO BUT THIS 7317 04:46:40,720 --> 04:46:42,480 IS THE TEAM THAT'S PUSHED US 7318 04:46:42,480 --> 04:46:43,400 FORWARD FOR THE LAST 5 YEARS AND 7319 04:46:43,400 --> 04:46:47,120 MANY OF US WILL MOVE FORWARD 7320 04:46:47,120 --> 04:46:49,120 INTO THE NEXT INCARNATION OF 7321 04:46:49,120 --> 04:47:02,120 GLYGEN AND I WILL STOP THERE. 7322 04:47:02,120 --> 04:47:05,520 AND STOP SHARING MY SCREEN AND 7323 04:47:05,520 --> 04:47:07,200 READY FOR QUESTIONS. 7324 04:47:07,200 --> 04:47:08,760 SO AGAIN, THAIRK YOU FOR ALL THE 7325 04:47:08,760 --> 04:47:10,280 SPEAKERS FOR GREAT TALKS AND IF 7326 04:47:10,280 --> 04:47:11,600 YOU CAN TURN ON YOUR CAMERAS AND 7327 04:47:11,600 --> 04:47:14,760 WE WILL GO TO THE CHAT. 7328 04:47:14,760 --> 04:47:15,800 AGAIN, INDIVIDUALS, AGAIN THE 7329 04:47:15,800 --> 04:47:17,920 AUDIENCE AGAIN YOU CAN SEND YOUR 7330 04:47:17,920 --> 04:47:20,520 QUESTIONS VIA THE SEND LIVE 7331 04:47:20,520 --> 04:47:23,640 FEEDBACK LINK AND GOING BACK, I 7332 04:47:23,640 --> 04:47:27,800 HAD ASKED HUGO A QUESTION AND 7333 04:47:27,800 --> 04:47:29,720 MAYBE HE CAN RESPOND, DO PHOTO 7334 04:47:29,720 --> 04:47:34,440 RECEPTOR VS A LIMITED CAPACITY 7335 04:47:34,440 --> 04:47:35,280 FOR LYSOSOMA DEGRADATION FOR 7336 04:47:35,280 --> 04:47:37,120 SUCH A PATHWAY TO SECRETE 7337 04:47:37,120 --> 04:47:38,920 MATERIALS TO OTHER CELLS SUCH AS 7338 04:47:38,920 --> 04:47:41,720 GLUE MARIOUSA TO DEGRADE? 7339 04:47:41,720 --> 04:47:45,480 >> NO, I THINK THE PHOTO 7340 04:47:45,480 --> 04:47:46,440 RECEPTORS ARE VERY SIMILAR TO 7341 04:47:46,440 --> 04:47:50,320 OTHER CELLS AND OTHER NEURONS, 7342 04:47:50,320 --> 04:47:51,960 WHEN YOU ACTIVATE OTHER NEURONS 7343 04:47:51,960 --> 04:47:53,760 YOU PRODUCE DPLIEWK O CERAMIDE 7344 04:47:53,760 --> 04:47:55,520 AND IT IS TRANSFERRED TO GLUE 7345 04:47:55,520 --> 04:47:55,880 MARIOUSA. 7346 04:47:55,880 --> 04:47:58,280 SIMILARLY IN THE VERTEBRATE GLUE 7347 04:47:58,280 --> 04:48:00,120 MARIOUSA AND NEURONS CO CULTURE 7348 04:48:00,120 --> 04:48:02,320 MUCH OF THE DPLIEWK O CERAMIDE 7349 04:48:02,320 --> 04:48:04,920 IS TRANSFERRED TO GLUE MARIOUSA 7350 04:48:04,920 --> 04:48:06,120 WHERE IT'S DEGRADED. 7351 04:48:06,120 --> 04:48:07,840 IN YOU CO CULTURE THEM, I THINK 7352 04:48:07,840 --> 04:48:09,360 THE MAIN DIFFERENCE IS THAT 7353 04:48:09,360 --> 04:48:13,240 IMPLIES IT SEEMS LIKE THIS IS 7354 04:48:13,240 --> 04:48:15,520 THE SOLE PATHWAY. 7355 04:48:15,520 --> 04:48:18,640 GLUE MARIOUSA EXPRESS THE ENZYME 7356 04:48:18,640 --> 04:48:23,000 TO THE GLUCOCERAMIDE AND OTHER 7357 04:48:23,000 --> 04:48:24,880 CELLS JUST DON'T AND THEREFORE 7358 04:48:24,880 --> 04:48:27,320 THEY ALL TD NEURONS HAVE TO 7359 04:48:27,320 --> 04:48:29,840 COMMUNICATE WITH THE VERTEBRATE, 7360 04:48:29,840 --> 04:48:33,200 IT'S CLEAR THAT THE ENZYME THAT 7361 04:48:33,200 --> 04:48:34,840 DEGRADES GLUCOCERAMIDE IS ALSO 7362 04:48:34,840 --> 04:48:36,560 PRESENT IN SOME NEURONS, AND 7363 04:48:36,560 --> 04:48:42,360 PLAYS A ROLE IN NEURONS AS WELL. 7364 04:48:42,360 --> 04:48:44,600 BUT IT'S CLEAR BASED ON THE 7365 04:48:44,600 --> 04:48:47,000 EXPRESSION DATA THAT TYPICALLY, 7366 04:48:47,000 --> 04:48:50,840 DPLIA EXPRESS A LOT MORE, EVEN 7367 04:48:50,840 --> 04:48:54,000 INVERTEBRATE DATABASES OF THE 7368 04:48:54,000 --> 04:48:56,240 ENZYME THAN NEURONS AND SO, ALSO 7369 04:48:56,240 --> 04:49:02,480 IF YOU THINK ABOUT IT, IF YOU 7370 04:49:02,480 --> 04:49:04,480 PRODUCE GLUCOCERAMIDE, IT'S A IN 7371 04:49:04,480 --> 04:49:07,000 YOUR SYNAPSE IN YOUR 7372 04:49:07,000 --> 04:49:07,720 NEUROMUSCULAR JUNCTION BECAUSE 7373 04:49:07,720 --> 04:49:08,920 THERE IS ACTIVITY, IF YOU HAVE 7374 04:49:08,920 --> 04:49:10,560 TO DEGRADE IT IN THE LYSOSOME 7375 04:49:10,560 --> 04:49:13,960 YOU WOULD HAVE TO TRANSPORT 7376 04:49:13,960 --> 04:49:15,360 APPROXIMATE BACK TO THE 7377 04:49:15,360 --> 04:49:17,880 [INDISCERNIBLE] AND THAT'S A LOT 7378 04:49:17,880 --> 04:49:20,400 OF ENERGY AND PATH TO GO, IT'S 7379 04:49:20,400 --> 04:49:21,840 PROBABLY MUCH EASIER TO JUST 7380 04:49:21,840 --> 04:49:23,720 DUMP IT NEXT DOOR IN YOUR DPLEEL 7381 04:49:23,720 --> 04:49:29,840 CELLS AND GET RID OF IT. 7382 04:49:29,840 --> 04:49:30,960 >> HOW MUCH OF THE DPLIEWK O 7383 04:49:30,960 --> 04:49:32,440 CELL SERIES POINTS MID THAT'S 7384 04:49:32,440 --> 04:49:35,280 ACTIVITY RELATED IN TERMS OF ITS 7385 04:49:35,280 --> 04:49:38,080 PRODUCTION IS COMING FROM 7386 04:49:38,080 --> 04:49:39,720 BIOSYNTHESIS VERSUS DEGRADATION 7387 04:49:39,720 --> 04:49:42,760 OF OTHER GLYCO EXTENDED GLYCO 7388 04:49:42,760 --> 04:49:43,320 SINGLE LIPITS? 7389 04:49:43,320 --> 04:49:46,040 >> I DON'T KNOW THE ANSWER BUT, 7390 04:49:46,040 --> 04:49:48,400 YOU SEE BARELY ANY GRIEWK O 7391 04:49:48,400 --> 04:49:49,920 CERAMIDE WHEN THERE IS NO 7392 04:49:49,920 --> 04:49:52,720 NEURONAL ACTIVITY AND WHEN YOU 7393 04:49:52,720 --> 04:49:53,920 INDUCE NEURONAL ACTIVITY YOU SEE 7394 04:49:53,920 --> 04:49:55,520 THE DPLIEWK O CERAMIDE BEING 7395 04:49:55,520 --> 04:49:58,120 PRODUCED AND IF YOU KNOCK OUT 7396 04:49:58,120 --> 04:50:01,240 THE ENZYME THAT PRODUCING THE 7397 04:50:01,240 --> 04:50:04,320 GLUCOCERAMIDE, YOU SEE NO 7398 04:50:04,320 --> 04:50:04,680 GLUCOCERAMIDE. 7399 04:50:04,680 --> 04:50:14,720 SO, THE ANSWER WOULD BE NOT MUCH 7400 04:50:14,720 --> 04:50:16,640 ABOUT THE GLYCOL SIS. 7401 04:50:16,640 --> 04:50:17,920 >> YOU HAVE ANY IDEA WHAT'S 7402 04:50:17,920 --> 04:50:19,120 GOING ON LONG FOR THE RIDE IN 7403 04:50:19,120 --> 04:50:19,720 THE EXOSTUDIES OF MULTIPLE 7404 04:50:19,720 --> 04:50:21,720 ENDOCRINES IS THAT AN 7405 04:50:21,720 --> 04:50:22,160 ADDRESSABLE QUESTION? 7406 04:50:22,160 --> 04:50:23,800 >> VERY INTERESTING QUESTION, 7407 04:50:23,800 --> 04:50:27,760 SPECIALLY WITH RERELATIONSHIP TO 7408 04:50:27,760 --> 04:50:28,200 PARKINSON'S DISEASE. 7409 04:50:28,200 --> 04:50:31,640 OUR DAILY BASIS THEA SUGGESTS IN 7410 04:50:31,640 --> 04:50:37,520 NUCLEI SO IT TURNS OUTTA WHEN 7411 04:50:37,520 --> 04:50:39,000 THE LEVELS ARE ELEVATE YOU TEND 7412 04:50:39,000 --> 04:50:42,040 TO PRODUCE A LOT MORE SIN 7413 04:50:42,040 --> 04:50:44,200 NUCLEIN, AND IN FACTORS RECENTLY 7414 04:50:44,200 --> 04:50:46,840 SHOWN THAT THE SERIES POINTS 7415 04:50:46,840 --> 04:50:52,040 MIDS CAN KIND OF MODEL THE 7416 04:50:52,040 --> 04:50:53,280 FORMATION OF SIN NUCLEIN 7417 04:50:53,280 --> 04:50:55,120 AGGREGATES AND BASED ON THE 7418 04:50:55,120 --> 04:50:56,280 PRELIMINARY DATA WE HAVE 7419 04:50:56,280 --> 04:50:58,400 ALTHOUGH IT'S NOT VERY SOLID 7420 04:50:58,400 --> 04:51:00,280 BECAUSE THERE'S NO SIN NUCLEIN 7421 04:51:00,280 --> 04:51:01,440 EXAM, WE NEED DO SPECIAL 7422 04:51:01,440 --> 04:51:03,920 EXPERIMENTS TO EXPRESS THE SIN 7423 04:51:03,920 --> 04:51:07,320 NUCLEIN, IT SEEMS LIKE THE SIN 7424 04:51:07,320 --> 04:51:08,240 NUCLEIN AGGREGATION IS PROMOTED 7425 04:51:08,240 --> 04:51:14,920 BY THE INCREASE IN CERAMIDES. 7426 04:51:14,920 --> 04:51:18,280 AND THAT THEY RIDE ON THE SAME 7427 04:51:18,280 --> 04:51:18,920 AX O STUDIES OF MULTIPLE 7428 04:51:18,920 --> 04:51:25,560 ENDOCRINES AS THE DPLU O 7429 04:51:25,560 --> 04:51:26,000 CERAMIDES. 7430 04:51:26,000 --> 04:51:26,400 --GLUCOCERAMIDES. 7431 04:51:26,400 --> 04:51:28,240 >> THERE'S A QUESTION FROM LYNN 7432 04:51:28,240 --> 04:51:30,000 FROM RAJA, THERE ARE LOTS OF 7433 04:51:30,000 --> 04:51:30,960 RESOURCES THAT USE DISEASE 7434 04:51:30,960 --> 04:51:32,800 ONTOLOGY, DO YOU HAVE EXAMPLES 7435 04:51:32,800 --> 04:51:37,360 OF HOW INDIVIDUAL SCIENTISTS OR 7436 04:51:37,360 --> 04:51:39,280 CLINICIAN RESEARCHERS MIGHT USE 7437 04:51:39,280 --> 04:51:39,440 DOL? 7438 04:51:39,440 --> 04:51:40,400 >> THANK YOU VERY MUCH NANCY. 7439 04:51:40,400 --> 04:51:41,800 DISCIPLINARY PUT AN ANSWER IN 7440 04:51:41,800 --> 04:51:44,240 THE CHAT BUT WHAT I ALSO WANT TO 7441 04:51:44,240 --> 04:51:46,120 MENTION IS WE GET A LOT OF WHYS 7442 04:51:46,120 --> 04:51:47,360 FROM MASTER STUDENT WHO IS ARE 7443 04:51:47,360 --> 04:51:50,400 USING THE DID, OH TO EXPLORE NOW 7444 04:51:50,400 --> 04:51:53,040 AREAS OF RESEARCH AND SO WE DO 7445 04:51:53,040 --> 04:51:54,840 PROVIDE, WITH BOTH DATA SETS 7446 04:51:54,840 --> 04:51:56,000 DOWNLOADING DIFFERENT PORTIONS 7447 04:51:56,000 --> 04:51:58,120 OF ONTOLOGY, FOR THEIR USE AS 7448 04:51:58,120 --> 04:51:59,200 WELL, AND THEN RESOURCES AS 7449 04:51:59,200 --> 04:52:02,120 WELL, BUT WE REAL LEGAL DO WORK 7450 04:52:02,120 --> 04:52:03,600 HAND IN HAND WITH RESEARCHERS 7451 04:52:03,600 --> 04:52:06,000 EVERY WEEK ON AREAS OF 7452 04:52:06,000 --> 04:52:09,560 EXPERTISIES, THEY WILL SUGGEST 7453 04:52:09,560 --> 04:52:10,720 REVISIONS, NEW TERMS, WE WORK 7454 04:52:10,720 --> 04:52:15,120 WITH A LOT OF CLINICIANS, 7455 04:52:15,120 --> 04:52:15,880 MOLECULAR SUBSTIEPSOR CANCERS 7456 04:52:15,880 --> 04:52:18,000 AND WE BRING THAT DATA IN THE 7457 04:52:18,000 --> 04:52:21,480 AND PROVIDE FEEDBACK THROUGH THE 7458 04:52:21,480 --> 04:52:22,440 TRACKER SYSTEM. 7459 04:52:22,440 --> 04:52:30,680 THANKS FOR THE QUESTION RAJA. 7460 04:52:30,680 --> 04:52:31,040 >> GREAT. 7461 04:52:31,040 --> 04:52:31,240 GREAT. 7462 04:52:31,240 --> 04:52:32,320 I HAD A QUESTION EXPWRUOF THE 7463 04:52:32,320 --> 04:52:34,240 ABOUT THE PROCESS SO FOR CASE 7464 04:52:34,240 --> 04:52:36,120 STUDIES, SO, YOU KNOW SOME CASE 7465 04:52:36,120 --> 04:52:37,280 STUDIES OBVIOUSLY HAVE MORE 7466 04:52:37,280 --> 04:52:40,600 INFORMATION THAN OTHERS, SO HOW 7467 04:52:40,600 --> 04:52:42,200 DO YOU ANNOTATE THAT YOU KNOW 7468 04:52:42,200 --> 04:52:43,520 WITH SUCH VARIABILITY AND WHAT 7469 04:52:43,520 --> 04:52:46,800 INFORMATION MIGHT BE PROVIDED IN 7470 04:52:46,800 --> 04:52:48,440 VARIOUS CASE STUDIES. 7471 04:52:48,440 --> 04:52:50,080 >> YEAH, IT LEGAL IS VERY 7472 04:52:50,080 --> 04:52:50,320 TRICKY. 7473 04:52:50,320 --> 04:52:53,520 WE HAVE TENDED TO INCLUDE ALL 7474 04:52:53,520 --> 04:52:58,200 CASE STUDIES WHEN THERE'S AT 7475 04:52:58,200 --> 04:52:59,840 LEAST 1 FAMILY INVOLVED IN THE 7476 04:52:59,840 --> 04:53:00,880 STUDY, WE HIGHLIGHT THESE AND 7477 04:53:00,880 --> 04:53:03,600 BRING THEM IN AS PUBMED 7478 04:53:03,600 --> 04:53:05,560 REFERENCES AND THEN WE WILL ADD 7479 04:53:05,560 --> 04:53:07,320 MORE INFORMATION TO THE TEXTURAL 7480 04:53:07,320 --> 04:53:10,920 DEFINITION IF THERE'S VARIATION 7481 04:53:10,920 --> 04:53:12,760 SEEN ACROSS THOSE INDIVIDUALS OR 7482 04:53:12,760 --> 04:53:13,040 FAMILIES. 7483 04:53:13,040 --> 04:53:15,840 WE DO IN THIS CONJUNCTION WITH 7484 04:53:15,840 --> 04:53:17,720 OMMANDED CAN THE WHAT WE MAKE 7485 04:53:17,720 --> 04:53:18,440 SURE WE HAVE ENOUGH THAT 7486 04:53:18,440 --> 04:53:20,080 EVIDENCE THERE IS A NEW SUBTYPE 7487 04:53:20,080 --> 04:53:21,880 OF DISEASE AND THEN WE BRING IT 7488 04:53:21,880 --> 04:53:28,320 AND WE ANNOTATE IT THROUGH THE 7489 04:53:28,320 --> 04:53:28,680 PUBLICATIONS. 7490 04:53:28,680 --> 04:53:30,120 >> OKAY, GREAT, THANK YOU. 7491 04:53:30,120 --> 04:53:34,160 THERE WAS A QUESTION FOR 7492 04:53:34,160 --> 04:53:35,920 [INDISCERNIBLE] THIS, IS FROM 7493 04:53:35,920 --> 04:53:36,960 [INDISCERNIBLE], THE QUESTION IS 7494 04:53:36,960 --> 04:53:41,640 MIRROR IMAGE TOMMICS PUBLICLY 7495 04:53:41,640 --> 04:53:42,120 AVAILABLE? 7496 04:53:42,120 --> 04:53:44,080 >> YES, SO, CURRENTLY THE DAILY 7497 04:53:44,080 --> 04:53:45,960 BASIS THEA COULD BE ACCESSED ALL 7498 04:53:45,960 --> 04:53:47,400 THE PROCESSED DATA ON THE ROLE 7499 04:53:47,400 --> 04:53:48,920 AND THE UNDERLYING DAILY BASIS 7500 04:53:48,920 --> 04:53:53,640 THEA COULD BE ACCESS AT THE 7501 04:53:53,640 --> 04:53:55,840 MITOMICS.APP WEBSITE AND WE HAVE 7502 04:53:55,840 --> 04:53:57,240 MOVED SINCE THE PAPER WAS 7503 04:53:57,240 --> 04:53:58,440 ACCEPTED SO ANYONE CAN GO AND 7504 04:53:58,440 --> 04:54:00,720 INTERACT WITH THE DATA, EXPLORE 7505 04:54:00,720 --> 04:54:02,920 IT AND DOWNLOAD IT AND REANALYZE 7506 04:54:02,920 --> 04:54:04,520 WHICHEVER YOU WOULD LIKE FELT 7507 04:54:04,520 --> 04:54:11,280 ONCE THE PAPER CURES IN WE WILL 7508 04:54:11,280 --> 04:54:12,240 GET SUPPLEMENTALS FROM SO THAT 7509 04:54:12,240 --> 04:54:15,320 IS ALL THE DATA AVAILABLE AS OF 7510 04:54:15,320 --> 04:54:15,680 RIGHT NOW. 7511 04:54:15,680 --> 04:54:19,120 >> I HAVE A FOLLOW UP QUESTION. 7512 04:54:19,120 --> 04:54:20,560 LIKE DO HAVE YOU SOME KIND OF 7513 04:54:20,560 --> 04:54:23,120 LICENSE INFORMATION ON THE 7514 04:54:23,120 --> 04:54:23,600 WEBSITE? 7515 04:54:23,600 --> 04:54:25,720 WHAT YOU VERBALLY SAID IT LOOKS 7516 04:54:25,720 --> 04:54:27,560 LIKE A CC-0 TYPE OF LICENSE OR 7517 04:54:27,560 --> 04:54:30,640 YOU DO NOT HAVE THAT EXPLICITLY 7518 04:54:30,640 --> 04:54:30,960 STATED THERE? 7519 04:54:30,960 --> 04:54:35,240 THE REASON I'M ASKING IS THAT IN 7520 04:54:35,240 --> 04:54:37,680 GLYGEN WE NEED TO KNOW THAT IF 7521 04:54:37,680 --> 04:54:39,880 YOU LET'S SAY USE ANY OF THE 7522 04:54:39,880 --> 04:54:40,960 INFORMATION THAT IS AVAILABLE 7523 04:54:40,960 --> 04:54:44,800 HOW DO WE REFERENCE IT AND HOW 7524 04:54:44,800 --> 04:54:50,880 DO WE SITE IT BACK AND SO ON? 7525 04:54:50,880 --> 04:54:53,120 >> SO FOR IF YOU USE THE DATA 7526 04:54:53,120 --> 04:54:55,960 YOU WOULD PROBABLY NEED 7527 04:54:55,960 --> 04:55:00,600 TO--SORRY CITE THE APPLICATION, 7528 04:55:00,600 --> 04:55:01,200 OTHERWISE WELL, OTHERWISE 7529 04:55:01,200 --> 04:55:04,600 WHATEVER DAT AWE GET FROM THE 7530 04:55:04,600 --> 04:55:12,960 WEBSITE ARE YOURS FOR ANALYZING? 7531 04:55:12,960 --> 04:55:13,520 >> THAT'S GOOD, THANKS. 7532 04:55:13,520 --> 04:55:15,240 >> THANK YOU BUT IF WE WANT TO 7533 04:55:15,240 --> 04:55:17,720 SUCK IT UP WITH THE GLYGEN WE 7534 04:55:17,720 --> 04:55:19,600 NEED SOME ARE THE SOPHISTICATED 7535 04:55:19,600 --> 04:55:20,120 OF LICENSE ARRANGEMENT. 7536 04:55:20,120 --> 04:55:22,480 >> WHAT WE TRY TO ENCOURAGE IS 7537 04:55:22,480 --> 04:55:24,080 THAT WHEN ANYBODY PUTS UP A 7538 04:55:24,080 --> 04:55:25,120 WEBSITE, THIS BRINGS BACK A 7539 04:55:25,120 --> 04:55:27,320 QUESTION THAT DOUG HAD ASKED 7540 04:55:27,320 --> 04:55:30,520 EARLIER IN THE PREVIOUS SESSION, 7541 04:55:30,520 --> 04:55:32,440 WHEN SOMEBODY PUTS UP A 7542 04:55:32,440 --> 04:55:36,160 DATABASE, HAVING AN EXPLICIT 7543 04:55:36,160 --> 04:55:37,360 DECLARATION OF THE LICENSE GOES 7544 04:55:37,360 --> 04:55:40,400 A LONG WAY, WE DID A WORKSHOP IN 7545 04:55:40,400 --> 04:55:46,040 BIOCURATION A FEW YEARS AGO 7546 04:55:46,040 --> 04:55:47,720 ABOUT THE PROS AND CONS OF THE 7547 04:55:47,720 --> 04:55:50,240 LICENSES AND WE DID A SURVEY AND 7548 04:55:50,240 --> 04:55:51,520 IT URNS OUT THAT MOST PEOPLE 7549 04:55:51,520 --> 04:55:54,760 LIKE YOU WOULD WANT A CC4 PBT 0 7550 04:55:54,760 --> 04:55:57,000 OR ZC0 BUT SOMETHING SIMILAR BUT 7551 04:55:57,000 --> 04:55:58,160 IT'S NOT EXPLICITLY STATED 7552 04:55:58,160 --> 04:55:59,360 BECAUSE IT'S NOT STATED THAT 7553 04:55:59,360 --> 04:56:03,520 FORMS A BARRIER FOR DATA 7554 04:56:03,520 --> 04:56:03,720 SHARING. 7555 04:56:03,720 --> 04:56:05,120 >> I SEE, THEN YEAH WE SHOULD 7556 04:56:05,120 --> 04:56:06,120 DEFINITELY CONSIDER AND I WILL 7557 04:56:06,120 --> 04:56:07,480 BRING IT BACK TO THE TEAM TO 7558 04:56:07,480 --> 04:56:10,920 THINK ABOUT THAT FOR SURE. 7559 04:56:10,920 --> 04:56:11,160 YEAH. 7560 04:56:11,160 --> 04:56:13,040 >> HE WOULD NOT BE ABLE TO 7561 04:56:13,040 --> 04:56:13,840 DOWNLOAD THE UNDERLYING 7562 04:56:13,840 --> 04:56:15,320 DATABASES FROM THE SIDE, YOU 7563 04:56:15,320 --> 04:56:18,280 WOULD DOWNLOAD THE DATA IN THE 7564 04:56:18,280 --> 04:56:19,720 FORM OF EXCEL SPREADSHEET IN THE 7565 04:56:19,720 --> 04:56:25,360 CASE BUT YEAH IT'S WORTH 7566 04:56:25,360 --> 04:56:26,200 DISCUSSING THINGS AND YOU 7567 04:56:26,200 --> 04:56:28,200 MENTIONED YOU ARE NOT GOING TO 7568 04:56:28,200 --> 04:56:30,080 TALK ABOUT GLYCOSYLATION OR POST 7569 04:56:30,080 --> 04:56:30,760 TRANSLATIONAL MODIFICATIONS BUT 7570 04:56:30,760 --> 04:56:32,640 IS THAT ALSO WITHIN MIGHT O 7571 04:56:32,640 --> 04:56:34,360 GENICS THAT THERE'S POST 7572 04:56:34,360 --> 04:56:39,920 TRANSLATIONAL MODIIVES DATA? 7573 04:56:39,920 --> 04:56:41,000 >> YES, WITH THE POMT 7574 04:56:41,000 --> 04:56:41,640 METHODOLOGIES AT THE POINT IN 7575 04:56:41,640 --> 04:56:43,520 OUR HANDS AT LEAST, MAYBE 7576 04:56:43,520 --> 04:56:46,320 SOMEONE ELSE OUT THERE IS 7577 04:56:46,320 --> 04:56:50,120 BETTER, JUST NOT COMPATIBLE WITH 7578 04:56:50,120 --> 04:56:54,200 SUCH A LARGE STUDY OF SEVERAL 7579 04:56:54,200 --> 04:56:55,680 HUNDRED SAMPLES, SO WE NEVER 7580 04:56:55,680 --> 04:56:56,200 ATTEMPTED THEM. 7581 04:56:56,200 --> 04:57:00,280 THAT SAID, I WOULD THINK 1 7582 04:57:00,280 --> 04:57:01,080 ACCOUNT PROBABLY FILTER THROUGH 7583 04:57:01,080 --> 04:57:03,880 THE CELL LINES AND PRIORITIZE 7584 04:57:03,880 --> 04:57:06,680 SMALL SEB SET FOR THOSE PTM 7585 04:57:06,680 --> 04:57:08,640 ANALYSIS IN THE CASE OF 7586 04:57:08,640 --> 04:57:10,160 MITOCHONDRIA I WOULD ADVOCATE 7587 04:57:10,160 --> 04:57:13,320 FOR ACETYLATION AS BEING THE 7588 04:57:13,320 --> 04:57:15,320 MOST PROMISING PTM TO ELECTRIC 7589 04:57:15,320 --> 04:57:16,640 AT BEFORE GLYCOSYLATION AS IT'S 7590 04:57:16,640 --> 04:57:18,720 KNOWN TO BE INVOLVED APPROXIMATE 7591 04:57:18,720 --> 04:57:20,440 WITH METABOLISM HEAVILY AND 7592 04:57:20,440 --> 04:57:21,640 THERE ARE LOT OF MITOCHONDRIA 7593 04:57:21,640 --> 04:57:22,880 PROTEINS THAT REGULATE THROUGH 7594 04:57:22,880 --> 04:57:23,960 ACETYLATION SO THAT WOULD BE THE 7595 04:57:23,960 --> 04:57:29,960 1 TO LOOK AT IT FIRST. 7596 04:57:29,960 --> 04:57:30,360 >> IN MY MIND. 7597 04:57:30,360 --> 04:57:32,240 >> I HAVE A QUESTION FOR DANIEL 7598 04:57:32,240 --> 04:57:35,640 QUH IF YOU DON'T MIND ME 7599 04:57:35,640 --> 04:57:35,880 HOGGING? 7600 04:57:35,880 --> 04:57:37,560 SO DAN I WAS REALLY INTRIGUED, 7601 04:57:37,560 --> 04:57:41,640 YOU KNOW TALKING ABOUT THE MUCUS 7602 04:57:41,640 --> 04:57:42,560 BARRIER, PROTECTIVE MUCUS 7603 04:57:42,560 --> 04:57:45,120 BARRIER OF THE EPITHELIAL LAYER 7604 04:57:45,120 --> 04:57:48,920 BUT ENDED UP FOCUSING ON A 7605 04:57:48,920 --> 04:57:52,920 COMPONENT OF THE OLIGIO SACK O 7606 04:57:52,920 --> 04:57:53,880 TRANSFER ACE GLYCOSYLATION AND 7607 04:57:53,880 --> 04:57:58,240 MUCH OF THAT BARRIER AND OLYCANS 7608 04:57:58,240 --> 04:58:00,200 SO MAYBE THERE'S OBVIOUSLY GOING 7609 04:58:00,200 --> 04:58:01,920 TO BE IMPORTANT BALANCE THAT HAS 7610 04:58:01,920 --> 04:58:03,040 TO HAPPEN BUT IN A THINNING 7611 04:58:03,040 --> 04:58:03,920 BARRIER THAT YOU SLEEP APNEA AND 7612 04:58:03,920 --> 04:58:07,160 OBESITYY IN THE 7613 04:58:07,160 --> 04:58:07,920 EPITHELIAL--EPITHELIAL APICKAL 7614 04:58:07,920 --> 04:58:09,880 END IS THAT LESS PROTEIN AND YOU 7615 04:58:09,880 --> 04:58:11,520 KNOW SO IT'S JUST A FOLDING 7616 04:58:11,520 --> 04:58:12,920 PROBLEM GETTING ENOUGH PROTEINS 7617 04:58:12,920 --> 04:58:14,360 FOLDED CORRECTLY TO GET OUT 7618 04:58:14,360 --> 04:58:16,360 THERE, O THERE'S ACTUALLY--OR IS 7619 04:58:16,360 --> 04:58:17,560 THERE ACTUALLY A GLUE MARIOUS 7620 04:58:17,560 --> 04:58:29,000 COMIC SHIFT IN THE MUCUS LAYER 7621 04:58:29,000 --> 04:58:29,560 IN THE OLIGIOTRANSFERAISE? 7622 04:58:29,560 --> 04:58:35,800 >> THERE ARE A COUPLE ELEMENTS 7623 04:58:35,800 --> 04:58:37,160 TO BARRIER ACTIVITY AND 7624 04:58:37,160 --> 04:58:40,280 GLYCOSYLATION SO THE MAIN EFFECT 7625 04:58:40,280 --> 04:58:43,320 OF IMPAIRED AND LINKED 7626 04:58:43,320 --> 04:58:45,240 GLYCOSYLATION APPEARS TO BE AN 7627 04:58:45,240 --> 04:58:47,000 EFFECT ON ER HOMEOSTASIS SO 7628 04:58:47,000 --> 04:58:50,520 THAT'S INTRINSIC TO THE 7629 04:58:50,520 --> 04:58:52,120 EPITHELIAL CELL AND THEIR 7630 04:58:52,120 --> 04:58:53,880 BARRIER FUNCTION RELATED TO 7631 04:58:53,880 --> 04:58:57,080 FORMING JUNCTIONS WITH 1 ANOTHER 7632 04:58:57,080 --> 04:59:00,920 AND MAKING AN IMPERMEABLE 7633 04:59:00,920 --> 04:59:01,160 BARRIER. 7634 04:59:01,160 --> 04:59:03,840 AND THEN SECONDAR TOW THAT IS 7635 04:59:03,840 --> 04:59:18,840 SECRETION OF THE MUSEINS AND THE 7636 04:59:18,840 --> 04:59:20,120 GLYCOICAL EX AND THAT'S THE 7637 04:59:20,120 --> 04:59:22,000 STRUCTURES AND A WHOLE SERIES OF 7638 04:59:22,000 --> 04:59:28,880 OTHER GENES IMPACT THOSE TYPES 7639 04:59:28,880 --> 04:59:30,000 OF BARRIER FUNCTIONS. 7640 04:59:30,000 --> 04:59:33,320 ALL RIGHT, SO, IT'S INTERESTING 7641 04:59:33,320 --> 04:59:39,320 TO SEE WHEN YOU DISRUPT THE 7642 04:59:39,320 --> 04:59:40,920 OLIGIOTRANSFER ACE HOW DOES THAT 7643 04:59:40,920 --> 04:59:42,960 SPILL OVER INTO MUSEIN 7644 04:59:42,960 --> 04:59:43,720 GLYCOSYLATION, I WOULDN'T BE 7645 04:59:43,720 --> 04:59:45,120 SURPRISE IF IT DOES BUT IT WOULD 7646 04:59:45,120 --> 04:59:47,280 BE INTERESTING TO EXPLORE IT A 7647 04:59:47,280 --> 04:59:47,440 BIT. 7648 04:59:47,440 --> 04:59:48,760 >> I AGREE, I'M SURE IT WILL. 7649 04:59:48,760 --> 04:59:55,320 IT'S BEEN HARD TO DISENTANGLE ER 7650 04:59:55,320 --> 04:59:57,880 STRESS FROM YOU KNOW THE ROUGH 7651 04:59:57,880 --> 05:00:01,120 ATOM TEENS THAT ARE SECRETED 7652 05:00:01,120 --> 05:00:01,880 THROUGH THE ER. 7653 05:00:01,880 --> 05:00:11,560 OOTD BEEN A CHALLENGE FOR US. 7654 05:00:11,560 --> 05:00:13,920 SO FOR DANIEL THERE ARE A COUPLE 7655 05:00:13,920 --> 05:00:17,280 QUESTIONS RELATED TO THE 7656 05:00:17,280 --> 05:00:18,200 MANGANESE TRANSPORTER SO, IT'S 7657 05:00:18,200 --> 05:00:19,440 ASKED THAT DO YOU FIND IN YOUR 7658 05:00:19,440 --> 05:00:22,240 SCREEN OF OTHER MEMBERS OF SLC39 7659 05:00:22,240 --> 05:00:24,720 BESIGHTS A8 FAMILY THAT REGULATE 7660 05:00:24,720 --> 05:00:26,040 DISCIPLINARY VALENTINEDENT IONS 7661 05:00:26,040 --> 05:00:28,920 ALSO HAVE AN IMPACT ON 7662 05:00:28,920 --> 05:00:29,440 GLYCOSYLATION? 7663 05:00:29,440 --> 05:00:33,920 >> WE DON'T, IT'S VERY SPECIFIC 7664 05:00:33,920 --> 05:00:36,400 FOR SLC39 A 8. 7665 05:00:36,400 --> 05:00:42,320 SO THE CARGO FOR 39 A8 IS ZINC 7666 05:00:42,320 --> 05:00:43,800 AND MANGANESE PRIMARILY BUT THEY 7667 05:00:43,800 --> 05:00:46,240 ALSO TRAN PORT LIKE LIKES 7668 05:00:46,240 --> 05:00:48,680 CADMIUM AND A FEW OTHER 7669 05:00:48,680 --> 05:00:49,560 DISCIPLINARY VALENTINEDENT CAT 7670 05:00:49,560 --> 05:00:53,720 IONS AND AMONGST THE 39 A-FAMILY 7671 05:00:53,720 --> 05:00:58,480 THERE ARE 4 OR 5 MEMBERS THAT 7672 05:00:58,480 --> 05:00:59,680 ALSO TRANSPORT DISCIPLINARY 7673 05:00:59,680 --> 05:01:01,760 VALENTINEDENT CAT IONS NAMELY 7674 05:01:01,760 --> 05:01:02,000 ZINC. 7675 05:01:02,000 --> 05:01:04,480 SO WHETHER WE KNOCKED OUT 39 A8, 7676 05:01:04,480 --> 05:01:07,920 WE HAD NO EFFECT ON ZINC. 7677 05:01:07,920 --> 05:01:09,280 IT ONLY EFFECTED MAINING AN EASE 7678 05:01:09,280 --> 05:01:12,720 SO THIS SEEMS TO BE A 7679 05:01:12,720 --> 05:01:14,320 NONREDUNDANT FUNCTION OF 39 A8 7680 05:01:14,320 --> 05:01:16,120 WITH MAINING AN EASE WHERE THE 7681 05:01:16,120 --> 05:01:18,160 OTHER CAT IONS CAN BE TRANSPORT 7682 05:01:18,160 --> 05:01:20,000 BY OTHER FAMILY MEMBERS. 7683 05:01:20,000 --> 05:01:21,120 >> OKAY ISSUES GREAT. 7684 05:01:21,120 --> 05:01:27,400 TLR WAS A QUESTION BY 7685 05:01:27,400 --> 05:01:29,040 [INDISCERNIBLE], WAS GLYCO 7686 05:01:29,040 --> 05:01:30,000 PROTEOMIC PROTILES BY MASS SPEC 7687 05:01:30,000 --> 05:01:33,360 DOWN IN CASES OF THE 39 A8 AND 7688 05:01:33,360 --> 05:01:35,280 IF THAT SHOWED ALTERED PROFILE 7689 05:01:35,280 --> 05:01:39,880 ABUNDANCE COMPARED TO NORMAL? 7690 05:01:39,880 --> 05:01:41,960 >> SO I SHOULD PREFACE THIS BY 7691 05:01:41,960 --> 05:01:43,360 STATING THAT WE'RE VERY MUCH 7692 05:01:43,360 --> 05:01:44,320 INTERESTED IN FINDING 7693 05:01:44,320 --> 05:01:46,360 COLLABORATORS WHO CAN HELP US 7694 05:01:46,360 --> 05:01:48,400 WITH DPLI COMICS AND GLYCO 7695 05:01:48,400 --> 05:01:50,560 PROTEOMICS, I BEING THERE'S A 7696 05:01:50,560 --> 05:01:51,720 HUGE OPPORTUNITY THEREENTIOUS 7697 05:01:51,720 --> 05:01:53,520 SPECIALLY IN GUT BARRIER 7698 05:01:53,520 --> 05:01:55,720 FUNCTIONS FOR LOOKING AT THESE 7699 05:01:55,720 --> 05:01:57,920 TYPES OF OMICS MEASUREMENTS. 7700 05:01:57,920 --> 05:01:59,400 HAVING SAID THAT, WE'VE DON A 7701 05:01:59,400 --> 05:02:02,800 LITTLE BIT WITH SOME HELP, I CAN 7702 05:02:02,800 --> 05:02:05,040 TELL YOU SOME KIND OF GENERAL 7703 05:02:05,040 --> 05:02:07,000 TAKE AWAYS ON MY IMPRESSIONS OF 7704 05:02:07,000 --> 05:02:08,400 WHAT WE'VE SEEN SO FAR. 7705 05:02:08,400 --> 05:02:10,800 SO FIRST WHEN WE'VE DONE GLUE 7706 05:02:10,800 --> 05:02:13,920 MARIOUS KOAMICS ON EPITHELIAL 7707 05:02:13,920 --> 05:02:16,480 CELLS FROM THE COLON, IT'S 7708 05:02:16,480 --> 05:02:18,120 INCREDIBLY DIVERSE, ALL OF THE 7709 05:02:18,120 --> 05:02:21,000 GLYCAN SPECIES THAT ARE 7710 05:02:21,000 --> 05:02:21,280 RECOVERED. 7711 05:02:21,280 --> 05:02:26,800 SO THERE'S I THINK A NEED TO 7712 05:02:26,800 --> 05:02:29,320 MORE READILY IDENTIFY EACH OF 7713 05:02:29,320 --> 05:02:31,640 THOSE SPECIES IN COMPUTATIONALLY 7714 05:02:31,640 --> 05:02:35,520 FACILE WAY, AND WITH ACCURACY. 7715 05:02:35,520 --> 05:02:37,320 AND SECONDARILY, THERE'S A 7716 05:02:37,320 --> 05:02:38,400 CHALLENGE IN BEING QUANTITATIVE 7717 05:02:38,400 --> 05:02:41,200 SO MAKING SO MANY MEASUREMENTS 7718 05:02:41,200 --> 05:02:43,120 OF DIVERSE ENTITIES THAT 7719 05:02:43,120 --> 05:02:44,560 DIFFERENT ABUNDANCES, CREATES A 7720 05:02:44,560 --> 05:02:49,000 REAL CHALLENGE FOR BEING 7721 05:02:49,000 --> 05:02:49,480 QUANTITATIVE. 7722 05:02:49,480 --> 05:02:53,120 AND SO, THINKING MORE ABOUT 7723 05:02:53,120 --> 05:02:55,080 POWER ANALYSIS, AND VARIANTS AND 7724 05:02:55,080 --> 05:02:56,400 HOW MANY SAMPLES DO WE NEED AND 7725 05:02:56,400 --> 05:02:58,000 THINGS LIKE THIS IS ANOTHER 7726 05:02:58,000 --> 05:03:01,720 CONSIDERATION THAT I THINK IS AN 7727 05:03:01,720 --> 05:03:03,960 UNSOLVED PROBLEM AND SO, THAT'S 7728 05:03:03,960 --> 05:03:05,720 KIND OF MY TWO-CENTS ON WHERE WE 7729 05:03:05,720 --> 05:03:07,920 ARE BUT AGAIN, I THINK IT'S 7730 05:03:07,920 --> 05:03:12,320 EXCITING AREA TO LOOK INTO. 7731 05:03:12,320 --> 05:03:13,640 >> AND THERE WAS 1 OTHER 7732 05:03:13,640 --> 05:03:15,920 QUESTION FROM WESLEY ROBERTS. 7733 05:03:15,920 --> 05:03:18,280 HE'S ASKING ABOUT LOW MANGANESE 7734 05:03:18,280 --> 05:03:21,240 AND THAT'S CORRELATED TO GUT 7735 05:03:21,240 --> 05:03:21,680 DISMORPHISM? 7736 05:03:21,680 --> 05:03:24,040 SO HE'S ASKING WHAT 7737 05:03:24,040 --> 05:03:24,880 CONCENTRATIONS MANGANESE ARE 7738 05:03:24,880 --> 05:03:27,120 HEALTHY WHAT'S TOO MUCH OR TOO 7739 05:03:27,120 --> 05:03:30,160 LITTLE AND IS LOW MANGANESE 7740 05:03:30,160 --> 05:03:32,160 CORRELATED TO ALL MUSEUM MAN 7741 05:03:32,160 --> 05:03:34,920 GENETICS OR PHENOTYPES LIKELY TO 7742 05:03:34,920 --> 05:03:37,480 HAVE LOW MANGANESE AND OF COURSE 7743 05:03:37,480 --> 05:03:43,600 APPLAUSE ON GREAT TALKS. 7744 05:03:43,600 --> 05:03:46,600 >> SO, MANGANESE REALLY IS A KEY 7745 05:03:46,600 --> 05:03:47,080 MICRONUTRIENT. 7746 05:03:47,080 --> 05:03:49,680 IT'S A CO FACTOR FOR MANY 7747 05:03:49,680 --> 05:03:50,760 DIFFERENT ENZYMES THAT PERFORM 7748 05:03:50,760 --> 05:03:52,440 MANY DIFFERENT FUNCTIONS AND I 7749 05:03:52,440 --> 05:04:00,920 THINK THE GLYCOSYLATION PATHWAY 7750 05:04:00,920 --> 05:04:02,320 IS 1 OF MANY. 7751 05:04:02,320 --> 05:04:04,880 SO IF YOU LOOK IN LARGE COHORTS 7752 05:04:04,880 --> 05:04:06,840 OF PATIENTS OF HEALTHY PEOPLE 7753 05:04:06,840 --> 05:04:12,880 WHO ARE CARRIERS FOR AT391 7754 05:04:12,880 --> 05:04:16,280 TVARIANT FOR SLC39 A8, WE SEE 7755 05:04:16,280 --> 05:04:17,800 REDUCED MANGANESE LEVELS IN THE 7756 05:04:17,800 --> 05:04:18,000 BLOOD. 7757 05:04:18,000 --> 05:04:20,720 SOPHISTICATEDY THAT'S A COMMON 7758 05:04:20,720 --> 05:04:21,240 ENDOPHENOTYPE FOR THIS. 7759 05:04:21,240 --> 05:04:24,200 BUT AS I MENTIONED, THE DISEASE 7760 05:04:24,200 --> 05:04:26,280 PHENOTYPES CAN VARY AND THAT'S 7761 05:04:26,280 --> 05:04:28,240 PROBABLY DEPENDENT ON 7762 05:04:28,240 --> 05:04:31,080 ENVIRONMENTAL FACTORS, ANOTHER 7763 05:04:31,080 --> 05:04:31,640 GENETIC FACTORS. 7764 05:04:31,640 --> 05:04:33,000 BUT MAINING AN EASE THERE'S A 7765 05:04:33,000 --> 05:04:34,680 SWEET SPOT IN HOW MUCH, YOU KNOW 7766 05:04:34,680 --> 05:04:39,560 TOO LITTLE IS BAD AND TOO MUCH 7767 05:04:39,560 --> 05:04:40,560 IS BAD. 7768 05:04:40,560 --> 05:04:42,160 SO TOO LITTLE IS ASSOCIATED WITH 7769 05:04:42,160 --> 05:04:44,240 IBD, IF YOU HAVE OTHER RISK 7770 05:04:44,240 --> 05:04:48,560 FACTORS IT'S ASSOCIATED WITH 7771 05:04:48,560 --> 05:04:50,480 SCHIZOPHRENIA, IT'S ASSOCIATED 7772 05:04:50,480 --> 05:04:53,800 WITH CARDIOVASCULAR TRAITS AND 7773 05:04:53,800 --> 05:04:56,080 THEN TOO MUCH IS SOCKED WITH 7774 05:04:56,080 --> 05:04:57,840 NEUROTOXICITY SO WELDERS WHO 7775 05:04:57,840 --> 05:05:02,560 HAVE HIGH EXPOSE TOWER MANGANESE 7776 05:05:02,560 --> 05:05:04,080 SOMETIMES DEVELOP TOXICITIES AND 7777 05:05:04,080 --> 05:05:11,120 TACKERIN SONS LIKE SYMPTOMS THAT 7778 05:05:11,120 --> 05:05:11,480 ARE TRANSIENT. 7779 05:05:11,480 --> 05:05:14,080 SO AGAIN I THINK THERE'S A GOLDY 7780 05:05:14,080 --> 05:05:15,760 LOCK PHENOMENON, TOO MUCH IS 7781 05:05:15,760 --> 05:05:18,240 BAD, TOO LITTLE IS BAD. 7782 05:05:18,240 --> 05:05:20,200 >> AND IN A CONVERSATION WITH 7783 05:05:20,200 --> 05:05:22,480 KELLEY [INDISCERNIBLE] A COUPLE 7784 05:05:22,480 --> 05:05:25,320 MONTHS AGO, THOSE TRANSFERAISES 7785 05:05:25,320 --> 05:05:27,520 THEY HAVE A HIGH MANGANESE 7786 05:05:27,520 --> 05:05:30,000 REQUIREMENT, MORE SO THAN OTHER 7787 05:05:30,000 --> 05:05:31,600 TRANSFERAISES SO THOSE ENZYMES 7788 05:05:31,600 --> 05:05:33,920 THAT MAKE COMPLEX GLYCANS ARE 7789 05:05:33,920 --> 05:05:35,960 EXZINDERITLY SENSITIVE TO 7790 05:05:35,960 --> 05:05:36,400 MANGANESE LEVELS. 7791 05:05:36,400 --> 05:05:40,520 BEFORE WE FINISH UP A HAD A 7792 05:05:40,520 --> 05:05:42,680 QUESTION FOR CHIARA DO I MISS IT 7793 05:05:42,680 --> 05:05:50,240 OR DID THE KNOCK DOWN FISH HAVE 7794 05:05:50,240 --> 05:05:50,720 A BRAIN PHENOTYPE. 7795 05:05:50,720 --> 05:05:53,280 >> SO THEY HAVE A BRAIN 7796 05:05:53,280 --> 05:05:54,760 PHENOTYPE BUT THEY ALSO SHOW 7797 05:05:54,760 --> 05:05:57,680 DROSOPHILA WITH THE MORPH O LINE 7798 05:05:57,680 --> 05:06:00,680 O, THE POMT 1 KNOCK OUT SO FAR 7799 05:06:00,680 --> 05:06:03,080 WE ONLY--WE ARE ONLY SEEING 7800 05:06:03,080 --> 05:06:04,880 RETINAL PHENOTYPES, WE HAVE 7801 05:06:04,880 --> 05:06:06,080 HAVEN'T LOOKED IN DETAIL THAT 7802 05:06:06,080 --> 05:06:07,240 ACT IN GUIDANCE WHICH IS AN 7803 05:06:07,240 --> 05:06:09,760 ISSUE IN THE MICE, BUT WHAT WE 7804 05:06:09,760 --> 05:06:11,720 THINK IS GOING ON IS THAT 1 OF 7805 05:06:11,720 --> 05:06:13,680 THE PROBLEMS WITH THE POMT 1 IMK 7806 05:06:13,680 --> 05:06:16,680 OUT IS THAT THERE'S MATERNAL 7807 05:06:16,680 --> 05:06:17,880 MRNA THAT'S PROVIDED. 7808 05:06:17,880 --> 05:06:19,120 THERE IS DPLIEK COSALATED TPHREU 7809 05:06:19,120 --> 05:06:21,320 RACING KAN--KANA FOR THE FIRST 4 7810 05:06:21,320 --> 05:06:22,960 OR 5 DAYS BECAUSE THE DPLI 7811 05:06:22,960 --> 05:06:24,480 KAN--KANA IS PRETTY STABLE SO 7812 05:06:24,480 --> 05:06:26,000 NEW WE'RE LOOKING AT THE EARLIER 7813 05:06:26,000 --> 05:06:28,640 STAGES AND THEN IT GOES AWAY. 7814 05:06:28,640 --> 05:06:30,560 AND SO WE CRISPR OTHER 7815 05:06:30,560 --> 05:06:32,600 APPROACHES WE CAN GO IN AND TRY 7816 05:06:32,600 --> 05:06:35,040 AND REMOVE THE MATERNAL MRNA AND 7817 05:06:35,040 --> 05:06:36,360 ACTUALLY SEE IF WE CAN PUSH IT 7818 05:06:36,360 --> 05:06:39,880 TO A MUCH MORE SEVERE PHENOTYPE. 7819 05:06:39,880 --> 05:06:43,600 AND ALSO DO A DOUBLE POMT1 AND 2 7820 05:06:43,600 --> 05:06:44,200 KNOCK OUT. 7821 05:06:44,200 --> 05:06:46,680 BUT YEAH, RIGHT NOW WE HAVE 7822 05:06:46,680 --> 05:06:50,280 OCULAR AND MUSCLE PHENOTYPES IN 7823 05:06:50,280 --> 05:06:53,120 THE KNOCK OUT. 7824 05:06:53,120 --> 05:06:53,480 >> THANK YOU. 7825 05:06:53,480 --> 05:06:56,080 >> WELL WE'VE GONE BEYOND OUR 7826 05:06:56,080 --> 05:06:57,160 TIME NANCY. 7827 05:06:57,160 --> 05:06:58,840 SO I THINK WE SHOULD DO 1 FINAL 7828 05:06:58,840 --> 05:07:00,280 THANK YOU TO ALL THE SPEAKERS 7829 05:07:00,280 --> 05:07:02,320 OVER THE LASTED 2 DAYS BUT 7830 05:07:02,320 --> 05:07:04,920 ESPECIALLY THE LAST SESSION AND 7831 05:07:04,920 --> 05:07:05,680 THIS RECORDING WILL BE AVAILABLE 7832 05:07:05,680 --> 05:07:07,680 FOR A WHILE AND YOU CAN SEE HOW 7833 05:07:07,680 --> 05:07:08,720 LONGOT WEBSITE FOR THE MEETING 7834 05:07:08,720 --> 05:07:12,040 BUT THANK TO YOU EVERYBODY FOR 7835 05:07:12,040 --> 05:07:12,520 YOUR PARTICIPATION. 7836 05:07:12,520 --> 05:07:14,720 >> AND THANK YOU TO MIKE AND 7837 05:07:14,720 --> 05:07:17,880 ROGER FOR ORGANIZING THIS 7838 05:07:17,880 --> 05:07:18,680 WONDERFUL SYMPOSIUM AND BEHIND 7839 05:07:18,680 --> 05:07:20,680 THE SCENES FOR PAMELA AND 7840 05:07:20,680 --> 05:07:23,800 AMANDA, SO AGAIN, THANK YOU 7841 05:07:23,800 --> 05:07:24,080 EVERYONE. 7842 05:07:24,080 --> 00:00:00,000 >> THANK YOU EVERYBODY.