1 00:00:05,200 --> 00:00:07,920 >> WELCOME, EVERYBODY. 2 00:00:07,920 --> 00:00:10,120 OUR FIRST SESSION IS SCHEDULED 3 00:00:10,120 --> 00:00:11,840 TO START AT 10:00. 4 00:00:11,840 --> 00:00:14,160 LANCE WELLS WILL CHAIR THAT 5 00:00:14,160 --> 00:00:19,720 SESSION WHICH IS ROUGHLY CALLED 6 00:00:19,720 --> 00:00:21,840 GLYCOPROTEOMICS AND MULTI-OMICS. 7 00:00:21,840 --> 00:00:25,040 BEFORE WE GET STARTED, RAJA AND 8 00:00:25,040 --> 00:00:27,600 I WHO CO-ORGANIZED THE EVENT 9 00:00:27,600 --> 00:00:29,040 WANTED TO EXPRESS OUR 10 00:00:29,040 --> 00:00:32,840 APPRECIATION TO PAMELA MARINO 11 00:00:32,840 --> 00:00:34,400 AND AMANDA, WHO HELPED US 12 00:00:34,400 --> 00:00:36,320 COORDINATE TO GET EVERYBODY 13 00:00:36,320 --> 00:00:36,560 TOGETHER. 14 00:00:36,560 --> 00:00:40,000 WE HAVE OVER 320 REGISTRANTS 15 00:00:40,000 --> 00:00:40,520 PARTICIPATING, SO THERE'S 16 00:00:40,520 --> 00:00:42,840 OBVIOUSLY GREAT INTEREST IN WHAT 17 00:00:42,840 --> 00:00:43,920 WE'RE TALKING ABOUT. 18 00:00:43,920 --> 00:00:45,520 I WANT TO POINT OUT AT THE 19 00:00:45,520 --> 00:00:47,520 BEGINNING TOO WE HAVE FOUR 20 00:00:47,520 --> 00:00:54,640 SESSIONS THAT HAVE RATHER BROAD 21 00:00:54,640 --> 00:00:55,080 TITLES. 22 00:00:55,080 --> 00:00:56,400 MANY SPEAKERS MAY NOT SEEM LIKE 23 00:00:56,400 --> 00:00:59,000 THEY FIT INTO THE TITLES, 24 00:00:59,000 --> 00:00:59,560 REFLECTING DIFFICULTIES IN 25 00:00:59,560 --> 00:01:00,920 SCHEDULED PEOPLE FROM AROUND THE 26 00:01:00,920 --> 00:01:02,160 WORLD BUT ALSO REFLECTS THE FACT 27 00:01:02,160 --> 00:01:03,960 THAT MANY OF THE THINGS WE'RE 28 00:01:03,960 --> 00:01:06,720 TRYING TO TALK ABOUT HERE ARE 29 00:01:06,720 --> 00:01:09,520 CROSS-CUTTING AND CUT ACROSS 30 00:01:09,520 --> 00:01:10,440 DIFFERENT DOMAINS OF 31 00:01:10,440 --> 00:01:12,080 BIOINFORMATICS AND BIOLOGY, AND 32 00:01:12,080 --> 00:01:15,320 WE HOPE THAT FROM THIS TWO-DAY 33 00:01:15,320 --> 00:01:19,600 SYMPOSIUM THEMES WILL EMERGE 34 00:01:19,600 --> 00:01:22,720 THAT MAKE IT CLEAR 35 00:01:22,720 --> 00:01:23,480 BIOINFORMATICS AND GLYCOSCIENCE 36 00:01:23,480 --> 00:01:26,080 ARE MERGING TOGETHER AS A 37 00:01:26,080 --> 00:01:29,080 PRODUCTIVE AREA OF INTERACTION 38 00:01:29,080 --> 00:01:31,520 AND WE CAN LEARN FROM DOMAINS 39 00:01:31,520 --> 00:01:36,320 THAT MAY BE MORE MANURE THAN 40 00:01:36,320 --> 00:01:36,720 GLYCOINFORMATICS. 41 00:01:36,720 --> 00:01:38,520 WE HAVE A SERIES OF 20-MINUTE 42 00:01:38,520 --> 00:01:41,520 TALKS, AT THE END WE'LL HAVE A 43 00:01:41,520 --> 00:01:43,920 20-MINUTE CHUNK OF TIME TO 44 00:01:43,920 --> 00:01:45,120 DISCUSS ANYTHING ABOUT THOSE 45 00:01:45,120 --> 00:01:46,520 20-MINUTE TALKS. 46 00:01:46,520 --> 00:01:47,600 AS YOU HAVE QUESTIONS, PLEASE 47 00:01:47,600 --> 00:01:51,480 FEEL FREE TO PUT THEM INTO THE 48 00:01:51,480 --> 00:01:53,400 FEEDBACK SO FROM YOUR END YOU 49 00:01:53,400 --> 00:01:58,440 SHOULD SEE A SEND LIVE FEEDBACK 50 00:01:58,440 --> 00:01:59,640 BUTTON, CLICK AND INTEREST A 51 00:01:59,640 --> 00:02:01,120 QUESTION THAT WILL SHOW UP IN 52 00:02:01,120 --> 00:02:04,440 THE CHAT FOR THE PRESENTERS AND 53 00:02:04,440 --> 00:02:05,160 FOR ORGANIZERS. 54 00:02:05,160 --> 00:02:06,720 WE'LL RESPOND TO THOSE QUESTIONS 55 00:02:06,720 --> 00:02:07,960 DURING THE 20-MINUTE DISCUSSION. 56 00:02:07,960 --> 00:02:09,320 WE'LL GO BACK THROUGH THEM AND 57 00:02:09,320 --> 00:02:10,800 MAKE SURE THAT EVERYBODY'S 58 00:02:10,800 --> 00:02:12,120 QUESTIONS GET ANSWERED. 59 00:02:12,120 --> 00:02:13,560 IF WE CAN'T ANSWER DURING THE 60 00:02:13,560 --> 00:02:15,320 DISCUSSION THE SPEAKERS WILL 61 00:02:15,320 --> 00:02:18,480 HAVE THE OPPORTUNITY TO RESPOND 62 00:02:18,480 --> 00:02:23,480 DIRECTLY TO YOUR QUESTIONS AS 63 00:02:23,480 --> 00:02:24,080 WELL. 64 00:02:24,080 --> 00:02:25,320 WE'RE LOOKING FORWARD TO LIVELY 65 00:02:25,320 --> 00:02:27,120 CONVERSATION AND HOPEFULLY NEW 66 00:02:27,120 --> 00:02:28,360 CONCEPTS WILL EMERGE. 67 00:02:28,360 --> 00:02:31,320 BEFORE I TURN IT OVER TO LANCE, 68 00:02:31,320 --> 00:02:33,320 RAJA, ANYTHING YOU WANT TO ADD? 69 00:02:33,320 --> 00:02:37,920 >> NO, LET'S GET STARTED. 70 00:02:37,920 --> 00:02:44,920 THANK YOU ATTENDING, EVERYBODY. 71 00:02:44,920 --> 00:02:47,200 THANK YOU, LANCE. 72 00:02:47,200 --> 00:02:50,920 >> I'M GOING TO WAIT TILL 73 00:02:50,920 --> 00:02:52,400 EXACTLY 9:59 TO INTRODUCE THE 74 00:02:52,400 --> 00:02:54,960 FIRST SPEAKER. 75 00:02:54,960 --> 00:02:56,440 FIRST SESSION IS GLYCOPROTEOMICS 76 00:02:56,440 --> 00:03:04,080 AND MULTI-OMICS. 77 00:03:04,080 --> 00:03:05,720 MIKE MENTIONED YOU CAN ASK 78 00:03:05,720 --> 00:03:09,320 QUESTIONS THROUGH SEND LIVE 79 00:03:09,320 --> 00:03:10,360 FEEDBACK WITH A 20-MINUTE PANEL 80 00:03:10,360 --> 00:03:11,400 DISCUSSION AT NOON EASTERN TIME 81 00:03:11,400 --> 00:03:13,400 FOR THIS ENTIRE SESSION. 82 00:03:13,400 --> 00:03:20,000 YOU CAN PUT YOUR QUESTIONS IN 83 00:03:20,000 --> 00:03:23,480 THE SEND LIVE FEEDBACK AND 84 00:03:23,480 --> 00:03:25,360 SPEAKERS CAN ADDRESS THOSE AT 85 00:03:25,360 --> 00:03:25,560 NOON. 86 00:03:25,560 --> 00:03:29,000 THE FIRST SESSION IS 87 00:03:29,000 --> 00:03:30,960 GLYCOPROTEOMICS AND MULTI-OMIC, 88 00:03:30,960 --> 00:03:31,520 EACH INDIVIDUAL GIVES A 20 89 00:03:31,520 --> 00:03:35,000 MINUTE TALK ON THE DOT. 90 00:03:35,000 --> 00:03:37,520 WE'LL START OFF WITH DR. 91 00:03:37,520 --> 00:03:39,520 STEPHANIE OLIVIER VAN STICHELEN 92 00:03:39,520 --> 00:03:40,800 FROM MEDICAL COLLEGE OF 93 00:03:40,800 --> 00:03:58,400 WISCONSIN TALKING ABOUT THE 94 00:03:58,400 --> 00:03:59,320 O-GlcNAc DATABASE. 95 00:03:59,320 --> 00:04:01,880 >> THANK YOU FOR THE 96 00:04:01,880 --> 00:04:02,320 INTRODUCTION. 97 00:04:02,320 --> 00:04:04,160 THANK YOU, MIKE, RAJA, PAM, 98 00:04:04,160 --> 00:04:06,320 LINDA, THE TEAM BEHIND FOR 99 00:04:06,320 --> 00:04:08,480 ORGANIZING THIS MEETING. 100 00:04:08,480 --> 00:04:09,920 WE HAVE A GREAT PROGRAM TODAY, 101 00:04:09,920 --> 00:04:12,240 I'M HAPPY TO START IT OFF. 102 00:04:12,240 --> 00:04:17,600 TODAY I'M GOING TO TALK ABOUT 103 00:04:17,600 --> 00:04:22,200 THE O-GlcNAc DATABASE AND WE 104 00:04:22,200 --> 00:04:29,000 TRIED TO SORT OUT LITERATURE, 105 00:04:29,000 --> 00:04:30,920 PROTEOMIC STUDY AND TRANSFORM 106 00:04:30,920 --> 00:04:32,480 THAT INTO A FRIENDLY DATABASE 107 00:04:32,480 --> 00:04:35,400 PEOPLE CAN USE FOR RESEARCH AND 108 00:04:35,400 --> 00:04:40,440 HOPEFULLY BOOST THE FIELD 109 00:04:40,440 --> 00:04:41,720 FORWARD. 110 00:04:41,720 --> 00:04:43,520 SO IF YOU WANT TO GO INTO THE 111 00:04:43,520 --> 00:04:44,640 DATABASE, THAT'S WHAT YOU NEED 112 00:04:44,640 --> 00:04:47,880 TO DO, IT'S A COUPLE SLIDES 113 00:04:47,880 --> 00:04:49,600 LATER AS WELL. 114 00:04:49,600 --> 00:04:59,600 O-GlcNAc IS THIS ADDITION OF 115 00:04:59,600 --> 00:05:01,520 ONE SUGAR, IT HAS BEEN A FIELD, 116 00:05:01,520 --> 00:05:04,480 MY POSTDOC IS ON IT, MY LAB 117 00:05:04,480 --> 00:05:07,960 STARTED THREE YEARS AGO WORKING 118 00:05:07,960 --> 00:05:10,400 ON THIS AS WELL, BEFORE I 119 00:05:10,400 --> 00:05:13,840 STARTED SCIENCE IN 1984 THE 120 00:05:13,840 --> 00:05:14,280 FIRST PUBLICATION ON 121 00:05:14,280 --> 00:05:16,000 O-GlcNAc WAS DONE, AND SINCE 122 00:05:16,000 --> 00:05:19,600 THAT WE HAD THIS INCREASING 123 00:05:19,600 --> 00:05:21,680 NUMBER OF PUBLICATIONS ON THIS 124 00:05:21,680 --> 00:05:23,520 MODIFICATION AND WE'RE ABOUT 125 00:05:23,520 --> 00:05:29,360 LIKE 200+ A YEAR AND THAT'S 126 00:05:29,360 --> 00:05:30,640 INCLUDING ARTICLES, REVIEWS, 127 00:05:30,640 --> 00:05:32,680 METHODS PAPERS, ET CETERA, AND 128 00:05:32,680 --> 00:05:35,720 OVERALL WE'RE REACHING 2,000 129 00:05:35,720 --> 00:05:37,840 PRIMARY ARTICLES ON 130 00:05:37,840 --> 00:05:40,560 O-GlcNAc, YOU CAN IMAGINE 131 00:05:40,560 --> 00:05:48,360 ANY NEW PURINE WE MAY HAVE 132 00:05:48,360 --> 00:05:50,120 IDENTIFIED, RATIO IN RED, 133 00:05:50,120 --> 00:05:52,320 ARTICLES THAT IDENTIFIED PURINE 134 00:05:52,320 --> 00:05:53,920 THAT WOULD TENSIONALLY WOULD 135 00:05:53,920 --> 00:06:00,480 NEED TO BE CONSOLIDATED INTO A 136 00:06:00,480 --> 00:06:00,800 DATABASE. 137 00:06:00,800 --> 00:06:03,280 THE PROBLEM IS THERE WAS A LOT 138 00:06:03,280 --> 00:06:18,760 OF DIFFERENT WAYS TO IDENTIFY 139 00:06:18,760 --> 00:06:19,440 O-GlcNAcYLATION, ENZYMEATIC 140 00:06:19,440 --> 00:06:24,560 LABELING, THAT IS AN EASY WAY TO 141 00:06:24,560 --> 00:06:35,000 SOMETIMES PULL THIS OUT, GETTING 142 00:06:35,000 --> 00:06:36,800 THE HUGE EXCEL SPREADSHEET. 143 00:06:36,800 --> 00:06:42,080 THE NANOBODY WAS A SPREADSHEET, 144 00:06:42,080 --> 00:06:47,880 THAT'S EASIER. 145 00:06:47,880 --> 00:06:50,760 IN VITRO O-GlcNAcYLATION AND 146 00:06:50,760 --> 00:06:56,600 SITES ARE NOT REALLY FRIENDLY ON 147 00:06:56,600 --> 00:06:58,840 AN EXCEL SPREADSHEET SO WE 148 00:06:58,840 --> 00:07:01,120 NEEDED TO UNCOUPLE THOSE THAT 149 00:07:01,120 --> 00:07:01,840 WERE EASIER. 150 00:07:01,840 --> 00:07:04,320 THERE WAS AN ATTEMPT. 151 00:07:04,320 --> 00:07:08,480 WE HAD AN O-GlcNAc DATABASE, 152 00:07:08,480 --> 00:07:12,400 THE DBOGA, WELL USED AND CLOSED 153 00:07:12,400 --> 00:07:14,640 EVENTUALLY AT SOME POINT. 154 00:07:14,640 --> 00:07:19,880 IN 2020 WITH A REALLY TRAUMATIC 155 00:07:19,880 --> 00:07:21,960 EVENT, CLICKING NOSE STICKING 156 00:07:21,960 --> 00:07:23,920 EVERY DAY, THE COVID PANDEMIC, 157 00:07:23,920 --> 00:07:26,440 MY LAB WAS OPEN FOR A YEAR AND A 158 00:07:26,440 --> 00:07:27,320 HALF. 159 00:07:27,320 --> 00:07:29,040 SO WE ENDED UP, ALL OF US AT 160 00:07:29,040 --> 00:07:31,720 HOME, ALL MY LAB AT HOME. 161 00:07:31,720 --> 00:07:33,320 IT WAS NOT OPEN FOR A LONG OF 162 00:07:33,320 --> 00:07:36,880 TIME, HAD A TON OF PAPERS TO 163 00:07:36,880 --> 00:07:37,080 WRITE. 164 00:07:37,080 --> 00:07:38,080 WE WERE THINKING ABOUT WHAT TO 165 00:07:38,080 --> 00:07:40,440 DO DURING THAT TIME AND THOUGHT 166 00:07:40,440 --> 00:07:42,680 ABOUT WRITING A REVIEW, CATCH UP 167 00:07:42,680 --> 00:07:44,800 ON OUR FAVORITE TV SHOWS, ET 168 00:07:44,800 --> 00:07:46,640 CETERA, EVERYBODY PEOPLE DID AND 169 00:07:46,640 --> 00:07:48,600 WE ADDED TO THIS, DECIDED TO 170 00:07:48,600 --> 00:07:50,560 CREATE A DATABASE. 171 00:07:50,560 --> 00:07:53,880 SO THAT'S WHAT CAME OUT OF IT. 172 00:07:53,880 --> 00:08:01,720 WE PUBLISHED THIS IN JANUARY 173 00:08:01,720 --> 00:08:03,840 2021, AND CALLED IT THE 174 00:08:03,840 --> 00:08:06,600 O-GlcNAcOME DATABASE, TO GET 175 00:08:06,600 --> 00:08:07,880 A SPREADSHEET SHEET AND DIDN'T 176 00:08:07,880 --> 00:08:11,160 HAVE A STRUCTURE. 177 00:08:11,160 --> 00:08:12,720 WE USED THE SPREADSHEET TO 178 00:08:12,720 --> 00:08:19,520 ANALYZE AND HAVE A VIEW OF THE 179 00:08:19,520 --> 00:08:20,680 HUMAN O-GlcNAcOME. 180 00:08:20,680 --> 00:08:27,120 WE WERE AT THE SAME TIME TO 181 00:08:27,120 --> 00:08:29,600 RELEASE A DATABASE FOR 182 00:08:29,600 --> 00:08:30,800 O-GlcNAc, THE ATLAS. 183 00:08:30,800 --> 00:08:32,400 WE BOTH THOUGHT ABOUT THE SAME 184 00:08:32,400 --> 00:08:34,480 THING AND YOU SHOULD CHECK OUT 185 00:08:34,480 --> 00:08:37,160 THIS ONE, A DIFFERENT WAY OF 186 00:08:37,160 --> 00:08:37,800 DOING THINGS. 187 00:08:37,800 --> 00:08:41,000 I'LL FOCUS ON OUR DATABASE 188 00:08:41,000 --> 00:08:43,080 TODAY. 189 00:08:43,080 --> 00:08:46,760 BUT THIS HAS MORE POTENTIAL. 190 00:08:46,760 --> 00:08:48,320 HOW DID WE DO IT? 191 00:08:48,320 --> 00:08:52,480 WE NEEDED TO DO AN INITIAL 192 00:08:52,480 --> 00:08:55,000 CURATION OF ALL THE PAPERS AND 193 00:08:55,000 --> 00:08:57,080 AVAILABLE LITERATURE ON THIS. 194 00:08:57,080 --> 00:09:01,800 WE STARTED BY DOING A PubMed 195 00:09:01,800 --> 00:09:03,720 SEARCH FOR O-GlcNAc WORDS I 196 00:09:03,720 --> 00:09:05,320 WOULD SEARCH FOR, REMOVE THE 197 00:09:05,320 --> 00:09:10,360 REVIEW, ON TOP OF THIS COMBINED 198 00:09:10,360 --> 00:09:14,440 WITH THE OMIC DATABASE TO GET 199 00:09:14,440 --> 00:09:18,400 THE LIST WE HAD A HARD TIME, 200 00:09:18,400 --> 00:09:19,920 SUPPLEMENTARY DATA NOT AS 201 00:09:19,920 --> 00:09:23,920 FRIENDLY, SO OVERALL WE ENDED UP 202 00:09:23,920 --> 00:09:24,680 WITH 1700 ARTICLES. 203 00:09:24,680 --> 00:09:29,200 WE EXCLUDED A BUNCH BECAUSE WE 204 00:09:29,200 --> 00:09:29,720 NEEDED SOMETHING THAT WAS 205 00:09:29,720 --> 00:09:33,560 FEASIBLE IN THE TIME WE HAD AND 206 00:09:33,560 --> 00:09:36,600 SOMETHING WE DISCUSSED RIGHT 207 00:09:36,600 --> 00:09:37,480 AWAY. 208 00:09:37,480 --> 00:09:39,920 SO, WE STARTED WITH REMOVING ALL 209 00:09:39,920 --> 00:09:44,440 OF THE NON-HUMAN MODELS, FOCUSED 210 00:09:44,440 --> 00:09:47,640 ON THE HUMAN O-GlcNAcOME, 211 00:09:47,640 --> 00:09:49,600 AND REMOVED REVIEWS, NON-PRIMARY 212 00:09:49,600 --> 00:09:52,400 RESEARCH, SO ONCE WE REVIEWED 213 00:09:52,400 --> 00:09:53,720 METHODS DEVELOPMENT, WE REMOVED 214 00:09:53,720 --> 00:09:57,440 THOSE AS WELL. 215 00:09:57,440 --> 00:10:01,840 WE ENDED UP WITH 755 ARTICLES 216 00:10:01,840 --> 00:10:05,000 THAT WERE WORKING ON 217 00:10:05,000 --> 00:10:10,720 O-GlcNAcOME IN HUMANS, HUMAN 218 00:10:10,720 --> 00:10:12,440 MODELS, HUMAN TISSUE, 378 219 00:10:12,440 --> 00:10:15,920 ARTICLES IDENTIFYING 220 00:10:15,920 --> 00:10:16,320 O-GlcNAc PROTEIN. 221 00:10:16,320 --> 00:10:17,760 IT'S A LOT OF MANUAL CURATION. 222 00:10:17,760 --> 00:10:22,040 THAT'S THE ONLY WAY WE FOUND TO 223 00:10:22,040 --> 00:10:23,320 START SOMETHING FROM IT. 224 00:10:23,320 --> 00:10:25,200 WE'RE TRYING TO MAKE IT BETTER 225 00:10:25,200 --> 00:10:26,680 FOR EVERYBODY. 226 00:10:26,680 --> 00:10:27,920 THANKS TO THOSE AMAZING PEOPLE 227 00:10:27,920 --> 00:10:31,160 THEY SPENT THEIR TIME WITH ME 228 00:10:31,160 --> 00:10:33,880 LOOKING THROUGH ARTICLES, 229 00:10:33,880 --> 00:10:35,720 TALKING ABOUT O-GlcNAc 230 00:10:35,720 --> 00:10:39,760 TRYING TO FIND WHICH PROTEINS 231 00:10:39,760 --> 00:10:41,880 WERE O-GlcNAcATEED. 232 00:10:41,880 --> 00:10:43,840 AND THEN WE SEPARATED THEM, 233 00:10:43,840 --> 00:10:49,120 THOSE THAT DIDN'T HAVE A SITE, 234 00:10:49,120 --> 00:10:52,480 THEY DID MAPPING, SOMETIMES 235 00:10:52,480 --> 00:10:56,240 POINT MUTATION, SOMETIMES BY 236 00:10:56,240 --> 00:10:56,800 MASS SPECTROMETRY, 7,000 237 00:10:56,800 --> 00:11:10,400 O-GlcNAc SITES AT THE END, 238 00:11:10,400 --> 00:11:13,880 USING THE SEQUENCE AS A 239 00:11:13,880 --> 00:11:14,520 REFERENCE. 240 00:11:14,520 --> 00:11:19,880 ALL THAT WITH A REFERENCE NUMBER 241 00:11:19,880 --> 00:11:22,360 FOR EACH PROTEIN CREATEED THE 242 00:11:22,360 --> 00:11:22,760 DATABASE. 243 00:11:22,760 --> 00:11:23,920 THANKS TO THOSE THAT HELPED US 244 00:11:23,920 --> 00:11:29,480 TO PUT IT INTO A FORMAT 245 00:11:29,480 --> 00:11:31,120 ACCESSIBLE TO EVERYBODY, AND IT 246 00:11:31,120 --> 00:11:36,080 HELPS US DO THE QUALITY CONTROL. 247 00:11:36,080 --> 00:11:37,560 EVENTUALLY FLORIAN CAME INTO THE 248 00:11:37,560 --> 00:11:41,320 LAB AS A POSTDOC AND CREATED AND 249 00:11:41,320 --> 00:11:47,080 DEVELOPED THE WEBSITE THAT IS 250 00:11:47,080 --> 00:11:48,400 NOW THE DATABASE. 251 00:11:48,400 --> 00:11:51,840 AND SO THIS WAS A MAJOR STEP 252 00:11:51,840 --> 00:11:58,640 FORWARD, WE'RE DOING EVERYTHING 253 00:11:58,640 --> 00:12:00,920 ON THAT WEBSITE AND UPDATE AS 254 00:12:00,920 --> 00:12:01,440 WELL. 255 00:12:01,440 --> 00:12:03,480 HOW DO WE EXTEND THE CURATION 256 00:12:03,480 --> 00:12:07,000 AND HOW DO WE IMPROVE CURATION? 257 00:12:07,000 --> 00:12:11,160 YOU CAN TELL THIS IS A HEAVY 258 00:12:11,160 --> 00:12:14,280 MANUAL LABOR TO DO ALL OF THOSE 259 00:12:14,280 --> 00:12:15,360 PAPERS BY HAND. 260 00:12:15,360 --> 00:12:17,920 AND IF WE WERE ON TOP OF IT, I 261 00:12:17,920 --> 00:12:19,640 THINK IT'S EASIER TO GET A PAPER 262 00:12:19,640 --> 00:12:24,280 A WEEK OR SOMETHING DONE. 263 00:12:24,280 --> 00:12:27,160 BUT WE STARTING WITH MORE THAN 264 00:12:27,160 --> 00:12:29,800 2,000 PAPERS TO GO FORWARD, 265 00:12:29,800 --> 00:12:30,880 HUMAN AND NON-HUMAN MODELS, AND 266 00:12:30,880 --> 00:12:33,080 NOW WE HAVE ANOTHER BATCH OF 267 00:12:33,080 --> 00:12:34,480 PAPERS WAITING TO BE CURATED AS 268 00:12:34,480 --> 00:12:37,520 WELL SO WE'VE DONE THE HUMAN, 269 00:12:37,520 --> 00:12:38,920 WHICH IS ABOUT 47% OF THE ENTIRE 270 00:12:38,920 --> 00:12:39,840 PAPER LIST WE HAD. 271 00:12:39,840 --> 00:12:43,960 AND NOW WE HAVE ALL OF THE OTHER 272 00:12:43,960 --> 00:12:51,120 MODELS THAT ALSO IDENTIFY 273 00:12:51,120 --> 00:12:52,080 O-GlcNAcATED PROTEIN, RATS, 274 00:12:52,080 --> 00:12:53,360 MOUSE, MIXED USING DIFFERENT 275 00:12:53,360 --> 00:12:55,600 CELL LINES FROM DIFFERENT 276 00:12:55,600 --> 00:12:59,120 MODELS, ALSO LIKE A LOT OF 277 00:12:59,120 --> 00:12:59,720 SMALLER REPRESENTATION MODELS 278 00:12:59,720 --> 00:13:01,840 BUT ALSO A LOT OF INTERESTING 279 00:13:01,840 --> 00:13:03,520 ONES WE WANT TO INCLUDE. 280 00:13:03,520 --> 00:13:05,920 HOW DO WE TRY TO MAKE IT QUICKER 281 00:13:05,920 --> 00:13:12,800 FOR EVERYBODY AND EASIER ON 282 00:13:12,800 --> 00:13:13,920 EVERYBODY? 283 00:13:13,920 --> 00:13:15,320 SO, WE IMPLEMENTED A BACKGROUND 284 00:13:15,320 --> 00:13:19,480 SYSTEM FOR THE DATABASE. 285 00:13:19,480 --> 00:13:22,480 FIRST WE'RE AUTOMATICALLY WITH 286 00:13:22,480 --> 00:13:23,880 THE NEWLY PUBLISHED ARTICLES. 287 00:13:23,880 --> 00:13:25,240 EVERYBODY MONTH SENDING A 288 00:13:25,240 --> 00:13:27,000 REQUEST, TRYING TO SEARCH THE 289 00:13:27,000 --> 00:13:28,520 NEW ARTICLES THAT WERE PUBLISHED 290 00:13:28,520 --> 00:13:32,600 SO WE DON'T ACTUALLY HAVE TO 291 00:13:32,600 --> 00:13:36,240 REDO THE INITIAL CURATION. 292 00:13:36,240 --> 00:13:37,240 A SMALL STEP SAVED A LITTLE BIT 293 00:13:37,240 --> 00:13:39,840 OF TIME AT A TIME, MAKING OUR 294 00:13:39,840 --> 00:13:41,880 SYSTEM MORE VIABLE. 295 00:13:41,880 --> 00:13:43,920 WE CREATED A FRIENDLY INTERFACE 296 00:13:43,920 --> 00:13:45,120 FOR REVIEW. 297 00:13:45,120 --> 00:13:48,920 THIS IS OUR BACKGROUND. 298 00:13:48,920 --> 00:13:52,720 ACCESSIBLE TO ME AND STUDENTS 299 00:13:52,720 --> 00:13:53,800 THAT ARE PARTICIPATING WITH 300 00:13:53,800 --> 00:13:56,400 CURATION, THE MAIN POINT IS WE 301 00:13:56,400 --> 00:13:58,000 CAN GIVE THE LOG-IN ALSO TO 302 00:13:58,000 --> 00:14:00,760 STUDENTS THAT ARE COMING IN AND 303 00:14:00,760 --> 00:14:05,480 WANT TO PARTICIPATE, AND WE'RE 304 00:14:05,480 --> 00:14:06,680 HAVING EVERYBODY PARTICIPATE IN 305 00:14:06,680 --> 00:14:07,800 THE SYSTEM. 306 00:14:07,800 --> 00:14:11,200 HERE THIS IS THE INTERFACE WE'RE 307 00:14:11,200 --> 00:14:13,400 GETTING, SO WE SEARCH THE NEW 308 00:14:13,400 --> 00:14:15,800 ARTICLE, HAVE THE ABSTRACT, THEN 309 00:14:15,800 --> 00:14:17,440 WE'RE DOWNLOADING THE PDF, 310 00:14:17,440 --> 00:14:19,360 UPLOADING THE PDF ON THIS TO 311 00:14:19,360 --> 00:14:20,320 READ IT QUICKLY. 312 00:14:20,320 --> 00:14:22,840 AND THEN WE ARE -- WE HAVE A 313 00:14:22,840 --> 00:14:24,440 FRIENDLY INPUT BOX, SO WE PUT IN 314 00:14:24,440 --> 00:14:28,840 WHAT WE FOUND IN THAT PAPER TO 315 00:14:28,840 --> 00:14:30,640 THE O-GlcNAc AND SAVE THE 316 00:14:30,640 --> 00:14:32,960 UPDATE AND AT SOME POINT PUSHING 317 00:14:32,960 --> 00:14:35,120 UPTAKE FOR THE WEBSITE. 318 00:14:35,120 --> 00:14:39,160 AND THEN WE'RE USING TEXT MINING 319 00:14:39,160 --> 00:14:40,440 AND MACHINE LEARNING TO 320 00:14:40,440 --> 00:14:45,720 ACCELERATE CURATION, THAT'S WHAT 321 00:14:45,720 --> 00:14:46,960 THOSE BOTTOM BOXES ARE. 322 00:14:46,960 --> 00:14:49,680 WE USE OUR NETWORK AND TRAIN 323 00:14:49,680 --> 00:14:55,920 THAT NEURONETWORK -- NEURAL 324 00:14:55,920 --> 00:14:56,200 NETWORK. 325 00:14:56,200 --> 00:14:58,400 WE'RE TRAINING THIS NEURAL 326 00:14:58,400 --> 00:14:59,560 NETWORK TO RECOGNIZE PAPERS AND 327 00:14:59,560 --> 00:15:03,840 THE TEXT IN THOSE PAPERS THAT 328 00:15:03,840 --> 00:15:07,320 ARE LOOKING THAT THEY HAVE 329 00:15:07,320 --> 00:15:09,360 IDENTIFIED O-GlcNAc SITES OR 330 00:15:09,360 --> 00:15:09,600 PROTEIN. 331 00:15:09,600 --> 00:15:10,960 WE GET BACK PREDICTIONS WHICH 332 00:15:10,960 --> 00:15:19,920 ONE WOULD BE, YES, THERE'S 333 00:15:19,920 --> 00:15:21,280 DEFINITELY AN O-GlcNAcYLATED 334 00:15:21,280 --> 00:15:23,960 PROTEIN, AND TO ZERO, LIKELY 335 00:15:23,960 --> 00:15:28,000 NOT, NO TRANSLATION IDENTIFIED 336 00:15:28,000 --> 00:15:29,920 IN THAT PAPER, MOSTLY JOURNALS 337 00:15:29,920 --> 00:15:30,720 WITH CHANGES. 338 00:15:30,720 --> 00:15:34,520 WE'RE TRYING TO GET OUT SOME 339 00:15:34,520 --> 00:15:37,320 INFO, THE NUMBERS, SO WE DON'T 340 00:15:37,320 --> 00:15:40,440 HAVE TO SEARCH EVERY TIME, ALSO 341 00:15:40,440 --> 00:15:43,000 POTENTIAL SITE, ET CETERA. 342 00:15:43,000 --> 00:15:47,800 WHAT WE HAVE IS SENTENCES FROM 343 00:15:47,800 --> 00:15:49,120 THAT PAPER THAT WE EXTRACT 344 00:15:49,120 --> 00:15:51,200 MAKING THE DECISION FOR THE 345 00:15:51,200 --> 00:15:51,960 NEURAL NETWORK AND HOPEFULLY 346 00:15:51,960 --> 00:15:56,080 THOSE SENTENCES ARE CLEAR 347 00:15:56,080 --> 00:15:59,720 ENOUGH SO WE KNOW THAT THIS 348 00:15:59,720 --> 00:16:03,040 PROTEIN IS O-GlcNAcYLATED ON 349 00:16:03,040 --> 00:16:04,000 THAT SITE. 350 00:16:04,000 --> 00:16:07,880 IT HELPS THE DECISION BUT DOES 351 00:16:07,880 --> 00:16:09,440 NOT REPLACE MANUAL CURATION, 352 00:16:09,440 --> 00:16:10,480 HELPS CONFIRM CURATION SOMETIMES 353 00:16:10,480 --> 00:16:13,080 WHEN THE STUDENTS ARE DOING IT 354 00:16:13,080 --> 00:16:15,920 AND ARE NOT USED TO IT BUT IT 355 00:16:15,920 --> 00:16:17,840 DOES NOT REPLACE IT FULLY. 356 00:16:17,840 --> 00:16:21,040 I WANT TO MENTION WE'VE CREATED 357 00:16:21,040 --> 00:16:23,960 A RESOURCE, EDUCATIONAL RESOURCE 358 00:16:23,960 --> 00:16:27,120 FOR TEACHERS, STUDENTS, 359 00:16:27,120 --> 00:16:28,760 SCIENTISTS THAT WOULD LIKE TO 360 00:16:28,760 --> 00:16:30,920 LEARN NEURAL NETWORK AND USE IT 361 00:16:30,920 --> 00:16:37,240 IN A FRIENDLY WAY. 362 00:16:37,240 --> 00:16:39,080 THIS IS WITH EPYNN.NET, THIS 363 00:16:39,080 --> 00:16:47,920 PAPER IS IN REVIEW RIGHT NOW. 364 00:16:47,920 --> 00:16:49,840 THE PREDICTION FROM THE NEURAL 365 00:16:49,840 --> 00:16:50,920 NETWORK LOOKS LIKE THIS. 366 00:16:50,920 --> 00:16:53,320 THIS PAPER FOR EXAMPLE WE HAVE A 367 00:16:53,320 --> 00:16:57,480 GOOD PREDICTION OF HAVING 368 00:16:57,480 --> 00:16:58,880 O-GlcNAcYLATED PROTEIN, NO 369 00:16:58,880 --> 00:17:00,920 WAY WE CAN DESIGN ON THIS ONE, 370 00:17:00,920 --> 00:17:01,880 IT'S IN THE MIDDLE. 371 00:17:01,880 --> 00:17:04,120 THIS WAS A DISCOVERY BY VIRTUAL 372 00:17:04,120 --> 00:17:06,320 SCREENING, WE'RE NOT GOING TO 373 00:17:06,320 --> 00:17:08,440 IDENTIFY, THAT'S A ZERO 374 00:17:08,440 --> 00:17:09,520 PREDICTION. 375 00:17:09,520 --> 00:17:11,600 SO, BECAUSE OF THAT SYSTEM WE 376 00:17:11,600 --> 00:17:13,680 ARE ABLE TO MAKE THE CURATION 377 00:17:13,680 --> 00:17:17,320 QUICKER AND KEEP ON TOP OF IT SO 378 00:17:17,320 --> 00:17:18,760 WE STARTED OBVIOUSLY IN COVID 379 00:17:18,760 --> 00:17:24,160 ABOUT MARCH 2020 TO DO THE FIRST 380 00:17:24,160 --> 00:17:25,600 CURATION, ENDED IN NOVEMBER WITH 381 00:17:25,600 --> 00:17:29,360 THE FIRST CURATION OF THE HUMAN 382 00:17:29,360 --> 00:17:30,400 O-GlcNAcOME AND RELEASE OF 383 00:17:30,400 --> 00:17:32,840 THE WEBSITE OF THE PAPER IN 384 00:17:32,840 --> 00:17:35,720 JANUARY, AND THEN WE DID IN 385 00:17:35,720 --> 00:17:37,120 MARCH 2021, SO ONLY THREE 386 00:17:37,120 --> 00:17:38,920 MONTHS, WE DID THE ENTIRE OTHER 387 00:17:38,920 --> 00:17:40,400 SET. 388 00:17:40,400 --> 00:17:43,720 SO EVERY SINGLE OTHER SPECIES, 389 00:17:43,720 --> 00:17:47,520 42 SPECIES AT THAT POINT, 14,000 390 00:17:47,520 --> 00:17:48,240 PROTEINS, 11,000 SITES, ABOUT 391 00:17:48,240 --> 00:17:52,160 2,000 ARTICLES THAT WERE DONE. 392 00:17:52,160 --> 00:17:54,160 AND THEN THIS ENTIRE CURATION 393 00:17:54,160 --> 00:17:56,400 AND SYSTEM IN THE BACKGROUND, 394 00:17:56,400 --> 00:17:59,320 ALL THAT IS PUBLISHED IN THAT 395 00:17:59,320 --> 00:17:59,880 OTHER PAPER. 396 00:17:59,880 --> 00:18:04,400 NOW AS MUCH LAST MONTH WE'RE AT 397 00:18:04,400 --> 00:18:05,880 43 EXPERIENCE, 16,000 PROTEINS, 398 00:18:05,880 --> 00:18:06,600 1200 SITES. 399 00:18:06,600 --> 00:18:08,840 AND OBVIOUSLY ALL OF THAT IS 400 00:18:08,840 --> 00:18:11,120 BECAUSE OF THE -- NOT BECAUSE, 401 00:18:11,120 --> 00:18:12,800 THANKS TO THE STUDENTS, THE 402 00:18:12,800 --> 00:18:14,560 INITIAL CURATION AS WELL AS 403 00:18:14,560 --> 00:18:17,560 EVERYBODY THAT CAME TO THE LAB 404 00:18:17,560 --> 00:18:18,920 THAT WORKED ON THIS, THE 405 00:18:18,920 --> 00:18:19,880 O-GlcNAc PROJECT, A 406 00:18:19,880 --> 00:18:22,760 CONTRIBUTION TO TRY TO GET THAT 407 00:18:22,760 --> 00:18:23,200 GOING. 408 00:18:23,200 --> 00:18:26,520 SO, NOW WE'VE CREATED A WEBSITE 409 00:18:26,520 --> 00:18:28,120 INTERFACE FOR THAT AS WELL, 410 00:18:28,120 --> 00:18:28,440 RIGHT? 411 00:18:28,440 --> 00:18:29,640 SO IN ADDITION TO TRYING TO KEEP 412 00:18:29,640 --> 00:18:31,440 IT UP WE WANTED TO MAKE IT 413 00:18:31,440 --> 00:18:33,840 FRIENDLY TO SEARCH AND USEFUL 414 00:18:33,840 --> 00:18:35,240 FOR EVERYBODY IN DIFFERENT WAYS 415 00:18:35,240 --> 00:18:38,200 BECAUSE PEOPLE ARE LOOKING FOR 416 00:18:38,200 --> 00:18:39,120 DIFFERENT THINGS IN A DATABASE. 417 00:18:39,120 --> 00:18:41,600 SOMETIMES YOU WANT TO SEEP THE 418 00:18:41,600 --> 00:18:50,120 ENTIRE O-GLYCOME AT LOOK AT ONE 419 00:18:50,120 --> 00:18:50,360 PROTEIN. 420 00:18:50,360 --> 00:18:52,280 CAN YOU GET INTO SEARCHING FOR 421 00:18:52,280 --> 00:18:53,760 YOUR PROTEIN OR EXPLORE FOR ONE 422 00:18:53,760 --> 00:18:58,520 SPECIES IN PARTICULAR IF YOU 423 00:18:58,520 --> 00:18:59,720 WANTED TO. 424 00:18:59,720 --> 00:19:02,720 BUT, FOR EXAMPLE, FROM THIS WE 425 00:19:02,720 --> 00:19:05,720 NOW HAVE THE PROTEIN WITH 426 00:19:05,720 --> 00:19:07,360 HIGHEST NUMBER OF O-GlcNAc 427 00:19:07,360 --> 00:19:12,360 SITES DEFINED TO DATE, THAT 428 00:19:12,360 --> 00:19:16,880 WOULD BE 14 WITH 185, I WAS 429 00:19:16,880 --> 00:19:19,080 SURPRISED BY THE HIGHER NUMBER 430 00:19:19,080 --> 00:19:21,000 ON ONE PROTEIN, THAT WAS PRETTY 431 00:19:21,000 --> 00:19:21,280 CRAZY. 432 00:19:21,280 --> 00:19:23,280 AND THEN WE ALSO WERE ABLE TO 433 00:19:23,280 --> 00:19:27,720 COME OUT, WE HAD A LOT OF 434 00:19:27,720 --> 00:19:29,840 SEQUENCE, THERE WAS A LOT OF 435 00:19:29,840 --> 00:19:30,960 THOSE PUBLISHED AROUND THE -- 436 00:19:30,960 --> 00:19:32,400 WE'RE TRYING TO MAKE ONE THE 437 00:19:32,400 --> 00:19:34,800 MOST UP TO DATE SO WE KNOW 438 00:19:34,800 --> 00:19:43,640 THERE'S NO EXACT SEQUENCE BUT 439 00:19:43,640 --> 00:19:46,520 SOMETHING WE KNOW, ALANINE PLUS 440 00:19:46,520 --> 00:19:48,280 TO, PROLINE, SOMETIMES WE'RE 441 00:19:48,280 --> 00:19:50,320 GETTING MORE FOR MINOR SPECIES, 442 00:19:50,320 --> 00:19:51,960 WE CAN UPDATE FOR THOSE AS WELL 443 00:19:51,960 --> 00:19:57,520 BUT FOR NOW HAVING IT FOR HUMAN, 444 00:19:57,520 --> 00:19:58,640 RATS, MOUSE, I BELIEVE. 445 00:19:58,640 --> 00:20:00,200 AND THEN WE'RE TRYING TO GET 446 00:20:00,200 --> 00:20:02,280 BETTER AT THE OTHER ONE BUT NEED 447 00:20:02,280 --> 00:20:05,520 A GOOD BASE OF NUMBER OF 448 00:20:05,520 --> 00:20:07,720 O-GlcNAc SITES AS WELL. 449 00:20:07,720 --> 00:20:10,200 IF YOU WANT TO KNOW YOUR 450 00:20:10,200 --> 00:20:14,560 EXPERIMENT, YOU CAN GO INTO THIS 451 00:20:14,560 --> 00:20:16,720 AND INPUT ALL OF YOUR PROTEIN 452 00:20:16,720 --> 00:20:20,000 IDENTIFIED FROM YOUR STUDY AS 453 00:20:20,000 --> 00:20:21,840 WELL AS THE SITE, IT WILL COME 454 00:20:21,840 --> 00:20:26,040 BACK AS YES OR NO, IS IT IN THE 455 00:20:26,040 --> 00:20:26,720 DATABASE. 456 00:20:26,720 --> 00:20:28,360 SO IF YOU PUBLISH SOMETHING, 457 00:20:28,360 --> 00:20:31,760 IT'S NOT IN THE DATABASE, YOU'RE 458 00:20:31,760 --> 00:20:32,400 LIKE, WHAT? 459 00:20:32,400 --> 00:20:34,920 SO WE HAVE AN INPUT SYSTEM. 460 00:20:34,920 --> 00:20:39,080 YOU CAN -- WE'RE HUMAN AND WE'RE 461 00:20:39,080 --> 00:20:43,160 DOING EVERYTHING MANUALLY. 462 00:20:43,160 --> 00:20:45,400 SO WE HAVE AN INPUT PAGE PEOPLE 463 00:20:45,400 --> 00:20:46,320 CAN SEND THEIR REQUEST. 464 00:20:46,320 --> 00:20:48,440 WE'VE HAD THAT IN THE PAST AND 465 00:20:48,440 --> 00:20:50,920 HAVE INCLUDED THEM. 466 00:20:50,920 --> 00:20:58,960 IF YOU'RE PROTEIN OF INTEREST IS 467 00:20:58,960 --> 00:20:59,520 O-GlcNAcYLATED, YOU WANT TO 468 00:20:59,520 --> 00:20:59,760 KNOW. 469 00:20:59,760 --> 00:21:01,800 THIS IS WHAT YOU GET. 470 00:21:01,800 --> 00:21:04,360 WE'RE MAPPING THIS ON THE 471 00:21:04,360 --> 00:21:06,760 SEQUENCE AS WELL AS PUBLIC 472 00:21:06,760 --> 00:21:07,520 DATABASES AS WELL. 473 00:21:07,520 --> 00:21:16,880 AND POTENTIALLY IF YOU HAVE A 474 00:21:16,880 --> 00:21:19,520 DUAL SIDE O-GlcNAc, WE HAVE 475 00:21:19,520 --> 00:21:19,720 THAT. 476 00:21:19,720 --> 00:21:23,160 WE CROSS-REFERENCE, , YOU HAVE 477 00:21:23,160 --> 00:21:24,240 ALL THE REFERENCE OF THE 478 00:21:24,240 --> 00:21:27,680 PROTEINS, IF YOU WANT TO GET THE 479 00:21:27,680 --> 00:21:30,400 LIST OF EVERYTHING SHOWN, EVERY 480 00:21:30,400 --> 00:21:33,440 SINGLE PAPER, THIS IS WHERE YOU 481 00:21:33,440 --> 00:21:34,480 WOULD HAVE IT, CLICK ALL 482 00:21:34,480 --> 00:21:36,400 REFERENCE AND GET THE LIST. 483 00:21:36,400 --> 00:21:42,600 WE CROSS-REFERENCE WITH OTHER 484 00:21:42,600 --> 00:21:43,800 DATABASES, GlyGen IF YOU 485 00:21:43,800 --> 00:21:46,680 WANT TO GO BACK, AND COMMENTS SO 486 00:21:46,680 --> 00:21:48,280 PEOPLE CAN PUT COMMENTS IF YOU 487 00:21:48,280 --> 00:21:49,880 THINK THERE'S SOMETHING WRONG. 488 00:21:49,880 --> 00:21:51,400 IF THERE IS ANOTHER SPECIES YOU 489 00:21:51,400 --> 00:21:56,960 WILL SEE IT IF IT HAS THE SAME 490 00:21:56,960 --> 00:21:57,480 NAME. 491 00:21:57,480 --> 00:22:00,520 HOW CONFIDENT ARE WE? 492 00:22:00,520 --> 00:22:05,200 HOW DO WE DEFINE PROTEINS, WHICH 493 00:22:05,200 --> 00:22:06,720 METHODS ARE VALID, VERSUS NONE, 494 00:22:06,720 --> 00:22:08,480 SO WE DID NOT WANT TO MAKE THE 495 00:22:08,480 --> 00:22:11,960 CHOICE SO WE CAME UP WITH 496 00:22:11,960 --> 00:22:13,240 O-GlcNAc SCORING SYSTEM. 497 00:22:13,240 --> 00:22:16,120 THE SCORE WE HAVE FOR EACH 498 00:22:16,120 --> 00:22:17,160 PROTEIN CONSISTS OF THIS. 499 00:22:17,160 --> 00:22:22,200 IT'S A NUMBER OF PROTEINS THAT 500 00:22:22,200 --> 00:22:24,880 PUBLISHED THIS, NUMBER OF 501 00:22:24,880 --> 00:22:29,600 CITATIONS THOSE REFERENCES, 502 00:22:29,600 --> 00:22:30,560 EVERYTHING IS NORMALIZED BETWEEN 503 00:22:30,560 --> 00:22:32,720 0 AND 1. 504 00:22:32,720 --> 00:22:33,560 TIME SPENT BETWEEN PUBLICATION, 505 00:22:33,560 --> 00:22:37,520 SO IF IT'S BEEN IDENTIFIED 20 506 00:22:37,520 --> 00:22:41,360 YEARS AGO AND AGAIN, WITH THE 507 00:22:41,360 --> 00:22:43,120 CHANGES IN INSTRUMENTATION AND 508 00:22:43,120 --> 00:22:45,120 ALL, IT'S PROBABLY A GOOD SIGN 509 00:22:45,120 --> 00:22:48,320 OF STILL BEING IDENTIFIED AGAIN. 510 00:22:48,320 --> 00:22:50,520 IF IT WAS IDENTIFIED 20 YEARS 511 00:22:50,520 --> 00:22:54,080 AGO MIGHT HAVE BEEN A DEFOLD OF 512 00:22:54,080 --> 00:22:55,080 FAULT IN THE MACHINE CREATING 513 00:22:55,080 --> 00:22:55,920 FALSE IDENTIFICATION AT THAT 514 00:22:55,920 --> 00:22:58,640 POINT IF IT'S NOT IDENTIFIED 515 00:22:58,640 --> 00:23:00,920 SINCE THEN, IT'S PROBABLY NOT A 516 00:23:00,920 --> 00:23:01,320 REDEFINE. 517 00:23:01,320 --> 00:23:03,320 AND A NUMBER OF FIRST AND LAST 518 00:23:03,320 --> 00:23:05,480 AUTHORS ON THIS PAPER WE CAME UP 519 00:23:05,480 --> 00:23:08,120 WITH THIS THING LIKE DIFFERENT 520 00:23:08,120 --> 00:23:10,400 INSTRUMENTATION CAN BRING 521 00:23:10,400 --> 00:23:11,920 DIFFERENT ERRORS, MULTIPLE FIRST 522 00:23:11,920 --> 00:23:15,440 AND LAST AUTHORS HAVE COME UP 523 00:23:15,440 --> 00:23:16,720 WITH THE SAME IDENTIFICATION, 524 00:23:16,720 --> 00:23:18,480 IT'S A GOOD SIGN AS WELL. 525 00:23:18,480 --> 00:23:21,680 WE COME UP WITH A BONUS AS WELL, 526 00:23:21,680 --> 00:23:25,400 MOST OF THE ERRORS USUALLY COME 527 00:23:25,400 --> 00:23:31,520 FROM BIG PROTEOMIC STUDY WHERE 528 00:23:31,520 --> 00:23:33,320 WE HAVE A LOT, BIG MASS SPEC 529 00:23:33,320 --> 00:23:36,040 STUDY DOES NOT GET AS MUCH AS A 530 00:23:36,040 --> 00:23:37,920 BONUS AS SOMETHING WE DO, A 531 00:23:37,920 --> 00:23:48,720 POINT MUTATION OF A PROTEIN TO 532 00:23:48,720 --> 00:23:49,360 SHOW O-GlcNAcYLATION. 533 00:23:49,360 --> 00:23:51,120 WE COME UP WITH THAT LINE, THIS 534 00:23:51,120 --> 00:23:52,960 IS REALLY NOT A CONFIDENT 535 00:23:52,960 --> 00:23:55,200 IDENTIFICATION AND EVERYTHING 536 00:23:55,200 --> 00:23:58,480 THAT'S UP AND AFTER BECOMES 537 00:23:58,480 --> 00:24:00,760 SIGNIFICANT TO US AND HAS A 538 00:24:00,760 --> 00:24:02,120 COUPLE REFERENCES, A COUPLE 539 00:24:02,120 --> 00:24:03,800 YEARS APART, SOUNDS LIKE A GOOD 540 00:24:03,800 --> 00:24:04,440 PROTEIN. 541 00:24:04,440 --> 00:24:05,720 OBVIOUSLY WE'RE SAYING TO 542 00:24:05,720 --> 00:24:08,160 EVERYBODY THAT EVERYTHING SHOULD 543 00:24:08,160 --> 00:24:11,880 BE DOUBLE CHECKED. 544 00:24:11,880 --> 00:24:14,320 AND THAT'S WHAT THE O-GlcNAc 545 00:24:14,320 --> 00:24:16,720 SCORE LOOKS LIKE. 546 00:24:16,720 --> 00:24:19,920 THIS PROTEIN, LOW GlcNAc 547 00:24:19,920 --> 00:24:23,280 SCORE, ONLY TWO REFERENCE, ONE 548 00:24:23,280 --> 00:24:25,920 IN PARTICULAR PUBLISHED, THREE 549 00:24:25,920 --> 00:24:31,760 CITATION TOTAL, ONLY ONE YEAR, 550 00:24:31,760 --> 00:24:32,640 BASICALLY NOTHING IN BETWEEN. 551 00:24:32,640 --> 00:24:36,560 IT'S LOST IN THE BIG PROTEOMIC 552 00:24:36,560 --> 00:24:38,280 STUDY, A MORE FOCUSED STUDY WILL 553 00:24:38,280 --> 00:24:39,520 HELP DEFINE THAT ONE. 554 00:24:39,520 --> 00:24:45,440 YOU HAVE SOMETHING IN THE MIDDLE 555 00:24:45,440 --> 00:24:47,160 WITH FOUR YEARS BETWEEN 556 00:24:47,160 --> 00:24:50,560 IDENTIFICATION AND KIND OF LIKE 557 00:24:50,560 --> 00:24:51,600 PROTEOMIC STUDY AND WE'RE 558 00:24:51,600 --> 00:24:53,440 GETTING REALLY CONFIDENT ON THAT 559 00:24:53,440 --> 00:24:54,120 ONE. 560 00:24:54,120 --> 00:24:58,200 SOMETHING LIKE THIS ACTUALLY HAS 561 00:24:58,200 --> 00:25:01,760 A LOT OF CITATIONS, EIGHT YEARS 562 00:25:01,760 --> 00:25:07,000 BETWEEN, FOCUS STUDY IN I.T. 563 00:25:07,000 --> 00:25:09,080 MUTATION, ET CETERA, TWO 564 00:25:09,080 --> 00:25:11,400 REFERENCE BUT TWO TEAMS. 565 00:25:11,400 --> 00:25:13,280 THAT'S AN IDEA WHAT THIS IS, 566 00:25:13,280 --> 00:25:15,160 KNOWING WE'RE ONLY DECIDING THAT 567 00:25:15,160 --> 00:25:17,840 THE REALLY LOW SCORE IS NOT 568 00:25:17,840 --> 00:25:18,680 GOOD, IDENTIFICATION, EVERYTHING 569 00:25:18,680 --> 00:25:23,240 AFTER THAT SHOULD BE CONFIDENT. 570 00:25:23,240 --> 00:25:25,320 I'M GOING TO CONCLUDE, I THINK 571 00:25:25,320 --> 00:25:26,880 I'M ON TIME. 572 00:25:26,880 --> 00:25:30,760 WE'VE DONE THIS EXTENSIVE 573 00:25:30,760 --> 00:25:31,720 CATALOG OF O-GlcNAcYLATED 574 00:25:31,720 --> 00:25:33,720 PROTEIN, TRIED TO USE MINING AND 575 00:25:33,720 --> 00:25:36,400 MACHINE LEARNING TO ACCELERATE 576 00:25:36,400 --> 00:25:37,960 CURATION BUT IT IS OBVIOUSLY 577 00:25:37,960 --> 00:25:40,400 SOMETHING THAT WE'RE TRYING TO 578 00:25:40,400 --> 00:25:41,800 IMPROVE AS WELL BECAUSE TEXT 579 00:25:41,800 --> 00:25:43,880 MINING IN THE PAPERS IS HARD 580 00:25:43,880 --> 00:25:48,400 BECAUSE THEY ARE STRUCTURED 581 00:25:48,400 --> 00:25:48,720 DIFFERENTLY. 582 00:25:48,720 --> 00:25:50,440 BUT THAT ALLOWS BIMONTHLY 583 00:25:50,440 --> 00:25:52,520 UPDATE, MOSTLY BY STUDENTS, 584 00:25:52,520 --> 00:25:55,720 DOUBLE CHECKED BY MORE SENIOR 585 00:25:55,720 --> 00:25:58,320 STUDENT OR MYSELF, TRYING TO BE 586 00:25:58,320 --> 00:25:58,960 IMPARTIAL IN IDENTIFICATION NOT 587 00:25:58,960 --> 00:26:04,240 CHOOSE CHOOSING WHICH ARE GOOD 588 00:26:04,240 --> 00:26:07,920 OR NOT GOOD TECHNIQUE, TRYING TO 589 00:26:07,920 --> 00:26:10,200 SCORE RESULT OBJECTIVELY. 590 00:26:10,200 --> 00:26:12,760 CREATED A FRIENDLY INTERFACE FOR 591 00:26:12,760 --> 00:26:14,440 DATA AND EVERYBODY FIND THEIR 592 00:26:14,440 --> 00:26:14,600 WAY. 593 00:26:14,600 --> 00:26:16,880 WE KNOW THERE'S ROOM FOR 594 00:26:16,880 --> 00:26:21,320 IMPROVEMENT, WE LOVE FOR YOU TO 595 00:26:21,320 --> 00:26:22,120 LEAVE COMMENTS, FEEDBACK, 596 00:26:22,120 --> 00:26:23,640 SUGGESTIONS, AND OUR DEVELOPERS 597 00:26:23,640 --> 00:26:25,520 JUST MOVE ON TO ANOTHER JOB SO 598 00:26:25,520 --> 00:26:29,000 WE'RE GOING TO HAVE TO FILL THAT 599 00:26:29,000 --> 00:26:31,120 SPOT AS WELL. 600 00:26:31,120 --> 00:26:34,040 HOPEFULLY SO EVERYTHING DONE BY 601 00:26:34,040 --> 00:26:35,840 STUDENTS MOSTLY, HEY, WE SHOULD 602 00:26:35,840 --> 00:26:36,320 DO THIS. 603 00:26:36,320 --> 00:26:40,120 SO THIS IS THE TEAM THAT DID ALL 604 00:26:40,120 --> 00:26:44,200 THE WORK AND I'M SO GRATEFUL 605 00:26:44,200 --> 00:26:45,800 DURING COVID, IT WAS A GREAT 606 00:26:45,800 --> 00:26:47,520 THING TO DO AND I'M SO HAPPY 607 00:26:47,520 --> 00:26:54,000 ABOUT IT BUT I HAVE TO 608 00:26:54,000 --> 00:26:54,920 ACKNOWLEDGE SUPER CREATIVE DOING 609 00:26:54,920 --> 00:26:55,880 IT. 610 00:26:55,880 --> 00:26:58,320 WE DIDN'T HAVE A DEVELOPER, RAJA 611 00:26:58,320 --> 00:26:59,960 HELPED A LOT. 612 00:26:59,960 --> 00:27:01,160 THANKS FOR PUTTING THAT OFF THE 613 00:27:01,160 --> 00:27:07,040 GROUND AND THEN THE TEAM THAT IS 614 00:27:07,040 --> 00:27:08,400 DEVELOPING EPYNN, MAKING IT 615 00:27:08,400 --> 00:27:12,560 FRIENDLY TO USE NEURAL NETWORK, 616 00:27:12,560 --> 00:27:16,400 AND EARLY DEVELOPMENT OF THE 617 00:27:16,400 --> 00:27:17,920 WEBSITE AND TESTING. 618 00:27:17,920 --> 00:27:19,920 CHECK OUT YOUR PROTEIN PLEASE. 619 00:27:19,920 --> 00:27:20,840 >> ALL RIGHT. 620 00:27:20,840 --> 00:27:23,000 THANK YOU, STEPHANIE. 621 00:27:23,000 --> 00:27:26,400 REMINDER TO EVERYONE, YOU CAN 622 00:27:26,400 --> 00:27:28,440 PUT YOUR COMMENTS IN THE -- 623 00:27:28,440 --> 00:27:31,560 CLICK ON SEND LIVE FEEDBACK. 624 00:27:31,560 --> 00:27:32,680 STEPHANIE WILL ADDRESS 625 00:27:32,680 --> 00:27:35,000 QUESTIONS, APPROXIMATELY AROUND 626 00:27:35,000 --> 00:27:38,040 NOON EASTERN TIME TODAY. 627 00:27:38,040 --> 00:27:40,360 NEXT SPEAKER IS JOSHUA SHULMAN 628 00:27:40,360 --> 00:27:42,160 FROM BAYLOR COLLEGE OF MEDICINE, 629 00:27:42,160 --> 00:27:45,080 TALKING TO US ABOUT FUNCTIONAL 630 00:27:45,080 --> 00:27:47,400 GLYCOMICS OF THE LYSOSOME IN 631 00:27:47,400 --> 00:27:48,080 PARKINSON'S DISEASE. 632 00:27:48,080 --> 00:27:49,960 TAKE IT AWAY, JOSH. 633 00:27:49,960 --> 00:27:50,800 >> OKAY. 634 00:27:50,800 --> 00:27:51,760 YOU SEE MY SCREEN OKAY? 635 00:27:51,760 --> 00:27:55,080 >> YES, SIR. 636 00:27:55,080 --> 00:27:55,400 >> PERFECT. 637 00:27:55,400 --> 00:27:56,320 THANKS TO EVERYONE, ORGANIZERS 638 00:27:56,320 --> 00:27:57,920 FOR INVITING ME TO TALK HERE. 639 00:27:57,920 --> 00:27:59,760 I'M GOING TO SHIFT GEARS AND 640 00:27:59,760 --> 00:28:02,640 TELL YOU ABOUT OUR WORK ON 641 00:28:02,640 --> 00:28:04,360 PARKINSON'S DISEASE WHICH 642 00:28:04,360 --> 00:28:09,320 OVERLAPS WITH GLYCOMICS AND 643 00:28:09,320 --> 00:28:09,720 GLYCOINFORMATICS. 644 00:28:09,720 --> 00:28:12,440 SO, THE LYSOSOME OBVIOUSLY IS A 645 00:28:12,440 --> 00:28:16,480 HUB FOR HOMEOSTASIS OF COMPLEX 646 00:28:16,480 --> 00:28:18,760 CARBOHYDRATES INCLUDING 647 00:28:18,760 --> 00:28:20,440 GLYCOLIPIDS AND GLYCOPROTEINS, 648 00:28:20,440 --> 00:28:25,600 AND IT'S ALSO A HUB FOR RISK AND 649 00:28:25,600 --> 00:28:27,120 PATHOGENESIS OF PARKINSON'S. 650 00:28:27,120 --> 00:28:29,200 WE RECOGNIZE AN IMPORTANT ROLE 651 00:28:29,200 --> 00:28:34,600 FOR LYSOSOME IN THE TURNOVER OF 652 00:28:34,600 --> 00:28:35,720 ALPHA-SYNUCLEIN PROTEIN WHICH 653 00:28:35,720 --> 00:28:40,040 FORMS THE LEWY BODY, TINY 654 00:28:40,040 --> 00:28:41,960 PATHOLOGIC FEATURE OF 655 00:28:41,960 --> 00:28:43,280 PARKINSON'S DISEASE. 656 00:28:43,280 --> 00:28:43,920 ALPHA-SYNUCLEIN ITSELF BASED ON 657 00:28:43,920 --> 00:28:48,200 A LARGE BODY OF WORK DISRUPTS 658 00:28:48,200 --> 00:28:48,920 LYSOSOMAL TRAFFICKING AND 659 00:28:48,920 --> 00:28:51,920 AUTOPHAGY, SO LYSOSOMAL FUNCTION 660 00:28:51,920 --> 00:28:54,360 IS DISRUPTED BY ALPHA-SYNUCLEIN. 661 00:28:54,360 --> 00:28:57,520 AND WHAT'S MOVE WHEN THE 662 00:28:57,520 --> 00:29:00,240 LYSOSOME IS DYSFUNCTIONAL, 663 00:29:00,240 --> 00:29:01,840 SUBSTRATES INCLUDING 664 00:29:01,840 --> 00:29:08,920 GLYCOLIPIDS, PARTICULARLY 665 00:29:08,920 --> 00:29:12,040 SPHINGOLIPIDS AND SERUMIDES 666 00:29:12,040 --> 00:29:14,520 APPEAR TO TRIGGER 667 00:29:14,520 --> 00:29:14,920 ALPHA-SYNUCLEIN. 668 00:29:14,920 --> 00:29:16,360 AS ILLUSTRATED IN THE SCHEMATIC 669 00:29:16,360 --> 00:29:18,920 MANY PARKINSON'S DISEASE GENES 670 00:29:18,920 --> 00:29:19,880 ARE IMPLICATING LYSOSOMAL 671 00:29:19,880 --> 00:29:22,360 BIOLOGY AS IMPORTANT FOR DISEASE 672 00:29:22,360 --> 00:29:22,880 RISK. 673 00:29:22,880 --> 00:29:29,600 I'M GOING TO TELL YOU TWO SHORT 674 00:29:29,600 --> 00:29:32,960 VIGNETTES, FIRST RELATES TO THE 675 00:29:32,960 --> 00:29:41,400 RETRO MER. 676 00:29:41,400 --> 00:29:43,920 IN 2011, AUTOSOMAL VARIANTS 677 00:29:43,920 --> 00:29:47,240 CAUSED LATE ONSET PARKINSON'S 678 00:29:47,240 --> 00:29:49,360 DISEASE, AND VPS35 ENCODES A 679 00:29:49,360 --> 00:29:55,880 CORE COMPONENT OF THIS CELLULAR 680 00:29:55,880 --> 00:29:56,600 COMPLEX, RETROMER, TRIMERIC AND 681 00:29:56,600 --> 00:30:03,240 CONTAINS 29 AND 26. 682 00:30:03,240 --> 00:30:04,640 THE RETROMER HAS AN IMPORTANT 683 00:30:04,640 --> 00:30:06,240 ROLE IN TRACKING IN THE SYSTEM, 684 00:30:06,240 --> 00:30:09,000 IN PARTICULAR A ROLE IN THE 685 00:30:09,000 --> 00:30:13,360 TRAFFICKING OF A NUMBER OF 686 00:30:13,360 --> 00:30:14,920 LYSOSOMAL ENZYMES, AND RETROMER 687 00:30:14,920 --> 00:30:16,600 IS STUDIED IN A VARIETY OF CELL 688 00:30:16,600 --> 00:30:19,920 TIMES BUT ROLE IN NEURONS AND IN 689 00:30:19,920 --> 00:30:25,880 AGING BRAIN IS STILL RATHER 690 00:30:25,880 --> 00:30:27,320 POORLY UNDERSTOOD. 691 00:30:27,320 --> 00:30:29,440 VPS35 INCLUDING THE FRUIT FLY 692 00:30:29,440 --> 00:30:31,720 ARE LETHAL, ESSENTIAL GENES, AND 693 00:30:31,720 --> 00:30:34,760 WE GOT LUCKY BECAUSE IT TURNS 694 00:30:34,760 --> 00:30:37,760 OUT WHEN YOU MUTATE VPS29 WE 695 00:30:37,760 --> 00:30:39,720 CAN -- WE HAVE VIABLE FLIES WE 696 00:30:39,720 --> 00:30:41,920 CAN STUDY AS THEY AGE INCLUDING 697 00:30:41,920 --> 00:30:43,360 STUDIES OF THEIR ADULT BRAIN. 698 00:30:43,360 --> 00:30:47,720 SO I WANT TO SHOW WHAT HAPPENS 699 00:30:47,720 --> 00:30:49,880 IN VPS29 MUTANT FLIES. 700 00:30:49,880 --> 00:30:52,920 FIRST OF ALL, THIS IS THE 701 00:30:52,920 --> 00:30:55,680 DROSOPHILA ADULT BRAIN, 702 00:30:55,680 --> 00:30:58,400 EXPRESSION OF VPS29 AND 35, TWO 703 00:30:58,400 --> 00:31:00,320 COMPONENTS OF THE RETROMER, THEY 704 00:31:00,320 --> 00:31:02,400 ARE VERY STRONGLY OVERLAPPING 705 00:31:02,400 --> 00:31:04,840 AND LARGELY CO-LOCALIZING. 706 00:31:04,840 --> 00:31:07,160 AND HIGHER MAGNIFICATION ASSUME 707 00:31:07,160 --> 00:31:15,240 A PUNCTATE DISTRIBUTION WITHIN 708 00:31:15,240 --> 00:31:16,840 THE CYTOPLASM CONSISTENT WITH 709 00:31:16,840 --> 00:31:19,920 THE PATHWAY. 710 00:31:19,920 --> 00:31:21,120 IN THE VPS29 NULL ANIMALS, 711 00:31:21,120 --> 00:31:24,120 VIABLE, AS WE AGE THEM THEY HAVE 712 00:31:24,120 --> 00:31:25,920 REDUCED LIFESPAN WHICH WE CAN 713 00:31:25,920 --> 00:31:28,920 RESCUE WHEN WE GIVE BACK VPS29 714 00:31:28,920 --> 00:31:31,720 WILDTYPE FUNCTION, AS WE AGE 715 00:31:31,720 --> 00:31:34,320 ANIMALS CLIMBING IS ALSO 716 00:31:34,320 --> 00:31:36,160 IMPAIRED. 717 00:31:36,160 --> 00:31:42,440 INTERESTINGLY, IN THE VPS29 718 00:31:42,440 --> 00:31:50,080 MUTANTS, VPS 35 APPEARS TO BE 719 00:31:50,080 --> 00:31:50,400 MISLOCALIZED. 720 00:31:50,400 --> 00:31:55,000 WE SEE VPS 35 FORMING PUNCTA 721 00:31:55,000 --> 00:32:00,360 THAT ARE PERINUCLEAR. 722 00:32:00,360 --> 00:32:02,560 WHAT HAPPENS AT A GRANULAR 723 00:32:02,560 --> 00:32:03,640 LEVEL? 724 00:32:03,640 --> 00:32:05,360 IT APPEARS SYNAPTIC TRANSMISSION 725 00:32:05,360 --> 00:32:07,720 IS IMPAIRED, I'M SHOWING HERE 726 00:32:07,720 --> 00:32:10,840 HIGH FREQUENCY STIMULATION OF 727 00:32:10,840 --> 00:32:12,480 THE DROSOPHILA RETINA, AND WE 728 00:32:12,480 --> 00:32:15,400 SEE GRADUAL AND PROGRESSESSIVE 729 00:32:15,400 --> 00:32:16,120 REDUCTION OF TRANSIENT 730 00:32:16,120 --> 00:32:18,520 POTENTIALS THAT REFLECT SYNAPTIC 731 00:32:18,520 --> 00:32:19,320 TRANSMISSION. 732 00:32:19,320 --> 00:32:23,800 THIS IS A PHENOTYPE TYPICAL OF 733 00:32:23,800 --> 00:32:24,520 SYNAPTIC VESICLE RECYCLING 734 00:32:24,520 --> 00:32:27,360 MUTANTS, AND IN FURTHER STUDIES 735 00:32:27,360 --> 00:32:29,640 OF THE NEUROMUSCULAR JUNCTION 736 00:32:29,640 --> 00:32:31,920 WHERE WE USE FLUORESCENT DYE TO 737 00:32:31,920 --> 00:32:34,760 LOOK AT UPTAKE AND REPLENISHMENT 738 00:32:34,760 --> 00:32:39,760 WE SEE A LOSS IN VPS29 UNITS. 739 00:32:39,760 --> 00:32:42,920 WE STUDY MATURATION OF LYSOSOMAL 740 00:32:42,920 --> 00:32:45,840 ENZYMES, WE SEE THAT THERE'S A 741 00:32:45,840 --> 00:32:49,800 DISRUPTION THAT IS AGE DEPENDENT 742 00:32:49,800 --> 00:32:55,160 IN THE VPS19 MUTANT IN RED WITH 743 00:32:55,160 --> 00:32:58,640 ACCUMULATION OF IMMATURE PRO 744 00:32:58,640 --> 00:32:59,440 FORMS. 745 00:32:59,440 --> 00:33:00,400 ELECTRON MICROSCOPIC LEVEL 746 00:33:00,400 --> 00:33:01,920 PROFOUND DISRUPTIONS. 747 00:33:01,920 --> 00:33:04,320 WE'RE WITHIN THE DROSOPHILA 748 00:33:04,320 --> 00:33:07,120 RETINA WE SEE VERY ENLARGED 749 00:33:07,120 --> 00:33:08,320 LYSOSOMAL STRUCTURES FILLED WITH 750 00:33:08,320 --> 00:33:11,520 ELECTRON DENSE MATERIAL WHICH 751 00:33:11,520 --> 00:33:13,120 CLEARLY REPRESENT UNDIGESTED 752 00:33:13,120 --> 00:33:14,080 SUBSTRATES. 753 00:33:14,080 --> 00:33:15,720 WE SEE SIMILAR ACCUMULATIONS IN 754 00:33:15,720 --> 00:33:19,920 THE ADULT FLY BRAIN, AND I THINK 755 00:33:19,920 --> 00:33:29,920 THESE LOOK LIKE LITTLE BACLAVA, 756 00:33:29,920 --> 00:33:32,120 APPEARANCE OF LITTLE LYSOSOMES, 757 00:33:32,120 --> 00:33:34,520 LIPID LAYERS ACCUMULATING SO A 758 00:33:34,520 --> 00:33:36,600 SIGNIFICANT LYSOSOMAL FAILURE IN 759 00:33:36,600 --> 00:33:40,600 THESE MUTANT FLIES. 760 00:33:40,600 --> 00:33:48,080 WE'VE DONE UNBIASED MASS SPEC 761 00:33:48,080 --> 00:33:48,800 PROTEOMICS COLLABORATIVELY WITH 762 00:33:48,800 --> 00:33:53,280 NICK SEYFRIED AT EMORY, IN OUR 763 00:33:53,280 --> 00:33:55,160 VPS 29 MUTANT SLIDES COMPARED TO 764 00:33:55,160 --> 00:33:57,480 CONTROLS, LOOKED AT FLY HEADS. 765 00:33:57,480 --> 00:34:00,720 ONE REMARKABLE RESULT OF THE 766 00:34:00,720 --> 00:34:02,120 PROTEOMIC STUDIES WAS A VERY 767 00:34:02,120 --> 00:34:09,520 LARGE NUMBER OF SUBUNITS OF THE 768 00:34:09,520 --> 00:34:21,880 VACUOLE AIR VACUOLER APRs. 769 00:34:21,880 --> 00:34:25,600 I WANTED TO HIGHLIGHT I'M 770 00:34:25,600 --> 00:34:27,640 SHOWING A TABLE OF OTHER 771 00:34:27,640 --> 00:34:28,360 LYSOSOMAL ENZYMES INCLUDING 772 00:34:28,360 --> 00:34:33,720 ENZYMES WITH IMPORTANT ROLES IN 773 00:34:33,720 --> 00:34:35,400 METABOLISM OF COMPLEX 774 00:34:35,400 --> 00:34:38,960 CARBOHYDRATES INCREASED IN THE 775 00:34:38,960 --> 00:34:42,320 VPS29 MUTANT, FLY GENE AND HOME 776 00:34:42,320 --> 00:34:43,040 HOMOLOGS. 777 00:34:43,040 --> 00:34:46,920 MANY CAUSE LYSOSOMAL STORAGE 778 00:34:46,920 --> 00:34:50,920 DISORDERS IN HUMANS, AND I 779 00:34:50,920 --> 00:34:52,320 SPECULATE IT MIGHT REFLECT A 780 00:34:52,320 --> 00:34:53,040 COMPENSATORY CHANGE IN THE 781 00:34:53,040 --> 00:34:56,400 SYSTEM IN THE FACE OF A LYSOSOME 782 00:34:56,400 --> 00:34:59,720 THAT IS DYSFUNCTIONAL. 783 00:34:59,720 --> 00:35:01,680 WE'VE ALSO IN PUBLISHED WORK BY 784 00:35:01,680 --> 00:35:05,840 A STUDENT, NOW A BACH IN MY LAB, 785 00:35:05,840 --> 00:35:08,280 TWO HAS DONE WHAT I'M SHOWING, 786 00:35:08,280 --> 00:35:13,440 IN THE VPS 29 MUTANT GLUCOSAL 787 00:35:13,440 --> 00:35:14,080 CERAMIDE ACCUMULATES, GREEN IN 788 00:35:14,080 --> 00:35:24,000 THE RETINA IN THE ABSENCE OF 789 00:35:24,000 --> 00:35:25,440 RETROMER FUNCTION. 790 00:35:25,440 --> 00:35:28,120 ACCUMULATION IS A DEFINING 791 00:35:28,120 --> 00:35:31,880 FEATURE OF GAUCHER DISEASE, AND 792 00:35:31,880 --> 00:35:34,160 I'M SHOWING HERE THE APPEARANCE 793 00:35:34,160 --> 00:35:37,840 OF A GAUCHER CELL, A LIPID-LADEN 794 00:35:37,840 --> 00:35:39,840 MACROPHAGE THAT IS DIAGNOSTIC OF 795 00:35:39,840 --> 00:35:40,680 GAUCHER DISEASE. 796 00:35:40,680 --> 00:35:45,240 THIS IS A RECESSIVE LYSOSOMAL 797 00:35:45,240 --> 00:35:47,200 DISORDER WITH ACCUMULATION DUE 798 00:35:47,200 --> 00:35:58,320 TO LOSS OF ENZYME GBA, AND YOU 799 00:35:58,320 --> 00:36:04,480 MAY KNOW THAT ABOUT TEN YEARS 800 00:36:04,480 --> 00:36:06,680 AGO, SIDRANSKI'S GROUP BEGAN TO 801 00:36:06,680 --> 00:36:11,040 RECOGNIZE THE FAMILIES OF PRO 802 00:36:11,040 --> 00:36:15,800 BAN PATIENTS WITH GAUCHER'S 803 00:36:15,800 --> 00:36:17,640 DISEASE, FAMILIES APPEAR TO BE 804 00:36:17,640 --> 00:36:23,200 ENRICHED FOR RISK FOR 805 00:36:23,200 --> 00:36:24,080 PARKINSON'S DISEASE, THE 806 00:36:24,080 --> 00:36:25,000 PEDIGREE, WHO GRANDFATHERS HAVE 807 00:36:25,000 --> 00:36:26,360 PARKINSON'S DISEASE, ONE PARENT 808 00:36:26,360 --> 00:36:29,560 HAS A TREMOR THAT MIGHT BE 809 00:36:29,560 --> 00:36:31,120 CONSISTENT OF EARLY PARKINSON'S 810 00:36:31,120 --> 00:36:31,360 DISEASE. 811 00:36:31,360 --> 00:36:32,840 AND SO IN SUBSEQUENT WORK THAT 812 00:36:32,840 --> 00:36:35,480 IS NOW A LANDMARK STUDY OF THE 813 00:36:35,480 --> 00:36:37,680 PARKINSON'S DISEASE GENETICS 814 00:36:37,680 --> 00:36:41,400 FIELD, THOUSANDS OF CASES 815 00:36:41,400 --> 00:36:42,760 CONTROLS WERE ASSEMBLED, AND IT 816 00:36:42,760 --> 00:36:49,320 WAS SHOWN IF YOU CARRY ONE OF 817 00:36:49,320 --> 00:36:50,000 THESE GAUCHER-CAUSING MUTATIONS, 818 00:36:50,000 --> 00:36:52,360 HETEROZYGOUS, AT LEAST A 819 00:36:52,360 --> 00:36:56,520 FIVE-FOLD INCREASED RISK OF 820 00:36:56,520 --> 00:36:57,560 DEVELOPING PARKINSON'S DISEASE. 821 00:36:57,560 --> 00:37:00,400 ABOUT FIVE YEARS AGO MY TEAM 822 00:37:00,400 --> 00:37:01,840 DECIDED IN COLLABORATION WITH 823 00:37:01,840 --> 00:37:03,120 THE INTERNATIONAL PARKINSON'S 824 00:37:03,120 --> 00:37:05,320 DISEASE GENOMICS CONSORTIUM TO 825 00:37:05,320 --> 00:37:08,760 ASK THE QUESTION OF WHETHER 826 00:37:08,760 --> 00:37:13,120 BEYOND GBA, WHICH CAUSES 827 00:37:13,120 --> 00:37:14,560 GAUCHER'S DISEASE, DO OTHER 828 00:37:14,560 --> 00:37:15,160 LYSOSOMAL DISORDERS AFFECT 829 00:37:15,160 --> 00:37:16,440 PARKINSON'S DISEASE DISEASE OR 830 00:37:16,440 --> 00:37:18,800 RISK. 831 00:37:18,800 --> 00:37:22,720 WE DID THIS USING A GENETIC 832 00:37:22,720 --> 00:37:26,600 APPROACH EXAMINING RARE DAMAGING 833 00:37:26,600 --> 00:37:31,880 VARIANTS ACROSS 54 LYSOSOMAL 834 00:37:31,880 --> 00:37:34,600 STORAGE GENES AND AGGREGATES. 835 00:37:34,600 --> 00:37:36,920 AND WE ARE SHOWING THE DISCOVERY 836 00:37:36,920 --> 00:37:40,040 AND REPLICATION COHORT THAT WERE 837 00:37:40,040 --> 00:37:40,520 SIZABILITY, IMPORTANT 838 00:37:40,520 --> 00:37:41,360 DIFFERENCES BETWEEN THE 839 00:37:41,360 --> 00:37:42,360 EPIDEMIOLOGY OF PARKINSON'S 840 00:37:42,360 --> 00:37:45,120 DISEASE IN EACH OF THE COHORTS 841 00:37:45,120 --> 00:37:46,920 BUT SAW CONSISTENT RESULTS 842 00:37:46,920 --> 00:37:50,520 ACROSS THESE TWO INDEPENDENT 843 00:37:50,520 --> 00:37:50,920 DATASETS. 844 00:37:50,920 --> 00:37:53,160 THAT WAS THAT WHEN WE LOOK AT 845 00:37:53,160 --> 00:38:00,320 THE VARIANT BURDEN INNING A , 846 00:38:00,320 --> 00:38:01,880 THERE WAS ENRICHMENT. 847 00:38:01,880 --> 00:38:02,720 PATHOGENIC OR RARE DAMAGING 848 00:38:02,720 --> 00:38:03,440 VARIANTS IN ASSOCIATION WITH 849 00:38:03,440 --> 00:38:06,320 PARKINSON'S DISEASE RISK AND WE 850 00:38:06,320 --> 00:38:07,960 CAN REMOVE GBA FROM THE ANALYSIS 851 00:38:07,960 --> 00:38:12,440 ENTIRELY AND WE COULD STILL SEE 852 00:38:12,440 --> 00:38:14,960 RISK. 853 00:38:14,960 --> 00:38:20,560 THIS RESULT PUBLISHED IN 2017 854 00:38:20,560 --> 00:38:22,200 SUGGESTS BEYOND THE GBA GENE A 855 00:38:22,200 --> 00:38:24,320 BURDEN IS BROADLY ASSOCIATED 856 00:38:24,320 --> 00:38:27,960 WITH INCREASED RISK OF 857 00:38:27,960 --> 00:38:28,440 PARKINSON'S DISEASE. 858 00:38:28,440 --> 00:38:30,120 AND SO KIND OF A CONCEPTUAL 859 00:38:30,120 --> 00:38:33,440 MODEL FOR THINKING ABOUT THIS IS 860 00:38:33,440 --> 00:38:36,320 THAT WITH NEAR ABSOLUTE LOSS OF 861 00:38:36,320 --> 00:38:40,120 FUNCTION IN THESE GENES, YOU 862 00:38:40,120 --> 00:38:43,880 MANIFEST LYSOSOMAL STORAGE 863 00:38:43,880 --> 00:38:44,120 DISORDER. 864 00:38:44,120 --> 00:38:46,120 WITH MODEST PARTIAL LOSS OF 865 00:38:46,120 --> 00:38:47,520 FUNCTION, COMBINED WITH AGING, 866 00:38:47,520 --> 00:38:49,120 LATE IN LIFE YOU APPEAR TO HAVE 867 00:38:49,120 --> 00:38:51,640 A RISK OF PARKINSON'S DISEASE. 868 00:38:51,640 --> 00:38:52,800 ONE CAN IMAGINE HYPOTHETICALLY 869 00:38:52,800 --> 00:38:55,840 THAT THIS WOULD BE DUE TO 870 00:38:55,840 --> 00:38:58,560 ALTERED LYSOSOMAL FUNCTION AND 871 00:38:58,560 --> 00:39:01,880 HOMEOSTASIS AND PROTEOSTASIS OF 872 00:39:01,880 --> 00:39:02,680 PROTEINS LIKE ALPHA-SYNUCLEIN. 873 00:39:02,680 --> 00:39:04,360 NOW, ONE OF THE CHALLENGES WITH 874 00:39:04,360 --> 00:39:11,320 THIS WORK IS THESE VARIANTS ARE 875 00:39:11,320 --> 00:39:14,000 RARE, WE DID NOT HAVE POWER IN 876 00:39:14,000 --> 00:39:16,880 THE STUDY TO TELL WHICH SPECIFIC 877 00:39:16,880 --> 00:39:18,600 STORAGE DISORDER GENES BEYOND 878 00:39:18,600 --> 00:39:19,040 GBA WERE ASSOCIATED. 879 00:39:19,040 --> 00:39:23,240 THERE ARE SOME CLUES FROM OTHER 880 00:39:23,240 --> 00:39:23,680 STUDIES. 881 00:39:23,680 --> 00:39:27,560 FOR EXAMPLE SMPD 1 HAS BEEN 882 00:39:27,560 --> 00:39:29,040 IMPLICATED INPARKINSON'S DISEASE 883 00:39:29,040 --> 00:39:30,000 RISK INDEPENDENTLY BUT WE'VE 884 00:39:30,000 --> 00:39:35,080 BEEN TRYING TO GETS AT SPECIFIC 885 00:39:35,080 --> 00:39:36,720 GENES AND MECHANISMS. 886 00:39:36,720 --> 00:39:38,680 ONE APPROACH WE'VE TAKEN A 887 00:39:38,680 --> 00:39:43,320 LESSON FROM EARLY WORK BY 888 00:39:43,320 --> 00:39:46,120 SIDRANSKI, BEGAN TO RECRUIT 889 00:39:46,120 --> 00:39:48,400 FAMILIES OF PATIENTS WITH 890 00:39:48,400 --> 00:39:50,040 LYSOSOMAL STORAGE DISORDERS, THE 891 00:39:50,040 --> 00:39:52,120 SONIC PROJECT WITH A COUPLE 892 00:39:52,120 --> 00:39:56,200 DOZEN FAMILIES RECRUITED AND WE 893 00:39:56,200 --> 00:40:03,800 DO EXTENSIVE INTERVIEWS OF THE 894 00:40:03,800 --> 00:40:06,320 FAMILIES TO LEARN IF THERE WAS A 895 00:40:06,320 --> 00:40:07,760 HISTORY OF THOSE WITH 896 00:40:07,760 --> 00:40:08,920 PARKINSON'S DISEASE OR SIGNS OF 897 00:40:08,920 --> 00:40:11,440 PARKINSON'S DISEASE AND WE'RE 898 00:40:11,440 --> 00:40:16,920 BEGINNING TO RECRUIT POTENTIAL 899 00:40:16,920 --> 00:40:18,840 CARRIERS FOR GENOTYPING AND 900 00:40:18,840 --> 00:40:19,120 EXAMINATION. 901 00:40:19,120 --> 00:40:21,760 ONE PEDIGREE SHOWN HERE IN WHICH 902 00:40:21,760 --> 00:40:27,400 THE CHILD, PROBAND, HAS A 903 00:40:27,400 --> 00:40:30,200 DISORDER, MUCOPOLYSACCHARIDE, 904 00:40:30,200 --> 00:40:31,120 TWO GENERATIONS REMOVED THERE 905 00:40:31,120 --> 00:40:32,520 WAS A FAMILY MEMBER WITH 906 00:40:32,520 --> 00:40:34,520 PARKINSON'S DISEASE, AND IN BOTH 907 00:40:34,520 --> 00:40:36,440 ONE AND TWO GENERATIONS REMOVED 908 00:40:36,440 --> 00:40:39,600 THERE ARE INDIVIDUALS WHO HAD 909 00:40:39,600 --> 00:40:41,160 PARKINSONIAN SIGNS USING 910 00:40:41,160 --> 00:40:42,720 VALIDATED QUESTIONNAIRE 911 00:40:42,720 --> 00:40:43,120 INSTRUMENT. 912 00:40:43,120 --> 00:40:44,200 IT'S CHALLENGING WITH HUMAN 913 00:40:44,200 --> 00:40:46,480 STUDIES ALONE TO GET AT THE 914 00:40:46,480 --> 00:40:47,520 LEVEL OF PRECISION WE'RE LOOKING 915 00:40:47,520 --> 00:40:50,120 FOR SO WE'VE TURNED AGAIN TO 916 00:40:50,120 --> 00:40:54,160 FRUIT FRY MODELS. 917 00:40:54,160 --> 00:40:57,480 WE OF -- FRUITS OF FRUIT FLY 918 00:40:57,480 --> 00:40:57,720 MODELS. 919 00:40:57,720 --> 00:40:59,680 WE HAVE MODELS OF PARKINSON'S 920 00:40:59,680 --> 00:41:00,840 DISEASE, WE EXPRESS 921 00:41:00,840 --> 00:41:09,520 ALPHA-SYNUCLEIN WHICH FORMS LEWY 922 00:41:09,520 --> 00:41:11,440 BODY THROUGHOUT THE NERVOUS 923 00:41:11,440 --> 00:41:22,400 SYSTEM, WITH DOPAMINERGIC LOSS, 924 00:41:22,400 --> 00:41:23,960 AS YOU AGE THERE'S PROGRESSIVE 925 00:41:23,960 --> 00:41:25,080 LOCOMOTORROR DYSFUNCTION. 926 00:41:25,080 --> 00:41:34,080 WE DID A GENETIC SCREEN OF THE 927 00:41:34,080 --> 00:41:36,240 HOMOLOGS IN FRUIT FLY. 928 00:41:36,240 --> 00:41:39,520 80% ARE CONSERVED IN FLIES, 929 00:41:39,520 --> 00:41:41,320 FUNDAMENTAL METABOLIC ENZYMES. 930 00:41:41,320 --> 00:41:43,520 THE TEST, EACH OF THE GENES WHEN 931 00:41:43,520 --> 00:41:44,560 MANIPULATED IN THE FRUIT FLY AS 932 00:41:44,560 --> 00:41:49,920 TO WHETHER OR NOT THEY MODIFY 933 00:41:49,920 --> 00:41:51,320 ALPHA-SYNUCLEIN-INDUCED 934 00:41:51,320 --> 00:41:53,080 LOCOMOTOR IMPAIRMENT, THIS WORK 935 00:41:53,080 --> 00:41:55,880 WAS DONE BY GRADUATE STUDENT IN 936 00:41:55,880 --> 00:41:59,520 MY LAB IN COLLABORATION WITH MY 937 00:41:59,520 --> 00:42:01,840 COLLEAGUE AT BAYLOR, YU AND 938 00:42:01,840 --> 00:42:02,040 BOTAS. 939 00:42:02,040 --> 00:42:06,440 YOU CAN SEE ON THE RIGHT SLOWER 940 00:42:06,440 --> 00:42:10,320 CLIMBING THAN CONTROLS. 941 00:42:10,320 --> 00:42:13,920 WE'RE USING A ROBOTIC-ASSISTED 942 00:42:13,920 --> 00:42:16,480 LOCOMOTOR SCREENING ASSAY WITH 943 00:42:16,480 --> 00:42:18,040 VIDEO TRACKING, TESTED 94 944 00:42:18,040 --> 00:42:21,120 HOMOLOGS OF 40 CONSERVED HUMAN 945 00:42:21,120 --> 00:42:24,440 LYSOSOMAL STORAGE DISORDER GENES 946 00:42:24,440 --> 00:42:26,160 WHICH INVOLVED LOOKING AT MORE 947 00:42:26,160 --> 00:42:28,920 THAN 300 RNA INTERFERENCE 948 00:42:28,920 --> 00:42:30,840 KNOCKDOWN STRAINS AND FOLLOWED 949 00:42:30,840 --> 00:42:31,920 LOOKING AT OVEREXPRESSION OF 950 00:42:31,920 --> 00:42:34,160 ENZYMES WHERE POSSIBLE, WHEN THE 951 00:42:34,160 --> 00:42:36,000 REAGENTS WERE AVAILABLE. 952 00:42:36,000 --> 00:42:39,600 SO THESE ARE SOME OF THE 953 00:42:39,600 --> 00:42:40,120 REPRESENTATIVE RESULTS. 954 00:42:40,120 --> 00:42:41,600 AND SO WHAT I'M SHOWING, I WILL 955 00:42:41,600 --> 00:42:49,680 FOCUS ON THE RIGHT, THE FLY GENE 956 00:42:49,680 --> 00:42:55,920 IS THE HOMOLOG OF NPC1, YOU CAN 957 00:42:55,920 --> 00:42:59,120 SEE AGE DEPENDENT CONTROL 958 00:42:59,120 --> 00:43:00,640 ANIMALS, NPC1A OVERLAPPING WITH 959 00:43:00,640 --> 00:43:01,640 CONTROLS. 960 00:43:01,640 --> 00:43:03,800 HERE IS THE ALPHA-SYNUCLEIN. 961 00:43:03,800 --> 00:43:06,320 PROGRESSIVE LOCOMOTOR 962 00:43:06,320 --> 00:43:06,640 DYSFUNCTION. 963 00:43:06,640 --> 00:43:11,600 WHEN YOU REMOVE 50% OF NPC1A 964 00:43:11,600 --> 00:43:13,720 STRONG ENHANCEMENT OF LOCOMOTOR 965 00:43:13,720 --> 00:43:16,080 PHENOTYPE CAUSED BY 966 00:43:16,080 --> 00:43:16,440 ALPHA-SYNUCLEIN. 967 00:43:16,440 --> 00:43:21,720 SO, WE'VE THROUGH THE SCREEN 968 00:43:21,720 --> 00:43:24,920 IDENTIFIED 15 LYSOSOMAL 969 00:43:24,920 --> 00:43:26,600 IDENTIFIEDERS OF TOXICITY, 970 00:43:26,600 --> 00:43:29,760 POTENTIALLY QUITE INTERESTING 971 00:43:29,760 --> 00:43:32,280 THAT THE GENES COLLAPSE INTO 972 00:43:32,280 --> 00:43:42,120 METABOLIC PATHWAYS INCLUDING 973 00:43:42,120 --> 00:43:44,520 THOSE RELEVANT TO GLUCOBIOLOGY, 974 00:43:44,520 --> 00:43:45,520 BESIDES GBA WHICH WE ALSO 975 00:43:45,520 --> 00:43:48,440 RECOVERED FROM THE SCREEN 976 00:43:48,440 --> 00:43:50,240 INVOLVED IN SINGLE LIPID 977 00:43:50,240 --> 00:43:51,400 METABOLISM, CHOLESTEROL 978 00:43:51,400 --> 00:43:51,720 METABOLISM. 979 00:43:51,720 --> 00:43:54,080 SEVERAL GENES HAVE INDEPENDENT 980 00:43:54,080 --> 00:43:55,720 EVIDENCE FOR HUMAN GENETIC RISK 981 00:43:55,720 --> 00:43:57,120 OF PARKINSON'S DISEASE FROM OUR 982 00:43:57,120 --> 00:43:59,720 OWN WORK AND OTHER PUBLISHED 983 00:43:59,720 --> 00:43:59,920 WORK. 984 00:43:59,920 --> 00:44:02,680 AND WHAT WE'RE NOW TRYING TO DO 985 00:44:02,680 --> 00:44:06,520 IS MAP SOME FINDINGS ONTO 986 00:44:06,520 --> 00:44:08,680 METABOLIC PATHWAYS, AND BRINGING 987 00:44:08,680 --> 00:44:09,520 IN METABOLOMICS. 988 00:44:09,520 --> 00:44:11,720 SO USUALLY THIS IS WHERE I STOP 989 00:44:11,720 --> 00:44:13,400 BUT I JUST SAY THIS IS WORK IN 990 00:44:13,400 --> 00:44:15,040 PROGRESS BUT BECAUSE OF THE 991 00:44:15,040 --> 00:44:17,240 THEME OF THE SESSION, MULTIOMIC 992 00:44:17,240 --> 00:44:19,400 INTEGRATION, I THOUGHT I WOULD 993 00:44:19,400 --> 00:44:20,040 STRUGGLE THROUGH ONE ADDITIONAL 994 00:44:20,040 --> 00:44:25,680 SLIDE OF WHAT WE'RE TRYING TO DO 995 00:44:25,680 --> 00:44:29,080 WHICH IS VERY PRELIMINARY BUT A 996 00:44:29,080 --> 00:44:30,320 ROTATION STUDENT HELPED US PULL 997 00:44:30,320 --> 00:44:31,920 TOGETHER THIS DATA TO SHOW YOU 998 00:44:31,920 --> 00:44:36,480 AS A PROOF OF PRINCIPLE. 999 00:44:36,480 --> 00:44:37,760 WE'VE OBTAINED MASS SPEC 1000 00:44:37,760 --> 00:44:38,680 LIPIDOMICS FROM ALPHA-SYNUCLEIN 1001 00:44:38,680 --> 00:44:40,400 AND CONTROL ANIMALS, THIS IS 1002 00:44:40,400 --> 00:44:41,920 FROM FLY HEADS. 1003 00:44:41,920 --> 00:44:45,160 WE LOOKED AT TWO TIME POINTS, 5 1004 00:44:45,160 --> 00:44:58,920 AND 20 DAYS, DETECTED SENSE 1005 00:44:58,920 --> 00:45:04,760 SENSITIVELY LIPIDS. 1006 00:45:04,760 --> 00:45:09,120 THERE WAS SIGNIFICANT INCREASE 1007 00:45:09,120 --> 00:45:14,920 IN HEX 1 CERAMIDE, FOCUSING ON 1008 00:45:14,920 --> 00:45:17,440 THIS TWO ADJACENT METABOLIC 1009 00:45:17,440 --> 00:45:18,920 TRANSFORMATIONS BECAUSE THE GOAL 1010 00:45:18,920 --> 00:45:20,920 OF THIS TYPE OF INTEGRATION AT 1011 00:45:20,920 --> 00:45:21,600 LEAST FROM PERSPECTIVE WE'RE 1012 00:45:21,600 --> 00:45:25,840 TAKING IS TRY TO UNDERSTAND 1013 00:45:25,840 --> 00:45:27,480 MECHANISM BY WHICH HEXCER WOULD 1014 00:45:27,480 --> 00:45:28,720 ACCUMULATE IN PRESENCE OF 1015 00:45:28,720 --> 00:45:29,640 ALPHA-SYNUCLEIN IN OUR 1016 00:45:29,640 --> 00:45:30,880 PARKINSON'S DISEASE FLY MODEL. 1017 00:45:30,880 --> 00:45:35,520 WHAT WE NEXT DO IS OVERLAY 1018 00:45:35,520 --> 00:45:36,400 LONGITUDINAL TRANSCRIPTOME 1019 00:45:36,400 --> 00:45:37,920 PROFILES FROM THE SAME MODELS. 1020 00:45:37,920 --> 00:45:39,440 WE HAVE DATA FROM MANY TIME 1021 00:45:39,440 --> 00:45:44,760 POINTS AS YOU CAN SEE HERE. 1022 00:45:44,760 --> 00:45:45,840 WE COMPUTE AGE-ADJUSTED 1023 00:45:45,840 --> 00:45:47,520 DIFFERENTIAL EXPRESSION ACROSS 1024 00:45:47,520 --> 00:45:49,840 THE WHOLE TRANSCRIPTOME, AND 1025 00:45:49,840 --> 00:45:52,240 THEN WHAT WE PULLED OUT ARE 1026 00:45:52,240 --> 00:45:54,040 CHANGES IN MESSENGER RNAs THAT 1027 00:45:54,040 --> 00:45:55,800 ARE SIGNIFICANT FOR ALL ENZYMES 1028 00:45:55,800 --> 00:45:59,000 WE MAP TO THE METABOLIC 1029 00:45:59,000 --> 00:46:00,320 TRANSFORMATIONS THAT AFFECT HEX 1030 00:46:00,320 --> 00:46:01,560 1 CERAMIDE. 1031 00:46:01,560 --> 00:46:04,960 SO YOU CAN SEE THAT THERE ARE 1032 00:46:04,960 --> 00:46:07,080 SEVERAL MESSENGERS FOR ENZYMES 1033 00:46:07,080 --> 00:46:09,520 THAT GO UP SIGNIFICANTLY AND IN 1034 00:46:09,520 --> 00:46:10,680 ONE CASE DOWN SIGNIFICANTLY. 1035 00:46:10,680 --> 00:46:18,200 AND I'M SHOWING YOU FOR ONE THE 1036 00:46:18,200 --> 00:46:19,080 AGE-DEPENDENT INCREASE IN 1037 00:46:19,080 --> 00:46:21,400 CONTROL ANIMALS BUT SIGNIFICANT 1038 00:46:21,400 --> 00:46:23,120 SHIFT IN THE EXPRESSION OF THIS 1039 00:46:23,120 --> 00:46:26,680 GENE FROM THE RNAseq DATA IN 1040 00:46:26,680 --> 00:46:27,280 THE ALPHA-SYNUCLEIN FLY. 1041 00:46:27,280 --> 00:46:31,400 THE QUESTION IS WHAT EFFECT 1042 00:46:31,400 --> 00:46:38,960 WOULD MANIP CHANGES HAVE ON 1043 00:46:38,960 --> 00:46:39,200 HEX1CER? 1044 00:46:39,200 --> 00:46:41,200 DOES IT AFFECT TRANSFORMATION IN 1045 00:46:41,200 --> 00:46:44,320 WHICH DIRECTION IN OF? 1046 00:46:44,320 --> 00:46:50,640 WHICH DIRECTIONS, PROMOTING THE 1047 00:46:50,640 --> 00:46:53,000 FORMATION OF HEX1CER, BGA IS 1048 00:46:53,000 --> 00:46:54,320 HERE, INCREASING EXPRESSION, 1049 00:46:54,320 --> 00:46:55,320 THIS SUPPORTS, AND MOST OF THE 1050 00:46:55,320 --> 00:46:57,840 CHANGES EXCEPT WHAT WE SEE FOR 1051 00:46:57,840 --> 00:47:01,200 THESE ENZYMES SUPPORT AN 1052 00:47:01,200 --> 00:47:03,400 INCREASE IN HEX1CER, SUPPORTS 1053 00:47:03,400 --> 00:47:05,080 THE MECHANISM OF WHAT WE OBSERVE 1054 00:47:05,080 --> 00:47:07,480 WITHIN OUR DATA. 1055 00:47:07,480 --> 00:47:07,960 OKAY. 1056 00:47:07,960 --> 00:47:11,120 I SEE THAT I'M COMING ON THE END 1057 00:47:11,120 --> 00:47:11,600 OF MY TIME. 1058 00:47:11,600 --> 00:47:14,080 DO I HAVE A MINUTE LEFT? 1059 00:47:14,080 --> 00:47:15,280 ONE MINUTE. 1060 00:47:15,280 --> 00:47:15,480 OKAY. 1061 00:47:15,480 --> 00:47:20,720 WE'RE VERY INTERESTED IN THE 1062 00:47:20,720 --> 00:47:25,440 POSSIBILITY OF OLIGOGENETIC. 1063 00:47:25,440 --> 00:47:28,080 A FIFTH HAVE MORE THAN ONE 1064 00:47:28,080 --> 00:47:31,040 VARIANT, MULTIPLE GENETIC 1065 00:47:31,040 --> 00:47:33,880 LESIONS IN THE PATHWAY MIGHT 1066 00:47:33,880 --> 00:47:36,080 INTERACT IN AN OLIGOGENIC MODEL 1067 00:47:36,080 --> 00:47:38,160 TO AFFECT PARKINSON'S DISEASE 1068 00:47:38,160 --> 00:47:41,520 RISK, DIFFICULT TO ADDRESS USING 1069 00:47:41,520 --> 00:47:43,880 HUMAN GENETICS AND STATISTICS SO 1070 00:47:43,880 --> 00:47:46,880 WE'RE LOOKING AT SINGLE CASES. 1071 00:47:46,880 --> 00:47:49,760 HERE IS A FAMILY THAT WE'VE BEEN 1072 00:47:49,760 --> 00:47:51,480 IN CONTACT WITH, AN INDIVIDUAL 1073 00:47:51,480 --> 00:47:53,320 WITH PARKINSON'S DISEASE AND 1074 00:47:53,320 --> 00:47:55,920 FAMILY HISTORY OF PARKINSON'S 1075 00:47:55,920 --> 00:48:08,480 DISEASE HAS MUTATION IN GBA AND 1076 00:48:08,480 --> 00:48:09,000 ARSA, AFFECTING CERAMIDE 1077 00:48:09,000 --> 00:48:09,400 BIOLOGY. 1078 00:48:09,400 --> 00:48:11,720 A LOT OF EVIDENCE FROM 1079 00:48:11,720 --> 00:48:13,400 PARKINSON'S DISEASE GENETICS 1080 00:48:13,400 --> 00:48:16,440 SUPPORTING LYSOSOMAL BIOLOGY AND 1081 00:48:16,440 --> 00:48:19,840 ENZYMES THAT AFFECT THE 1082 00:48:19,840 --> 00:48:20,120 GLYCOGENOME. 1083 00:48:20,120 --> 00:48:21,960 AND SO I THINK I DON'T WANT TO 1084 00:48:21,960 --> 00:48:23,720 OBSCURE THE FACT THERE'S A LOT 1085 00:48:23,720 --> 00:48:25,360 OF EVIDENCE ACCUMULATING IN THE 1086 00:48:25,360 --> 00:48:29,520 FIELD THAT PARKINSON'S DISEASE 1087 00:48:29,520 --> 00:48:33,120 IS A LYSOSOMAL DISORDER AND MY 1088 00:48:33,120 --> 00:48:34,520 SUMMARY SLIDE, I DON'T HAVE TO 1089 00:48:34,520 --> 00:48:38,600 GO OVER THIS, I WANT TO GET BACK 1090 00:48:38,600 --> 00:48:39,280 ON TIME. 1091 00:48:39,280 --> 00:48:40,640 I THANK THOSE WHO CONTRIBUTED TO 1092 00:48:40,640 --> 00:48:42,680 THE WORK WHICH I TRIED TO 1093 00:48:42,680 --> 00:48:45,720 RECOGNIZE ALONG THE WAY. 1094 00:48:45,720 --> 00:48:47,280 MY COLLABORATORS, AND OUR 1095 00:48:47,280 --> 00:48:50,520 FUNDERS AND THANK YOU FOR YOUR 1096 00:48:50,520 --> 00:48:54,840 ATTENTION AND INVITING ME TO 1097 00:48:54,840 --> 00:48:55,080 PRESENT. 1098 00:48:55,080 --> 00:49:00,120 >> THANK YOU, JOSH. 1099 00:49:00,120 --> 00:49:01,320 WE'RE LOOKING FORWARD TO HAVING 1100 00:49:01,320 --> 00:49:02,320 DISCUSSION AROUND NOON. 1101 00:49:02,320 --> 00:49:04,080 IF YOU HAVE ANY QUESTIONS FOR 1102 00:49:04,080 --> 00:49:07,480 JOSH, YOU CAN PUT THEM IN THE 1103 00:49:07,480 --> 00:49:08,280 SEND LIVE FEEDBACK. 1104 00:49:08,280 --> 00:49:11,600 AND JOSH WILL ADDRESS THOSE IN A 1105 00:49:11,600 --> 00:49:14,320 COUPLE HOURS. 1106 00:49:14,320 --> 00:49:16,640 NEXT SPEAKER IS ANAND MEHTA FROM 1107 00:49:16,640 --> 00:49:18,040 MEDICAL UNIVERSITY OF SOUTH 1108 00:49:18,040 --> 00:49:22,440 CAROLINA, HE'S GOING TO TALK 1109 00:49:22,440 --> 00:49:23,600 ABOUT GLYCOMICS OF LIVER CANCER. 1110 00:49:23,600 --> 00:49:24,280 >> THANK YOU VERY MUCH. 1111 00:49:24,280 --> 00:49:26,120 IF YOU CAN'T SEE THE SCREEN JUST 1112 00:49:26,120 --> 00:49:28,320 YELL OUT AND I'LL TRY TO DO 1113 00:49:28,320 --> 00:49:29,520 SOMETHING. 1114 00:49:29,520 --> 00:49:30,520 >> WE'RE GOOD. 1115 00:49:30,520 --> 00:49:33,240 >> I'M GOING TO TALK TODAY ABOUT 1116 00:49:33,240 --> 00:49:35,800 WHAT WE'VE BEEN DOING ON 1117 00:49:35,800 --> 00:49:40,440 GLYCOMICS OF LIVER CANCER. 1118 00:49:40,440 --> 00:49:41,680 USUALLY PEOPLE TALK ABOUT 1119 00:49:41,680 --> 00:49:42,920 GLYCANS, WE SAY THEY ARE 1120 00:49:42,920 --> 00:49:44,120 COMPLICATE AND DIFFICULT. 1121 00:49:44,120 --> 00:49:45,680 ANOTHER TITLE COULD BE GLYCANS 1122 00:49:45,680 --> 00:49:48,760 ARE EASY, THE CANCER IS 1123 00:49:48,760 --> 00:49:49,080 COMPLICATED. 1124 00:49:49,080 --> 00:49:54,000 THAT IS THE ROOT OF WHAT WE SEE. 1125 00:49:54,000 --> 00:49:56,400 I WOULD MAKE THE ARGUMENT 1126 00:49:56,400 --> 00:49:58,840 GLYCOMICS IN LIVER CANCER HAS A 1127 00:49:58,840 --> 00:50:01,640 LONG HISTORY, PROBABLY THE MOST 1128 00:50:01,640 --> 00:50:02,840 STUDIED CANCER OUT THERE. 1129 00:50:02,840 --> 00:50:04,200 CAN BE A MODEL DISEASE FOR OTHER 1130 00:50:04,200 --> 00:50:07,680 PEOPLE TO LOOK AT AS WELL. 1131 00:50:07,680 --> 00:50:09,200 WHEN I TALK ABOUT LIVER CANCER 1132 00:50:09,200 --> 00:50:11,280 I'M GOING TO TALK ABOUT TWO 1133 00:50:11,280 --> 00:50:14,880 MAJOR FORMS OF LIVER CANCER THAT 1134 00:50:14,880 --> 00:50:15,440 ARISE. 1135 00:50:15,440 --> 00:50:18,880 THE TYPE OF CANCER REALLY STEMS 1136 00:50:18,880 --> 00:50:20,320 FROM THE ORIGIN CELL FROM WHICH 1137 00:50:20,320 --> 00:50:22,800 THAT CANCER ORIGINATES. 1138 00:50:22,800 --> 00:50:24,240 WE TALK ABOUT HEPATOCELLULAR 1139 00:50:24,240 --> 00:50:27,040 CARCINOMA ON THE LEFT THAT 1140 00:50:27,040 --> 00:50:30,720 ARISES, CANCER OF THE 1141 00:50:30,720 --> 00:50:33,120 HEPATOCYTES, 80% OF LIVER 1142 00:50:33,120 --> 00:50:33,880 CANCERS WE SEE. 1143 00:50:33,880 --> 00:50:41,960 THE OTHER FORM OF LIVER CANCER 1144 00:50:41,960 --> 00:50:52,400 ARISES FROM BILE DUCTS, 1145 00:50:52,400 --> 00:50:52,960 CHOLANGIOCYTES. 1146 00:50:52,960 --> 00:51:00,320 PEOPLE GET LIVER CANCER FROM 1147 00:51:00,320 --> 00:51:04,160 UNDERLYING INFLAMMATORY PROCESS. 1148 00:51:04,160 --> 00:51:05,720 VIRAL HEPATITIS, ALCOHOL, NOW 1149 00:51:05,720 --> 00:51:07,960 FATTY LIVER DISEASE, THE LARGER 1150 00:51:07,960 --> 00:51:09,120 DRIVER OF LIVER CANCER IN THE 1151 00:51:09,120 --> 00:51:10,800 UNITED STATES, THE SAME THING 1152 00:51:10,800 --> 00:51:15,560 DRIVING THE RISK OF INCREASED 1153 00:51:15,560 --> 00:51:16,960 RISK AND INCREASED DEVELOPMENT 1154 00:51:16,960 --> 00:51:18,160 OF CHOLANGIOCYTES CARCINOMA. 1155 00:51:18,160 --> 00:51:20,160 THE UNDERLYING ISSUE IS 1156 00:51:20,160 --> 00:51:22,760 INFLAMMATION THAT LEADS TO 1157 00:51:22,760 --> 00:51:24,760 FIBROSIS CIRRHOSIS, LEADING TO 1158 00:51:24,760 --> 00:51:32,400 CANCER THAT EVENTUALLY CAN BE 1159 00:51:32,400 --> 00:51:32,800 LIFE-THREATENING. 1160 00:51:32,800 --> 00:51:34,280 BECAUSE HGC IS THE PRIMARY FORM, 1161 00:51:34,280 --> 00:51:40,400 I'M GOING TO TALK ABOUT THAT, 1162 00:51:40,400 --> 00:51:42,240 WE'LL TALK ABOUT CHOLANGEO 1163 00:51:42,240 --> 00:51:43,440 CARCINOMA AT THE END. 1164 00:51:43,440 --> 00:51:51,000 THE SIMPLE FACT WE HAVE NO GOOD 1165 00:51:51,000 --> 00:51:52,400 TREATMENTS, DETECTING EARLY IS 1166 00:51:52,400 --> 00:51:53,160 ESSENTIAL, SURGICAL RESECTION, 1167 00:51:53,160 --> 00:51:54,160 CUT IT OUT. 1168 00:51:54,160 --> 00:51:56,120 IF YOU HAVE A SMALL TUMOR 1169 00:51:56,120 --> 00:51:58,280 OVERALL SURVIVAL IS GOOD, FOR 1170 00:51:58,280 --> 00:52:02,000 THE MOST PART, 50 TO 60%. 1171 00:52:02,000 --> 00:52:06,000 PEOPLE CAN LIVE FOR OVER FIVE 1172 00:52:06,000 --> 00:52:06,240 YEARS. 1173 00:52:06,240 --> 00:52:07,760 IT'S CONSIDERED IDEAL. 1174 00:52:07,760 --> 00:52:09,760 WELL, NOT IDEAL BUT BETTER IN 1175 00:52:09,760 --> 00:52:10,600 THAT SITUATION. 1176 00:52:10,600 --> 00:52:13,720 IF YOU DON'T CATCH IT EARLY, THE 1177 00:52:13,720 --> 00:52:18,200 OUTCOME IS BAD, NO MATTER WHAT. 1178 00:52:18,200 --> 00:52:21,080 AND THAT'S BECAUSE CUTTING OUT A 1179 00:52:21,080 --> 00:52:23,360 3-CENTIMETER LESION IS DOABLE, 1180 00:52:23,360 --> 00:52:24,320 CUTTING OUT A 10-CENTIMETER 1181 00:52:24,320 --> 00:52:26,920 LESION IS NOT GOOD AT ALL. 1182 00:52:26,920 --> 00:52:28,040 EARLY DETECTION IS ESSENTIAL. 1183 00:52:28,040 --> 00:52:31,520 AND PEOPLE HAVE BEEN TRYING TO 1184 00:52:31,520 --> 00:52:32,520 FIND BIOMARKERS FOR YEARS. 1185 00:52:32,520 --> 00:52:34,480 BUT IT'S SOMETHING THAT'S BEEN I 1186 00:52:34,480 --> 00:52:41,160 WOULD SAY FOR GLYCOMA COMMUNITY 1187 00:52:41,160 --> 00:52:41,920 A SUCCESS. 1188 00:52:41,920 --> 00:52:45,920 FROM JAPAN IN THE EARLY '80s 1189 00:52:45,920 --> 00:52:47,400 AND '90s, THEY SHOWED, AND 1190 00:52:47,400 --> 00:52:49,320 LOTS OF VERY MANY OF PEOPLE HAVE 1191 00:52:49,320 --> 00:52:50,920 SHOWN, GLYCANS CHANGE IN SERUM 1192 00:52:50,920 --> 00:52:55,960 OF PATIENTS WITH LIVER CANCER. 1193 00:52:55,960 --> 00:53:01,360 IN THIS CASE IDENTIFYING CHANGES 1194 00:53:01,360 --> 00:53:02,320 IN FUCOSYLATION, ON AFP, WE'LL 1195 00:53:02,320 --> 00:53:05,920 COME BACK TO THAT. 1196 00:53:05,920 --> 00:53:07,960 THAT'S BEEN FOLLOWED BY OTHER 1197 00:53:07,960 --> 00:53:09,640 GROUPS. 1198 00:53:09,640 --> 00:53:11,440 WE SHOWED THAT CHANGES IN 1199 00:53:11,440 --> 00:53:12,720 ANOTHER PROTEIN AND MANY GROUPS 1200 00:53:12,720 --> 00:53:15,920 LOOKED AT TIME WHERE THEY CAN 1201 00:53:15,920 --> 00:53:18,680 LOOK AT EITHER TOTAL SERUM 1202 00:53:18,680 --> 00:53:19,320 GLYCOANALYSIS OR GLYCOPROTEOMICS 1203 00:53:19,320 --> 00:53:28,240 TO SO THERE ARE GLYCAN CHANGES 1204 00:53:28,240 --> 00:53:30,400 LIVER CANCER, IT'S ACCEPTED, 1205 00:53:30,400 --> 00:53:31,960 FDA-APPROVED TEST, PART OF THE 1206 00:53:31,960 --> 00:53:35,240 ALGORITHM FOR DETECTION OF LIVER 1207 00:53:35,240 --> 00:53:35,880 CANCER, BEING DEVELOPED 1208 00:53:35,880 --> 00:53:37,000 COMMERCIALLY BY OTHER GROUPS. 1209 00:53:37,000 --> 00:53:40,840 MOST OF THAT WORK WAS DONE IN 1210 00:53:40,840 --> 00:53:41,040 SERUM. 1211 00:53:41,040 --> 00:53:44,960 WHAT IS HAPPENING IN THE TISSUE? 1212 00:53:44,960 --> 00:53:48,920 NOT WELL KNOWN. 1213 00:53:48,920 --> 00:53:49,640 DO ALTERED GLYCANS AND 1214 00:53:49,640 --> 00:53:51,040 GLYCOPROTEIN COME FROM THE 1215 00:53:51,040 --> 00:53:52,440 TUMOR, THE STROMA, NOT 1216 00:53:52,440 --> 00:53:53,840 ASSOCIATED WITH THE LIVER? 1217 00:53:53,840 --> 00:53:56,440 THAT'S NOT BEEN VERY WELL 1218 00:53:56,440 --> 00:53:58,720 STUDIED AND VERY WELL ANALYZED. 1219 00:53:58,720 --> 00:54:02,200 SO WE DECIDED TO DO THAT AND DID 1220 00:54:02,200 --> 00:54:06,320 THAT USING APPROACH REFERRED TO 1221 00:54:06,320 --> 00:54:08,000 HERE AS SPATIAL-GLYCOMICS, 1222 00:54:08,000 --> 00:54:14,680 ANOTHER TIME OF OMICS, SPATIAL 1223 00:54:14,680 --> 00:54:21,120 OMICS, SO SPATIAL GLYCOMICS 1224 00:54:21,120 --> 00:54:22,840 USING MALDI-IMS, USING ENZYMES 1225 00:54:22,840 --> 00:54:26,200 WE MADE THAT SEEM TO BE SUITED 1226 00:54:26,200 --> 00:54:28,160 FOR THIS APPLICATION. 1227 00:54:28,160 --> 00:54:30,240 I KNOW THIS HAS BEEN TALKED 1228 00:54:30,240 --> 00:54:32,840 ABOUT AT LENGTH BY OTHER GROUPS 1229 00:54:32,840 --> 00:54:42,160 BUT THE KEY THING, CAN YOU USE 1230 00:54:42,160 --> 00:54:44,440 PARAFFIN-EMBEDDED SLIDES, SPREAD 1231 00:54:44,440 --> 00:54:47,920 A THIN LAYER OF ENZYME OVER THE 1232 00:54:47,920 --> 00:54:50,760 TISSUE, ACTIVITY IN LOCALIZED 1233 00:54:50,760 --> 00:54:51,840 REGIONS, GLYCANS WILL STAY WHERE 1234 00:54:51,840 --> 00:54:52,960 THEY ARE RELEASED. 1235 00:54:52,960 --> 00:55:00,400 YOU CAN USE A WIDE VARIETY OF 1236 00:55:00,400 --> 00:55:01,520 ENZYMES. 1237 00:55:01,520 --> 00:55:09,000 WE USE PNGASE, SIALIDASE, WE 1238 00:55:09,000 --> 00:55:10,520 MAKE ALL OF THESE IN HOUSE. 1239 00:55:10,520 --> 00:55:20,560 CAN YOU DO VARIOUS THINGS, 1240 00:55:20,560 --> 00:55:29,520 ANALYZE TISSUE USING MALDI MASS 1241 00:55:29,520 --> 00:55:30,320 SPECTROMETRIER. 1242 00:55:30,320 --> 00:55:31,640 A PATHOLOGIST WILL SAY, OH, 1243 00:55:31,640 --> 00:55:32,520 THERE'S THE CANCER IN THE MIDDLE 1244 00:55:32,520 --> 00:55:34,200 OF THE BIG TISSUE AND WE CAN 1245 00:55:34,200 --> 00:55:36,960 LOOK AT THE DATA AND YOU CAN SAY 1246 00:55:36,960 --> 00:55:38,920 WHAT GLYCAN IS KNOCKED DOWN IN 1247 00:55:38,920 --> 00:55:43,360 THE TISSUE AND YOU'LL SEE IT 1248 00:55:43,360 --> 00:55:45,440 KNOCKED OUT OF THE TUMOR BUT 1249 00:55:45,440 --> 00:55:46,960 FOUND IN SURROUNDING TISSUE, 1250 00:55:46,960 --> 00:55:50,800 BAM, YOU GET A MULTI-FUCOSLYATED 1251 00:55:50,800 --> 00:55:53,920 GLYCAN FOUND JUST IN THE TUMOR 1252 00:55:53,920 --> 00:55:54,920 AND NOWHERE ELSE. 1253 00:55:54,920 --> 00:55:57,400 YOU COULD LOOK AND SAY THAT'S AN 1254 00:55:57,400 --> 00:55:59,160 EASY ANSWER, RIGHT? 1255 00:55:59,160 --> 00:56:05,360 SO THE FUCOSYLATION COMES FROM 1256 00:56:05,360 --> 00:56:07,840 THE TUMOR, THAT'S WHAT YOU GET. 1257 00:56:07,840 --> 00:56:10,120 WELL, IT'S NOT THAT EASY. 1258 00:56:10,120 --> 00:56:11,800 IF YOU START LOOKING AT MORE 1259 00:56:11,800 --> 00:56:13,960 PATIENTS, WE'VE LOOKED AT A 1260 00:56:13,960 --> 00:56:16,480 THOUSAND PATIENTS NOW, EITHER BY 1261 00:56:16,480 --> 00:56:18,440 TISSUE MICROARRAY OR INDIVIDUAL 1262 00:56:18,440 --> 00:56:20,840 PATIENTS, WHAT YOU'LL SEE IS, 1263 00:56:20,840 --> 00:56:24,800 WELL, IT'S COMPLICATED WITH LOTS 1264 00:56:24,800 --> 00:56:25,560 OF VARIATION. 1265 00:56:25,560 --> 00:56:27,560 EACH SPOT REPRESENTS A DIFFERENT 1266 00:56:27,560 --> 00:56:30,040 TISSUE AND DIFFERENT PATIENT. 1267 00:56:30,040 --> 00:56:33,120 ONE TEAM AT THE TOP, ONE AT THE 1268 00:56:33,120 --> 00:56:33,840 BOTTOM. 1269 00:56:33,840 --> 00:56:35,720 CANCER PATIENTS ARE SEGREGATED 1270 00:56:35,720 --> 00:56:37,680 UP HERE, CIRHOTTIC ON THE 1271 00:56:37,680 --> 00:56:40,400 BOTTOM, NORMAL HERE. 1272 00:56:40,400 --> 00:56:42,640 BOTTOM TMA PLUS CANCER MINUS 1273 00:56:42,640 --> 00:56:44,400 ADJACENT TISSUE NEXT TO THE 1274 00:56:44,400 --> 00:56:44,720 CANCER. 1275 00:56:44,720 --> 00:56:48,280 WHAT YOU SEE IS WE SEE LOTS OF 1276 00:56:48,280 --> 00:56:49,800 BRANCH GLYCAN, SOME PATIENTS 1277 00:56:49,800 --> 00:56:53,360 HAVE IT, SOME DON'T. 1278 00:56:53,360 --> 00:56:54,520 BRANCH FUCOSLYATED GLYCAN, SOME 1279 00:56:54,520 --> 00:56:56,520 DO, SOME DON'T. 1280 00:56:56,520 --> 00:56:58,520 IT VARIES QUITE DRAMATICALLY BUT 1281 00:56:58,520 --> 00:57:02,080 IF DO YOU STATISTICS IT LOOKS 1282 00:57:02,080 --> 00:57:03,800 GOOD. 1283 00:57:03,800 --> 00:57:07,760 YOU'LL IDENTIFY LOTS OF GLYCAN 1284 00:57:07,760 --> 00:57:08,400 INCREASED IN CANCER, FANTASTIC 1285 00:57:08,400 --> 00:57:10,360 P-VALUES, TEN TO THE MINUS 16, 1286 00:57:10,360 --> 00:57:13,600 TEN TO THE MINUS 8, WHATEVER, 1287 00:57:13,600 --> 00:57:15,040 ROCKS LOOK GREAT TOO. 1288 00:57:15,040 --> 00:57:18,040 IT LOOKS AGAIN LIKE YOU COULD 1289 00:57:18,040 --> 00:57:21,960 SAY THE CANCER IS EASY. 1290 00:57:21,960 --> 00:57:23,160 YOU HAVE BRANCH FUCOSLYATED 1291 00:57:23,160 --> 00:57:25,080 GLYCAN ASSOCIATED WITH VAST 1292 00:57:25,080 --> 00:57:26,400 MAJORITY OF CANCERS, BUT, AGAIN, 1293 00:57:26,400 --> 00:57:27,320 IT'S NOT THAT SIMPLE. 1294 00:57:27,320 --> 00:57:35,080 THERE ARE LOTS OF GLYCAN 1295 00:57:35,080 --> 00:57:35,920 CHANGES. 1296 00:57:35,920 --> 00:57:38,280 THE BLUE REPRESENTS CANCER, RED 1297 00:57:38,280 --> 00:57:39,080 RECOMMENDS NORMAL ADJACENT 1298 00:57:39,080 --> 00:57:39,320 TISSUE. 1299 00:57:39,320 --> 00:57:41,040 WHAT YOU'LL FIND IS, YEAH, THERE 1300 00:57:41,040 --> 00:57:43,360 ARE LOTS OF GLYCANS HIGHER IN 1301 00:57:43,360 --> 00:57:45,040 THE NORMAL TISSUE, LOW IN CANCER 1302 00:57:45,040 --> 00:57:55,080 TISSUE, LOTS IT'S A PRODUCT 1303 00:57:55,080 --> 00:57:55,920 RELATIONSHIP. 1304 00:57:55,920 --> 00:57:58,120 YOU WOULD EXPECT SOMETHING 1305 00:57:58,120 --> 00:57:59,600 FUCOSLYATED, NOT FUCOSLYATED. 1306 00:57:59,600 --> 00:58:01,200 THERE'S VARIATION, WE HAVEN'T 1307 00:58:01,200 --> 00:58:02,680 IDENTIFIED ALL THE VARIATION. 1308 00:58:02,680 --> 00:58:05,240 EVERY CANCER WE LOOKED AT HAS 1309 00:58:05,240 --> 00:58:06,720 SOME GLYCAN CHANGE BUT NOT 1310 00:58:06,720 --> 00:58:08,440 ALWAYS CONSISTENT. 1311 00:58:08,440 --> 00:58:10,000 THAT'S THE THING THAT'S 1312 00:58:10,000 --> 00:58:10,440 IMPORTANT. 1313 00:58:10,440 --> 00:58:13,120 EVERY TUMOR TISSUE WE LOOK AT IN 1314 00:58:13,120 --> 00:58:14,600 LIVER CANCER HAS A GLYCAN CHAIN 1315 00:58:14,600 --> 00:58:18,400 BUT NOT ALWAYS CONSISTENT. 1316 00:58:18,400 --> 00:58:20,320 THAT'S THE KEY POINT. 1317 00:58:20,320 --> 00:58:22,880 A GREAT EXAMPLE IS HERE, TEN 1318 00:58:22,880 --> 00:58:25,920 PATIENTS FROM TMA, THE SAME 1319 00:58:25,920 --> 00:58:28,120 PATIENTS, THESE PATIENTS ARE 1320 00:58:28,120 --> 00:58:29,720 THESE PATIENTS. 1321 00:58:29,720 --> 00:58:34,880 NOT SURPRISING, THIS IS THE 1322 00:58:34,880 --> 00:58:40,880 LEVEL OF 2293, WE LOOKED BY 1323 00:58:40,880 --> 00:58:41,440 ORTHOGONAL METHODS, PATIENTS 1324 00:58:41,440 --> 00:58:49,120 WITH HIGH LEVELS DON'T TEND TO 1325 00:58:49,120 --> 00:58:58,840 HAVE LOTS OF THIS VERSION. 1326 00:58:58,840 --> 00:59:01,920 YOU COULD MAKE THE ARGUE, THAT'S 1327 00:59:01,920 --> 00:59:03,000 NOT SURPRISING, YOU HAVE TO HAVE 1328 00:59:03,000 --> 00:59:04,800 THIS TO GET THIS. 1329 00:59:04,800 --> 00:59:06,360 IT'S JUST A RANDOM EVENT OF 1330 00:59:06,360 --> 00:59:08,240 WHETHER OR NOT YOU HAVE 1331 00:59:08,240 --> 00:59:09,440 FUCOSYLATION IN THE CELL. 1332 00:59:09,440 --> 00:59:11,880 WE WANT TO LOOK AT THAT MORE 1333 00:59:11,880 --> 00:59:13,440 CAREFULLY AND SAY IS THAT REALLY 1334 00:59:13,440 --> 00:59:15,280 TRUE? 1335 00:59:15,280 --> 00:59:17,920 IS IT JUST A RANDOM -- 1336 00:59:17,920 --> 00:59:19,960 FUCOSLYATED OR NOT OR RELATED TO 1337 00:59:19,960 --> 00:59:20,960 CANCER ITSELF? 1338 00:59:20,960 --> 00:59:25,800 TO LOOK AT THAT WE PARTNERED 1339 00:59:25,800 --> 00:59:31,680 WITH A GUY THAT WAS AT MOUNT 1340 00:59:31,680 --> 00:59:34,520 SINAI AT FIRST, NOW AT U.T. 1341 00:59:34,520 --> 00:59:37,280 SOUTHWEST, PUBLISHED IN THE 1342 00:59:37,280 --> 00:59:37,960 EARLY 2000s, 2010, NEW ENGLAND 1343 00:59:37,960 --> 00:59:41,640 JOURNAL OF MEDICINE, SUBTYPING 1344 00:59:41,640 --> 00:59:43,920 SYSTEM FOR LIVER CANCER. 1345 00:59:43,920 --> 00:59:47,840 SO, THESE CANCERS VARY IN THEIR 1346 00:59:47,840 --> 00:59:48,400 GENETICS. 1347 00:59:48,400 --> 00:59:55,680 THEY VARY IN AGGRESSIVENESS. 1348 00:59:55,680 --> 00:59:57,080 VERY IN WHAT BIOMARKERS DETECT 1349 00:59:57,080 --> 00:59:59,680 THEM AND OUTCOME. 1350 00:59:59,680 --> 01:00:01,920 CONFIRMED BY A PAPER DONE BY A 1351 01:00:01,920 --> 01:00:03,120 HEPATOLOGIST OUT OF MAYO, LOUIS 1352 01:00:03,120 --> 01:00:05,360 ROBERTS, WHO GOT THE SAME THING 1353 01:00:05,360 --> 01:00:06,600 USING A LARGER DATABASE. 1354 01:00:06,600 --> 01:00:09,560 SO IT'S KIND OF GETTING SOME 1355 01:00:09,560 --> 01:00:11,040 LEVEL OF TRACTION. 1356 01:00:11,040 --> 01:00:11,400 MEANINGFUL YET? 1357 01:00:11,400 --> 01:00:14,040 WE DON'T KNOW BUT WE'RE LOOKING. 1358 01:00:14,040 --> 01:00:16,000 WE HAD A STUDENT, ANDREW, WHO 1359 01:00:16,000 --> 01:00:18,640 DECIDED TO LOOK AT THESE 1360 01:00:18,640 --> 01:00:19,920 PATIENTS ALREADY SUBTYPED AND 1361 01:00:19,920 --> 01:00:22,680 SAY WHAT ARE THE GLYCANS THAT 1362 01:00:22,680 --> 01:00:23,360 CHANGE HERE? 1363 01:00:23,360 --> 01:00:25,280 IS HETEROGENEITY WHEN WE DIDN'T 1364 01:00:25,280 --> 01:00:26,800 KNOW THE SUBTYPE ACTUALLY 1365 01:00:26,800 --> 01:00:28,480 RELATED TO SUBTYPE OF CANCER? 1366 01:00:28,480 --> 01:00:30,320 TO MAKE A LONG STORY SHORT THE 1367 01:00:30,320 --> 01:00:31,160 ANSWER IS YES. 1368 01:00:31,160 --> 01:00:33,680 SO THAT IF YOU LOOK, FOR 1369 01:00:33,680 --> 01:00:36,920 EXAMPLE, AT THE S1 TYPE TUMORS, 1370 01:00:36,920 --> 01:00:39,000 TUMORS THAT ARE STROMAL IN 1371 01:00:39,000 --> 01:00:44,680 NATURE BY GENETICS IN SOME WAY, 1372 01:00:44,680 --> 01:00:47,920 BY INFLAMMATION, THESE ARE P53 1373 01:00:47,920 --> 01:00:53,240 MUTANT TUMORS, TGF-BETA DRIVEN, 1374 01:00:53,240 --> 01:01:04,920 BIG HONKING GLYCAN CHANGES, 1375 01:01:04,920 --> 01:01:05,240 FUCOSLYATED. 1376 01:01:05,240 --> 01:01:06,520 AP POSITIVE, AGGRESSIVE, MOST 1377 01:01:06,520 --> 01:01:08,000 GLYCAN CHANGES ARE NOT IN THE 1378 01:01:08,000 --> 01:01:22,040 TUMOR AT ALL, THEY ARE IN 1379 01:01:22,040 --> 01:01:24,440 STROMA, NOT WHAT WE EXPECTED, 1380 01:01:24,440 --> 01:01:26,680 NOT DIRECTLY IN THE TUMOR. 1381 01:01:26,680 --> 01:01:37,520 S3 TUMORS TENDED TO HAVE -- 1382 01:01:37,520 --> 01:01:40,440 THIS WAS CONSISTENTLY SEEN WITH 1383 01:01:40,440 --> 01:01:41,960 LOTS OF TUMORS. 1384 01:01:41,960 --> 01:01:43,040 S1 TUMORS WHEN YOU RESECT THEM, 1385 01:01:43,040 --> 01:01:45,880 IF YOU CATCH THEM EARLY AND 1386 01:01:45,880 --> 01:01:48,240 RESECT THEM, THEIR OUTCOME IS 1387 01:01:48,240 --> 01:01:48,440 GOOD. 1388 01:01:48,440 --> 01:01:50,800 THOSE PEOPLE DO DO THE BEST. 1389 01:01:50,800 --> 01:01:55,800 S2 TUMORS HAVE BAD OUTCOMES. 1390 01:01:55,800 --> 01:01:56,160 THEY ACTUALLY -- 1391 01:01:56,160 --> 01:01:57,000 WHEN YOU RESECT THEY ARE THE 1392 01:01:57,000 --> 01:02:00,720 ONES THAT HAVE THE BIGGEST 1393 01:02:00,720 --> 01:02:01,520 ISSUES. 1394 01:02:01,520 --> 01:02:02,680 SO, THAT STROMA AND GLYCAN 1395 01:02:02,680 --> 01:02:04,280 CHANGES WITHIN THAT STROMA WE 1396 01:02:04,280 --> 01:02:05,560 THINK ARE ACTUALLY CONTRIBUTING 1397 01:02:05,560 --> 01:02:07,280 TO THAT POOR OUTCOME. 1398 01:02:07,280 --> 01:02:12,040 AND WE'RE STUDYING THAT NOW. 1399 01:02:12,040 --> 01:02:14,000 S3 TUMORS UNFORTUNATELY ARE VERY 1400 01:02:14,000 --> 01:02:15,640 WELL TREATED IF CAUGHT EARLY BUT 1401 01:02:15,640 --> 01:02:18,200 MOST ARE MISSED BECAUSE THERE'S 1402 01:02:18,200 --> 01:02:20,000 NO GOOD BIOMARKERS. 1403 01:02:20,000 --> 01:02:21,520 AP NEGATIVE, NOT REALLY 1404 01:02:21,520 --> 01:02:23,320 SYMPTOMATIC, SO PATIENTS SHOW UP 1405 01:02:23,320 --> 01:02:24,680 WITH A 14-CENTIMETER TUMOR AND 1406 01:02:24,680 --> 01:02:27,120 NO MATTER WHAT YOU WANT TO DO 1407 01:02:27,120 --> 01:02:28,080 EVEN THOUGH IT'S NOT AGGRESSIVE 1408 01:02:28,080 --> 01:02:30,320 THEY ARE NOT CANDIDATES FOR 1409 01:02:30,320 --> 01:02:31,920 TRANSPLANTS, NOT CANDIDATES FOR 1410 01:02:31,920 --> 01:02:32,920 RESECTION, SO THEY UNFORTUNATELY 1411 01:02:32,920 --> 01:02:34,520 HAVE BAD OUTCOMES. 1412 01:02:34,520 --> 01:02:35,720 WE'RE MISSING THESE PATIENTS 1413 01:02:35,720 --> 01:02:38,040 FROM A BIOMARKER PERSPECTIVE 1414 01:02:38,040 --> 01:02:38,320 COMPLETELY. 1415 01:02:38,320 --> 01:02:40,320 AND THIS GRAPH SHOWS THE 1416 01:02:40,320 --> 01:02:42,600 ANALYSIS IN THE PATIENT SET, TWO 1417 01:02:42,600 --> 01:02:45,560 PATIENT SETS WE LOOKED AT, 1418 01:02:45,560 --> 01:02:46,640 ANALYZED BY TWO INSTRUMENT, THE 1419 01:02:46,640 --> 01:02:49,360 TEND IS THE SAME THAT THESE S1 1420 01:02:49,360 --> 01:02:52,320 TYPE TUMORS THAT WE HAVE THE 1421 01:02:52,320 --> 01:02:54,360 MOST GLYCAN CHANGES IN THE 1422 01:02:54,360 --> 01:02:58,080 TUMOR, S3 TUMORS TEND TO HAVE 1423 01:02:58,080 --> 01:02:59,800 NONFUCOSLYATED VERSION, AND 1424 01:02:59,800 --> 01:03:01,440 OTHER CHANGES OCCUR BUT 1425 01:03:01,440 --> 01:03:01,720 CONSISTENT. 1426 01:03:01,720 --> 01:03:04,000 WE'VE NOW GOTTEN ANOTHER SAMPLE 1427 01:03:04,000 --> 01:03:05,720 SET COMPLETELY -- WELL, BLINDED 1428 01:03:05,720 --> 01:03:09,880 TO SUBTYPE TO US, AND WE'RE 1429 01:03:09,880 --> 01:03:10,240 LOOKING AT THEM. 1430 01:03:10,240 --> 01:03:12,880 THERE ARE ROUGHLY 70 TUMORS, AND 1431 01:03:12,880 --> 01:03:21,480 70 ADJACENT TUMOR SECTIONS WE'RE 1432 01:03:21,480 --> 01:03:24,520 LOOKING AT, TO PREDICT AND GIVE 1433 01:03:24,520 --> 01:03:27,520 BACK TO CLINICIANS, S1, S2, S3. 1434 01:03:27,520 --> 01:03:29,720 WE HOPE TO GET SERUM SAMPLES TO 1435 01:03:29,720 --> 01:03:31,520 MATCH PATIENTS, WE HAVE 26 SERUM 1436 01:03:31,520 --> 01:03:33,320 SAMPLES THAT MATCH WITH THE 1437 01:03:33,320 --> 01:03:33,520 TISSUE. 1438 01:03:33,520 --> 01:03:35,280 SO WE'RE GOING TO TAKE A LOOK AT 1439 01:03:35,280 --> 01:03:36,120 THAT. 1440 01:03:36,120 --> 01:03:39,080 I'LL SHOW YOU DATA, 1441 01:03:39,080 --> 01:03:41,240 CHERRY-PICKED, DESIGNED TO SEE A 1442 01:03:41,240 --> 01:03:43,760 DIFFERENCE, WE'LL GO TO THAT IN 1443 01:03:43,760 --> 01:03:44,160 A SECOND. 1444 01:03:44,160 --> 01:03:47,760 BECAUSE OF THE SMALL SIZE WE'RE 1445 01:03:47,760 --> 01:03:50,920 POWERED TO SEE BIG DIFFERENCES, 1446 01:03:50,920 --> 01:03:52,280 SMALL DIFFERENCES WILL NOT BE 1447 01:03:52,280 --> 01:03:53,720 SEEN BUT WE'LL GET INTO THAT. 1448 01:03:53,720 --> 01:03:55,600 HERE'S WHAT IT LOOKS LIKE. 1449 01:03:55,600 --> 01:03:58,200 AGAIN, WE HAVE A PIECE OF 1450 01:03:58,200 --> 01:04:01,160 TISSUE, TUMOR IN THE MIDDLE, AND 1451 01:04:01,160 --> 01:04:03,080 THIS TUMOR WHEN ANDREW LOOKS HAS 1452 01:04:03,080 --> 01:04:04,720 A LOT OF GLYCAN CHANGES JUST 1453 01:04:04,720 --> 01:04:05,600 WITHIN THE TUMOR THAT LOOK 1454 01:04:05,600 --> 01:04:12,480 PERFECT AND AS YOU WOULD EXPECT. 1455 01:04:12,480 --> 01:04:13,200 THERE IS INTRATUMOR 1456 01:04:13,200 --> 01:04:14,520 HETEROGENEITY, THAT MAY BE 1457 01:04:14,520 --> 01:04:16,480 RELATED TO HOW THEY ARE HANDLED, 1458 01:04:16,480 --> 01:04:16,720 TREATED. 1459 01:04:16,720 --> 01:04:18,560 BUT A PATIENT LIKE THIS I WOULD 1460 01:04:18,560 --> 01:04:20,920 SAY WITH CONFIDENCE TO THE 1461 01:04:20,920 --> 01:04:22,160 CLINICIAN, THAT'S AN S1 TUMOR, 1462 01:04:22,160 --> 01:04:23,120 WE CAN MOVE ON. 1463 01:04:23,120 --> 01:04:25,320 SO IS THAT THE EASY PART? 1464 01:04:25,320 --> 01:04:25,840 WELL, NO. 1465 01:04:25,840 --> 01:04:28,520 SO YOU WOULD HAVE A TUMOR LIKE 1466 01:04:28,520 --> 01:04:31,240 THIS THAT LOOKS SIMILAR TOO, 1467 01:04:31,240 --> 01:04:33,120 THAT HAS THE BRANCHED NOT 1468 01:04:33,120 --> 01:04:34,120 FUCOSLYATED GLYCAN IN THE TUMOR 1469 01:04:34,120 --> 01:04:37,480 AND THEN HAS THE BRANCHED 1470 01:04:37,480 --> 01:04:39,720 FUCOSLYATED GLYCAN OUT OF TUMOR, 1471 01:04:39,720 --> 01:04:41,080 PROBABLY S2 OR S3. 1472 01:04:41,080 --> 01:04:43,760 THAT'S A BIG DIFFERENCE. 1473 01:04:43,760 --> 01:04:45,200 AND SO IT'S COMPLICATED. 1474 01:04:45,200 --> 01:04:47,360 IT'S NOT AS EASY AS WE THINK. 1475 01:04:47,360 --> 01:04:53,520 CANCERS ARE NOT FALLING INTO 1476 01:04:53,520 --> 01:04:54,400 WELL-DEFINED GENOMIC CATEGORIES. 1477 01:04:54,400 --> 01:04:57,560 ONE THING WE'RE DOING NOW IS 1478 01:04:57,560 --> 01:04:59,280 SAYING, LOOK, THE GLYCOMICS IN 1479 01:04:59,280 --> 01:05:01,360 SOME WAYS ARE JUST AS IMPORTANT 1480 01:05:01,360 --> 01:05:03,400 AS THE GENOMICS. 1481 01:05:03,400 --> 01:05:07,360 SO WE'RE MOVING TO REPLACE THE 1482 01:05:07,360 --> 01:05:07,920 GENOMIC CLASSIFICATION WITH 1483 01:05:07,920 --> 01:05:10,400 GLYCOMIC CLASSIFICATION. 1484 01:05:10,400 --> 01:05:12,320 IT'S IMPORTANT TO REALIZE THAT 1485 01:05:12,320 --> 01:05:13,520 GENOMICS HAS GREAT VALUE. 1486 01:05:13,520 --> 01:05:15,960 I'M NOT JUST MISSING THAT. 1487 01:05:15,960 --> 01:05:17,320 GLYCOMICS IN SOME WAYS HAS JUST 1488 01:05:17,320 --> 01:05:21,160 AS VITAL INFORMATION AND YOU CAN 1489 01:05:21,160 --> 01:05:22,520 DO GLYCOMIC CLASSIFICATION OF 1490 01:05:22,520 --> 01:05:25,280 THE TUMORS JUST AS EASILY AS YOU 1491 01:05:25,280 --> 01:05:27,120 CAN GENOMIC CLASSIFICATION OF 1492 01:05:27,120 --> 01:05:27,480 TUMORS. 1493 01:05:27,480 --> 01:05:39,640 WE'RE MOVING IN THAT DIRECTION 1494 01:05:39,640 --> 01:05:40,440 NOW. 1495 01:05:40,440 --> 01:05:45,320 SO CHOLANGIOCARCINOMA IS 1496 01:05:45,320 --> 01:05:45,640 COMPLICATED. 1497 01:05:45,640 --> 01:05:51,960 UP TOP THIS IS A BRANCH GLYCAN, 1498 01:05:51,960 --> 01:05:54,680 FOUND IN HCC, NOT IN 1499 01:05:54,680 --> 01:05:55,920 CHOLANGIOCARS NO, MA'AMA TRUE IN 1500 01:05:55,920 --> 01:05:59,920 THE FIRST TMA AND SECOND TMA. 1501 01:05:59,920 --> 01:06:03,560 IN CONTRAST YOU'LL SEE A SMALLER 1502 01:06:03,560 --> 01:06:04,200 GLYCAN, FUCOSLYATED, WE HAVEN'T 1503 01:06:04,200 --> 01:06:06,720 CONFIRMED YET BUT LOOKS LIKE 1504 01:06:06,720 --> 01:06:08,760 IT'S A BISECTED GLYCAN WITH 1505 01:06:08,760 --> 01:06:19,960 FUCOSE, ONE OR TWO FUCOSES, 1506 01:06:19,960 --> 01:06:22,920 HIGHLY EXPECTED IN CHOLANGIO 1507 01:06:22,920 --> 01:06:23,160 CARCINOMA. 1508 01:06:23,160 --> 01:06:29,320 HCC, LOTS OF DRIVE CAN -- 1509 01:06:29,320 --> 01:06:30,720 GLYCAN CHANGES, THE FUCOSE 1510 01:06:30,720 --> 01:06:34,560 DEFINES WHAT SUBTYPE IT IS AND 1511 01:06:34,560 --> 01:06:35,320 GENETICS AND DEFINES THE OUTCOME 1512 01:06:35,320 --> 01:06:37,320 OF THAT PATIENT AND HOW 1513 01:06:37,320 --> 01:06:41,200 AGGRESSIVE THE CANCER WILL GROW 1514 01:06:41,200 --> 01:06:42,200 AND METASTASIZE. 1515 01:06:42,200 --> 01:06:43,960 STROMA AND GLYCANS IN THE STROMA 1516 01:06:43,960 --> 01:06:45,840 PLAY AN IMPORTANT ROLE IN THE 1517 01:06:45,840 --> 01:06:47,080 OUTCOME OF THE PATIENT, LOOKING 1518 01:06:47,080 --> 01:06:47,240 NOW. 1519 01:06:47,240 --> 01:06:55,400 THERE ARE LOTS OF OTHER CHANGES, 1520 01:06:55,400 --> 01:06:56,520 BISECTS FOUND IN 1521 01:06:56,520 --> 01:06:57,840 HEPATOCARCINOMA, TO A SMALLER 1522 01:06:57,840 --> 01:07:00,360 DEGREE. 1523 01:07:00,360 --> 01:07:18,320 WE'RE LOOKING INTO THAT. 1524 01:07:18,320 --> 01:07:19,520 GENETICS ARE DRIVING. 1525 01:07:19,520 --> 01:07:22,760 WHAT DOES THIS MEAN IN TERMS OF 1526 01:07:22,760 --> 01:07:23,040 BIOMARKER? 1527 01:07:23,040 --> 01:07:23,880 FOR THE MOST PART, THE BIOMARKER 1528 01:07:23,880 --> 01:07:27,320 THAT PEOPLE HAVE BEEN USING, 1529 01:07:27,320 --> 01:07:29,920 AFP, DETECTS ONE TYPE. 1530 01:07:29,920 --> 01:07:31,200 FUCOSLYATEED VERSIONS AND 1531 01:07:31,200 --> 01:07:32,120 PROTEINS WE'VE IDENTIFIED 1532 01:07:32,120 --> 01:07:36,120 COMPLEMENT AND CAN DETECT BOTH 1533 01:07:36,120 --> 01:07:38,880 OF THESE. 1534 01:07:38,880 --> 01:07:41,240 THESE BRANCHED FOUND PRIMARILY 1535 01:07:41,240 --> 01:07:43,560 IN S3-TYPE TUMORS ARE MISSED 1536 01:07:43,560 --> 01:07:45,360 RIGHT NOW BY MOST BIOMARKERS. 1537 01:07:45,360 --> 01:07:47,280 WE'RE NOW HAVING TO ADDRESS 1538 01:07:47,280 --> 01:07:48,080 THAT. 1539 01:07:48,080 --> 01:07:49,760 WHAT I WILL SAY, WHAT'S 1540 01:07:49,760 --> 01:07:51,520 INTERESTING, THIS IS CHERRY 1541 01:07:51,520 --> 01:07:53,320 PICKED DATA, THAT THOSE PATIENTS 1542 01:07:53,320 --> 01:07:55,280 THAT HAVE HIGH LEVELS OF 1543 01:07:55,280 --> 01:07:57,440 FUCOSYLATION IN TISSUE TEND TO 1544 01:07:57,440 --> 01:07:59,520 HAVE HIGH LEVELS OF FUCOSYLATION 1545 01:07:59,520 --> 01:07:59,720 SERUM. 1546 01:07:59,720 --> 01:08:02,040 THOSE PATIENTS WITH LOW LEVELS 1547 01:08:02,040 --> 01:08:03,720 OF FUCOSYLATION IN TISSUE HAVE 1548 01:08:03,720 --> 01:08:05,200 LOW LEVELS IN SERUM. 1549 01:08:05,200 --> 01:08:07,480 IF YOU JUST CHERRY PICK HIGHS 1550 01:08:07,480 --> 01:08:08,440 AND LOWS WE'VE LOOKED IT THE 1551 01:08:08,440 --> 01:08:10,520 HIGHS AND LOWS TO START WITH, 1552 01:08:10,520 --> 01:08:12,200 THAT'S THE PROBLEM. 1553 01:08:12,200 --> 01:08:13,960 WE DID IT TO SEE WILL IT HOLD 1554 01:08:13,960 --> 01:08:14,520 UP. 1555 01:08:14,520 --> 01:08:19,720 THE RELATIONSHIP IS STRONG, FOR 1556 01:08:19,720 --> 01:08:22,520 UNFUCOSLYATED, THERE'S A STRONG 1557 01:08:22,520 --> 01:08:24,560 RELATIONSHIP BETWEEN TISSUE AND 1558 01:08:24,560 --> 01:08:25,160 SERUM. 1559 01:08:25,160 --> 01:08:28,480 WE'LL EXPLOIT THAT DOING A 1560 01:08:28,480 --> 01:08:30,200 METHOD REFERRED TO AS 1561 01:08:30,200 --> 01:08:36,880 GLYCOTYPER, REPLACING THE TISSUE 1562 01:08:36,880 --> 01:08:40,480 WITH ANTIBODY ARRAY, YOU REPLACE 1563 01:08:40,480 --> 01:08:42,080 AND GET ANTIBODY SPECIFIC 1564 01:08:42,080 --> 01:08:45,120 CAPTURE INFORMATION AND GLYCAN 1565 01:08:45,120 --> 01:08:47,000 INFORMATION, THE METHOD 1566 01:08:47,000 --> 01:08:49,320 DEVELOPED OUT OF THE 1567 01:08:49,320 --> 01:08:50,760 GLYCOALLIANCE THAT KRUEGER RUNS 1568 01:08:50,760 --> 01:08:54,600 AND A COLLABORATION WITH BRIAN, 1569 01:08:54,600 --> 01:08:56,360 KNOWING BRIAN HAAB, WE COULD USE 1570 01:08:56,360 --> 01:09:01,880 THAT METHOD TO DO GLYCAN 1571 01:09:01,880 --> 01:09:03,920 ANALYSIS, TRUE GLYCAN ANALYSIS, 1572 01:09:03,920 --> 01:09:05,160 HIGH-THROUGHPUT WAY, PUSHED BY A 1573 01:09:05,160 --> 01:09:06,440 STUDENT ALLISON BLACK IN THE 1574 01:09:06,440 --> 01:09:09,240 LAB, JUSTING ON A BE ANTIBODY 1575 01:09:09,240 --> 01:09:12,120 ARRAY TO RAPTURE PROTEINS OF 1576 01:09:12,120 --> 01:09:13,200 INTEREST, RELEASING GLYCAN, 1577 01:09:13,200 --> 01:09:15,840 EXACTED SAME TISSUE WAY, DOES 1578 01:09:15,840 --> 01:09:18,920 GLYCAN ANALYSIS, USING THIS 1579 01:09:18,920 --> 01:09:22,240 METHOD TO LOOK AT 140 CANCER 1580 01:09:22,240 --> 01:09:24,080 PATIENTS, 270 CIRHOTTIC 1581 01:09:24,080 --> 01:09:32,280 PATIENTS, JUST STARTED WITH 6 1582 01:09:32,280 --> 01:09:34,040 PROTEINS, AND WITH JUST THOSE 1583 01:09:34,040 --> 01:09:36,400 LOOKING AT A MIXTURE OF GLYCAN 1584 01:09:36,400 --> 01:09:37,680 WE CAN GET UP, NOW THERE'S LOTS 1585 01:09:37,680 --> 01:09:40,360 OF DATA HERE BECAUSE YOU HAVE 1586 01:09:40,360 --> 01:09:45,520 MULTIPLE PROTEINS, 15, 20, 30 1587 01:09:45,520 --> 01:09:47,760 GLYCANS PER PROTEIN, WE'RE 1588 01:09:47,760 --> 01:09:48,720 ADDING PROTEINS TO THAT. 1589 01:09:48,720 --> 01:09:50,720 THAT'S HOW WE'RE GOING TO 1590 01:09:50,720 --> 01:09:52,800 EXPLOIT THE GLYCANS IN TISSUE TO 1591 01:09:52,800 --> 01:09:54,480 LOOK IN SERUM TO IDENTIFY 1592 01:09:54,480 --> 01:10:01,440 EVERYBODY THAT'S GOT LIVER 1593 01:10:01,440 --> 01:10:01,680 CANCER. 1594 01:10:01,680 --> 01:10:05,520 USING IMAGING WE SHOW GLYCAN 1595 01:10:05,520 --> 01:10:08,120 CHANGES IN HCC TISSUE, CAN USE 1596 01:10:08,120 --> 01:10:09,880 THAT INFORMATION TO SUBTYPE 1597 01:10:09,880 --> 01:10:11,520 TISSUE, AND MOVING TO DEVELOP 1598 01:10:11,520 --> 01:10:12,720 ANTIBODY ARRAYS TO ALLOW US TO 1599 01:10:12,720 --> 01:10:14,040 LOOK AT THIS IN BOTH SERUM AND 1600 01:10:14,040 --> 01:10:16,480 OF IN A WAY THAT REFLECTS WHAT'S 1601 01:10:16,480 --> 01:10:18,360 HAPPENING IN THE TISSUE. 1602 01:10:18,360 --> 01:10:19,160 WITH THAT I'LL END. 1603 01:10:19,160 --> 01:10:21,720 ACKNOWLEDGE THE WIDE VARIETY OF 1604 01:10:21,720 --> 01:10:22,760 COLLABORATORS, APOLOGIZE FOR THE 1605 01:10:22,760 --> 01:10:25,040 YELLOW TYPE, IT'S HARD TO SEE ON 1606 01:10:25,040 --> 01:10:26,720 MY SCREEN, PROBABLY ON YOURS. 1607 01:10:26,720 --> 01:10:29,040 AND I WOULD LIKE TO THANK THE 1608 01:10:29,040 --> 01:10:30,520 CLINICAL COLLABORATORS THAT GAVE 1609 01:10:30,520 --> 01:10:31,920 US SAMPLES AND THE PATIENTS WHO 1610 01:10:31,920 --> 01:10:34,320 HAVE GIVEN THE TISSUE AND SERUM 1611 01:10:34,320 --> 01:10:35,640 WE USE FOR ANALYSIS. 1612 01:10:35,640 --> 01:10:36,360 WE'RE SAMPLE HOGS. 1613 01:10:36,360 --> 01:10:38,320 DO EVERYTHING IN HUMAN SERUM AND 1614 01:10:38,320 --> 01:10:39,560 HUMAN TISSUE AND CAN'T DO 1615 01:10:39,560 --> 01:10:40,560 ANYTHING OUT THE PATIENTS THAT 1616 01:10:40,560 --> 01:10:46,800 GIVE THAT SAMP AM -- SAMPLE TO 1617 01:10:46,800 --> 01:10:48,480 US. 1618 01:10:48,480 --> 01:10:57,240 I'M INDEBTED TO THAT 1619 01:10:57,240 --> 01:10:57,680 INDIVIDUALS. 1620 01:10:57,680 --> 01:11:01,680 >> THANK YOU FOR AN EXCITING 1621 01:11:01,680 --> 01:11:01,920 TALK. 1622 01:11:01,920 --> 01:11:03,120 REMINDER, YOU CAN SEND QUESTIONS 1623 01:11:03,120 --> 01:11:06,200 TO HIM OR ANY SPEAKERS AT SEND 1624 01:11:06,200 --> 01:11:08,520 LIVE FEEDBACK, WE'LL ADDRESS 1625 01:11:08,520 --> 01:11:12,520 THOSE IN AN HOUR. 1626 01:11:12,520 --> 01:11:21,600 NEXT SPEAKER IS REBEKAH GUNDRY, 1627 01:11:21,600 --> 01:11:23,000 FROM UNIVERSITY OF NEBRASKA 1628 01:11:23,000 --> 01:11:24,760 MEDICAL CENTER. 1629 01:11:24,760 --> 01:11:26,840 >> GOOD MORNING. 1630 01:11:26,840 --> 01:11:31,520 THANKS FOR THE INVITE TO SPEAK. 1631 01:11:31,520 --> 01:11:33,160 I'M DELIGHTED TO HAVE THE TIME 1632 01:11:33,160 --> 01:11:35,080 TO TELL YOU ABOUT A FEW 1633 01:11:35,080 --> 01:11:36,440 DIFFERENT BIOINFORMATIC TOOLS 1634 01:11:36,440 --> 01:11:38,120 WE'VE DEVELOPED TO HELP OVERCOME 1635 01:11:38,120 --> 01:11:44,240 SOME UNIQUE CHALLENGES WE FACE 1636 01:11:44,240 --> 01:11:47,320 WHEN PERFORMING CELL SURFACE 1637 01:11:47,320 --> 01:11:49,080 PROTEOMICS, IT'S INVOLVED IN THE 1638 01:11:49,080 --> 01:11:50,520 PROGRESSION OF DISEASE. 1639 01:11:50,520 --> 01:11:51,920 BY KNOWING WHICH PROTEINS RESIDE 1640 01:11:51,920 --> 01:11:54,520 ON THE CELL SURFACE AND HOW THEY 1641 01:11:54,520 --> 01:11:56,280 CHANGE AMONG CELL TIMES AND 1642 01:11:56,280 --> 01:11:59,000 DISEASE PROGRESSION WE CAN LEARN 1643 01:11:59,000 --> 01:12:00,880 HOW CELLS RESPOND TO STRESS AND 1644 01:12:00,880 --> 01:12:04,400 DISEASE, FIND TARGETS FOR DRUGS 1645 01:12:04,400 --> 01:12:09,120 AND DELIVERING PAYLOADS TO 1646 01:12:09,120 --> 01:12:11,320 SPECIFIC CELL TYPES AND REGIONS 1647 01:12:11,320 --> 01:12:15,160 AND BECAUSE THEY CAN BE CLEAVED, 1648 01:12:15,160 --> 01:12:17,200 THEY CAN BE EXPLOITED. 1649 01:12:17,200 --> 01:12:18,760 WE KNOW RELATIVELY LITTLE ABOUT 1650 01:12:18,760 --> 01:12:20,200 WHICH PROTEINS RESIDE ON THE 1651 01:12:20,200 --> 01:12:24,720 SURFACE OF MOST HUMAN CELL 1652 01:12:24,720 --> 01:12:27,440 TYPES DUE TO LIMITATIONS OF 1653 01:12:27,440 --> 01:12:31,000 COMMON APPROACHES TO ANALYZE. 1654 01:12:31,000 --> 01:12:32,520 ANTIBODY BASED SCREEN, THERE 1655 01:12:32,520 --> 01:12:35,080 AREN'T ENOUGH GOOD ANTIBODIES. 1656 01:12:35,080 --> 01:12:36,200 TRANSCRIPTOMICS CAN'T DEFINE IT 1657 01:12:36,200 --> 01:12:38,000 BECAUSE mRNA DOESN'T ITEM YOU 1658 01:12:38,000 --> 01:12:40,920 ABOUT PROTEIN ABUNDANCE OR 1659 01:12:40,920 --> 01:12:41,840 LOCATION. 1660 01:12:41,840 --> 01:12:46,760 GENERIC PROTEOMICS CAN'T DEFINE 1661 01:12:46,760 --> 01:12:49,000 IT, THEY ARE NOT WELL 1662 01:12:49,000 --> 01:12:49,920 REPRESENTED. 1663 01:12:49,920 --> 01:12:51,200 TRADITIONAL APPROACHES DO NOT 1664 01:12:51,200 --> 01:12:51,800 EXPERIMENTAL DEFINE PROTEINS 1665 01:12:51,800 --> 01:12:57,400 THAT RESIDE AT THE CELL SURFACE. 1666 01:12:57,400 --> 01:13:00,200 TO GET GOOD COVERAGE YOU NEED TO 1667 01:13:00,200 --> 01:13:02,920 DO ENRICHMENT FOR LOWER 1668 01:13:02,920 --> 01:13:04,240 ABUNDANCE AND HYDROPHOBIC 1669 01:13:04,240 --> 01:13:04,520 PROTEINS. 1670 01:13:04,520 --> 01:13:05,520 THERE HAVE BEEN STRATEGIES 1671 01:13:05,520 --> 01:13:07,840 DEVELOPED AND APPLIED TO MORE 1672 01:13:07,840 --> 01:13:10,320 THAN 300 SURFACE PROTEOMIC 1673 01:13:10,320 --> 01:13:11,920 STUDIES, LOTS OF CHEMISTRIES 1674 01:13:11,920 --> 01:13:12,960 AVAILABLE BUT GENERALLY ONE MAIN 1675 01:13:12,960 --> 01:13:15,080 DISTINCTION IN THE STUDY DESIGN 1676 01:13:15,080 --> 01:13:16,760 ARE THAT RESULTING MASS 1677 01:13:16,760 --> 01:13:18,040 SPECTROMETRY DATA EITHER 1678 01:13:18,040 --> 01:13:19,400 CONTAINS SOME TYPE OF STAR OR 1679 01:13:19,400 --> 01:13:21,000 TAG ON THE PEPTIDES THAT CAN BE 1680 01:13:21,000 --> 01:13:23,000 USED AS EVIDENCE THAT THE 1681 01:13:23,000 --> 01:13:24,600 PEPTIDE IDENTIFIED BY THE METHOD 1682 01:13:24,600 --> 01:13:26,440 ORIGINATED FROM THE 1683 01:13:26,440 --> 01:13:28,520 EXTRACELLULAR DOMAIN OR DATA DO 1684 01:13:28,520 --> 01:13:31,160 NOT CONTAIN EVIDENCE SO RESULTS 1685 01:13:31,160 --> 01:13:35,080 MUST BE ANNOTATED BASED ON 1686 01:13:35,080 --> 01:13:35,360 PREDICTION. 1687 01:13:35,360 --> 01:13:36,960 THERE ARE SOME CHALLENGES. 1688 01:13:36,960 --> 01:13:38,520 A LOT OF STRATEGIES. 1689 01:13:38,520 --> 01:13:40,800 THE CHOICE THAT YOU ARE GOING TO 1690 01:13:40,800 --> 01:13:43,520 USE WILL DEPEND ON APPLICATION 1691 01:13:43,520 --> 01:13:45,680 AND GOALS, RIGHT NOW CHALLENGING 1692 01:13:45,680 --> 01:13:47,600 TO COMPARE RESULTS WITH NO 1693 01:13:47,600 --> 01:13:49,640 CONSENSUS WHAT CRITERIA ARE USED 1694 01:13:49,640 --> 01:13:51,120 TO DEFINE SURFACE PROTEIN. 1695 01:13:51,120 --> 01:13:53,120 THAT MEANS STARTING FROM THE 1696 01:13:53,120 --> 01:13:55,080 SAME EXPERIMENTAL DATA DIFFERENT 1697 01:13:55,080 --> 01:13:56,000 LABORATORIES COULD REPORT 1698 01:13:56,000 --> 01:13:57,360 DIFFERENT INTERPRETATIONS 1699 01:13:57,360 --> 01:13:58,920 DEPENDING ON WHICH GENE ONTOLOGY 1700 01:13:58,920 --> 01:14:01,440 TRENDS THEY USE OR WHICH 1701 01:14:01,440 --> 01:14:04,320 DATABASE ANNOTATIONS ARE USED. 1702 01:14:04,320 --> 01:14:06,720 MOST USE AFFINITY ENRICHMENT 1703 01:14:06,720 --> 01:14:08,600 STEP, REAGENTED PLAGUED BY 1704 01:14:08,600 --> 01:14:09,960 NON-SPECIFIC BINDERS, NO 1705 01:14:09,960 --> 01:14:10,520 EXPERIMENTAL EVIDENCE IN 1706 01:14:10,520 --> 01:14:12,040 RESULTING DATA, IT CAN BE 1707 01:14:12,040 --> 01:14:14,400 CHALLENGING TO HAVE CONFIDENCE 1708 01:14:14,400 --> 01:14:19,760 PROTEINS IDENTIFIED WERE 1709 01:14:19,760 --> 01:14:20,520 LOCATED AT THE CELL SURFACE AT 1710 01:14:20,520 --> 01:14:22,000 THE TIME. 1711 01:14:22,000 --> 01:14:23,600 IT CAN BE CHALLENGING TO 1712 01:14:23,600 --> 01:14:25,400 PRIORITIZE THE FOCUS OF 1713 01:14:25,400 --> 01:14:25,800 FOLLOW-UP STUDIES. 1714 01:14:25,800 --> 01:14:27,920 TODAY I'M GOING TO TELL YOU 1715 01:14:27,920 --> 01:14:32,840 ABOUT THREE TOOLS TO OVERCOME 1716 01:14:32,840 --> 01:14:33,480 THESE CHALLENGES. 1717 01:14:33,480 --> 01:14:36,200 FIRST A BRIEF OVERVIEW OF THE 1718 01:14:36,200 --> 01:14:40,000 PURPOSE AND FEATURES AND SHOW 1719 01:14:40,000 --> 01:14:44,520 REAL WORLD APPLICATION. 1720 01:14:44,520 --> 01:14:45,720 I'LL BEGIN WITH CIRFESS, 1721 01:14:45,720 --> 01:14:49,640 CHALLENGES INCLUDE HOW CAN YOU 1722 01:14:49,640 --> 01:14:51,000 QUICKLY PREDICT WHICH OF THESE 1723 01:14:51,000 --> 01:14:54,040 METHODS WOULD COVER YOUR 1724 01:14:54,040 --> 01:14:54,920 PROTEOME SUBSET OF INTEREST 1725 01:14:54,920 --> 01:14:56,000 DEPENDING WHICH CHEMISTRY IS 1726 01:14:56,000 --> 01:14:56,320 USED. 1727 01:14:56,320 --> 01:14:58,240 ONCE YOU HAVE DATA HOW CAN YOU 1728 01:14:58,240 --> 01:14:59,960 EVALUATE IF THE PROTEINS THAT 1729 01:14:59,960 --> 01:15:02,720 YOU IDENTIFY IN YOUR EXPERIMENT 1730 01:15:02,720 --> 01:15:03,360 ARE ACTUALLY THEORETICALLY 1731 01:15:03,360 --> 01:15:05,600 POSSIBLE BY THAT METHOD GIVING 1732 01:15:05,600 --> 01:15:06,640 EVIDENCE YOU SPECIFICALLY 1733 01:15:06,640 --> 01:15:09,720 IDENTIFIED THEM OTHER ARE THEY 1734 01:15:09,720 --> 01:15:12,480 LIKELY NON-SPECIFIC BINDERS. 1735 01:15:12,480 --> 01:15:15,160 SO BEFORE DO YOU AN EXPERIMENT 1736 01:15:15,160 --> 01:15:16,480 YOU CAN PREDICT WHICH METHOD 1737 01:15:16,480 --> 01:15:19,440 WILL GIVE YOU THE BEST COVERAGE, 1738 01:15:19,440 --> 01:15:20,720 AND AFTER THE EXPERIMENT CAN 1739 01:15:20,720 --> 01:15:22,400 CHECK WHETHER A PROTEIN YOU 1740 01:15:22,400 --> 01:15:24,320 IDENTIFIED IS EXPECTED TO BE 1741 01:15:24,320 --> 01:15:26,080 CAPTURED BY THAT METHOD TO GIVE 1742 01:15:26,080 --> 01:15:27,520 CONFIDENCE THAT YOU'RE SEEING IT 1743 01:15:27,520 --> 01:15:28,840 BECAUSE IT WAS SPECIFICALLY 1744 01:15:28,840 --> 01:15:35,800 CAPTURED BY THE CHEMISTRY YOU'RE 1745 01:15:35,800 --> 01:15:36,000 USING. 1746 01:15:36,000 --> 01:15:43,560 CIRFESS INTEGRATES WHAT IS 1747 01:15:43,560 --> 01:15:45,480 NECESSARY FOR MASS SPECTROMETRY, 1748 01:15:45,480 --> 01:15:46,960 IF EXTRACELLULAR PEPTIDES ARE 1749 01:15:46,960 --> 01:15:48,320 ABLE TO BE ENRICHED AND 1750 01:15:48,320 --> 01:15:49,720 IDENTIFIED BY MASS SPECTROMETRY. 1751 01:15:49,720 --> 01:15:52,920 AND YOU CAN DO EITHER A SINGLE 1752 01:15:52,920 --> 01:15:54,840 PROTEIN OR BATCH LOOKUP AND FOR 1753 01:15:54,840 --> 01:15:57,480 EACH ENTRY YOU CAN SEE A LOT OF 1754 01:15:57,480 --> 01:15:59,080 DIFFERENT INFORMATION, YOU CAN 1755 01:15:59,080 --> 01:16:05,560 SEE THE SURFACE PROTEIN 1756 01:16:05,560 --> 01:16:07,720 CONSENSUS SCORE AND OUTPUT FROM 1757 01:16:07,720 --> 01:16:13,720 THREE SIGNAL PEPTIDE PREDICTIONS 1758 01:16:13,720 --> 01:16:14,840 AND TWO TRANSMEMBRANE 1759 01:16:14,840 --> 01:16:15,120 PREDICTION. 1760 01:16:15,120 --> 01:16:20,200 FOR EACH THE NUMBER OF PREDICTED 1761 01:16:20,200 --> 01:16:25,440 MASS SPECTROMETRY PEPTIDES IS 1762 01:16:25,440 --> 01:16:25,800 DISPLAYED. 1763 01:16:25,800 --> 01:16:27,200 SO FOR A PROTEIN THAT YOU 1764 01:16:27,200 --> 01:16:28,880 IDENTIFY IN EXPERIMENT, YOU CAN 1765 01:16:28,880 --> 01:16:30,520 SEE IF YOU WOULD EXPECT TO SEE 1766 01:16:30,520 --> 01:16:32,480 WITH YOUR APPROACH OR IS IT 1767 01:16:32,480 --> 01:16:34,600 LIKELY NON-SPECIFIC BINDER? 1768 01:16:34,600 --> 01:16:42,000 HERE I'M SHOWING EXAMPLE OF A 1769 01:16:42,000 --> 01:16:50,720 NON-GLYCOSYLATED PROTEIN. 1770 01:16:50,720 --> 01:16:52,040 THERE'S NO EXTRACELLULAR 1771 01:16:52,040 --> 01:16:52,320 LOCALIZED. 1772 01:16:52,320 --> 01:17:00,240 YOU CAN SEE DISCREPANCY OR 1773 01:17:00,240 --> 01:17:00,520 CONSISTENCY. 1774 01:17:00,520 --> 01:17:02,520 AND YOU CAN SEE THEORETICAL 1775 01:17:02,520 --> 01:17:08,320 COVERAGE OF PROTEOMIC BASED ON 1776 01:17:08,320 --> 01:17:11,800 LABELING CHEMISTRIES. 1777 01:17:11,800 --> 01:17:13,200 OVERALL IT CAN HELP EVALUATE 1778 01:17:13,200 --> 01:17:14,880 RESULTS TO DETERMINE IF A 1779 01:17:14,880 --> 01:17:17,440 PROTEIN MAKES SENSE OR IF THEY 1780 01:17:17,440 --> 01:17:23,360 ARE LIKELY NON-SPECIFIC BINDERS. 1781 01:17:23,360 --> 01:17:29,600 NEXT UP IS VENEER, LACK OF 1782 01:17:29,600 --> 01:17:30,720 STANDARDIZATION, GENE ONTOLOGY 1783 01:17:30,720 --> 01:17:32,320 AND DATABASE ANNOTATIONS ARE 1784 01:17:32,320 --> 01:17:34,200 USED TO ASSERT PROTEINS 1785 01:17:34,200 --> 01:17:36,400 IDENTIFIED IN AN EXPERIMENT ARE 1786 01:17:36,400 --> 01:17:38,000 CELL SURFACE PROTEINS, STRATEGY 1787 01:17:38,000 --> 01:17:40,720 IS LIMITED BECAUSE ONE PROTEIN 1788 01:17:40,720 --> 01:17:42,080 CAN HAVE MULTIPLE ASSOCIATED 1789 01:17:42,080 --> 01:17:43,360 SUBCELLULAR LOCATIONS THAT 1790 01:17:43,360 --> 01:17:47,040 CHANGE AMONG CELL TYPES AND 1791 01:17:47,040 --> 01:17:48,560 CONDITIONS, EVIDENCE IN ONE IS 1792 01:17:48,560 --> 01:17:52,440 NOT EVIDENCE OF LOCATION IN 1793 01:17:52,440 --> 01:17:54,040 ANOTHER CELL TYPE, NO CONSENSUS 1794 01:17:54,040 --> 01:17:57,120 TO USE TO DEFINE SURFACE 1795 01:17:57,120 --> 01:17:57,320 PROTEIN. 1796 01:17:57,320 --> 01:18:02,280 CONSEQUENCES THAT IF WE ASSUME 1797 01:18:02,280 --> 01:18:06,320 LOCATIONS, WE COULD WASTE TIME 1798 01:18:06,320 --> 01:18:07,480 PURSUING PROTEINS NOT LOCALIZED 1799 01:18:07,480 --> 01:18:09,840 TO CELL SURFACE. 1800 01:18:09,840 --> 01:18:11,560 WE DEVELOPED A WEB-BASED 1801 01:18:11,560 --> 01:18:14,720 APPLICATION, VENEER, PROVIDING A 1802 01:18:14,720 --> 01:18:17,000 WAY TO ASSESS DATA. 1803 01:18:17,000 --> 01:18:19,520 IT USES EXPERIMENTAL DATA AND 1804 01:18:19,520 --> 01:18:21,440 CRITERIA TO CLASSIFY PROTEINS AS 1805 01:18:21,440 --> 01:18:23,120 SURFACE LOCALIZED. 1806 01:18:23,120 --> 01:18:25,920 BY HAVING DETAILS IN AN EASY 1807 01:18:25,920 --> 01:18:28,240 FORMAT WITH OUTPUT FROM MULTIPLE 1808 01:18:28,240 --> 01:18:30,600 TOOLS FOR CONTEXT THIS HELPS 1809 01:18:30,600 --> 01:18:32,440 USER HAVE CONFIDENCE THE 1810 01:18:32,440 --> 01:18:34,840 PROTEINS ARE REALLY COMING FROM 1811 01:18:34,840 --> 01:18:39,480 THE CELL SURFACE. 1812 01:18:39,480 --> 01:18:42,160 IT WILL FILTER, ANNOTATE AND 1813 01:18:42,160 --> 01:18:43,240 SUMMARIZE DATA, APPLICABLE TO 1814 01:18:43,240 --> 01:18:51,800 VARIETY OF METHODS DESCRIBED 1815 01:18:51,800 --> 01:18:54,920 THAT ENRICH GLYCOPEPTIDES, THIS 1816 01:18:54,920 --> 01:19:00,160 IS THE MOST SPECIFIC METHOD FOR 1817 01:19:00,160 --> 01:19:00,560 SURFACE PROTEINS. 1818 01:19:00,560 --> 01:19:01,800 IT'S AGNOSTIC OF MASS 1819 01:19:01,800 --> 01:19:03,400 SPECTROMETRY PLATFORM OR SEARCH 1820 01:19:03,400 --> 01:19:03,600 TOOLS. 1821 01:19:03,600 --> 01:19:05,480 WHATEVER TOOLS YOU HAVE 1822 01:19:05,480 --> 01:19:06,920 AVAILABLE ARE COMPATIBLE. 1823 01:19:06,920 --> 01:19:10,440 YOU CAN IMMEDIATELY SEE A 1824 01:19:10,440 --> 01:19:14,360 SNAPSHOT VIEW OF THE PROTEINS 1825 01:19:14,360 --> 01:19:16,280 AND BINDERS AND DOWNLOAD. 1826 01:19:16,280 --> 01:19:19,720 OUTPUT FILE DATA ARE CLASSIFIED 1827 01:19:19,720 --> 01:19:21,240 AS NON-SPECIFIC BINDERS, OR 1828 01:19:21,240 --> 01:19:22,440 SPECIFIC BINDERS, YOU CAN FIND 1829 01:19:22,440 --> 01:19:26,040 EACH CATEGORY IN A SEPARATE TAB, 1830 01:19:26,040 --> 01:19:27,960 NON-SPECIFIC BINDERS ARE 1831 01:19:27,960 --> 01:19:32,000 PROTEINS THAT WERE IDENTIFIED BY 1832 01:19:32,000 --> 01:19:36,960 PEPTIDES THAT DIDN'T CONTAIN 1833 01:19:36,960 --> 01:19:38,520 DEAMINATION IN SEQUENCE 1834 01:19:38,520 --> 01:19:39,640 MUTATION. 1835 01:19:39,640 --> 01:19:41,480 CANDIDATE SURFACE PROTEINS 1836 01:19:41,480 --> 01:19:45,960 CONTAIN PEPTIDES WITH 1837 01:19:45,960 --> 01:19:48,160 DEAMINATION IN SEQUENCE MOTIF 1838 01:19:48,160 --> 01:19:50,760 AND A SUBSET FIT EXTRA CRITERIA 1839 01:19:50,760 --> 01:19:53,720 INCLUDING THEY HAVE A SURFACE 1840 01:19:53,720 --> 01:19:56,040 SCORE INDICATING THAT THERE 1841 01:19:56,040 --> 01:19:56,920 SHOULD BE EXTRACELLULAR 1842 01:19:56,920 --> 01:19:58,840 GLYCOPEPTIDES OR THEY HAVE A 1843 01:19:58,840 --> 01:20:00,440 SURFACE PROTEIN CONSENSUS SCORE 1844 01:20:00,440 --> 01:20:03,960 GREATER THAN 2 INDICATING THEY 1845 01:20:03,960 --> 01:20:07,440 HAVE BEEN PREDICTED OR CONTAIN 1846 01:20:07,440 --> 01:20:09,400 PREDICTED PEPTIDE. 1847 01:20:09,400 --> 01:20:11,680 THE JUSTIFICATION, THERE'S NO 1848 01:20:11,680 --> 01:20:12,320 PREDICTION ALGORITHM THAT'S 1849 01:20:12,320 --> 01:20:17,120 PERFECT SO IF A PROTEIN SLIPS 1850 01:20:17,120 --> 01:20:18,480 THROUGH FOR ONE, LIKELY CAUGHT 1851 01:20:18,480 --> 01:20:20,360 BY ANOTHER. 1852 01:20:20,360 --> 01:20:22,120 ALL THE DATA CAN DECIDE HOW THEY 1853 01:20:22,120 --> 01:20:24,720 WANT TO USE DATA BASED ON CLEAR 1854 01:20:24,720 --> 01:20:25,800 EVIDENCE. 1855 01:20:25,800 --> 01:20:27,520 SO TO AVOID HAVING TO QUERY 1856 01:20:27,520 --> 01:20:29,480 REPOSITORIES ONCE YOU HAVE YOUR 1857 01:20:29,480 --> 01:20:33,200 DATABASE, YOUR LIST OF PROTEINS 1858 01:20:33,200 --> 01:20:35,960 IDENTIFIED VENEER ANNOTATES 1859 01:20:35,960 --> 01:20:37,520 EVERY ENTRY WITH INFORMATION 1860 01:20:37,520 --> 01:20:40,400 FROM A DOZEN RESOURCES RELEVANT 1861 01:20:40,400 --> 01:20:42,640 FOR CELL SURFACE PROTEINS. 1862 01:20:42,640 --> 01:20:44,080 ALL OF THE CURATION, ANNOTATION 1863 01:20:44,080 --> 01:21:01,520 AND OUTPUT ARE STANDARDIZED. 1864 01:21:01,520 --> 01:21:14,160 A TSV FILE IS FORM ATED. 1865 01:21:14,160 --> 01:21:17,920 VENEER PROVIDES STANDARDIZING 1866 01:21:17,920 --> 01:21:18,320 AND PROCESSING. 1867 01:21:18,320 --> 01:21:19,120 FINALLY SURFACE GENIE. 1868 01:21:19,120 --> 01:21:21,520 ONCE YOU GENERATE A LIST OF 1869 01:21:21,520 --> 01:21:25,320 PROTEINS IT CAN BE CHALLENGING 1870 01:21:25,320 --> 01:21:28,320 TO PRIORITIZE WHICH PROTEINS TO 1871 01:21:28,320 --> 01:21:29,320 PURSUE. 1872 01:21:29,320 --> 01:21:29,960 SOMETIMES DEPENDING ON THE 1873 01:21:29,960 --> 01:21:31,320 SAMPLES YOU'RE INTERESTED IN YOU 1874 01:21:31,320 --> 01:21:35,760 MIGHT NOT BE ABLE TO DO A 1875 01:21:35,760 --> 01:21:36,400 SURFACE PROTEOMIC EXPERIMENT BUT 1876 01:21:36,400 --> 01:21:40,320 WANT TO USE DATA TO PREDICT 1877 01:21:40,320 --> 01:21:41,320 USEFUL SURFACE MARKERS. 1878 01:21:41,320 --> 01:21:43,400 SO THIS PROVIDES A SOLUTION TO 1879 01:21:43,400 --> 01:21:45,480 CHALLENGES BY COMBINING A RAPID 1880 01:21:45,480 --> 01:21:47,320 WAY TO PRIORITIZE BASED ON 1881 01:21:47,320 --> 01:21:50,480 SIGNAL DISPARITY AND BECAUSE IT 1882 01:21:50,480 --> 01:21:51,040 INTEGRATES CONSENSUS BASED 1883 01:21:51,040 --> 01:21:53,240 PREDICTION OF LOCATION, CAN ALSO 1884 01:21:53,240 --> 01:21:55,360 BE USED TO RANK ORDER CANDIDATES 1885 01:21:55,360 --> 01:21:59,840 STARTING WITH DATA THAT DOES NOT 1886 01:21:59,840 --> 01:22:04,400 PROVIDE EVIDENCE OF LOCATION. 1887 01:22:04,400 --> 01:22:07,680 IT TAKES A LARGE DATASET, 1888 01:22:07,680 --> 01:22:08,920 PRIORITIZING MOLECULES AND GIVES 1889 01:22:08,920 --> 01:22:11,800 INDEX WHETHER IT'S LIKELY TO BE 1890 01:22:11,800 --> 01:22:22,680 A SURFACE PROTEIN. 1891 01:22:22,680 --> 01:22:25,800 OTHER PERMUTATIONS. 1892 01:22:25,800 --> 01:22:32,880 USER CAN SELECT A SCORING. 1893 01:22:32,880 --> 01:22:34,640 YOU COULD USE OMNIGENIE, OR IF 1894 01:22:34,640 --> 01:22:38,040 YOU USE mRNA OR GLOBAL 1895 01:22:38,040 --> 01:22:41,200 PROTEOMICS, YOU USE THE 1896 01:22:41,200 --> 01:22:41,720 GENIESCORE. 1897 01:22:41,720 --> 01:22:42,680 SO, THE VISUALS SHOW 1898 01:22:42,680 --> 01:22:44,000 DISTRIBUTION OF PROTEINS THAT 1899 01:22:44,000 --> 01:22:46,880 HAVE BEEN PREVIOUSLY PREDICTED 1900 01:22:46,880 --> 01:22:49,560 TO BE SURFACE LOCALIZED AMONG 1901 01:22:49,560 --> 01:22:51,080 FOUR PREDICTION ALGORITHMS OR 1902 01:22:51,080 --> 01:22:53,320 PUBLICATIONS, THE GRAPH SHOWS 1903 01:22:53,320 --> 01:22:54,560 RANK ORDER PRIORITIZATION OF 1904 01:22:54,560 --> 01:22:56,080 PROTEINS IN THE DATASET BASED ON 1905 01:22:56,080 --> 01:22:57,760 SCORING OPTIONS SELECTED. 1906 01:22:57,760 --> 01:22:59,560 HIGHEST RANK ARE THOSE PROTEINS 1907 01:22:59,560 --> 01:23:01,720 THAT ARE MOST DISTINCT BETWEEN 1908 01:23:01,720 --> 01:23:04,560 THE DATASETS, THIS COULD BE 1909 01:23:04,560 --> 01:23:09,720 BETWEEN CELL TYPES OR 1910 01:23:09,720 --> 01:23:10,920 BIOLOGICAL CONDITIONS, 1911 01:23:10,920 --> 01:23:15,920 DOWNLOADED FOR FURTHER ANALYSIS. 1912 01:23:15,920 --> 01:23:18,680 SURFACEGENIE IS THE TOOL WE USE. 1913 01:23:18,680 --> 01:23:22,040 THESE TOOLS ARE FREELY AVAILABLE 1914 01:23:22,040 --> 01:23:26,040 AS EASY TO USE WEB APPLICATIONS, 1915 01:23:26,040 --> 01:23:28,520 ALL SOURCE CODE IS AVAILABLE ON 1916 01:23:28,520 --> 01:23:28,840 GITHUB. 1917 01:23:28,840 --> 01:23:31,240 NOW I'M GOING TO SHOW EXAMPLES 1918 01:23:31,240 --> 01:23:33,800 OF HOW WE'VE APPLIED TOOLS TO 1919 01:23:33,800 --> 01:23:36,880 EVALUATE A NEW SURFACE PROTEIN 1920 01:23:36,880 --> 01:23:37,520 CAPTURE METHODOLOGY AND 1921 01:23:37,520 --> 01:23:39,200 DEMONSTRATE WHY WE BELIEVE 1922 01:23:39,200 --> 01:23:40,400 EXPERIMENTAL EVIDENCE IS 1923 01:23:40,400 --> 01:23:45,080 CRITICAL FOR SURFACE PROTEIN 1924 01:23:45,080 --> 01:23:45,880 MAPPING. 1925 01:23:45,880 --> 01:23:47,960 MAJOR FOCUS INVOLVES STUDYING 1926 01:23:47,960 --> 01:23:49,440 MOLECULAR AND CELLULAR EVENTS IN 1927 01:23:49,440 --> 01:23:52,120 PROGRESSION OF HEART FAILURE. 1928 01:23:52,120 --> 01:23:56,000 WE WORKED WITH HUMAN SAMPLES, 1929 01:23:56,000 --> 01:23:58,960 WITH SPECIAL REQUIREMENTS. 1930 01:23:58,960 --> 01:24:05,320 SO ADULT HUMAN CARDIAC MYOCYTES 1931 01:24:05,320 --> 01:24:07,240 DO NOT PROLIFERATE IN CULTURE 1932 01:24:07,240 --> 01:24:08,480 AND WE CAN'T USE METABOLIC 1933 01:24:08,480 --> 01:24:09,680 LABELS STRATEGIES, ONLY HAVE A 1934 01:24:09,680 --> 01:24:14,440 LIMITED AMOUNT OF SAMPLE 1935 01:24:14,440 --> 01:24:15,000 AVAILABLE. 1936 01:24:15,000 --> 01:24:19,320 CLASSIC METHODS ARE NOT 1937 01:24:19,320 --> 01:24:20,320 APPLICABLE. 1938 01:24:20,320 --> 01:24:25,080 TO IDENTIFYs FROM CELLS WE 1939 01:24:25,080 --> 01:24:26,400 ISOLATE, REENGINEERED A METHOD 1940 01:24:26,400 --> 01:24:28,280 FROM A DECADE AGO, TAKING 1941 01:24:28,280 --> 01:24:35,240 ADVANTAGE OF THE FACT MOST ARE 1942 01:24:35,240 --> 01:24:35,800 GLYCOSYLATED. 1943 01:24:35,800 --> 01:24:45,600 GLYCAN STRUCTURES ARE 1944 01:24:45,600 --> 01:24:47,320 BIATENYLATED, RELEASED, AND 1945 01:24:47,320 --> 01:24:49,560 IDENTIFIED BY MASS SPECTROMETRY. 1946 01:24:49,560 --> 01:24:53,920 WE USE UPDATED CHEMISTRY AND 1947 01:24:53,920 --> 01:24:57,920 FULLY AUTOMATED SYSTEM, APPLYING 1948 01:24:57,920 --> 01:25:01,880 THE METHOD TO IDENTIFY FROM A 1949 01:25:01,880 --> 01:25:04,920 FEW HUNDRED THOUSAND CELLS. 1950 01:25:04,920 --> 01:25:06,200 THIS METHOD WORKS WELL FOR A 1951 01:25:06,200 --> 01:25:12,480 RANGE OF CELL TIMES. 1952 01:25:12,480 --> 01:25:13,640 WE'RE DETECTING 3 TO 700 1953 01:25:13,640 --> 01:25:15,920 PROTEINS IN A SINGLE EXPERIMENT 1954 01:25:15,920 --> 01:25:17,360 WITH GREATER THAN 80% 1955 01:25:17,360 --> 01:25:19,120 SPECIFICITY OF CAPTURE EVERY 1956 01:25:19,120 --> 01:25:19,320 TIME. 1957 01:25:19,320 --> 01:25:22,320 VENEER IS WHAT WE USE TO 1958 01:25:22,320 --> 01:25:23,840 EVALUATE IN A CONSISTENT WAY TO 1959 01:25:23,840 --> 01:25:26,520 CALCULATE THE NUMBER OF PROTEINS 1960 01:25:26,520 --> 01:25:27,080 AND SPECIFICITY. 1961 01:25:27,080 --> 01:25:29,320 THE APPROACH IS WORKING WELL FOR 1962 01:25:29,320 --> 01:25:31,760 SAMPLE SIZES THAT WE EXPECT TO 1963 01:25:31,760 --> 01:25:33,320 OBTAIN FROM HUMAN HEARTS. 1964 01:25:33,320 --> 01:25:37,320 TO PUT THE RESULTS IN CONTEXT OF 1965 01:25:37,320 --> 01:25:38,280 PERFORMANCE OF PREVIOUS METHODS, 1966 01:25:38,280 --> 01:25:42,240 WE USE VENEER TO REANALYZE 282 1967 01:25:42,240 --> 01:25:44,600 FILES FROM STUDIES THAT ALSO USE 1968 01:25:44,600 --> 01:25:45,600 GLYCOCAPTURE METHOD. 1969 01:25:45,600 --> 01:25:47,080 YOU CAN SEE THAT THERE IS QUITE 1970 01:25:47,080 --> 01:25:52,920 A LOT OF VARIABILITY IN THE 1971 01:25:52,920 --> 01:25:53,680 SPECIFICITY. 1972 01:25:53,680 --> 01:25:55,440 SOME ARE NEAR 80% SPECIFICITY, 1973 01:25:55,440 --> 01:26:01,480 MINIMUM WE SEE IN A MICRO SCALE 1974 01:26:01,480 --> 01:26:02,800 EXPERIMENT MANY ARE BELOW 50%. 1975 01:26:02,800 --> 01:26:06,760 THE SAME CRITERIA ARE APPLIED TO 1976 01:26:06,760 --> 01:26:08,040 EACH DATASET. 1977 01:26:08,040 --> 01:26:09,840 TO ILLUSTRATE HOW IT'S HELPFUL, 1978 01:26:09,840 --> 01:26:12,520 I'LL SHOW A CLOSER LOOK AT TWO 1979 01:26:12,520 --> 01:26:16,000 STUDIES, BOTH RELIED ON GENE 1980 01:26:16,000 --> 01:26:19,520 ONTOLOGY INSTEAD OF EXPERIMENTAL 1981 01:26:19,520 --> 01:26:21,760 EVIDENCE TO ANNOTATE RESULTS. 1982 01:26:21,760 --> 01:26:24,760 THE REPORT FOR SURFACE PROTEINS 1983 01:26:24,760 --> 01:26:28,840 WAS 67%, WITH REANALYSIS THAT 1984 01:26:28,840 --> 01:26:29,040 DROPS. 1985 01:26:29,040 --> 01:26:30,320 CLOSER INSPECTION REVEALS SOME 1986 01:26:30,320 --> 01:26:32,080 PROTEINS REPORTED TO BE SURFACE 1987 01:26:32,080 --> 01:26:38,040 LOCAL ITSED BASED ON AN 1988 01:26:38,040 --> 01:26:40,000 VACCINATION INCLUDE ACTINOMYCIN. 1989 01:26:40,000 --> 01:26:42,920 IN THE NEXT EXAMPLE, THEY 1990 01:26:42,920 --> 01:26:44,400 CAPTURED WITH 78% SPECIFICITY 1991 01:26:44,400 --> 01:26:46,440 BUT VENEER CAN FIND EXPERIMENTAL 1992 01:26:46,440 --> 01:26:50,560 EVIDENCE FOR SURFACE 1993 01:26:50,560 --> 01:26:53,520 LOCALIZATION FOR 29%, USED TO 1994 01:26:53,520 --> 01:26:55,440 RAPIDLY EXTRACT EXPERIMENTAL 1995 01:26:55,440 --> 01:26:56,400 EVIDENCE OF SURFACE 1996 01:26:56,400 --> 01:27:00,320 LOCALIZATION, CONFIDENCE TO 1997 01:27:00,320 --> 01:27:01,960 PROTEINS NOT FULLY 1998 01:27:01,960 --> 01:27:02,320 CHARACTERIZED. 1999 01:27:02,320 --> 01:27:06,440 HOW DO YOU CONFIRM IT IS 2000 01:27:06,440 --> 01:27:08,040 WORKING? 2001 01:27:08,040 --> 01:27:11,960 WE APPLIED CELLSURFER PLATFORM, 2002 01:27:11,960 --> 01:27:13,000 COMBINATION WITH BIOINFORMATICS 2003 01:27:13,000 --> 01:27:15,400 TOOL APPLIED TO FOUR PRIMARY 2004 01:27:15,400 --> 01:27:16,920 HUMAN CARDIAC CELL TYPES 2005 01:27:16,920 --> 01:27:19,640 ISOLATED FROM HUMAN HEART. 2006 01:27:19,640 --> 01:27:21,920 WE'VE IDENTIFIED MORE THAN 1100 2007 01:27:21,920 --> 01:27:27,760 CELL SURFACE N GLYCOPROTEINS. 2008 01:27:27,760 --> 01:27:34,000 THIS ALLOWS TO SEE WHY 2009 01:27:34,000 --> 01:27:38,480 PREDICTIONS ARE NOT ENOUGH. 2010 01:27:38,480 --> 01:27:40,120 WE IDENTIFIED, HAVE EXPERIMENTAL 2011 01:27:40,120 --> 01:27:46,720 DATA FOR 30 THAT CONFLICT WITH 2012 01:27:46,720 --> 01:27:57,400 PREDICTED, 66 NOT PREDICTED TO 2013 01:27:57,400 --> 01:28:01,760 BE GLYCOSYLATED, 155 NOT 2014 01:28:01,760 --> 01:28:03,040 DETECTED IN RNAseq ANALYSES, 2015 01:28:03,040 --> 01:28:08,080 AND 429 NOT IN A RECENTLY 2016 01:28:08,080 --> 01:28:09,040 DESCRIBED PREDICTED HUMAN 2017 01:28:09,040 --> 01:28:10,720 SURFACE OME, WHY EXPERIMENTAL 2018 01:28:10,720 --> 01:28:14,320 DATA ARE SO IMPORTANT AND 2019 01:28:14,320 --> 01:28:15,680 DESPITE MODERN SEQUENCING 2020 01:28:15,680 --> 01:28:20,280 TECHNOLOGIES NOTHING COMPARES TO 2021 01:28:20,280 --> 01:28:22,000 AN ACTUAL EXPERIMENT. 2022 01:28:22,000 --> 01:28:24,440 WE IDENTIFIED A PROTEIN WE'VE 2023 01:28:24,440 --> 01:28:28,520 PREVIOUSLY ONLY OBSERVED IN 2024 01:28:28,520 --> 01:28:29,840 PRIMARY CARDIOMYOCYTES, WE HAVE 2025 01:28:29,840 --> 01:28:31,640 DATA FOR MORE THAN 90 HUMAN CELL 2026 01:28:31,640 --> 01:28:32,480 TYPES. 2027 01:28:32,480 --> 01:28:35,080 THIS IS A PROTEIN, NO 2028 01:28:35,080 --> 01:28:36,040 PUBLICATIONS, NO KNOWN FUNCTION, 2029 01:28:36,040 --> 01:28:40,920 NO PREVIOUS OBSERVATION IN THE 2030 01:28:40,920 --> 01:28:45,080 HEART. 2031 01:28:45,080 --> 01:28:48,400 ON ASKING MICRO SCALE CSE, WE 2032 01:28:48,400 --> 01:28:51,240 IDENTIFIED ALL FOUR REGIONS, 2033 01:28:51,240 --> 01:28:55,840 LOOK AT THIS PROTEIN SEQUENCE 2034 01:28:55,840 --> 01:28:57,360 USING CIRFESS, THEY PROVIDE 2035 01:28:57,360 --> 01:29:01,040 DIFFERENT RESULTS AND MAY 2036 01:29:01,040 --> 01:29:05,520 EXPLAIN WHY WHY OUR DATA 2037 01:29:05,520 --> 01:29:05,760 CONFLICTS. 2038 01:29:05,760 --> 01:29:07,520 WE USE THAT INFORMATION TO 2039 01:29:07,520 --> 01:29:09,320 DEVELOP NEW MONOCLONAL ANTIBODY 2040 01:29:09,320 --> 01:29:10,920 FOR EXTRACELLULAR REGION OF THE 2041 01:29:10,920 --> 01:29:11,120 PROTEIN. 2042 01:29:11,120 --> 01:29:13,480 THESE ANTIBODIES ARE USED FOR 2043 01:29:13,480 --> 01:29:15,320 IMAGING HEART TISSUE, SEEING 2044 01:29:15,320 --> 01:29:18,960 PROTEIN CO-LOCALIZED WITH CELLS 2045 01:29:18,960 --> 01:29:20,040 THAT EXPRESS CARDIOMYOCYTE 2046 01:29:20,040 --> 01:29:22,120 MARKER TROPONIN AND SHOW THE 2047 01:29:22,120 --> 01:29:23,800 PROTEIN IS ALONG THE MEMBRANE, 2048 01:29:23,800 --> 01:29:25,320 CO-LOCALIZES WITH KNOWN ION 2049 01:29:25,320 --> 01:29:30,120 CHANNELS WHICH I'M SHOWING HERE. 2050 01:29:30,120 --> 01:29:32,080 WHEN BROWSING RESOURCES TO SEE 2051 01:29:32,080 --> 01:29:34,080 WHAT'S KNOWN WE FOUND THE HUMAN 2052 01:29:34,080 --> 01:29:37,080 PROTEIN ATLAS DOES NOT PREDICT 2053 01:29:37,080 --> 01:29:44,200 THIS TO BE A PLASMA MEMBRANE 2054 01:29:44,200 --> 01:29:44,480 PROTEIN. 2055 01:29:44,480 --> 01:29:46,400 THESE ARE ALL CELL LINES THAT 2056 01:29:46,400 --> 01:29:49,560 OUR LAB AND THREE OTHERS HAVE 2057 01:29:49,560 --> 01:29:51,040 MAPPED USING CELL SURFACE 2058 01:29:51,040 --> 01:29:52,440 PROTEOMICS AND NEVER FOUND THE 2059 01:29:52,440 --> 01:29:54,720 PROTEIN IN THE CELL TYPES. 2060 01:29:54,720 --> 01:29:56,960 WHEN USE OUR MONOCLONAL ANTIBODY 2061 01:29:56,960 --> 01:29:58,880 WE DO NOT FIND EVIDENCE OF 2062 01:29:58,880 --> 01:30:03,440 PROTEIN IN CELL LINES AND 2063 01:30:03,440 --> 01:30:05,840 MOREOVER USING A TARGETED MASS 2064 01:30:05,840 --> 01:30:06,600 SPECTROMETRY DO NOT SEE THE 2065 01:30:06,600 --> 01:30:09,840 PROTEIN POINTING TO THE NEED FOR 2066 01:30:09,840 --> 01:30:12,720 CONTINUING VIGILANCE RELYING ON 2067 01:30:12,720 --> 01:30:15,480 PREDICTIONS WITH ANTIBODY-BASED 2068 01:30:15,480 --> 01:30:17,120 EVIDENCE FOR SURFACE PROTEIN 2069 01:30:17,120 --> 01:30:17,720 LOCALIZATION. 2070 01:30:17,720 --> 01:30:21,440 IF WE RELIED ONLY ON GENE 2071 01:30:21,440 --> 01:30:23,720 ONTOLOGY AND DATABASE WOULD HAVE 2072 01:30:23,720 --> 01:30:31,840 NEVER SELECTED THIS PROTEIN, 2073 01:30:31,840 --> 01:30:33,920 HELP US TO NOT OVERLOOK THE 2074 01:30:33,920 --> 01:30:36,080 PROTEIN OF INTEREST BECAUSE OUR 2075 01:30:36,080 --> 01:30:37,760 MOST RECENT EXPERIMENTS REVEALED 2076 01:30:37,760 --> 01:30:40,200 THIS DOES DECREASE IN ABUNDANCE 2077 01:30:40,200 --> 01:30:41,200 IN CARDIOMYOCYTES IN THE FAILING 2078 01:30:41,200 --> 01:30:41,400 HEART. 2079 01:30:41,400 --> 01:30:45,480 WE'RE GLAD WE HAVE ANTIBODIES 2080 01:30:45,480 --> 01:30:46,360 FOR NEXT-STEP STUDIES. 2081 01:30:46,360 --> 01:30:53,440 WE STARTED WITH A LIST OF 526 2082 01:30:53,440 --> 01:30:57,240 PROTEINS, AND COMPARING FROM 2083 01:30:57,240 --> 01:30:58,680 FAILING TO NON-FAILING HEARTS 2084 01:30:58,680 --> 01:31:00,080 AND PRIORITIZED PROTEINS OF 2085 01:31:00,080 --> 01:31:01,720 INTEREST FOR FUTURE STUDIES 2086 01:31:01,720 --> 01:31:04,440 SHOWING RANK ORDER BASED ON OMNI 2087 01:31:04,440 --> 01:31:05,720 GENIE SCORE FROM SURFACE GENIE 2088 01:31:05,720 --> 01:31:08,920 AND CORRESPONDING DO THE PLOTS 2089 01:31:08,920 --> 01:31:12,080 OF THOSE DIFFERENT BETWEEN 2090 01:31:12,080 --> 01:31:14,200 CARDIOMYOCYTES FROM FAILING AND 2091 01:31:14,200 --> 01:31:15,160 NON-FAILING HEARTS. 2092 01:31:15,160 --> 01:31:16,920 CHALLENGES INCLUDE LACK OF 2093 01:31:16,920 --> 01:31:19,280 STANDARDIZED ANALYSIS METHODS 2094 01:31:19,280 --> 01:31:23,920 WHICH MAKE IT CHALLENGING TO 2095 01:31:23,920 --> 01:31:26,880 GAIN CONFIDENCE. 2096 01:31:26,880 --> 01:31:31,200 WE'VE IDENTIFIED THREE TOOLS. 2097 01:31:31,200 --> 01:31:34,280 WHEN WE COMBINE WITH TECHNOLOGY 2098 01:31:34,280 --> 01:31:36,280 WE HAD RAPID STRATEGY FOR 2099 01:31:36,280 --> 01:31:38,880 AUTOMATED MAPPING APPLICABLE TO 2100 01:31:38,880 --> 01:31:41,640 NEARLY ANY HUMAN PRIMARY CELL 2101 01:31:41,640 --> 01:31:41,840 TYPE. 2102 01:31:41,840 --> 01:31:42,800 ONTOLOGY AND ANNOTATIONS ARE 2103 01:31:42,800 --> 01:31:44,720 VALUABLE, THEY ARE NOT ALWAYS 2104 01:31:44,720 --> 01:31:45,120 ENOUGH. 2105 01:31:45,120 --> 01:31:46,520 HAVING METHODS THAT GIVE ENDENS 2106 01:31:46,520 --> 01:31:54,040 OF LOCATION COMBINED WITH TOOLS 2107 01:31:54,040 --> 01:31:56,280 CAN HELP UNCOVER NAVIGATION, 2108 01:31:56,280 --> 01:32:02,160 APPLICABLE TO ANY HUMAN CELL 2109 01:32:02,160 --> 01:32:07,480 TYPE. 2110 01:32:07,480 --> 01:32:09,520 FINALLY MICRO SCALE AND VENEER 2111 01:32:09,520 --> 01:32:12,160 ARE LIMITED, WE LOOK FORWARD TO 2112 01:32:12,160 --> 01:32:15,960 NEW TOOLS TO INCLUDE INTACT 2113 01:32:15,960 --> 01:32:19,320 PROTEINS, AND NON-GLYCOSYLATED 2114 01:32:19,320 --> 01:32:19,560 PROTEINS. 2115 01:32:19,560 --> 01:32:24,320 EACH WERE DEVELOPED IN A 2116 01:32:24,320 --> 01:32:24,680 COLLABORATION. 2117 01:32:24,680 --> 01:32:27,080 I WANT TO ACKNOWLEDGE AMAZING 2118 01:32:27,080 --> 01:32:29,240 LAB MEMBERS AND THANKS TO MIKE 2119 01:32:29,240 --> 01:32:30,320 AND THE ORGANIZATION COMMITTEE 2120 01:32:30,320 --> 01:32:33,640 FOR THE INVITE TO PRESENT TODAY. 2121 01:32:33,640 --> 01:32:37,000 THANK YOU FOR ATTENDING. 2122 01:32:37,000 --> 01:32:38,480 >> THANK YOU, REBEKAH. 2123 01:32:38,480 --> 01:32:43,200 REBEKAH WILL BE ABLE TO ANSWER 2124 01:32:43,200 --> 01:32:44,720 QUESTIONS IN 40 MINUTES, DURING 2125 01:32:44,720 --> 01:32:47,720 THE PANEL DISCUSSION. 2126 01:32:47,720 --> 01:32:52,480 SEND YOUR QUESTIONS TO SEND LIVE 2127 01:32:52,480 --> 01:32:52,720 FEEDBACK. 2128 01:32:52,720 --> 01:32:56,040 NEXT IS DR. BRIAN HAAB FROM VAN 2129 01:32:56,040 --> 01:33:01,280 ANDEL INSTITUTE TALKING ABOUT A 2130 01:33:01,280 --> 01:33:02,120 UNIFIED APPROACH FOR GLYCAN 2131 01:33:02,120 --> 01:33:04,120 ARRAY DATA. 2132 01:33:04,120 --> 01:33:05,440 >> THANKS FOR THE OPPORTUNITY TO 2133 01:33:05,440 --> 01:33:08,120 SPEAK TODAY AND PRESENT THIS 2134 01:33:08,120 --> 01:33:08,320 WORK. 2135 01:33:08,320 --> 01:33:11,400 I'D LIKE TO TELL YOU ABOUT A 2136 01:33:11,400 --> 01:33:13,720 UNIFIED APPROACH AND TOOL SYSTEM 2137 01:33:13,720 --> 01:33:15,960 FOR HANDLING GLYCAN ARRAY DATA 2138 01:33:15,960 --> 01:33:20,000 FROM ANY PLATFORM IN ORDER TO 2139 01:33:20,000 --> 01:33:21,360 ANALYZE, USE, ACCESS THE GLYCAN 2140 01:33:21,360 --> 01:33:22,800 ARRAY DATA. 2141 01:33:22,800 --> 01:33:25,560 I WANT TO ACKNOWLEDGE -- I CAN 2142 01:33:25,560 --> 01:33:27,080 SHARE MY SCREEN, BY THE WAY. 2143 01:33:27,080 --> 01:33:30,520 LET ME TURN ON MY VIDEO SO YOU 2144 01:33:30,520 --> 01:33:31,440 CAN SEE ME. 2145 01:33:31,440 --> 01:33:32,600 JUST A SEC HERE. 2146 01:33:32,600 --> 01:33:35,480 I GUESS YOU CAN SEE ME THERE. 2147 01:33:35,480 --> 01:33:38,720 SO, I REALLY WANT TO ACKNOWLEDGE 2148 01:33:38,720 --> 01:33:41,800 ZACHARY, THE SCIENTIST AND 2149 01:33:41,800 --> 01:33:43,520 DEVELOPER, RESPONSIBLE FOR 2150 01:33:43,520 --> 01:33:45,840 BUILDING THIS AND DESIGNING THE 2151 01:33:45,840 --> 01:33:48,680 SCIENCE SO MUCH OF IT BEHIND IT 2152 01:33:48,680 --> 01:33:49,200 ALL. 2153 01:33:49,200 --> 01:33:51,840 SO, I'M PRESENTING THE TALK BUT 2154 01:33:51,840 --> 01:33:53,240 HE'S ONLINE RIGHT NOW AND WILL 2155 01:33:53,240 --> 01:33:57,680 BE AVAILABLE DURING THE PANEL 2156 01:33:57,680 --> 01:34:01,720 DISCUSSION AS WELL. 2157 01:34:01,720 --> 01:34:03,880 THIS WAS MOTIVATED -- I ADVANCE 2158 01:34:03,880 --> 01:34:11,720 USING -- OH, THE POINTER, OKAY. 2159 01:34:11,720 --> 01:34:14,440 HUGE INCREASE IN VOLUME AND 2160 01:34:14,440 --> 01:34:16,600 DIVERSITY OF GLYCAN ARRAY DATA. 2161 01:34:16,600 --> 01:34:18,880 THIS TIMELINE SHOWS THE 2162 01:34:18,880 --> 01:34:20,760 INTRODUCTION OF BRAND NEW 2163 01:34:20,760 --> 01:34:21,720 SYSTEMS, NOT JUST PUBLICATIONS 2164 01:34:21,720 --> 01:34:22,720 BUT BRAND NEW SYSTEMS. 2165 01:34:22,720 --> 01:34:24,960 YOU CAN SEE IN THE LAST FIVE OR 2166 01:34:24,960 --> 01:34:26,720 SIX YEARS THERE'S BEEN INCREASE 2167 01:34:26,720 --> 01:34:29,680 IN RATE OF NEW TYPES OF THINGS 2168 01:34:29,680 --> 01:34:30,160 COMING OUT. 2169 01:34:30,160 --> 01:34:33,760 FOR A LONG TIME SINCE THE EARLY 2170 01:34:33,760 --> 01:34:36,480 INTRODUCTION, EARLY DAYS OF 2171 01:34:36,480 --> 01:34:39,200 INTRODUCTION OF THE GLYCAN 2172 01:34:39,200 --> 01:34:39,720 ARRAY, EXPERIMENTS WERE 2173 01:34:39,720 --> 01:34:44,080 GENERALLY DONE THROUGH THE CFG 2174 01:34:44,080 --> 01:34:47,320 ARRAY, A GREAT PLATFORM, GENERAL 2175 01:34:47,320 --> 01:34:48,720 PLATFORM FOCUSING ON MAMMALIAN 2176 01:34:48,720 --> 01:34:52,080 BIOLOGY PRIMARILY BUT WORKED 2177 01:34:52,080 --> 01:34:53,320 VERY WELL. 2178 01:34:53,320 --> 01:34:55,640 THE MAIN VALUE, ONE OF THE HUGE 2179 01:34:55,640 --> 01:35:00,040 OUTCOMES OF THE CFG ARRAY WAS TO 2180 01:35:00,040 --> 01:35:00,840 ESTABLISH IN THE GLYCOBIOLOGY 2181 01:35:00,840 --> 01:35:03,920 COMMUNITY THIS WAS A POWERFUL 2182 01:35:03,920 --> 01:35:06,080 USEFUL PLATFORM. 2183 01:35:06,080 --> 01:35:07,720 IT STIMULATED DEVELOPMENT OF A 2184 01:35:07,720 --> 01:35:09,520 LOT OF BIOINFORMATICS TOOLS THAT 2185 01:35:09,520 --> 01:35:13,320 MADE USE OF THE HUGE AMOUNT OF 2186 01:35:13,320 --> 01:35:15,040 DATA THAT WERE MADE PUBLICLY 2187 01:35:15,040 --> 01:35:19,400 AVAILABLE, A VERY WIDELY HEAVILY 2188 01:35:19,400 --> 01:35:20,600 USED SUCCESSFUL TOOL. 2189 01:35:20,600 --> 01:35:28,120 BUT NO AARRAY WITH MEET THE 2190 01:35:28,120 --> 01:35:32,920 NEEDS OF EVERY PROJECT. 2191 01:35:32,920 --> 01:35:34,920 OTHER RESEARCHERS STARTED 2192 01:35:34,920 --> 01:35:38,080 DESIGNING THEIR OWN SYSTEMS FOR 2193 01:35:38,080 --> 01:35:39,840 COMPLEMENTING THE TECHNOLOGY OF 2194 01:35:39,840 --> 01:35:41,280 THE CFG ARRAY AND DESIGNING 2195 01:35:41,280 --> 01:35:49,760 CONTINUE -- CONTENT TO ASK 2196 01:35:49,760 --> 01:35:52,200 SPECIFIC QUESTIONS, SIALIC ACID 2197 01:35:52,200 --> 01:35:54,360 BIOLOGY, PLANT BIOLOGY, 2198 01:35:54,360 --> 01:35:55,240 STIMULATED BY DEVELOPMENT IN 2199 01:35:55,240 --> 01:36:03,520 SYNTHESIS OF GLYCANS THAT MOVED 2200 01:36:03,520 --> 01:36:16,600 THINGS ALONG MUCH FASTER. 2201 01:36:16,600 --> 01:36:21,920 OTHER TYPES OF TECHNOLOGIES 2202 01:36:21,920 --> 01:36:23,480 USING DNA SEQUENCING, MASS 2203 01:36:23,480 --> 01:36:26,040 SPECTROMETRY READOUTS, ANOTHER 2204 01:36:26,040 --> 01:36:28,240 BASED ON DNA SEQUENCING READOUT. 2205 01:36:28,240 --> 01:36:33,800 AND THEN THE GLYCANS COVER A 2206 01:36:33,800 --> 01:36:36,600 WIDE RANGE OF CONTENT. 2207 01:36:36,600 --> 01:36:42,320 WE HAVE CELL WALL ARRAY, A WIDE 2208 01:36:42,320 --> 01:36:46,000 VARIETY OF CONTENT NOW COVERING 2209 01:36:46,000 --> 01:36:49,200 GLYCANS, OLIGO MANNOSE, SO 2210 01:36:49,200 --> 01:36:49,760 FORTH. 2211 01:36:49,760 --> 01:37:02,160 THERE'S A HUGE INCREASE IN ARRAY 2212 01:37:02,160 --> 01:37:02,880 TYPES AND CONTENT. 2213 01:37:02,880 --> 01:37:06,160 THIS BRINGS TOGETHER A PICTURE 2214 01:37:06,160 --> 01:37:07,920 OF GLYCAN-BINDING PROTEINS, 2215 01:37:07,920 --> 01:37:11,080 GETTING BETTER PICTURE OF 2216 01:37:11,080 --> 01:37:13,440 SPECIFICITY, WIDER AVAILABILITY, 2217 01:37:13,440 --> 01:37:16,040 ALSO OF A CHALLENGE TO HANDLE 2218 01:37:16,040 --> 01:37:18,560 THIS TYPE OF DIVERSITY AND 2219 01:37:18,560 --> 01:37:19,000 ARRAYS. 2220 01:37:19,000 --> 01:37:22,120 WE NEED A COMMON MODE OF 2221 01:37:22,120 --> 01:37:23,720 ANALYZING THESE DIFFERENT TYPES 2222 01:37:23,720 --> 01:37:25,640 OF ARRAYS. 2223 01:37:25,640 --> 01:37:28,320 WE ALSO NEED COMMON MODE OF 2224 01:37:28,320 --> 01:37:31,120 OUTPUT WHICH THEN CAN INTEGRATE 2225 01:37:31,120 --> 01:37:32,480 THE ACCESS AND ANALYSIS. 2226 01:37:32,480 --> 01:37:35,480 SO, I WANT TO TELL YOU ABOUT 2227 01:37:35,480 --> 01:37:37,440 THESE THREE TOPICS HERE. 2228 01:37:37,440 --> 01:37:38,360 ANALYZING VARIOUS GLYCAN ARRAYS, 2229 01:37:38,360 --> 01:37:41,560 HOW DO WE DO THAT? 2230 01:37:41,560 --> 01:37:43,680 AND THEN ACCESSING THE ANALYZED 2231 01:37:43,680 --> 01:37:46,480 RESULTS AND THEN HOW DO WE USE 2232 01:37:46,480 --> 01:37:48,680 THAT, WHAT ARE SOME WAYS THAT 2233 01:37:48,680 --> 01:37:52,400 THIS RESOURCE CAN BE USED IN 2234 01:37:52,400 --> 01:37:54,240 DOWNSTREAM APPLICATIONS, A 2235 01:37:54,240 --> 01:37:55,120 COUPLE EXAMPLES OF THAT. 2236 01:37:55,120 --> 01:37:57,280 THERE ARE SOME CHALLENGES WE HAD 2237 01:37:57,280 --> 01:38:00,720 TO OVERCOME IN THE ANALYSIS OF 2238 01:38:00,720 --> 01:38:02,920 DATA FROM ALL PLATFORMS, ONE WAS 2239 01:38:02,920 --> 01:38:04,280 READING THE DATA. 2240 01:38:04,280 --> 01:38:09,840 IT BEGAN WITH BEING ABLE TO 2241 01:38:09,840 --> 01:38:15,960 PARSE THE GLYCAN NAMES WHICH 2242 01:38:15,960 --> 01:38:17,440 REALLY THE ONLY REQUIREMENT ARE 2243 01:38:17,440 --> 01:38:19,080 NAMES ARE IN TEXT FORMAT, THAT 2244 01:38:19,080 --> 01:38:26,080 IT IS BASED ON THE MODIFIED 2245 01:38:26,080 --> 01:38:26,880 IOPAC, CAN BE TRANSLATED, 2246 01:38:26,880 --> 01:38:30,720 THERE'S A LOT OF SLOPPINESS 2247 01:38:30,720 --> 01:38:32,440 BUILT IN, DOESN'T NEED TO BE 2248 01:38:32,440 --> 01:38:33,360 PERFECT. 2249 01:38:33,360 --> 01:38:39,720 DATA HAS TO BE ALIGNED WITH EACH 2250 01:38:39,720 --> 01:38:41,720 GLYCAN NAME, SOME SORT OF 2251 01:38:41,720 --> 01:38:42,400 QUANTIFICATION. 2252 01:38:42,400 --> 01:38:44,800 THE ALGORITHM FOR ANALYZING USES 2253 01:38:44,800 --> 01:38:45,400 ALL AVAILABLE CONCENTRATIONS, 2254 01:38:45,400 --> 01:38:47,040 WHEN THERE'S MORE THAN ONE 2255 01:38:47,040 --> 01:38:48,920 CONCENTRATION OF THE LECTIN OR 2256 01:38:48,920 --> 01:38:51,760 ANTIBODY APPLIED TO GET MORE 2257 01:38:51,760 --> 01:38:56,080 ACCURATE ANALYSES OF THE 2258 01:38:56,080 --> 01:38:56,400 SPECIFICITIES. 2259 01:38:56,400 --> 01:38:58,800 IT PUTS IT IN A COMMON FORMAT 2260 01:38:58,800 --> 01:39:00,880 THAT'S INDEPENDENT OF THE SCALE 2261 01:39:00,880 --> 01:39:02,080 OF THE QUANTIFICATION BECAUSE 2262 01:39:02,080 --> 01:39:08,080 THERE'S A WIDE VARIETY OF TYPES 2263 01:39:08,080 --> 01:39:14,640 OF OF QUANTIFICATION, ALLOWING 2264 01:39:14,640 --> 01:39:16,120 FOR RELATING BETWEEN DATASETS OR 2265 01:39:16,120 --> 01:39:25,240 USING THEM TOGETHER IN COMBINED 2266 01:39:25,240 --> 01:39:25,520 ANALYSES. 2267 01:39:25,520 --> 01:39:33,080 SO, WE DEVELOPED A COUPLE 2268 01:39:33,080 --> 01:39:36,720 SYSTEMS THAT MAKE IT USEFUL, ONE 2269 01:39:36,720 --> 01:39:39,720 FOR DEFINING SPECIFICITY OF A 2270 01:39:39,720 --> 01:39:40,160 LECTIN. 2271 01:39:40,160 --> 01:39:42,720 WE CAN'T EFFECTIVELY DEFINE 2272 01:39:42,720 --> 01:39:49,440 SPECIFICITY WITH JUST ONE SIMPLE 2273 01:39:49,440 --> 01:39:52,400 DEFINITION, SAY TERMINAL OR 2274 01:39:52,400 --> 01:39:54,440 INTERNAL LacNAc, NO MATTER 2275 01:39:54,440 --> 01:39:58,320 HOW COMPLEX, THE NATURE OF 2276 01:39:58,320 --> 01:39:59,880 LECTINS IS THAT THEY COMBINED A 2277 01:39:59,880 --> 01:40:04,400 FEW DISTINCT TYPES OF MOTIFS AND 2278 01:40:04,400 --> 01:40:07,080 WITHIN EACH ONE THERE CAN BE 2279 01:40:07,080 --> 01:40:11,520 TUNING OF THE AMOUNT OF BINDING 2280 01:40:11,520 --> 01:40:12,880 BASED ON SLIGHT ADJUSTMENTS OR 2281 01:40:12,880 --> 01:40:15,720 SLIGHT DIFFERENCES IN GLYCAN 2282 01:40:15,720 --> 01:40:16,080 ITSELF. 2283 01:40:16,080 --> 01:40:19,080 AND SO WE NOW USE A FAMILY OF 2284 01:40:19,080 --> 01:40:20,480 MOTIFS TO DEFINE THE 2285 01:40:20,480 --> 01:40:22,440 SPECIFICITY, CALL THIS THE 2286 01:40:22,440 --> 01:40:23,760 LECTIN MODEL. 2287 01:40:23,760 --> 01:40:25,880 SO, THERE'S TWO LAYERS OF THE 2288 01:40:25,880 --> 01:40:28,600 MOTIFS WE DEFINE. 2289 01:40:28,600 --> 01:40:30,720 ONE IS PRIMARY MOTIFS THAT BROAD 2290 01:40:30,720 --> 01:40:33,520 CATEGORIES ARE DIFFERENT TYPES 2291 01:40:33,520 --> 01:40:38,080 OF STRUCTURES THAT IT BINDS. 2292 01:40:38,080 --> 01:40:40,440 THE SECOND IS FINE SPECIFICITY, 2293 01:40:40,440 --> 01:40:42,520 THERE'S MODIFICATIONS OF THE 2294 01:40:42,520 --> 01:40:46,360 PRIMARY MOTIF THAT DEFINE A MORE 2295 01:40:46,360 --> 01:40:48,200 FINE GRADATION OF BINDING. 2296 01:40:48,200 --> 01:40:51,680 WE FIND THE FAMILY SYSTEM OR 2297 01:40:51,680 --> 01:40:54,640 THIS MODEL OF FINDENING IS MORE 2298 01:40:54,640 --> 01:40:55,520 USEFUL FOR DEFINING THE 2299 01:40:55,520 --> 01:40:58,160 SPECIFICITY AND FOR USING THE 2300 01:40:58,160 --> 01:41:00,080 OUTPUT AND DOWNSTREAM 2301 01:41:00,080 --> 01:41:00,440 APPLICATIONS. 2302 01:41:00,440 --> 01:41:05,200 SO THESE MOTIFS ALSO HAVE TO NOT 2303 01:41:05,200 --> 01:41:06,440 BE FIXED SUBSTRUCTURES BECAUSE 2304 01:41:06,440 --> 01:41:07,560 THERE'S SO MUCH VARIABILITY IN 2305 01:41:07,560 --> 01:41:09,960 THE GLYCANS THAT ARE OUT IN 2306 01:41:09,960 --> 01:41:13,680 BIOLOGY, AND ALSO BECAUSE THE 2307 01:41:13,680 --> 01:41:14,840 BINDING OF THE LECTIN ISN'T 2308 01:41:14,840 --> 01:41:17,200 NECESSARILY LINKED TO A FIXED 2309 01:41:17,200 --> 01:41:18,600 SUBSTRUCTURE BUT RATHER A 2310 01:41:18,600 --> 01:41:19,960 PATTERN THAT HAS VARIABILITY. 2311 01:41:19,960 --> 01:41:23,880 SO WE NEED A SYNTAX FOR DEFINING 2312 01:41:23,880 --> 01:41:25,760 PATTERNS THAT ARE MORE OR LESS 2313 01:41:25,760 --> 01:41:28,040 VARIABLE, SOMETIMES THE PATTERN 2314 01:41:28,040 --> 01:41:29,920 COULD BE A FIXED SUBSTRUCTURE 2315 01:41:29,920 --> 01:41:31,160 BUT IT MIGHT HAVE VARIABILITY IN 2316 01:41:31,160 --> 01:41:39,680 THE TYPE OF MONO SACCHARIDE, 2317 01:41:39,680 --> 01:41:42,120 TYPE OF LINKAGE, WHETHER THERE'S 2318 01:41:42,120 --> 01:41:43,360 GAPS BETWEEN CONTACT POINTS. 2319 01:41:43,360 --> 01:41:48,440 TO HANDLE THAT NEED WE DEVELOPED 2320 01:41:48,440 --> 01:41:50,080 A NEW SYNTAX THAT IS USEFUL. 2321 01:41:50,080 --> 01:41:52,040 THIS SYNTAX WHERE WE CAN BUILD 2322 01:41:52,040 --> 01:42:02,160 IN VARIABILITY INTO THE 2323 01:42:02,160 --> 01:42:11,080 MONOSACCHARIDE, USE WILDCARDS IN 2324 01:42:11,080 --> 01:42:12,760 EACH OF THOSE LOCATIONS ALLOWS 2325 01:42:12,760 --> 01:42:15,880 FOR DESIGNING WITH A SYSTEM 2326 01:42:15,880 --> 01:42:17,920 THAT'S STILL FAIRLY COMPACT, CAN 2327 01:42:17,920 --> 01:42:20,720 HAVE A TEXT REPRESENTATION, 2328 01:42:20,720 --> 01:42:21,960 HUMAN READABLE. 2329 01:42:21,960 --> 01:42:26,040 AND IT CAN ALSO BE EASILY 2330 01:42:26,040 --> 01:42:32,080 INTEGRATED WITH OTHER SEARCH AND 2331 01:42:32,080 --> 01:42:32,480 ANALYSIS SYSTEMS. 2332 01:42:32,480 --> 01:42:35,800 THOSE WERE CAPABILITIES THAT 2333 01:42:35,800 --> 01:42:37,480 THEN THE MOTIF FINDER ANALYSIS 2334 01:42:37,480 --> 01:42:39,560 SYSTEM FOR ANALYZING GLYCAN 2335 01:42:39,560 --> 01:42:43,520 ARRAYS WAS BUILT ON, AND THEN 2336 01:42:43,520 --> 01:42:48,440 THE OUTPUT IS A STANDARDIZED 2337 01:42:48,440 --> 01:42:50,040 OUTPUT WHERE IT'S GOT VARIOUS 2338 01:42:50,040 --> 01:42:52,400 FEATURES OF THE OUTPUT WHICH 2339 01:42:52,400 --> 01:42:55,320 ALLOW YOU TO VISUALIZE THE DATA, 2340 01:42:55,320 --> 01:42:58,160 THE RESULTS, IN A FEW WAYS. 2341 01:42:58,160 --> 01:43:01,360 PROVIDED IN A REPORT THAT IS 2342 01:43:01,360 --> 01:43:02,080 ONLINE ACCESSIBLE, DATABASE, 2343 01:43:02,080 --> 01:43:05,360 I'LL SHOW YOU IN A MINUTE. 2344 01:43:05,360 --> 01:43:07,000 AND THE PRIMARY MOTIFS, FIRST 2345 01:43:07,000 --> 01:43:13,720 LEVEL OF THE MAIN TYPES, ONE IS 2346 01:43:13,720 --> 01:43:16,040 A BOX SCATTER PLOT WHERE THESE 2347 01:43:16,040 --> 01:43:18,720 MOTIFS, THIS IS THE MAIN MOTIF, 2348 01:43:18,720 --> 01:43:21,640 AND THEN OTHERS, THESE ARE THE 2349 01:43:21,640 --> 01:43:22,960 RESIDUAL GLYCANS SO BASICALLY 2350 01:43:22,960 --> 01:43:24,080 THE NON-BINDERS, YOU CAN SEE 2351 01:43:24,080 --> 01:43:26,880 THERE'S A RANGE OF BINDING, AND 2352 01:43:26,880 --> 01:43:29,080 THEN A TABLE GIVES THE GRAPHICAL 2353 01:43:29,080 --> 01:43:31,000 STRUCTURE, LATER IN THE REPORT. 2354 01:43:31,000 --> 01:43:32,960 THERE'S ALSO A TEXT DEFINITION 2355 01:43:32,960 --> 01:43:33,840 OF THESE MOTIFS. 2356 01:43:33,840 --> 01:43:40,000 SO YOU CAN SEE FOR ECL THE TOP 2357 01:43:40,000 --> 01:43:54,720 MOTIF IS GAL BETA 4 GlcNAc. 2358 01:43:54,720 --> 01:43:58,560 ANOTHER VIEW GIVES THE FINE 2359 01:43:58,560 --> 01:44:01,000 SPECIFICITY MOTIF, THIS IS THE 2360 01:44:01,000 --> 01:44:07,040 PRIMARY MOTIF OF A, GRADATIONS 2361 01:44:07,040 --> 01:44:08,360 IN THE FINE SPECIFICITIES, 2362 01:44:08,360 --> 01:44:12,080 DEFINITIONS ARE HERE. 2363 01:44:12,080 --> 01:44:13,400 A-1, A-STAR, REMAINDER OF THE 2364 01:44:13,400 --> 01:44:28,520 OTHER TYPES OF MOTIFS OF THIS 2365 01:44:28,520 --> 01:44:29,440 PRIMARY SPECIFICITY. 2366 01:44:29,440 --> 01:44:31,760 MOTIF INTENSITY MAP IS USEFUL. 2367 01:44:31,760 --> 01:44:33,960 THESE ARE THE FINE SPECIFICITY 2368 01:44:33,960 --> 01:44:34,320 MOTIFS. 2369 01:44:34,320 --> 01:44:37,800 THESE ARE GLYCANS ON THE ARRAY. 2370 01:44:37,800 --> 01:44:40,520 YELLOW MEANS GLYCAN OR MOTIF IS 2371 01:44:40,520 --> 01:44:43,640 PRESENT IN THIS GLYCAN, AND THEN 2372 01:44:43,640 --> 01:44:46,960 THIS IS THE BINDING INTENSITY OF 2373 01:44:46,960 --> 01:44:49,320 THE LECTIN TO THAT GLYCAN. 2374 01:44:49,320 --> 01:44:53,760 YOU CAN SEE THAT FOR MOTIF A-1, 2375 01:44:53,760 --> 01:44:56,320 IT'S PRESENT IN PRIMARILY 2376 01:44:56,320 --> 01:44:57,920 GLYCANS THAT HAVE HIGH BINDING. 2377 01:44:57,920 --> 01:45:00,720 YOU CAN SEE AMOUNT OF 2378 01:45:00,720 --> 01:45:03,600 REPRESENTATION ON ARRAY, SO THIS 2379 01:45:03,600 --> 01:45:05,840 MOTIF HAS THREE GLYCANS THAT 2380 01:45:05,840 --> 01:45:07,440 CONTAIN IT, THIS ONE HAS QUITE A 2381 01:45:07,440 --> 01:45:07,840 FEW. 2382 01:45:07,840 --> 01:45:14,440 YOU CAN SEE THE SECONDARY MOTIF 2383 01:45:14,440 --> 01:45:19,000 IS MAINLY PRESENT IN WEAKER 2384 01:45:19,000 --> 01:45:19,240 BINDERS. 2385 01:45:19,240 --> 01:45:21,320 IT GIVES NICE INDICATION OF HOW 2386 01:45:21,320 --> 01:45:24,400 MANY GLYCANS THERE ARE, WHAT 2387 01:45:24,400 --> 01:45:28,080 LEVEL OF BINDING IS. 2388 01:45:28,080 --> 01:45:34,520 ALSO EXAMPLE GLYCANS IN ARRAY, 2389 01:45:34,520 --> 01:45:36,280 FROM HIGH, MODERATE, LOW, WHAT 2390 01:45:36,280 --> 01:45:38,960 ARE THE GLYCANS, NOT JUST MOTIF. 2391 01:45:38,960 --> 01:45:44,520 FOR A-1, THIS ONE WOULD BE THIS 2392 01:45:44,520 --> 01:45:46,320 TOP GLYCAN RIGHT HERE. 2393 01:45:46,320 --> 01:45:50,080 SO, THESE REPORTS ARE ACCESSIBLE 2394 01:45:50,080 --> 01:45:50,840 IN A DATABASE. 2395 01:45:50,840 --> 01:45:55,200 SO THE ABILITY TO DO THIS, 2396 01:45:55,200 --> 01:45:57,480 AUTOMATED ANALYSIS OF GLYCAN 2397 01:45:57,480 --> 01:46:00,400 ARRAYS FROM ANYPLACE PLATFORM, 2398 01:46:00,400 --> 01:46:02,800 THEN PROVIDED THE ABILITY TO 2399 01:46:02,800 --> 01:46:05,440 COMPILE GLYCAN ARRAY DATA FROM 2400 01:46:05,440 --> 01:46:10,080 MANY PLATFORMS, AND TO PUT THEM 2401 01:46:10,080 --> 01:46:12,360 TOGETHER, THE ANALYZED DATASETS, 2402 01:46:12,360 --> 01:46:15,560 INTO DATABASE, COMPILE DATA FROM 2403 01:46:15,560 --> 01:46:20,080 19 LABORATORIES OR COMPANIES, 35 2404 01:46:20,080 --> 01:46:24,400 TYPES OF ARRAYS, 5 METHODS, 13 2405 01:46:24,400 --> 01:46:28,480 GLYCAN FAMILIES, 185 UNIQUE 2406 01:46:28,480 --> 01:46:31,480 PROTEINS, FOR TOTAL OF 1125 2407 01:46:31,480 --> 01:46:35,760 DATASETS IN THE FIRST RELEASE OF 2408 01:46:35,760 --> 01:46:37,800 THE DATABASE. 2409 01:46:37,800 --> 01:46:40,320 SO, THAT PROVIDES A REALLY NICE 2410 01:46:40,320 --> 01:46:43,640 TOOL NOW FOR ACCESSING THE 2411 01:46:43,640 --> 01:46:45,640 ANALYZED GLYCAN ARRAY DATA. 2412 01:46:45,640 --> 01:46:48,320 SO, WE ASKED WHAT SORT OF 2413 01:46:48,320 --> 01:46:55,000 COVERAGE WE HAD IN THE DATABASE. 2414 01:46:55,000 --> 01:46:57,320 THIS RIGHT HERE SHOWS YOU THE 2415 01:46:57,320 --> 01:47:00,840 SUPPLIERS, THE SOURCES OF THE 2416 01:47:00,840 --> 01:47:03,520 GLYCAN ARRAYS. 2417 01:47:03,520 --> 01:47:08,080 THESE ARE MOTIFS, 118 MOTIFS 2418 01:47:08,080 --> 01:47:11,640 GATHERED FROM GlyGen, FROM 2419 01:47:11,640 --> 01:47:12,480 11 FAMILIES. 2420 01:47:12,480 --> 01:47:14,600 FOR EACH ARRAY SOURCE WE ASKED, 2421 01:47:14,600 --> 01:47:17,520 WE WANTED TO KNOW HOW GOOD THE 2422 01:47:17,520 --> 01:47:20,720 COVERAGE IS IN THIS DATABASE OF 2423 01:47:20,720 --> 01:47:23,960 VARIOUS MOTIFS, THIS ASKED DO 2424 01:47:23,960 --> 01:47:28,280 GLYCANS IN THIS ARRAY CONTAIN 2425 01:47:28,280 --> 01:47:28,600 THESE MOTIFS. 2426 01:47:28,600 --> 01:47:32,320 RED IS YES, WHITE IS NO. 2427 01:47:32,320 --> 01:47:33,840 YOU CAN SEE THAT ALL OF THE 2428 01:47:33,840 --> 01:47:36,440 MOTIFS ARE COVERED BY AT LEAST 2429 01:47:36,440 --> 01:47:38,320 ONE ARRAY. 2430 01:47:38,320 --> 01:47:39,200 SOME MOTIFS ARE COVERED. 2431 01:47:39,200 --> 01:47:41,680 THIS IS THE NUMBER OF ARRAYS 2432 01:47:41,680 --> 01:47:43,560 BY -- THIS IS THE NUMBER OF 2433 01:47:43,560 --> 01:47:45,640 MOTIFS THE ARRAY COVERS, SO THIS 2434 01:47:45,640 --> 01:47:50,080 ARRAY COVERS NEARLY ALL OF THE 2435 01:47:50,080 --> 01:47:50,680 MOTIFS. 2436 01:47:50,680 --> 01:47:52,400 SOME ARE MORE SPECIALIZED, PLANT 2437 01:47:52,400 --> 01:47:55,080 CELL WALL JUST HAS ONE HERE, AS 2438 01:47:55,080 --> 01:48:01,600 WELL AS HEPARAN SULFATE OF THESE 2439 01:48:01,600 --> 01:48:02,200 PRE-DEFINED GlyGen MOTIFS. 2440 01:48:02,200 --> 01:48:04,520 OVER THE RESOURCE OF THE 2441 01:48:04,520 --> 01:48:07,320 DATABASE BETWEEN THE ARRAYS THEY 2442 01:48:07,320 --> 01:48:09,560 COVER MOST MOTIF, ALL THE MOTIFS 2443 01:48:09,560 --> 01:48:12,480 THAT WERE PRE-DEFINED FROM THESE 2444 01:48:12,480 --> 01:48:13,040 GlyGen MOTIFS. 2445 01:48:13,040 --> 01:48:16,720 WE ALSO ASKED WHAT ABOUT THE 2446 01:48:16,720 --> 01:48:19,960 BINDERS, THE GLYCAN BINDING 2447 01:48:19,960 --> 01:48:21,840 PROTEINS REPRESENTED IN THE 2448 01:48:21,840 --> 01:48:24,480 DATABASE, ARE THEY BINDING MOST 2449 01:48:24,480 --> 01:48:27,320 OF THESE MOTIFS? 2450 01:48:27,320 --> 01:48:29,360 SO WE PREDICTED BINDING TO ALL 2451 01:48:29,360 --> 01:48:33,440 OF THE GLYCANS ON THE ARRAYS, 2452 01:48:33,440 --> 01:48:34,920 1800 GLYCANS REPRESENTED OVER 2453 01:48:34,920 --> 01:48:37,720 ALL OF THE ARRAYS. 2454 01:48:37,720 --> 01:48:39,960 AND THEN ASKED WHETHER THESE 2455 01:48:39,960 --> 01:48:43,800 MOTIFS ARE PRESENT IN THE 2456 01:48:43,800 --> 01:48:44,040 BINDERS. 2457 01:48:44,040 --> 01:48:47,800 WE SEE GOOD COVERAGE THERE. 2458 01:48:47,800 --> 01:48:51,000 SO THESE ARE THE SAME MOTIFS AND 2459 01:48:51,000 --> 01:48:52,880 THIS IS THE NUMBER OF LECTINS 2460 01:48:52,880 --> 01:48:54,000 THAT BIND EACH MOTIF. 2461 01:48:54,000 --> 01:48:59,280 SO THERE ARE SOME MOTIFS WHERE 2462 01:48:59,280 --> 01:49:01,040 THERE AREN'T ANY LECTINS BINDING 2463 01:49:01,040 --> 01:49:05,040 THEM BUT PERHAPS AS TIME GOES ON 2464 01:49:05,040 --> 01:49:06,040 WE'LL FIND SOME DATASETS WHERE 2465 01:49:06,040 --> 01:49:07,520 SOME OF THESE OTHER MOTIFS ARE 2466 01:49:07,520 --> 01:49:11,440 ACTUALLY BOUND BY THOSE LECTINS. 2467 01:49:11,440 --> 01:49:13,440 WHEN SOMEONE IS LEARNING FOR A 2468 01:49:13,440 --> 01:49:15,720 LECTIN THAT BINDS TO A 2469 01:49:15,720 --> 01:49:17,880 PARTICULAR MOTIF, FOR THIS MOTIF 2470 01:49:17,880 --> 01:49:20,080 THERE WOULD BE MANY LECTINS 2471 01:49:20,080 --> 01:49:22,000 AVAILABLE TO MORE OR LESS 2472 01:49:22,000 --> 01:49:29,920 DEGREE, AND THEN FOR SOME NOT 2473 01:49:29,920 --> 01:49:31,760 ANY. 2474 01:49:31,760 --> 01:49:41,200 THIS IS AVAILABLE THROUGH 2475 01:49:41,200 --> 01:49:42,360 CARBOGROVE.ORG. 2476 01:49:42,360 --> 01:49:43,800 THE SEARCH TOOL IS FLEXIBLE SO 2477 01:49:43,800 --> 01:49:45,920 IT DOESN'T NEED TO BE EXACT NAME 2478 01:49:45,920 --> 01:49:47,440 MATCHES. 2479 01:49:47,440 --> 01:49:48,480 THERE'S A LOT OF SLOPPINESS 2480 01:49:48,480 --> 01:49:48,800 BUILT IN. 2481 01:49:48,800 --> 01:49:52,360 IT WILL RETURN ALL THE DATASETS 2482 01:49:52,360 --> 01:49:53,720 THAT MATCH. 2483 01:49:53,720 --> 01:49:55,320 FOR SNA HERE ARE SOME OF THE 2484 01:49:55,320 --> 01:50:00,120 MANY SNA DATASETS IN THE 2485 01:50:00,120 --> 01:50:00,400 DATABASE. 2486 01:50:00,400 --> 01:50:04,160 IT GIVES THE SOURCE OF THE 2487 01:50:04,160 --> 01:50:10,040 PROTEIN, DATA SOURCE, SO CFG, 2488 01:50:10,040 --> 01:50:12,480 CUPRA, OTHERS. 2489 01:50:12,480 --> 01:50:14,840 CLICKING WILL SHOW DIFFERENT 2490 01:50:14,840 --> 01:50:16,480 CONCENTRATIONS AND MODEL REPORT, 2491 01:50:16,480 --> 01:50:19,680 CLICKING ON VIEW WILL SHOW VIEWS 2492 01:50:19,680 --> 01:50:21,000 I SHOWED BEFORE. 2493 01:50:21,000 --> 01:50:25,480 THERE'S AN API FUNCTION 2494 01:50:25,480 --> 01:50:26,080 AVAILABLE FOR BIOINFORMATICIANS 2495 01:50:26,080 --> 01:50:27,440 WHO WOULD LIKE TO ACCESS 2496 01:50:27,440 --> 01:50:32,440 DATABASE FOR DEVELOPMENT OF 2497 01:50:32,440 --> 01:50:32,920 OTHER APPLICATIONS. 2498 01:50:32,920 --> 01:50:38,040 I'D LIKE TO TELL YOU ABOUT USE 2499 01:50:38,040 --> 01:50:40,440 EXAMPLES NOW. 2500 01:50:40,440 --> 01:50:44,360 THE BASIC USES OF THIS RESOURCE 2501 01:50:44,360 --> 01:50:48,080 ARE -- YOU WANT TO USE -- YOU 2502 01:50:48,080 --> 01:50:49,520 ANALYZE GLYCAN BINDING PROTEIN 2503 01:50:49,520 --> 01:50:50,320 SPECIFICITY, PERHAPS YOU HAVE 2504 01:50:50,320 --> 01:50:52,920 ONE IN THE DATABASE AND WANT TO 2505 01:50:52,920 --> 01:50:54,840 LOOK AT THE DETAILED ANALYSIS OF 2506 01:50:54,840 --> 01:50:56,440 THAT GLYCAN BINDING PROTEIN. 2507 01:50:56,440 --> 01:50:58,680 WE HAVE THE STAND-ALONE MOTIF, 2508 01:50:58,680 --> 01:51:04,120 NEW GLYCAN ARRAY DATA OR WANT TO 2509 01:51:04,120 --> 01:51:05,160 REANALYZE, MOTIF FINDER SOFTWARE 2510 01:51:05,160 --> 01:51:07,440 FOR ANALYSIS OF GLYCAN ARRAYS IS 2511 01:51:07,440 --> 01:51:09,320 AVAILABLE AS WELL. 2512 01:51:09,320 --> 01:51:12,680 BUT THIS HAS THE ALREADY 2513 01:51:12,680 --> 01:51:13,600 ANALYZED DATASETS. 2514 01:51:13,600 --> 01:51:16,320 OR IF YOU WANT TO FIND THE 2515 01:51:16,320 --> 01:51:17,400 GLYCAN BINDING PROTEIN THAT 2516 01:51:17,400 --> 01:51:18,720 BINDS A PARTICULAR MOTIF YOU CAN 2517 01:51:18,720 --> 01:51:22,240 SEARCH THE MOTIF AND FIND THOSE. 2518 01:51:22,240 --> 01:51:23,720 AND THEN LOOK AT THOSE DATASETS 2519 01:51:23,720 --> 01:51:25,560 TO SEE HOW WELL IT MATCHES UP 2520 01:51:25,560 --> 01:51:26,920 WITH WHAT YOU WANT. 2521 01:51:26,920 --> 01:51:30,040 A COUPLE I'D LIKE TO FOCUS ON 2522 01:51:30,040 --> 01:51:34,760 FOR A FEW MINUTES HERE IS THESE 2523 01:51:34,760 --> 01:51:35,320 TWO HERE. 2524 01:51:35,320 --> 01:51:37,520 DESIGNING EXPERIMENTS THAT USE 2525 01:51:37,520 --> 01:51:40,280 GLYCAN BINDING PROTEINS OR 2526 01:51:40,280 --> 01:51:41,440 INTERPRETING DATA THAT USE 2527 01:51:41,440 --> 01:51:42,280 GLYCAN BINDING PROTEINS. 2528 01:51:42,280 --> 01:51:44,680 WHAT I MEAN BY THAT IS SO YOU 2529 01:51:44,680 --> 01:51:46,520 WANT TO DESIGN AN EXPERIMENT 2530 01:51:46,520 --> 01:51:49,880 WHERE YOU'D LIKE TO PROFILE AN 2531 01:51:49,880 --> 01:51:51,120 UNKNOWN BIOLOGICAL SAMPLE AND 2532 01:51:51,120 --> 01:51:55,720 COMPARE A COUPLE FOR A FEW 2533 01:51:55,720 --> 01:51:57,080 DIFFERENT -- YOU WANT TO USE 2534 01:51:57,080 --> 01:51:58,040 MAYBE INTEGRATED INFORMATION 2535 01:51:58,040 --> 01:52:01,080 FROM SELF LECTINS, HOW DO YOU 2536 01:52:01,080 --> 01:52:06,760 THEN CHOOSE THOSE OPTIMALLY? 2537 01:52:06,760 --> 01:52:08,120 OR YOU'RE DOING EXPERIMENTS 2538 01:52:08,120 --> 01:52:09,760 COLLECTING DATA WITH LECTINS 2539 01:52:09,760 --> 01:52:12,440 WITH UNKNOWN BIOLOGICAL SAMPLE 2540 01:52:12,440 --> 01:52:14,720 AND WANT TO KNOW WHAT DOES THE 2541 01:52:14,720 --> 01:52:16,600 DATA TELL YOU? 2542 01:52:16,600 --> 01:52:20,080 LECTINS 2, 3, 4 BIND RELATIVELY 2543 01:52:20,080 --> 01:52:21,760 STRONGLY, OTHERS DON'T. 2544 01:52:21,760 --> 01:52:23,720 EXPERTS CAN PORE OVER DATA 2545 01:52:23,720 --> 01:52:26,080 MANUALLY AND MAKE QUALITATIVE 2546 01:52:26,080 --> 01:52:27,280 ESTIMATIONS BUT IS THERE A 2547 01:52:27,280 --> 01:52:31,760 QUANTITATIVE WAY TO DO SO WITH 2548 01:52:31,760 --> 01:52:32,480 AN ALGORITHM? 2549 01:52:32,480 --> 01:52:36,480 KEY FUNCTION IS BEING ABLE TO 2550 01:52:36,480 --> 01:52:39,880 PREDICT BINDING TO VIRTUAL 2551 01:52:39,880 --> 01:52:40,080 GLYCANS. 2552 01:52:40,080 --> 01:52:42,040 BY THAT I MEAN THERE'S A GLYCAN 2553 01:52:42,040 --> 01:52:44,080 NOT IN THE DATABASE, HOW DO YOU 2554 01:52:44,080 --> 01:52:45,760 KNOW WHETHER THE GLYCAN BINDING 2555 01:52:45,760 --> 01:52:49,720 PROTEIN IS GOING TO BIND OR NOT? 2556 01:52:49,720 --> 01:52:52,480 WE HAVE BASED ON THE DATASET AN 2557 01:52:52,480 --> 01:52:54,720 ALGORITHM THAT CAN PREDICT 2558 01:52:54,720 --> 01:52:55,800 BINDING TO VIRTUAL GLYCANS. 2559 01:52:55,800 --> 01:52:59,280 SO, FOR EXAMPLE, HERE IS DATA 2560 01:52:59,280 --> 01:53:04,640 WHERE YOU CAN PROBE THE LECTIN 2561 01:53:04,640 --> 01:53:08,600 BINDING TO -- ANTIBODY ARRAY TO 2562 01:53:08,600 --> 01:53:13,280 PROTEIN CAPTURED, THESE ARE CELL 2563 01:53:13,280 --> 01:53:16,920 LINES, FOUR LINES, TWO BINDS 2564 01:53:16,920 --> 01:53:17,400 LECTIN, TWO UNDERLYING 2565 01:53:17,400 --> 01:53:22,280 STRUCTURES, GET MORE INFORMATION 2566 01:53:22,280 --> 01:53:25,080 BY TREATING WITH WHO SIALIDASES, 2567 01:53:25,080 --> 01:53:28,240 BINDING GOES UP OR DOWN BECAUSE 2568 01:53:28,240 --> 01:53:30,080 IT'S EXPOSING THE EPITOPE. 2569 01:53:30,080 --> 01:53:31,320 YOU GET INTERESTING BINDING 2570 01:53:31,320 --> 01:53:31,680 PATTERNS. 2571 01:53:31,680 --> 01:53:34,520 THIS IS FOR DIFFERENT CAPTURE 2572 01:53:34,520 --> 01:53:35,960 ANTIBODIES, DIFFERENT CELL 2573 01:53:35,960 --> 01:53:36,160 LINES. 2574 01:53:36,160 --> 01:53:39,600 YOUR LECTINS HERE, WHETHER THEY 2575 01:53:39,600 --> 01:53:42,520 ARE TREATED OR NOT, YOU CAN SEE 2576 01:53:42,520 --> 01:53:44,080 WIDE RANGE OF PATTERNS DEPENDING 2577 01:53:44,080 --> 01:53:45,920 ON CELL LINE, DEPENDING ON 2578 01:53:45,920 --> 01:53:48,080 CAPTURE ANTIBODY. 2579 01:53:48,080 --> 01:53:50,080 IT'S A HUGE RANGE OF PATTERNS. 2580 01:53:50,080 --> 01:53:53,320 HOW DO YOU MAKE SENSE OF THAT? 2581 01:53:53,320 --> 01:53:55,240 EVEN THE BEST EXPERT COULDN'T DO 2582 01:53:55,240 --> 01:53:56,880 THAT PROPERLY BECAUSE YOU'VE GOT 2583 01:53:56,880 --> 01:53:58,520 JUST TOO MUCH INFORMATION FROM 2584 01:53:58,520 --> 01:53:59,560 MULTIPLE LECTINS. 2585 01:53:59,560 --> 01:54:09,240 YET THERE'S REAL INFORMATION HERE. 2586 01:54:09,240 --> 01:54:11,320 CLEARLY YOU NEED SOFTWARE, WE 2587 01:54:11,320 --> 01:54:13,560 CALL THIS GLYCAN SOLVER. 2588 01:54:13,560 --> 01:54:16,520 TAKE THE TEST DATA WITH PATTERNS 2589 01:54:16,520 --> 01:54:18,160 I SHOWED, ENTER KNOWN 2590 01:54:18,160 --> 01:54:19,520 SPECIFICITY OF LECTINS AND 2591 01:54:19,520 --> 01:54:21,320 ENZYMES YOU USED. 2592 01:54:21,320 --> 01:54:22,640 YOU FEED IT POTENTIAL GLYCANS 2593 01:54:22,640 --> 01:54:24,560 THAT IT COULD BE. 2594 01:54:24,560 --> 01:54:28,680 HERE'S WHERE IT DOES PREDICTION 2595 01:54:28,680 --> 01:54:29,960 OF BINDING TO POTENTIAL GLYCANS 2596 01:54:29,960 --> 01:54:31,720 AND BASED ON THAT COMPARED TO 2597 01:54:31,720 --> 01:54:33,120 REAL BINDING TELLS YOU 2598 01:54:33,120 --> 01:54:34,480 LIKELIHOOD OF VARIOUS GLYCANS 2599 01:54:34,480 --> 01:54:38,000 AND MOTIFS IN THE SAMPLE. 2600 01:54:38,000 --> 01:54:40,920 OUTPUTS MOTIF ABUNDANCE ESTIMATE 2601 01:54:40,920 --> 01:54:41,760 FOR YOU. 2602 01:54:41,760 --> 01:54:46,080 THE WAY WE SEE THIS WORKING YOU 2603 01:54:46,080 --> 01:54:49,320 HAVE A HYPOTHESIS ABOUT THE 2604 01:54:49,320 --> 01:54:52,720 TYPES OF GLYCANS, USE 2605 01:54:52,720 --> 01:54:54,720 CARBOGROVE, COLLECT DATA, USE 2606 01:54:54,720 --> 01:54:56,440 GLYCAN SOLVER AND EVALUATE HOW 2607 01:54:56,440 --> 01:54:57,440 WELL IT DID. 2608 01:54:57,440 --> 01:54:58,400 IF THERE'S STILL A LOT OF 2609 01:54:58,400 --> 01:54:59,920 QUESTIONS THAT REMAIN YOU GO 2610 01:54:59,920 --> 01:55:01,360 BACK AND REDESIGN YOUR 2611 01:55:01,360 --> 01:55:02,440 EXPERIMENT AND REPEAT THE 2612 01:55:02,440 --> 01:55:04,000 PROCESS UNTIL YOU HAVE SOME 2613 01:55:04,000 --> 01:55:10,560 UNDERSTANDING OF GLYCOSYLATION. 2614 01:55:10,560 --> 01:55:12,240 IN SUMMARY I'VE TOLD YOU ABOUT 2615 01:55:12,240 --> 01:55:14,400 ANALYSIS AND ACCESS OF GLYCAN 2616 01:55:14,400 --> 01:55:17,800 ARAPE DATA FROM ANY PLATFORM. 2617 01:55:17,800 --> 01:55:21,720 OF USING THE MOTIF FINDER 2618 01:55:21,720 --> 01:55:22,600 SOFTWARE, COUPLED WITH 2619 01:55:22,600 --> 01:55:24,120 CARBOGROVE DATABASE. 2620 01:55:24,120 --> 01:55:27,200 AND USAGE EXAMPLES SEARCH AND AC 2621 01:55:27,200 --> 01:55:31,600 SELLS, DESIGN ANALYSIS OF 2622 01:55:31,600 --> 01:55:33,640 EXPERIMENTS, OTHER DOWNSTREAM 2623 01:55:33,640 --> 01:55:36,920 APPLICATIONS WOULD BE POSSIBLE, 2624 01:55:36,920 --> 01:55:40,240 MANY TYPES OF BIOINFORMATICS OR 2625 01:55:40,240 --> 01:55:41,040 ANALYSES. 2626 01:55:41,040 --> 01:55:44,160 WHAT WE HAVE PLANNED HERE, 2627 01:55:44,160 --> 01:55:46,520 FURTHER INTEGRATION OF THE 2628 01:55:46,520 --> 01:55:51,320 DATABASE WITH OTHER SYSTEMS. 2629 01:55:51,320 --> 01:55:52,360 AND APPLICATIONS, FURTHER 2630 01:55:52,360 --> 01:55:55,480 DEVELOPING REPORTS TO BE 2631 01:55:55,480 --> 01:56:04,320 INTERACTIVE, PLOTS FOR ALL THE 2632 01:56:04,320 --> 01:56:05,520 CONCENTRATIONS, GLYCAN BINDING 2633 01:56:05,520 --> 01:56:11,680 CURVES BASED ON CONCENTRATION, 2634 01:56:11,680 --> 01:56:14,680 LINKS, SOME THERE ALREADY. 2635 01:56:14,680 --> 01:56:18,200 UPDATED ANALYSES, ANALYSIS OF 2636 01:56:18,200 --> 01:56:20,520 THE SPACERS, DENSITY, 2637 01:56:20,520 --> 01:56:24,840 GLYCOPEPTIDES AS WELL. 2638 01:56:24,840 --> 01:56:34,720 SO, WITH THAT, AND THEN I'D LIKE 2639 01:56:34,720 --> 01:56:36,080 TO ACKNOWLEDGE ZACHARY KLAMER, 2640 01:56:36,080 --> 01:56:37,000 THE DRIVING FORCE. 2641 01:56:37,000 --> 01:56:38,040 OTHERS CONTRIBUTED TO DATA AND 2642 01:56:38,040 --> 01:56:42,480 IDEAS AND HOW WE COULD USE THESE 2643 01:56:42,480 --> 01:56:43,840 THINGS AND WE'VE HAD GOOD CORE 2644 01:56:43,840 --> 01:56:44,520 SUPPORT. 2645 01:56:44,520 --> 01:56:46,520 I WANT TO THANK THE COMMON FUND 2646 01:56:46,520 --> 01:56:50,080 FOR SUPPORT OF THIS WORK AND 2647 01:56:50,080 --> 01:56:52,520 ALSO STTR PROGRAM. 2648 01:56:52,520 --> 01:56:56,080 WE'VE WORKED WITH THE COMPANY Z 2649 01:56:56,080 --> 01:56:59,000 BIOTECH AND ALLIANCE OF 2650 01:56:59,000 --> 01:56:59,560 GLYCOBIOLOGYISTS. 2651 01:56:59,560 --> 01:57:04,080 SO, WITH THAT WE'LL GO TO THE 2652 01:57:04,080 --> 01:57:04,320 NEXT. 2653 01:57:04,320 --> 01:57:05,560 WE'RE GOING TO DO PANEL 2654 01:57:05,560 --> 01:57:08,560 DISCUSSION LATER. 2655 01:57:08,560 --> 01:57:09,520 >> THANK YOU, BRIAN. 2656 01:57:09,520 --> 01:57:11,920 IF YOU HAVE QUESTIONS USE THE 2657 01:57:11,920 --> 01:57:13,120 LINK FOR SEND LIVE FEEDBACK AND 2658 01:57:13,120 --> 01:57:16,200 I'M SURE BRIAN WILL BE HAPPY TO 2659 01:57:16,200 --> 01:57:18,240 ADDRESS THOSE QUESTIONS IN ABOUT 2660 01:57:18,240 --> 01:57:19,120 20 MINUTES. 2661 01:57:19,120 --> 01:57:23,040 MOVING ON TO OUR LAST SPEAKER OF 2662 01:57:23,040 --> 01:57:28,160 THE SESSION, DR. DEANNE TAYLOR 2663 01:57:28,160 --> 01:57:30,760 FROM CHILDREN'S HOSPITAL OF 2664 01:57:30,760 --> 01:57:31,960 PHILADELPHIA, HOW TO INTEGRATE 2665 01:57:31,960 --> 01:57:33,920 MULTIOMICS DATA TO IDENTIFY 2666 01:57:33,920 --> 01:57:40,480 GENETIC FEATURES AS RELATES TO 2667 01:57:40,480 --> 01:57:42,320 PEDIATRIC DISEASES AND 2668 01:57:42,320 --> 01:58:03,320 DISORDERS. 2669 01:58:03,320 --> 01:58:07,080 >> CAN YOU HEAR ME NOW? 2670 01:58:07,080 --> 01:58:08,280 WE 2671 01:58:08,280 --> 01:58:11,600 >> WE CAN HEAR YOU NOW. 2672 01:58:11,600 --> 01:58:12,960 OH, YOU'RE MUTED. 2673 01:58:12,960 --> 01:58:14,840 >> CAN YOU SEE MY SCREEN? 2674 01:58:14,840 --> 01:58:18,120 >> YES AND WE CAN HEAR YOU. 2675 01:58:18,120 --> 01:58:18,440 >> GREAT. 2676 01:58:18,440 --> 01:58:25,200 I'M GOING TO TALK ABOUT 2677 01:58:25,200 --> 01:58:26,200 INTEGRATION OF MULTIOMICS DATA 2678 01:58:26,200 --> 01:58:28,800 AS PART OF THE COMMON FUND, THE 2679 01:58:28,800 --> 01:58:31,840 CENTER AND MY LAB. 2680 01:58:31,840 --> 01:58:39,720 I'M WORKING WITH JOHNSON 2681 01:58:39,720 --> 01:58:40,040 SILVERSTEIN. 2682 01:58:40,040 --> 01:58:43,120 I'M NOT REPRESENTING THE KIDS 2683 01:58:43,120 --> 01:58:43,560 FIRST PROGRAM. 2684 01:58:43,560 --> 01:58:44,240 I'M REPRESENTING MYSELF AND I'M 2685 01:58:44,240 --> 01:58:46,320 ALSO ONE OF THE P.I.s OF THE 2686 01:58:46,320 --> 01:58:47,360 KIDS FITTER DATA RESOURCE 2687 01:58:47,360 --> 01:58:47,640 CENTER. 2688 01:58:47,640 --> 01:58:50,920 A LOT OF WORK HAS BEEN FUNDED BY 2689 01:58:50,920 --> 01:58:53,640 NIH COMMON FUND. 2690 01:58:53,640 --> 01:58:55,320 ALSO COMMON FUND DATA ECOSYSTEM 2691 01:58:55,320 --> 01:58:57,920 PROJECT AND IT'S AN ONGOING 2692 01:58:57,920 --> 01:59:00,720 COLLABORATION BETWEEN MULTIPLE 2693 01:59:00,720 --> 01:59:02,040 COMMON FUND DATA RESOURCES. 2694 01:59:02,040 --> 01:59:03,080 BEFORE I GO TO ANYTHING I'D LIKE 2695 01:59:03,080 --> 01:59:05,480 TO POINT OUT THE PEOPLE THAT 2696 01:59:05,480 --> 01:59:09,040 HELPED MAKE THIS RESEARCH 2697 01:59:09,040 --> 01:59:10,320 POSSIBLE. 2698 01:59:10,320 --> 01:59:13,120 BEN STEAR AND TAHA MOHSENI IN MY 2699 01:59:13,120 --> 01:59:16,920 LAB DOING MOST OF THE WORK. 2700 01:59:16,920 --> 01:59:19,520 ALSO WITH JONATHAN SILVERSTEIN 2701 01:59:19,520 --> 01:59:20,520 AND OTHER PEOPLE, I'LL GO BACK 2702 01:59:20,520 --> 01:59:21,840 OVER THEM AT THE END. 2703 01:59:21,840 --> 01:59:23,960 IT'S BEEN A VILLAGE WHEN IT 2704 01:59:23,960 --> 01:59:26,080 COMES TO INTEGRATING LARGE 2705 01:59:26,080 --> 01:59:27,320 AMOUNTS OF DATA. 2706 01:59:27,320 --> 01:59:34,400 WE STARTED WITH THE UNIFIED 2707 01:59:34,400 --> 01:59:37,240 MEDICAL LANGUAGE SYSTEM. 2708 01:59:37,240 --> 01:59:39,320 WE MOVED HERE WITH UNIFIED 2709 01:59:39,320 --> 01:59:47,600 MEDICAL LANGUAGE SYSTEM TO 2710 01:59:47,600 --> 01:59:51,920 INTEGRATE BIOMEDICAL 2711 01:59:51,920 --> 01:59:56,080 TERMINOLOGY, 200 ONTOLOGY AND 2712 01:59:56,080 --> 01:59:58,520 VOCABULARY, ESSENTIALLY HAVING 2713 01:59:58,520 --> 02:00:00,400 THEM LINKED TOGETHER ON CONCEPTS 2714 02:00:00,400 --> 02:00:03,560 OR TERMS. 2715 02:00:03,560 --> 02:00:05,720 MIGHT BE AN ICD-10 CODE, AND 2716 02:00:05,720 --> 02:00:07,720 SEVERAL OTHERS FROM HTO AND 2717 02:00:07,720 --> 02:00:09,480 OTHER SOURCES, BUT INSTEAD OF 2718 02:00:09,480 --> 02:00:11,640 HAVING EACH AS INDIVIDUAL 2719 02:00:11,640 --> 02:00:15,120 THINGS, THEY WILL LINK THEM INTO 2720 02:00:15,120 --> 02:00:17,320 ONE CONCEPT, AND THAN WILL NOW 2721 02:00:17,320 --> 02:00:22,080 HAVE TERMS FROM ALL OF THESE 2722 02:00:22,080 --> 02:00:23,480 MEDICAL LANGUAGE SYSTEMS, 2723 02:00:23,480 --> 02:00:25,040 ONTOLOGY LANGUAGE SYSTEMS THAT 2724 02:00:25,040 --> 02:00:28,840 INFORM THAT TERM, THAT CONCEPT. 2725 02:00:28,840 --> 02:00:31,680 THOSE CONCEPTS DOING THINGS FROM 2726 02:00:31,680 --> 02:00:33,800 UNIFIED LEVEL ALLOWS YOU TO LINK 2727 02:00:33,800 --> 02:00:39,320 IN TERMINOLOGIES AND A LOT OF 2728 02:00:39,320 --> 02:00:41,160 KNOWLEDGE SYSTEMS. 2729 02:00:41,160 --> 02:00:42,680 WITHOUT HAVING TO INCREASE THE 2730 02:00:42,680 --> 02:00:46,880 SIZE OF YOUR KNOWLEDGE BASTE. 2731 02:00:46,880 --> 02:00:51,080 IT ALSO BRINGS IN SNOMED, OMIM, 2732 02:00:51,080 --> 02:00:54,200 MeSH, THE HUMAN PHENOTYPE 2733 02:00:54,200 --> 02:00:56,080 ONTOLOGY. 2734 02:00:56,080 --> 02:00:58,520 YOU CAN USE THIS AS PART, ANYONE 2735 02:00:58,520 --> 02:01:01,640 CAN USE IF YOU REQUEST A 2736 02:01:01,640 --> 02:01:03,840 LICENSE, USE THIS FOR EXPLORING 2737 02:01:03,840 --> 02:01:04,800 RELATIONSHIPS OF KNOWLEDGE 2738 02:01:04,800 --> 02:01:06,360 BASES, CERTAIN DISEASES, YOU CAN 2739 02:01:06,360 --> 02:01:10,480 MOVE FROM LET'S SAY HUMAN TERM 2740 02:01:10,480 --> 02:01:13,600 DOWN TO LET'S SAY 2741 02:01:13,600 --> 02:01:16,040 DROSOPHILA-RELATED TERM, WITHIN 2742 02:01:16,040 --> 02:01:18,440 ONE DATABASE, ALLOWS FOR A LOT 2743 02:01:18,440 --> 02:01:22,400 OF GRAPH-LIKE QUERIES YOU CAN DO 2744 02:01:22,400 --> 02:01:23,280 ON YOUR UMLS. 2745 02:01:23,280 --> 02:01:25,360 BUT UMLS IS A DATABASE. 2746 02:01:25,360 --> 02:01:30,720 I WAS WORKING WITH JONATHAN 2747 02:01:30,720 --> 02:01:34,040 SILVERSTEIN, HE ORIGINALLY 2748 02:01:34,040 --> 02:01:35,680 STARTED OFF WITH A DATABASE 2749 02:01:35,680 --> 02:01:41,120 BASED . 2750 02:01:41,120 --> 02:01:47,560 IT BRINGS IN A LOT OF 2751 02:01:47,560 --> 02:01:48,600 INFORMATION. 2752 02:01:48,600 --> 02:01:52,360 SO JUST WHAT THIS LOOKS LIKE IN 2753 02:01:52,360 --> 02:01:53,880 JONATHAN'S GRAPH WE STARTED WITH 2754 02:01:53,880 --> 02:01:57,200 IN OUR COLLABORATION, HERE ARE 2755 02:01:57,200 --> 02:01:59,720 CONCEPTS I MENTIONED EARLIER, 2756 02:01:59,720 --> 02:02:08,120 CODES ARE RELATED TO SOME SORT 2757 02:02:08,120 --> 02:02:14,120 OF CLINICAL DRUG, FROM RxNORM, 2758 02:02:14,120 --> 02:02:16,480 A QUERY, SHOW ME ALL THE 2759 02:02:16,480 --> 02:02:17,280 INFORMATION RELATED TO THE 2760 02:02:17,280 --> 02:02:18,720 PATCH, ET CETERA. 2761 02:02:18,720 --> 02:02:21,800 THIS BRINGS IN THE DATA. 2762 02:02:21,800 --> 02:02:23,160 IT'S A LARGE KNOWLEDGE GRAPH BUT 2763 02:02:23,160 --> 02:02:24,600 YOU ONLY RETURN THE THINGS 2764 02:02:24,600 --> 02:02:26,360 YOU'RE LOOKING FOR. 2765 02:02:26,360 --> 02:02:30,080 IN THAT WAY, HE INTEGRATED ALSO 2766 02:02:30,080 --> 02:02:31,320 PHYSIOLOGY ONTOLOGY AND CELL 2767 02:02:31,320 --> 02:02:33,280 ONTOLOGY INTO THIS KNOWLEDGE 2768 02:02:33,280 --> 02:02:35,280 GRAPH TO SUPPORT WHAT THEY LIKE 2769 02:02:35,280 --> 02:02:39,480 TO DO FOR HUB MAP DATA. 2770 02:02:39,480 --> 02:02:41,320 THERE ARE ANIMAL BASED DATA IN 2771 02:02:41,320 --> 02:02:44,960 HERE BUT ONTOLOGIES IN HERE, 2772 02:02:44,960 --> 02:02:46,240 BACKUP NOT COMPLETE. 2773 02:02:46,240 --> 02:02:56,120 WE NEED IT TO INCLUDE MOUSE 2774 02:02:56,120 --> 02:02:56,320 MODEL. 2775 02:02:56,320 --> 02:02:58,920 MOST BRING ONTOLOGY TO THE DATA. 2776 02:02:58,920 --> 02:03:02,080 WE WOULD LIKE TO BRING DATA TO 2777 02:03:02,080 --> 02:03:03,240 ONTOLOGY, TO INTEGRATE MULTIPLE 2778 02:03:03,240 --> 02:03:04,400 DATASETS INTO THE ONTOLOGY SO 2779 02:03:04,400 --> 02:03:06,720 THAT NOW YOU HAVE AN INTEGRATED 2780 02:03:06,720 --> 02:03:09,800 NETWORK OF PRIMARY DATA, 2781 02:03:09,800 --> 02:03:20,120 SECONDARY DATA, AND COMPLETE 2782 02:03:20,120 --> 02:03:21,640 ONTOLOGICAL DATA. 2783 02:03:21,640 --> 02:03:25,240 THIS STRUCTURE WE'RE USING HERE 2784 02:03:25,240 --> 02:03:26,280 THAT JONATHAN AND UMLS DESIGNED 2785 02:03:26,280 --> 02:03:28,480 IS THE STRUCTURE WE'D LIKE TO 2786 02:03:28,480 --> 02:03:30,880 USE FOR INTEGRATING PRIMARY 2787 02:03:30,880 --> 02:03:33,640 EXPERIMENTAL DATA. 2788 02:03:33,640 --> 02:03:38,120 WHY ARE WE INTERESTED? 2789 02:03:38,120 --> 02:03:42,200 THERE'S AN ONGOING ISSUE WITH 2790 02:03:42,200 --> 02:03:45,360 ETIOLOGY DISCOVER OR VARIANT 2791 02:03:45,360 --> 02:03:46,400 DISCOVERY IN CHILDHOOD CANCER, 2792 02:03:46,400 --> 02:03:47,680 EVERYONE STRUGGLES WITH THIS. 2793 02:03:47,680 --> 02:03:50,120 IT'S A LARGE FEATURE SPACE, HOW 2794 02:03:50,120 --> 02:03:52,200 CAN WE REDUCE THAT FEATURE SPACE 2795 02:03:52,200 --> 02:03:54,560 BY LOOKING AT DATA AND TRYING TO 2796 02:03:54,560 --> 02:03:55,320 IDENTIFY THINGS ALREADY KNOWN, 2797 02:03:55,320 --> 02:03:57,280 THINGS THAT AREN'T KNOWN OR ARE 2798 02:03:57,280 --> 02:04:01,000 NOT NOTICED BUT ARE IN THE DATA. 2799 02:04:01,000 --> 02:04:02,680 ONE WAY THIS, FOR EXAMPLE, 2800 02:04:02,680 --> 02:04:03,640 VARIANT DISCOVER IS ONE FEATURE 2801 02:04:03,640 --> 02:04:09,520 WE'D LIKE TO WORK ON, SUPPORT 2802 02:04:09,520 --> 02:04:10,560 SELECTION OF SETS BASED ON 2803 02:04:10,560 --> 02:04:11,920 FEATURES THAT WE MAY HAVE DIM 2804 02:04:11,920 --> 02:04:15,160 KNOWLEDGE MUCH BECAUSE THERE'S 2805 02:04:15,160 --> 02:04:15,840 SO MANY. 2806 02:04:15,840 --> 02:04:18,520 COULD WE BRING THEM IN ONE 2807 02:04:18,520 --> 02:04:22,920 ENVIRONMENT AND DESILO AND 2808 02:04:22,920 --> 02:04:24,400 INTEROPERATE AND USE THE DATA TO 2809 02:04:24,400 --> 02:04:26,920 UNDERSTAND THESE CONDITIONS? 2810 02:04:26,920 --> 02:04:29,800 A CHALLENGE WAS INTEGRATING AND 2811 02:04:29,800 --> 02:04:35,400 QUERY THAT EMPIRICAL DATA AND 2812 02:04:35,400 --> 02:04:40,480 UNDERSTAND BIRTH DEFECTS IN 2813 02:04:40,480 --> 02:04:41,240 CANCER? 2814 02:04:41,240 --> 02:04:46,440 OUR GOAL WAS TO LINK MULTIOMICS 2815 02:04:46,440 --> 02:04:48,280 DATA THROUGH KNOWLEDGE APPROACH, 2816 02:04:48,280 --> 02:04:49,960 PROPOSING AS YET UNKNOWN CAUSES 2817 02:04:49,960 --> 02:04:50,920 FOR STRUCTURAL DEFECTINGS IN 2818 02:04:50,920 --> 02:04:52,440 CANCER. 2819 02:04:52,440 --> 02:04:57,120 WE HAVE THE EXAMPLE QUERY WITH 2820 02:04:57,120 --> 02:05:00,520 HUBMAP DATA, A KIDS FIRST 2821 02:05:00,520 --> 02:05:03,880 VARIANT, KIDS FIRST PHENOTYPE, 2822 02:05:03,880 --> 02:05:07,760 SHARED GENE, HUBMAP LOCATION, 2823 02:05:07,760 --> 02:05:09,800 ONE OF MANY RESULTS FOR ONE 2824 02:05:09,800 --> 02:05:11,440 QUERY, LIKE A DATABASE QUERY, 2825 02:05:11,440 --> 02:05:13,360 MANY RESULTS IN A TABLE. 2826 02:05:13,360 --> 02:05:14,800 INSTEAD OF GETTING -- YOU CAN 2827 02:05:14,800 --> 02:05:20,120 GET GRAPHICAL RESULTS FROM OUR 2828 02:05:20,120 --> 02:05:22,080 KNOWLEDGE GRAPH, FRP THE 2829 02:05:22,080 --> 02:05:23,680 DATABASE, MULTIPLE RETURNS AND 2830 02:05:23,680 --> 02:05:25,360 QUERY RETURNS IN THIS MATTER TO, 2831 02:05:25,360 --> 02:05:34,720 FOR EXAMPLE, SAY I WANT ALL THE 2832 02:05:34,720 --> 02:05:36,440 REFERENCE DATA, CELL TYPE 2833 02:05:36,440 --> 02:05:37,240 LOCATIONS IN THOSE TISSUES, ONE 2834 02:05:37,240 --> 02:05:40,400 QUERY, FOR EXAMPLE, THAT YOU CAN 2835 02:05:40,400 --> 02:05:40,880 DO. 2836 02:05:40,880 --> 02:05:50,320 SO WHAT WE DID IS -- WE'RE 2837 02:05:50,320 --> 02:05:55,320 MISSING -- HUB MAP CAME IN. 2838 02:05:55,320 --> 02:05:57,920 WE HAVE PUT THIS TOGETHER, 2839 02:05:57,920 --> 02:06:00,120 INCLUDED RECENTLY SINCE I WAS 2840 02:06:00,120 --> 02:06:03,400 INVITED TO THE TALK, PUT IN 2841 02:06:03,400 --> 02:06:05,880 GLYCOSYLATION FROM THE DATA 2842 02:06:05,880 --> 02:06:08,040 THAT'S ON THE GlyGen 2843 02:06:08,040 --> 02:06:08,360 WEBSITE. 2844 02:06:08,360 --> 02:06:14,880 IT'S OF IT WILL HELP WITH 2845 02:06:14,880 --> 02:06:16,200 PRIMARY EXPERIMENTAL DATA. 2846 02:06:16,200 --> 02:06:24,400 WE STARTED WITH KIDS FIRST DATA, 2847 02:06:24,400 --> 02:06:26,120 COULD BE ANY DATA 2848 02:06:26,120 --> 02:06:29,440 , QUERIED FROM SOURCES TO FIND 2849 02:06:29,440 --> 02:06:30,080 EXISTING EXPECTED RELATIONSHIPS 2850 02:06:30,080 --> 02:06:32,400 SO WE CAN GET ANY DATA BACK OUT, 2851 02:06:32,400 --> 02:06:35,080 SOAP ANY DATA IN THE TOP CAN BE 2852 02:06:35,080 --> 02:06:37,320 GOTTEN BACK OUT AGAIN WHEN YOU 2853 02:06:37,320 --> 02:06:38,320 DO YOUR QUERY, ON THIS KIND OF 2854 02:06:38,320 --> 02:06:40,920 DATA OR ON YOUR OWN DATA, GET 2855 02:06:40,920 --> 02:06:44,680 BACK THE DATA AND EXPAND OUT THE 2856 02:06:44,680 --> 02:06:44,960 QUERY. 2857 02:06:44,960 --> 02:06:52,440 YOU COULD SAY I WANT TO START 2858 02:06:52,440 --> 02:06:54,320 WITH GTEx, GLYCOSYLTRANSFERASE 2859 02:06:54,320 --> 02:06:56,000 AND OUTWARD, ALLOWS YOU TO 2860 02:06:56,000 --> 02:06:56,720 EXPAND AND TELL YOU BASED ON 2861 02:06:56,720 --> 02:06:58,640 YOUR KNOWLEDGE OF THE BIOLOGY. 2862 02:06:58,640 --> 02:07:01,920 SO, WE INTEGRATED MANY 2863 02:07:01,920 --> 02:07:02,200 ONTOLOGIES. 2864 02:07:02,200 --> 02:07:03,760 THIS IS SURFACE LEVEL BUT I 2865 02:07:03,760 --> 02:07:06,040 WANTED TO SHOW A LOT OF SUPPORT 2866 02:07:06,040 --> 02:07:08,880 FOR HUMAN DEVELOPMENTAL STAGES, 2867 02:07:08,880 --> 02:07:13,880 DISEASE ONTOLOGY, CELL ONTOLOGY, 2868 02:07:13,880 --> 02:07:16,480 WE HAVE HPO, THE HUMAN 2869 02:07:16,480 --> 02:07:19,120 PHENOTYPE, ALL THE ONTOLOGIES 2870 02:07:19,120 --> 02:07:20,320 INTEGRATED INTO OUR GRAPH, 2871 02:07:20,320 --> 02:07:23,080 INTRODUCING A LOT OF DATA, A LOT 2872 02:07:23,080 --> 02:07:27,720 OF SUPPORT FOR OUR DATA, 2873 02:07:27,720 --> 02:07:39,480 INTRODUCED GENES IN . 2874 02:07:39,480 --> 02:07:43,120 THE SIZES WE'VE DONE, INCLUDED 2875 02:07:43,120 --> 02:07:44,560 MAMMALIAN PHENOTYPE AND HUMAN 2876 02:07:44,560 --> 02:07:44,840 PHENOTYPE. 2877 02:07:44,840 --> 02:07:46,200 WE DON'T HAVE TO DO ANYTHING 2878 02:07:46,200 --> 02:07:49,080 WITH THAT, IT'S ALREADY THERE. 2879 02:07:49,080 --> 02:07:50,480 WE INTRODUCED MAMMALIAN 2880 02:07:50,480 --> 02:07:52,720 PHENOTYPE, AND THAT HAS ABOUT 2881 02:07:52,720 --> 02:07:54,800 13,000 DATA POINTS, INTERESTED 2882 02:07:54,800 --> 02:07:57,880 DATA FROM GTEx, eQTL, GENE 2883 02:07:57,880 --> 02:08:01,440 TISSUE EXPRESSION ON THE DATA 2884 02:08:01,440 --> 02:08:01,680 POINTS. 2885 02:08:01,680 --> 02:08:04,760 WE'VE GOT THE CELL RNAseq 2886 02:08:04,760 --> 02:08:06,720 DATA, THIS IS OUR SPECIFIC 2887 02:08:06,720 --> 02:08:08,480 DATASET I MIGHT HAVE TIME TO 2888 02:08:08,480 --> 02:08:24,440 TALK ABOUT LATER. 2889 02:08:24,440 --> 02:08:30,920 GEN CODE DATA, HUBMAP, HUBMAP 2890 02:08:30,920 --> 02:08:34,640 10X VERSION 3, 61 DATASETS OUT 2891 02:08:34,640 --> 02:08:35,520 OF THAT. 2892 02:08:35,520 --> 02:08:36,960 THAT INCLUDES CLUSTER 2893 02:08:36,960 --> 02:08:37,840 INFORMATION TISSUE AND GENES. 2894 02:08:37,840 --> 02:08:39,960 YOU CAN SEE THE REST OF THE 2895 02:08:39,960 --> 02:08:40,160 DATA. 2896 02:08:40,160 --> 02:08:42,400 THERE'S OTHER DATA HERE THAT'S 2897 02:08:42,400 --> 02:08:44,120 SPECIFICALLY BOTH FROM THE 2898 02:08:44,120 --> 02:08:45,800 COMMON FUND DATA ECOSYSTEM OR 2899 02:08:45,800 --> 02:08:48,200 SOME OUTSIDE SOURCES TO SUPPORT 2900 02:08:48,200 --> 02:08:51,520 IT. 2901 02:08:51,520 --> 02:08:54,760 AND THIS IS INTRODUCED AS 2902 02:08:54,760 --> 02:08:55,320 INTERESTING DATASETS WE CAN 2903 02:08:55,320 --> 02:08:56,440 QUERY AGAINST. 2904 02:08:56,440 --> 02:09:01,120 HOW DO WE DO QUERIES? 2905 02:09:01,120 --> 02:09:03,960 YOU COULD LOOK FOR HUMAN 2906 02:09:03,960 --> 02:09:07,520 PHENOTYPE CONCEPT AND JUMP TO 2907 02:09:07,520 --> 02:09:08,480 MAMMALIAN PHENOTYPE CONCEPT. 2908 02:09:08,480 --> 02:09:11,600 THIS IS STILL BEING WORKED ON. 2909 02:09:11,600 --> 02:09:12,960 MELISSA HANDEL WILL GIVE LOTS OF 2910 02:09:12,960 --> 02:09:15,720 GREAT INFORMATION ON THIS KIND 2911 02:09:15,720 --> 02:09:18,320 OF STUFF TOMORROW. 2912 02:09:18,320 --> 02:09:22,200 BUT WE HAVE OUR OWN PHENOTYPES 2913 02:09:22,200 --> 02:09:23,200 WE'VE MAPPED OURSELVES, 2914 02:09:23,200 --> 02:09:23,960 INTRODUCED THEM INTO THE 2915 02:09:23,960 --> 02:09:24,440 DATABASE. 2916 02:09:24,440 --> 02:09:28,000 WE HAVE A MOUSE GENE CONCEPT, 2917 02:09:28,000 --> 02:09:30,120 MAMMALIAN CONCEPT, HUMAN GENE 2918 02:09:30,120 --> 02:09:32,120 CONCEPT, GTEx, CAN MAP FROM 2919 02:09:32,120 --> 02:09:33,520 HUMAN PHENOTYPE THROUGH THE 2920 02:09:33,520 --> 02:09:35,000 MOUSE, BACK TO THE HUMAN AND 2921 02:09:35,000 --> 02:09:37,160 THROUGH TO GTEx. 2922 02:09:37,160 --> 02:09:38,960 FOR EXAMPLE, THERE'S A LOT OF 2923 02:09:38,960 --> 02:09:41,000 HEART DEFECTS THAT AREN'T REALLY 2924 02:09:41,000 --> 02:09:43,840 TESTED IN HUMANS BECAUSE WE 2925 02:09:43,840 --> 02:09:48,440 CAN'T KNOCK OUT GENES IN HUMANS, 2926 02:09:48,440 --> 02:09:50,000 NOT EVERYTHING IS RECORDED, 2927 02:09:50,000 --> 02:09:51,400 GENES WITH BIRTH DEFECTS ARE 2928 02:09:51,400 --> 02:09:53,080 RECORDED BECAUSE OF SURVIVOR 2929 02:09:53,080 --> 02:09:56,080 BIAS SO ANY KIND OF BIRTH DEFECT 2930 02:09:56,080 --> 02:09:59,480 THAT WOULD HAVE IN FACT AFFECTED 2931 02:09:59,480 --> 02:10:02,120 THE EARLY HUMAN HEART WOULDN'T 2932 02:10:02,120 --> 02:10:03,600 SHOW UP. 2933 02:10:03,600 --> 02:10:06,440 THIS IS OMIM, NOT VIABLE, NOT A 2934 02:10:06,440 --> 02:10:08,160 VIABLE PREGNANCY. 2935 02:10:08,160 --> 02:10:11,040 SO WE CAN GO THROUGH OUTCOMES 2936 02:10:11,040 --> 02:10:12,520 OF ANIMAL MODELS AND COME BACK 2937 02:10:12,520 --> 02:10:13,720 WITH HUMANS. 2938 02:10:13,720 --> 02:10:15,320 AND THEN EXPLORE HUMAN RESOURCES 2939 02:10:15,320 --> 02:10:16,480 THROUGH THE LENS OF THE ANIMAL 2940 02:10:16,480 --> 02:10:19,720 MODELS, WHICH WE'RE INTERESTED 2941 02:10:19,720 --> 02:10:23,680 IN FOR BIRTH DEFECTS. 2942 02:10:23,680 --> 02:10:25,840 WE CAN USE ANALYSES ON PATHWAYS. 2943 02:10:25,840 --> 02:10:29,320 I WANT TO SHOW THIS TO SHOW WE 2944 02:10:29,320 --> 02:10:31,440 ACTUALLY CAN USE NOT ONLY 2945 02:10:31,440 --> 02:10:33,880 REFERENCE DATA FROM DATASETS BUT 2946 02:10:33,880 --> 02:10:38,120 CAN INTRODUCE THINGS LIKE NCDB, 2947 02:10:38,120 --> 02:10:39,720 CURATED PATHWAYS, JUMPING 2948 02:10:39,720 --> 02:10:41,800 BETWEEN LIKE A GENE CONCEPT OR 2949 02:10:41,800 --> 02:10:44,120 IN THIS CASE HUMAN GENE, INTO A 2950 02:10:44,120 --> 02:10:47,000 PATHWAY AND BACK TO ANOTHER 2951 02:10:47,000 --> 02:10:48,440 HUMAN GENE RELATED IN THE SAME 2952 02:10:48,440 --> 02:10:49,880 PATHWAY OR LINKED BY A GENE. 2953 02:10:49,880 --> 02:10:52,160 WE'RE ABLE TO USE THIS 2954 02:10:52,160 --> 02:10:56,840 INFORMATION TO ALSO CONDITION 2955 02:10:56,840 --> 02:10:58,280 OUR QUERIES. 2956 02:10:58,280 --> 02:11:00,440 AND THE QUERY STRUCTURES ARE NOT 2957 02:11:00,440 --> 02:11:01,120 THAT BAD. 2958 02:11:01,120 --> 02:11:03,520 IT LOOKS COMPLICATED BUT SOME OF 2959 02:11:03,520 --> 02:11:06,720 THE PEOPLE WE WORKED WITH OVER 2960 02:11:06,720 --> 02:11:10,400 THE SUMMER, YOU KNOW, BASICALLY 2961 02:11:10,400 --> 02:11:11,120 UNDERGRADUATES CAN LEARN 2962 02:11:11,120 --> 02:11:13,040 LANGUAGE, HOW TO PUT IT TOGETHER 2963 02:11:13,040 --> 02:11:16,520 IN A SUMMER SEMESTER, IT'S NOT 2964 02:11:16,520 --> 02:11:22,920 OUTSIDE OF REACH OF MOST 2965 02:11:22,920 --> 02:11:24,120 INTERESTED IN PROGRAMMING 2966 02:11:24,120 --> 02:11:25,360 LANGUAGES. 2967 02:11:25,360 --> 02:11:26,400 REALLY ANY SCIENTIST. 2968 02:11:26,400 --> 02:11:28,480 IF YOU'VE DONE THIS TO QUERIES 2969 02:11:28,480 --> 02:11:29,920 BEFORE IT'S A LITTLE DIFFERENT 2970 02:11:29,920 --> 02:11:30,960 BECAUSE IT THINKS ALONG THE 2971 02:11:30,960 --> 02:11:35,040 LINES OF A GRAPH BUT IS 2972 02:11:35,040 --> 02:11:36,400 ESSENTIALLY A STRUCTURED QUERY 2973 02:11:36,400 --> 02:11:39,560 LANGUAGE OF ITS OWN ON A GRAPH 2974 02:11:39,560 --> 02:11:39,840 STRUCTURE. 2975 02:11:39,840 --> 02:11:41,600 I JUST GO THROUGH AN EXAMPLE 2976 02:11:41,600 --> 02:11:41,800 HERE. 2977 02:11:41,800 --> 02:11:44,800 IF YOU'D LIKE TO TALK MORE 2978 02:11:44,800 --> 02:11:48,960 LATER, I'M HAPPY TO. 2979 02:11:48,960 --> 02:11:50,760 WE HAVE HERE DATA THAT'S 2980 02:11:50,760 --> 02:11:52,440 RETURNED. 2981 02:11:52,440 --> 02:11:56,120 IF I WANT TO ASK ON SEPTAL 2982 02:11:56,120 --> 02:11:58,280 DEFECTS, I WANT TO QUERY, WHAT 2983 02:11:58,280 --> 02:12:00,440 YOU GET RETURNED IS AN ACTUAL 2984 02:12:00,440 --> 02:12:02,680 LEVEL OF -- NUMBER OF GENES, 2985 02:12:02,680 --> 02:12:03,520 CHROMOSOMES WHERE THEY ARE 2986 02:12:03,520 --> 02:12:07,760 FOUND, THIS IS WHAT WE ASKED FOR 2987 02:12:07,760 --> 02:12:09,760 A RETURN, I'LL GO MORE INTO THIS 2988 02:12:09,760 --> 02:12:11,120 IN A MINUTE. 2989 02:12:11,120 --> 02:12:13,360 BUT THIS IS ESSENTIALLY A QUERY 2990 02:12:13,360 --> 02:12:16,120 THAT'S BASED ON FINDING ALL THE 2991 02:12:16,120 --> 02:12:19,840 MOUSE GENES THAT ARE ASSOCIATED 2992 02:12:19,840 --> 02:12:21,960 WITH HL SEPTAL DEFECTS, HAVE A 2993 02:12:21,960 --> 02:12:24,400 HUGE EXPRESSION IN GTEx. 2994 02:12:24,400 --> 02:12:27,320 THIS WOULD STREAM 188 RECORDS, 2995 02:12:27,320 --> 02:12:29,520 IN LESS THAN 1 MILLISECOND. 2996 02:12:29,520 --> 02:12:31,720 AFTER 9 MILLISECONDS A QUERY IS 2997 02:12:31,720 --> 02:12:35,280 DONE ACROSS THE DATABASE ON ALL 2998 02:12:35,280 --> 02:12:36,200 THE GTEx TISSUES. 2999 02:12:36,200 --> 02:12:38,000 THIS IS A RAPID RETURN ON 3000 02:12:38,000 --> 02:12:40,440 INVESTMENT IF YOU'RE ABLE TO USE 3001 02:12:40,440 --> 02:12:44,120 EITHER OURS OR SOMEONE ELSE'S 3002 02:12:44,120 --> 02:12:45,000 DATABASE YOU POPULATED CAREFULLY 3003 02:12:45,000 --> 02:12:46,880 WITH YOUR DATA, YOU CAN GET BACK 3004 02:12:46,880 --> 02:12:48,320 A LOT OF QUERIES QUICKLY THAT 3005 02:12:48,320 --> 02:12:52,440 WILL ANSWER YOUR QUESTIONS. 3006 02:12:52,440 --> 02:12:53,640 3007 02:12:53,640 --> 02:12:56,440 SO, I'M GOING TO SKIP THROUGH 3008 02:12:56,440 --> 02:12:56,640 THIS. 3009 02:12:56,640 --> 02:12:59,880 LET ME GO TO THE DATA. 3010 02:12:59,880 --> 02:13:02,080 THIS IS REALLY RECENT STUFF. 3011 02:13:02,080 --> 02:13:05,920 THIS WILL SHOW HOW EASY IT IS TO 3012 02:13:05,920 --> 02:13:09,240 USE DATA, ALWAYS A CAUTION 3013 02:13:09,240 --> 02:13:12,520 BECAUSE I'M NOT A 3014 02:13:12,520 --> 02:13:14,120 GLYCOINFORMATICIAN YET, 3015 02:13:14,120 --> 02:13:16,480 HOPEFULLY SOMEDAY AS I WORK 3016 02:13:16,480 --> 02:13:17,840 WITH COLLEAGUES, BUT INTRODUCING 3017 02:13:17,840 --> 02:13:20,320 THIS DATA INTO THE KNOWLEDGE 3018 02:13:20,320 --> 02:13:23,760 GRAPH, IF DONE CAREFULLY, CAN 3019 02:13:23,760 --> 02:13:27,040 RESULT IN MEANINGFUL RESULTS IN 3020 02:13:27,040 --> 02:13:28,120 YOUR QUERIES. 3021 02:13:28,120 --> 02:13:30,880 YOU HAVE TO BE CAREFUL. 3022 02:13:30,880 --> 02:13:32,960 WE'VE DESIGNED OURS CAREFULLY 3023 02:13:32,960 --> 02:13:35,160 BASED ON OUR PARTICULAR SCHEMA 3024 02:13:35,160 --> 02:13:36,520 WHICH IS DIFFERENT THAN SOME 3025 02:13:36,520 --> 02:13:38,560 OTHERS BECAUSE IT'S BASED ON 3026 02:13:38,560 --> 02:13:42,440 THIS IDEA OF CONCEPTS THAT ARE 3027 02:13:42,440 --> 02:13:43,480 GUIDING MULTIPLE QUERIES INTO A 3028 02:13:43,480 --> 02:13:44,520 SINGLE CONCEPT. 3029 02:13:44,520 --> 02:13:48,440 WE CAN CREATE OUR OWN CONCEPTS. 3030 02:13:48,440 --> 02:13:52,920 THERE'S A GTEx CONCEPT, 3031 02:13:52,920 --> 02:13:54,800 ICD-10, ALL LINKED CONCEPTS, WE 3032 02:13:54,800 --> 02:13:56,880 CAN CREATE A CONCEPT AROUND A 3033 02:13:56,880 --> 02:14:03,600 PHENOTYPE AND THAT THAT CONCEPT 3034 02:14:03,600 --> 02:14:06,200 HAVE MULTIPLE SYSTEMS COME IN ON 3035 02:14:06,200 --> 02:14:09,920 THAT PHENOTYPE AND FOR GENES 3036 02:14:09,920 --> 02:14:12,280 MOSTLY HTMC CONCEPT, THERE'S 3037 02:14:12,280 --> 02:14:17,240 OTHER SOURCES, FOR EXAMPLE THIS 3038 02:14:17,240 --> 02:14:18,320 PROTEIN HAS A PROTEIN, CAN COME 3039 02:14:18,320 --> 02:14:22,160 BACK AND JOIN UP WITH THAT GENE. 3040 02:14:22,160 --> 02:14:24,760 SO, WHY WE'RE INTERESTED IN 3041 02:14:24,760 --> 02:14:26,040 STUDYING GLYCOINFORMATICS AS 3042 02:14:26,040 --> 02:14:27,400 ALL, ANY OF THESE INFORMATICS, 3043 02:14:27,400 --> 02:14:29,200 FOR KIDS FIRST, IT'S GOING BACK 3044 02:14:29,200 --> 02:14:36,320 TO WHAT WE DISCUSSED ON 3045 02:14:36,320 --> 02:14:37,120 DEVELOPMENT, WHEN DOES 3046 02:14:37,120 --> 02:14:38,680 SUSCEPTIBILITY DURING 3047 02:14:38,680 --> 02:14:40,400 DEVELOPMENT, I HIGHLIGHTED 3048 02:14:40,400 --> 02:14:42,720 HEART, BETWEEN THE AGES OF 3 AND 3049 02:14:42,720 --> 02:14:48,840 8 WEEKS, THE HEART IS 3050 02:14:48,840 --> 02:14:50,320 SUSCEPTIBLE TO PERTURBATIONS, 3051 02:14:50,320 --> 02:14:57,360 FROM A PARTICULAR BLOG. 3052 02:14:57,360 --> 02:15:00,160 BUT ESSENTIALLY KOMP 2R G 3053 02:15:00,160 --> 02:15:10,360 EFFECTS AND LINCs. 3054 02:15:10,360 --> 02:15:13,320 GLYCOSYLATION IS LINKED TO HEART 3055 02:15:13,320 --> 02:15:13,560 DEFECTS. 3056 02:15:13,560 --> 02:15:15,920 50 INBORN ERRORS OF METABOLISM 3057 02:15:15,920 --> 02:15:18,960 DESCRIBED DUE TO CONGENITAL 3058 02:15:18,960 --> 02:15:20,480 DEFECTS IN N-LINKED 3059 02:15:20,480 --> 02:15:22,120 GLYCOSYLATION. 3060 02:15:22,120 --> 02:15:22,640 CARDIAC COMPLICATIONS ARE 3061 02:15:22,640 --> 02:15:24,080 ANNOTATED IN 100 CONGENITAL 3062 02:15:24,080 --> 02:15:29,320 DISORDERS OF GLYCOSYLATION DUE 3063 02:15:29,320 --> 02:15:29,800 TO HYPOGLYCOSYLATION. 3064 02:15:29,800 --> 02:15:33,160 INBORN ERRORS IN METABOLISM MAY 3065 02:15:33,160 --> 02:15:36,640 HAVE SOMETHING TO DO WITH HEART 3066 02:15:36,640 --> 02:15:38,120 DEFECTS, CARDIAC COMPLICATIONS 3067 02:15:38,120 --> 02:15:40,120 ANNOTATED IN 100 CONGENITAL 3068 02:15:40,120 --> 02:15:42,880 DISORDERS OF GLYCOSYLATION. 3069 02:15:42,880 --> 02:15:45,840 VSD AND ASD ARE THE MOST 3070 02:15:45,840 --> 02:15:48,440 PREVALENT IN THAT PUBLICATION IN 3071 02:15:48,440 --> 02:15:48,920 CONGENITAL DISORDERS. 3072 02:15:48,920 --> 02:15:50,120 IF YOU LOOK THROUGH THE LIST, 3073 02:15:50,120 --> 02:15:52,520 THEY ARE PROBABLY THE MAJORITY 3074 02:15:52,520 --> 02:15:53,480 OF THEM. 3075 02:15:53,480 --> 02:15:56,120 THERE MAY BE OTHER TIMES OF 3076 02:15:56,120 --> 02:15:58,640 HEART DEFECTS AND SOMATIC 3077 02:15:58,640 --> 02:16:04,200 DEFECTS, RELATED. 3078 02:16:04,200 --> 02:16:15,120 FOR EXAMPLE GENE GALNT11, HERE 3079 02:16:15,120 --> 02:16:22,080 IS A HETEROTAXI. 3080 02:16:22,080 --> 02:16:25,480 TYPES ARE THE TYPES WE'RE ABLE 3081 02:16:25,480 --> 02:16:26,760 TO GO THROUGH. 3082 02:16:26,760 --> 02:16:29,960 WE MIGHT WANT TO START EARLY ON 3083 02:16:29,960 --> 02:16:36,280 WITH TRYING TO ASK WHAT TISSUES 3084 02:16:36,280 --> 02:16:38,520 HAVE ANYTHING TO DO WITH 3085 02:16:38,520 --> 02:16:40,000 GLYCOSYLTRANSFERASES ASSOCIATED 3086 02:16:40,000 --> 02:16:42,120 BEFORE WE GO BACK INTO THESE 3087 02:16:42,120 --> 02:16:42,960 SPECIFICS. 3088 02:16:42,960 --> 02:16:47,240 I WAS GOING TO SHOW FOR THESE 3089 02:16:47,240 --> 02:16:48,440 PARTICULAR ANALYSES WE'RE GOING 3090 02:16:48,440 --> 02:16:54,520 TO DO, WE'RE GOING TO LOOK AT 3091 02:16:54,520 --> 02:16:57,320 GENES ASSOCIATED WITH 3092 02:16:57,320 --> 02:16:57,920 GENE-TO-PHENOTYPE INFORMATION 3093 02:16:57,920 --> 02:17:01,360 FOR GLYCAN, PROTEIN 3094 02:17:01,360 --> 02:17:04,960 GLYCOSYLATION SITES, FOCUS ON 3095 02:17:04,960 --> 02:17:05,160 OMIN. 3096 02:17:05,160 --> 02:17:08,720 A ONE GENE PER ONE PHENOTYPE 3097 02:17:08,720 --> 02:17:12,480 MODEL, THAT'S WHAT THEY OFTEN 3098 02:17:12,480 --> 02:17:13,240 PUBLISH. 3099 02:17:13,240 --> 02:17:15,840 VARIANT TO PHENOTYPE MODEL. 3100 02:17:15,840 --> 02:17:18,120 THERE'S SURVIVOR BIAS. 3101 02:17:18,120 --> 02:17:18,720 INDIVIDUALS ARE PROBABLY 3102 02:17:18,720 --> 02:17:23,040 SURVIVING UNTIL BIRTH AND ARE 3103 02:17:23,040 --> 02:17:28,440 ABLING TO MEASURED FOR PHENOTYPE 3104 02:17:28,440 --> 02:17:30,200 VERSUS GENES. 3105 02:17:30,200 --> 02:17:34,600 HPO AND HGNC, AND GENE 3106 02:17:34,600 --> 02:17:34,920 NOMENCLATURE. 3107 02:17:34,920 --> 02:17:40,600 AND WE GOT THIS FROM JACKS. 3108 02:17:40,600 --> 02:17:47,480 WE STUCK WITH OMIM AT THIS 3109 02:17:47,480 --> 02:17:48,240 POINT. 3110 02:17:48,240 --> 02:17:51,280 WE CAN EXPAND THIS IN LATER 3111 02:17:51,280 --> 02:17:52,920 ANNUAL SEALS. 3112 02:17:52,920 --> 02:17:54,400 IMPC, THIS IS DATA BASED ON 3113 02:17:54,400 --> 02:17:56,120 KNOCKOUTS IN MICE. 3114 02:17:56,120 --> 02:17:58,280 WE HAVE THE HUMAN VARIANT DATA, 3115 02:17:58,280 --> 02:18:02,880 AND THE MOUSE KNOCKOUT DATA, 3116 02:18:02,880 --> 02:18:04,360 IDENTIFIED GENE PERTURBATION. 3117 02:18:04,360 --> 02:18:07,240 THERE'S ABOUT 8,000 KNOCKOUTS, 3118 02:18:07,240 --> 02:18:09,560 GENE PERTURBATIONS, I SHOULDN'T 3119 02:18:09,560 --> 02:18:10,800 SAY KNOCKOUTS BUT PERTURBATIONS. 3120 02:18:10,800 --> 02:18:15,640 THEY DON'T HAVE TO SURVIVE TILL 3121 02:18:15,640 --> 02:18:16,280 BIRTH. 3122 02:18:16,280 --> 02:18:19,040 DATA SOURCE WE'RE ABLE TO QUERY. 3123 02:18:19,040 --> 02:18:31,520 SYSTEMS ARE MP AND THE HUMAN 3124 02:18:31,520 --> 02:18:32,040 ORTHOLOG SET. 3125 02:18:32,040 --> 02:18:34,880 HGLT IS THE OTHER SOURCE. 3126 02:18:34,880 --> 02:18:38,120 A CHALLENGE IS NOT ALL THE MT 3127 02:18:38,120 --> 02:18:39,360 MAPS TO HTL, SO THAT'S A 3128 02:18:39,360 --> 02:18:41,960 CHALLENGE WE HAVE, WE HAVE TO 3129 02:18:41,960 --> 02:18:43,720 MANUALLY DO A CROSS-WALK ON SOME 3130 02:18:43,720 --> 02:18:45,040 OF THESE. 3131 02:18:45,040 --> 02:18:52,080 THAT WILL BE FIXED IN THE FUTURE 3132 02:18:52,080 --> 02:18:53,440 HOPEFULLY. 3133 02:18:53,440 --> 02:19:02,080 IF I WANT TO LOOK AT 3134 02:19:02,080 --> 02:19:05,120 GLYCOSYLTRANSFERATIONS, LOOK IN 3135 02:19:05,120 --> 02:19:09,000 GTEx, WHAT GENES ARE EXPRESSED 3136 02:19:09,000 --> 02:19:10,120 IN CERTAIN TISSUES. 3137 02:19:10,120 --> 02:19:11,880 I CAN'T SHOW THIS DATA RIGHT NOW 3138 02:19:11,880 --> 02:19:15,520 BUT I CAN SAY THAT WE COULD LOOK 3139 02:19:15,520 --> 02:19:18,400 AT GENES ABOVE A CERTAIN LEVEL, 3140 02:19:18,400 --> 02:19:19,720 COMPARED FROM TISSUE TO TISSUE 3141 02:19:19,720 --> 02:19:22,440 IF PEOPLE ARE INTERESTED, TRYING 3142 02:19:22,440 --> 02:19:24,680 TO UNDERSTAND HOW CERTAIN 3143 02:19:24,680 --> 02:19:28,440 GLYCOSYLTRANSFERATIONS FUNCTION, 3144 02:19:28,440 --> 02:19:30,520 TIMES OF TISSUES, WE CAN PULL 3145 02:19:30,520 --> 02:19:35,000 OUT ALL OF THIGHS -- THESE 3146 02:19:35,000 --> 02:19:39,280 DATA, GENERATED IN THE LAST 3147 02:19:39,280 --> 02:19:48,120 SEVERAL HOURS, JUST PULLED OUT 3148 02:19:48,120 --> 02:19:49,000 FOR ME. 3149 02:19:49,000 --> 02:19:52,040 AND THEN THERE ARE VERY FEW 3150 02:19:52,040 --> 02:19:54,520 RELATED TO THESE GENES AND THIS 3151 02:19:54,520 --> 02:19:55,680 IS IN MOUSE PHENOTYPES, BUT 3152 02:19:55,680 --> 02:19:56,440 THERE'S SOME. 3153 02:19:56,440 --> 02:19:59,520 SOMEONE MAY WANT TO IN RESEARCH 3154 02:19:59,520 --> 02:20:01,640 LOOK MORE INTO THESE. 3155 02:20:01,640 --> 02:20:04,440 A RAPID QUERY WE JUST DID. 3156 02:20:04,440 --> 02:20:07,320 ALL THESE HAVE GENES ASSOCIATED 3157 02:20:07,320 --> 02:20:21,280 WITH THEM, THERE ARE TWO 3158 02:20:21,280 --> 02:20:22,240 GLYCOSYLTRANSFERASES. 3159 02:20:22,240 --> 02:20:26,680 INTERESTINGLY ALL THESE 3160 02:20:26,680 --> 02:20:28,160 GLYCOSYLTRANSFERATIONS ARE HIGH 3161 02:20:28,160 --> 02:20:30,040 UP, EXPRESSING HIGH IN THE 3162 02:20:30,040 --> 02:20:36,440 TISSUES THEY ARE ASSOCIATED 3163 02:20:36,440 --> 02:20:36,680 WITH. 3164 02:20:36,680 --> 02:20:40,360 I'M GOING TO SKIP THROUGH THIS 3165 02:20:40,360 --> 02:20:40,640 WITH MICE. 3166 02:20:40,640 --> 02:20:43,320 THERE'S A QUERY. 3167 02:20:43,320 --> 02:20:45,840 ESSENTIALLY WE CAN GO FROM 3168 02:20:45,840 --> 02:20:49,520 MAMMALIAN TO HUMAN, TO 3169 02:20:49,520 --> 02:20:51,120 GLYCOSYLATION, AS WE HEARD THAT 3170 02:20:51,120 --> 02:20:52,960 MIGHT NOT BE THE MOST UP TO DATE 3171 02:20:52,960 --> 02:20:56,520 BUT WE CAN PUT PRIMARY DATA FROM 3172 02:20:56,520 --> 02:21:11,160 LET'S SAY PRIMARY SOURCES TO 3173 02:21:11,160 --> 02:21:14,320 INCREASE OUR NUMBERS. 3174 02:21:14,320 --> 02:21:16,520 THE NUMBER OF GENES, THESE ARE 3175 02:21:16,520 --> 02:21:19,120 ASSOCIATED WITH, OOPS, NUMBER OF 3176 02:21:19,120 --> 02:21:20,160 GENES ASSOCIATED WITH 3177 02:21:20,160 --> 02:21:22,120 PHENOTYPES, MIGHT BE HARD TO 3178 02:21:22,120 --> 02:21:23,400 READ. 3179 02:21:23,400 --> 02:21:25,200 THESE ARE NUMBER OF GENES 3180 02:21:25,200 --> 02:21:26,320 GLYCOSYLATED PROTEINS. 3181 02:21:26,320 --> 02:21:30,440 WE LOOKED AT THE OVERALL RATIO 3182 02:21:30,440 --> 02:21:32,240 VERSUS ALL GENES IN THE HUMAN 3183 02:21:32,240 --> 02:21:45,720 GENOME THAT COULD BE 3184 02:21:45,720 --> 02:21:47,920 GLYCOSYLATED, AND THEN THIS HAS 3185 02:21:47,920 --> 02:21:49,520 THE SURVIVOR BIAS, WE SEE 3186 02:21:49,520 --> 02:21:51,160 SIMILAR IN MOUSE DATA, 3187 02:21:51,160 --> 02:21:53,520 HETEROTAXI IN GENERAL HAS LOWER 3188 02:21:53,520 --> 02:22:00,400 RATIO OF GENES WITH GLYCOSYLATED 3189 02:22:00,400 --> 02:22:04,000 PROTEINS VERSUS NUMBER OF GENES 3190 02:22:04,000 --> 02:22:07,120 IN THOSE ASSOCIATED BETWEEN THE 3191 02:22:07,120 --> 02:22:28,440 DISEASE AND GENE LIST THEY HAVE. 3192 02:22:28,440 --> 02:22:36,440 OF THE THERE'S A DISTINCT 3193 02:22:36,440 --> 02:22:52,400 GLYCOPROTEIN. 3194 02:22:52,400 --> 02:22:59,360 THE NUMBER OF GENES. 3195 02:22:59,360 --> 02:23:07,520 ASD IS FURTHER DOWN. 3196 02:23:07,520 --> 02:23:10,720 THE RATIO BETWEEN ALL GENES AND 3197 02:23:10,720 --> 02:23:15,640 GENES WITH GLYCOSYLATED PROTEINS 3198 02:23:15,640 --> 02:23:16,840 IS LOWER. 3199 02:23:16,840 --> 02:23:17,960 AGAIN, THAT WAS STRANGE. 3200 02:23:17,960 --> 02:23:26,120 THEN WE LOOKED AT HEART DEFECTS 3201 02:23:26,120 --> 02:23:28,440 PHENOTYPES, LOOKED AT ACTUAL 3202 02:23:28,440 --> 02:23:28,680 GLYCANS. 3203 02:23:28,680 --> 02:23:34,680 AND WE THOUGHT THERE WERE 3204 02:23:34,680 --> 02:23:36,240 CERTAIN -- THESE ARE ON THE 3205 02:23:36,240 --> 02:23:39,400 MAJOR ISOFORM OF THE GENE, THIS 3206 02:23:39,400 --> 02:23:43,880 IS NORMALIZED FOR NUMBER OF 3207 02:23:43,880 --> 02:23:56,640 PROTEIN, ON AVERAGE WE SEE IN 3208 02:23:56,640 --> 02:24:03,760 HERE FOUND ON PROTEINS, MAJOR 3209 02:24:03,760 --> 02:24:06,040 ISOFORMS, HETEROTAXY HAD A FEW, 3210 02:24:06,040 --> 02:24:07,120 WHICH WAS INTERESTING. 3211 02:24:07,120 --> 02:24:13,480 >> WE NEED TO WRAP UP QUICKLY. 3212 02:24:13,480 --> 02:24:13,920 >> SORRY. 3213 02:24:13,920 --> 02:24:15,840 QUICKLY, WE'RE ABLE TO -- WE 3214 02:24:15,840 --> 02:24:18,680 NEED MORE REFERENCE AND PRIMARY 3215 02:24:18,680 --> 02:24:20,520 DATA AND I'LL STOP THERE. 3216 02:24:20,520 --> 02:24:22,880 20 MINUTES IS ALWAYS SO HARD. 3217 02:24:22,880 --> 02:24:24,280 SORRY ABOUT THAT. 3218 02:24:24,280 --> 02:24:27,320 >> NO WORRIES. 3219 02:24:27,320 --> 02:24:27,760 THANK YOU. 3220 02:24:27,760 --> 02:24:29,440 THANK YOU TO ALL SIX SPEAKERS. 3221 02:24:29,440 --> 02:24:31,920 WE SAW A LOT OF EXCITING DATA. 3222 02:24:31,920 --> 02:24:34,080 IF THE SIX SPEAKERS COULD TURN 3223 02:24:34,080 --> 02:24:40,480 THEIR CAMERAS ON AND UNMUTE 3224 02:24:40,480 --> 02:24:41,680 THEMSELVES. 3225 02:24:41,680 --> 02:24:44,400 PARTICIPANTS, YOU COULD SEND ANY 3226 02:24:44,400 --> 02:24:48,040 QUESTIONS THROUGH THE SEND LIVE 3227 02:24:48,040 --> 02:24:50,120 FEEDBACK BUTTON, I'LL START WITH 3228 02:24:50,120 --> 02:24:56,120 A FIRST QUESTION, ACTUALLY TO 3229 02:24:56,120 --> 02:24:56,680 STEPHANIE. 3230 02:24:56,680 --> 02:25:12,840 HOW COULD BE SERVED ARE OH 3231 02:25:12,840 --> 02:25:13,200 O-GlcNAc SITES? 3232 02:25:13,200 --> 02:25:16,440 >> WE WORK WITH HUMAN AND MOUSE, 3233 02:25:16,440 --> 02:25:18,840 ANYTHING AFTER THAT WE'RE UNDER 3234 02:25:18,840 --> 02:25:22,960 ABOUT 500 OR LESS SITES 3235 02:25:22,960 --> 02:25:24,120 IDENTIFIED, IT'S HARD TO DO A 3236 02:25:24,120 --> 02:25:31,040 SEQUENCE THAT WOULD BE VALID. 3237 02:25:31,040 --> 02:25:34,400 THERE'S AN EFFORT WE WERE TRYING 3238 02:25:34,400 --> 02:25:35,560 TO DO PREDICTION OBVIOUSLY 3239 02:25:35,560 --> 02:25:37,680 BECAUSE WE HAD SO MUCH DATA. 3240 02:25:37,680 --> 02:25:41,480 AND WE WERE CONSIDERING USING 3241 02:25:41,480 --> 02:25:43,120 NEGATIVE AMINO ACID, PRESENTING 3242 02:25:43,120 --> 02:25:48,400 TO USE THAT, IT'S NOT READY FOR 3243 02:25:48,400 --> 02:26:00,360 PRIME TIME YET OBVIOUSLY. 3244 02:26:00,360 --> 02:26:01,480 >> THANKS. 3245 02:26:01,480 --> 02:26:02,880 >> DEPENDING ON TERMS OR YOU'RE 3246 02:26:02,880 --> 02:26:04,720 TEACHING SET WHETHER IT HAS 3247 02:26:04,720 --> 02:26:07,200 TERMS YOU'RE INTERESTED IN, HAVE 3248 02:26:07,200 --> 02:26:09,520 YOU BROADENED OUT TERMS TO 3249 02:26:09,520 --> 02:26:12,440 CONSIDER REAGENTS WE KNOW AFFECT 3250 02:26:12,440 --> 02:26:13,200 O-GlcNAc, DRUGS AND THINGS 3251 02:26:13,200 --> 02:26:14,120 LIKE THAT? 3252 02:26:14,120 --> 02:26:17,200 HOW DO YOU KNOW WHEN YOU'VE GOT 3253 02:26:17,200 --> 02:26:20,440 EVERYTHING? 3254 02:26:20,440 --> 02:26:21,760 >> WE DON'T. 3255 02:26:21,760 --> 02:26:25,480 NO, WE TRY BEING INCLUSIVE AND 3256 02:26:25,480 --> 02:26:28,120 TAG TERMS, WE HAVE COMMON 3257 02:26:28,120 --> 02:26:29,840 TECHNIQUE, COMMON CELL LINES, 3258 02:26:29,840 --> 02:26:31,120 COMMON TISSUES, WE'RE TAGGING 3259 02:26:31,120 --> 02:26:33,520 TERMS LIKE THIS IN CATEGORIES SO 3260 02:26:33,520 --> 02:26:37,120 WE CAN PUT THEM AND GET THE 3261 02:26:37,120 --> 02:26:38,880 SENTENCES WHERE WE HAVE IN A 3262 02:26:38,880 --> 02:26:40,200 GlcNAc TERM AND TISSUE OUT 3263 02:26:40,200 --> 02:26:43,680 AND FIGURE OUT WHICH TISSUE 3264 02:26:43,680 --> 02:26:46,920 WE'RE IN, FOR EXAMPLE, WHICH 3265 02:26:46,920 --> 02:26:48,600 PROTEIN WE IDENTIFY, WE ORGANS. 3266 02:26:48,600 --> 02:26:51,120 WE HAVEN'T INCLUDED A DRUG TERM, 3267 02:26:51,120 --> 02:26:52,920 FOR EXAMPLE, AT ALL YET. 3268 02:26:52,920 --> 02:26:55,200 THAT COULD BE DONE IN THE FUTURE 3269 02:26:55,200 --> 02:26:59,400 BUT THIS TEXT MINING IS A 3270 02:26:59,400 --> 02:27:00,240 NIGHTMARE AS YOU KNOW IF YOU 3271 02:27:00,240 --> 02:27:06,120 TRIED TO DO THIS INCLUDING THE 3272 02:27:06,120 --> 02:27:10,240 FACT USING BETA, ALPHA, WHEN YOU 3273 02:27:10,240 --> 02:27:14,840 CONVERT AND TRANSLATE, A LOT OF 3274 02:27:14,840 --> 02:27:16,360 TUNING, WE HAVEN'T BROADENED 3275 02:27:16,360 --> 02:27:17,120 YET. 3276 02:27:17,120 --> 02:27:19,960 AND LIKE I SAID WE DON'T USE 3277 02:27:19,960 --> 02:27:23,240 THAT, WE DON'T TRUST THAT 3278 02:27:23,240 --> 02:27:25,760 PREDICTION 100%. 3279 02:27:25,760 --> 02:27:26,560 WE VERIFY EVERYTHING MANUALLY. 3280 02:27:26,560 --> 02:27:30,800 BUT IT'S QUICKER THAT WAY STILL. 3281 02:27:30,800 --> 02:27:34,520 >> SO, I WAS GOING TO MOVE ON, 3282 02:27:34,520 --> 02:27:37,280 THIS QUESTION FOR JOSH. 3283 02:27:37,280 --> 02:27:39,200 IT'S A COMBINATION OF A QUESTION 3284 02:27:39,200 --> 02:27:41,760 FOR ANAND AND MYSELF. 3285 02:27:41,760 --> 02:27:44,880 DO PEOPLE ARE LYSOSOMAL STORAGE 3286 02:27:44,880 --> 02:27:46,120 DISEASE ALSO GET PARKINSON'S 3287 02:27:46,120 --> 02:27:48,520 DISEASE OR IS THERE A 3288 02:27:48,520 --> 02:27:50,400 RELATIONSHIP WITH THE TAU OF 3289 02:27:50,400 --> 02:27:52,120 THESE LIKE WITH ALPHA-SYNUCLEIN 3290 02:27:52,120 --> 02:27:54,760 IN P.D.? 3291 02:27:54,760 --> 02:27:55,480 >> YEAH, THANKS, GREAT QUESTION. 3292 02:27:55,480 --> 02:28:01,440 THERE'S A LOT OF OF OVERLAPPING 3293 02:28:01,440 --> 02:28:02,760 MECHANISMS BETWEEN 3294 02:28:02,760 --> 02:28:04,360 NEURODEGENERATIVE DISEASE 3295 02:28:04,360 --> 02:28:09,800 INCLUDING ALZHEIMER'S AND 3296 02:28:09,800 --> 02:28:10,320 PARKINSON'S. 3297 02:28:10,320 --> 02:28:11,120 LYSOSOMAL PATHWAYS ARE IMPORTANT 3298 02:28:11,120 --> 02:28:12,240 IN BOTH. 3299 02:28:12,240 --> 02:28:14,160 IF YOU LOOK AT ALZHEIMER'S 3300 02:28:14,160 --> 02:28:18,000 DISEASE GENETIC RISK THERE IS 3301 02:28:18,000 --> 02:28:22,080 ENRICHMENT FOR PATHWAYS RELATED 3302 02:28:22,080 --> 02:28:22,800 TO ENDOLYSOSOMAL TRAFFICKING. 3303 02:28:22,800 --> 02:28:26,240 I THINK A NUMBER OF WORK GROUPS 3304 02:28:26,240 --> 02:28:29,840 ARE WORKING ON WHETHER OR NOT 3305 02:28:29,840 --> 02:28:31,120 LYSOSOMAL STORAGE DISORDERS, 3306 02:28:31,120 --> 02:28:31,760 GENETICS, SHOW SIMILAR 3307 02:28:31,760 --> 02:28:34,600 RELATIONSHIP TWO WHAT WE KNOW 3308 02:28:34,600 --> 02:28:35,520 ABOUT FOR PARKINSON'S DISEASE. 3309 02:28:35,520 --> 02:28:38,120 IN THE CASE OF ALZHEIMER'S 3310 02:28:38,120 --> 02:28:40,400 DISEASE, I'VE HEARD ABOUT SOME 3311 02:28:40,400 --> 02:28:41,800 SUPPORTIVE UNPUBLISHED WORK BUT 3312 02:28:41,800 --> 02:28:43,080 I DON'T KNOW IF TOO MUCH HAS 3313 02:28:43,080 --> 02:28:44,800 BEEN PUBLISHED. 3314 02:28:44,800 --> 02:28:53,360 ONE GOOD EXAMPLE THAT IS WIDELY 3315 02:28:53,360 --> 02:28:56,120 KNOWN, GENE GRN, PROGRANULIN, A 3316 02:28:56,120 --> 02:28:58,920 CAUSE OF LYSOSOMAL STORAGE 3317 02:28:58,920 --> 02:29:04,760 DISORDERS, AND IT IS MENDELIAN 3318 02:29:04,760 --> 02:29:09,960 GENE FOR FRONTOTEMPORAL ALS, BUT 3319 02:29:09,960 --> 02:29:11,720 GRN AFFECTS RISK OF PARKINSON'S 3320 02:29:11,720 --> 02:29:16,440 DISEASE AND ALZHEIMER'S, A LINK 3321 02:29:16,440 --> 02:29:17,200 ACROSS NEURODEGENERATIVE 3322 02:29:17,200 --> 02:29:21,000 DISORDERS AND LYSOSOMAL 3323 02:29:21,000 --> 02:29:21,400 DISORDERS. 3324 02:29:21,400 --> 02:29:22,680 THE LYSOSOME CLEAVES TAU AND 3325 02:29:22,680 --> 02:29:26,280 THERE'S A LOT OF INTEREST IN 3326 02:29:26,280 --> 02:29:29,120 LYSOSOMAL MODIFICATIONS THAT 3327 02:29:29,120 --> 02:29:32,040 MILD AFFECT TAUOPATHY. 3328 02:29:32,040 --> 02:29:34,520 >> A SELFISH QUESTION. 3329 02:29:34,520 --> 02:29:37,840 ARE THERE DATABASES THAT 3330 02:29:37,840 --> 02:29:40,680 ACTUALLY PULL TOGETHER HUMAN 3331 02:29:40,680 --> 02:29:41,760 GLYCOOH LIPID BIOSYNTHETIC 3332 02:29:41,760 --> 02:29:44,280 DISORDERS OTHER THAN THE SORT OF 3333 02:29:44,280 --> 02:29:46,680 STANDARD, YOU KNOW, OMIM AND 3334 02:29:46,680 --> 02:29:50,120 OTHER DATABASES THAT PULL REAL 3335 02:29:50,120 --> 02:29:52,440 PRIMARY DATA RELATED TO 3336 02:29:52,440 --> 02:29:57,120 GLYCOLIPID DISTRIBUTIONS OR 3337 02:29:57,120 --> 02:29:57,680 SYNTHESIS OR DEGRADATION? 3338 02:29:57,680 --> 02:29:59,320 >> IT'S NOT A QUESTION FOR ME, 3339 02:29:59,320 --> 02:30:00,920 IS IT? 3340 02:30:00,920 --> 02:30:04,840 >> YEAH, IT IS. 3341 02:30:04,840 --> 02:30:08,960 >> OR ANYBODY. 3342 02:30:08,960 --> 02:30:09,360 >> I DON'T KNOW. 3343 02:30:09,360 --> 02:30:10,000 I DON'T KNOW. 3344 02:30:10,000 --> 02:30:14,080 ARE YOU REFERRING TO LIKE 3345 02:30:14,080 --> 02:30:15,160 NEURODEGENERATIVE KIND OF 3346 02:30:15,160 --> 02:30:15,840 SPECIFIC? 3347 02:30:15,840 --> 02:30:18,040 >> WITHIN ANY DISEASE DOMAIN. 3348 02:30:18,040 --> 02:30:21,720 GLYCOLIPIDS TEND TO BE IGNORED. 3349 02:30:21,720 --> 02:30:31,120 YOU'RE ON THE FOREFRONT MUCH OF 3350 02:30:31,120 --> 02:30:32,480 PUTTING FUNCTION TO GLYCOLIPID. 3351 02:30:32,480 --> 02:30:34,720 >> I'M NOT AWARE OF ONE. 3352 02:30:34,720 --> 02:30:38,880 >> THAT PLAY A HUGE ROLE IN 3353 02:30:38,880 --> 02:30:40,440 VIRAL INFECTION, VIRUS 3354 02:30:40,440 --> 02:30:41,360 TRAFFICKING, THAT'S SOMETHING 3355 02:30:41,360 --> 02:30:42,400 THAT COULD BE USEFUL IN 3356 02:30:42,400 --> 02:30:44,520 EVERYTHING FROM CANCER TO VIRAL 3357 02:30:44,520 --> 02:30:44,920 INFECTION. 3358 02:30:44,920 --> 02:30:46,680 THAT'S ACTUALLY A REALLY GOOD 3359 02:30:46,680 --> 02:30:47,080 POINT. 3360 02:30:47,080 --> 02:30:49,040 IF THAT DOESN'T EXIST, I'VE 3361 02:30:49,040 --> 02:30:51,640 NEVER SEEN ONE, BUT THAT'S 3362 02:30:51,640 --> 02:30:56,640 REALLY -- I THINK IT WOULD BE 3363 02:30:56,640 --> 02:30:56,920 USEFUL. 3364 02:30:56,920 --> 02:31:00,400 >> THERE'S A LOT OF INTERESTS IN 3365 02:31:00,400 --> 02:31:03,160 SPECIES AS BIOMARKERS FOR 3366 02:31:03,160 --> 02:31:04,120 NEURODEGENERATIVE, DEFECTING IN 3367 02:31:04,120 --> 02:31:07,000 BLOOD, I DIDN'T TOUCH ON THAT 3368 02:31:07,000 --> 02:31:07,240 ASPECT. 3369 02:31:07,240 --> 02:31:08,280 WE NEED CAREFUL STUDIES TO 3370 02:31:08,280 --> 02:31:12,480 UNDERSTAND WHETHER THEY ARE 3371 02:31:12,480 --> 02:31:19,360 PRIMARY, SECONDARY, TERTIARY 3372 02:31:19,360 --> 02:31:21,440 PERTURBATIONS, CAUSAL OR NOT. 3373 02:31:21,440 --> 02:31:23,040 >> ANAND, YOU FOCUSED ON 3374 02:31:23,040 --> 02:31:26,640 FUCOSYLATION BUT COULD YOU 3375 02:31:26,640 --> 02:31:28,000 COMMENT ON SIALYATION AND 3376 02:31:28,000 --> 02:31:31,400 IMPORTANCE OF ALSO UNDERSTANDING 3377 02:31:31,400 --> 02:31:31,640 LINKAGE. 3378 02:31:31,640 --> 02:31:33,160 >> YEAH, WE DEFINITELY SEE 3379 02:31:33,160 --> 02:31:33,840 ALTERATIONS IN SIALYATION. 3380 02:31:33,840 --> 02:31:36,560 I KIND OF LEFT THAT FOR ANOTHER 3381 02:31:36,560 --> 02:31:36,920 DAY. 3382 02:31:36,920 --> 02:31:40,000 I EITHER TEND TO LIKE -- I LIKE 3383 02:31:40,000 --> 02:31:41,920 TO STABILIZE SO RICK DRAKE 3384 02:31:41,920 --> 02:31:45,120 DEVELOPED A NICE METHOD FOR 3385 02:31:45,120 --> 02:31:47,760 IMAGE AING APPLICATIONS 3386 02:31:47,760 --> 02:31:49,160 SIALIC ACID, FOR TISSUE AND 3387 02:31:49,160 --> 02:31:49,920 ANTIBODY ARRAYS. 3388 02:31:49,920 --> 02:31:52,480 SO WE CAN TALK ABOUT THAT AT 3389 02:31:52,480 --> 02:31:53,320 ANOTHER TALK. 3390 02:31:53,320 --> 02:31:55,280 THERE ARE DEFINITELY CHANGES IN 3391 02:31:55,280 --> 02:31:57,520 SIALIC ACID. 3392 02:31:57,520 --> 02:31:59,680 CHANGES ARE LINKAGE SPECIFIC AND 3393 02:31:59,680 --> 02:32:03,240 CERTAIN LINKAGES PLAY A GREATER 3394 02:32:03,240 --> 02:32:03,480 CONTROL. 3395 02:32:03,480 --> 02:32:05,440 SIALIC ACIDS CHANGE EARLY IN 3396 02:32:05,440 --> 02:32:08,160 DISEASE, EVEN IN INITIAL 3397 02:32:08,160 --> 02:32:10,320 DEVELOPMENT OF SOMETHING LIKE 3398 02:32:10,320 --> 02:32:12,160 HEPATITIS, A VERY IMPORTANT ROLE 3399 02:32:12,160 --> 02:32:16,000 IN RECRUITING IN AND KEEPING 3400 02:32:16,000 --> 02:32:18,880 IMMUNE CELLS WITHIN ENVIRONMENTS 3401 02:32:18,880 --> 02:32:20,480 IN THE LIVER. 3402 02:32:20,480 --> 02:32:25,520 WE'RE DOING THAT NOW, COMBINING 3403 02:32:25,520 --> 02:32:27,720 HYPERION CyTOF BASED SYSTEM 3404 02:32:27,720 --> 02:32:30,880 WITH GLYCOYEN IMAGING, YOU CAN 3405 02:32:30,880 --> 02:32:32,920 SEE IT NICELY, A PAPER BEING 3406 02:32:32,920 --> 02:32:34,400 PRESENTED IN VIENNA THURSDAY I 3407 02:32:34,400 --> 02:32:36,480 THINK. 3408 02:32:36,480 --> 02:32:39,560 I'M HERE, NOT IN VIENNA, BUT 3409 02:32:39,560 --> 02:32:42,120 HOPEFULLY WE'LL SEE THAT SOON. 3410 02:32:42,120 --> 02:32:45,560 FOR FUCOSYLATION LINKAGE IS ALSO 3411 02:32:45,560 --> 02:32:47,400 SPECIFIC AND VERY IMPORTANT. 3412 02:32:47,400 --> 02:32:52,960 MOSTLY WE SEE CORE FUCOSE 3413 02:32:52,960 --> 02:32:59,080 SPECIFIC, BY ANALYSIS, OR BY 3414 02:32:59,080 --> 02:33:03,480 OFFLINE ANALYSIS, SO A LOT OF 3415 02:33:03,480 --> 02:33:04,760 THESE AGGRESSIVE TUMORS HAVE 3416 02:33:04,760 --> 02:33:08,160 LOTS OF FUCOSE, CORE AND OUTER 3417 02:33:08,160 --> 02:33:10,560 ARM. 3418 02:33:10,560 --> 02:33:10,920 >> GREAT. 3419 02:33:10,920 --> 02:33:15,960 THAT TIES TO A QUESTION FOR 3420 02:33:15,960 --> 02:33:16,160 BRIAN. 3421 02:33:16,160 --> 02:33:18,480 THERE'S ALL THIS AND ALSO 3422 02:33:18,480 --> 02:33:20,480 TOUCHES ON REBEKAH'S WORK WHICH 3423 02:33:20,480 --> 02:33:26,520 IS THERE'S ALL THE CELL SURFACE 3424 02:33:26,520 --> 02:33:27,080 GLYCOPROTEOMIC ANALYSIS OR 3425 02:33:27,080 --> 02:33:30,240 GLYCOANALYSIS GOING ON. BRIAN, 3426 02:33:30,240 --> 02:33:33,880 YOU'VE DONE AN AMAZING JOB 3427 02:33:33,880 --> 02:33:35,120 COMBINES ARRAYS TO PREDICT 3428 02:33:35,120 --> 02:33:37,640 LECTIN BINDING. 3429 02:33:37,640 --> 02:33:42,720 CAN WE CONNECT THE CELL SURFACE 3430 02:33:42,720 --> 02:33:44,480 GLYCOPROTEOMIC WITH YOUR DATA? 3431 02:33:44,480 --> 02:33:49,920 JUST . 3432 02:33:49,920 --> 02:33:52,960 >> JUST CHATTING WITH ZAK, WITH 3433 02:33:52,960 --> 02:33:54,400 THE DATA TO CONNECT, WHAT WOULD 3434 02:33:54,400 --> 02:33:56,760 BE A GOOD APPROACH, WHEN IT'S 3435 02:33:56,760 --> 02:33:59,200 LESS DEFINED, WHEN THERE'S MANY 3436 02:33:59,200 --> 02:34:04,760 ISOMERS THAT ARE POSSIBLE TO USE 3437 02:34:04,760 --> 02:34:08,160 THE TOOL, THE MOTIF SEARCH AND 3438 02:34:08,160 --> 02:34:10,160 GLYCAN DEFINITION TOOL TO MAP 3439 02:34:10,160 --> 02:34:12,480 OUT ALL OF THE POTENTIAL GLYCANS 3440 02:34:12,480 --> 02:34:15,520 AND USE THOSE GLYCANS AS 3441 02:34:15,520 --> 02:34:17,320 COMPARED TO THE MODELS IN THE 3442 02:34:17,320 --> 02:34:18,920 DATABASE TO FIND THE VARIOUS 3443 02:34:18,920 --> 02:34:20,320 LECTINS THAT COULD BIND THE 3444 02:34:20,320 --> 02:34:24,600 RANGE OF GLYCANS THAT ARE COMING 3445 02:34:24,600 --> 02:34:25,720 OUT FROM THE GLYCOPROTEOMICS, 3446 02:34:25,720 --> 02:34:29,440 DEFINITELY THE FIRST STEP IS 3447 02:34:29,440 --> 02:34:31,360 TAKING THE GLYCOPROTEOMICS DATA 3448 02:34:31,360 --> 02:34:37,520 TO FINDING RANGE OF COMPLETE 3449 02:34:37,520 --> 02:34:39,600 GLYCANS TO SOME DEGREE, EASY 3450 02:34:39,600 --> 02:34:40,880 WITH PREDICTION TOOLS TO FIND 3451 02:34:40,880 --> 02:34:43,000 SET OF LECTINS THAT COULD BE 3452 02:34:43,000 --> 02:34:47,320 BINDING TO THAT SET OF GLYCANS. 3453 02:34:47,320 --> 02:34:50,840 THOSE EFFORTS ARE DEFINITELY 3454 02:34:50,840 --> 02:34:51,960 ENVISIONED, THE FIRST PART IS 3455 02:34:51,960 --> 02:34:54,120 UNDERWAY TO SOME DEGREE, TAKING 3456 02:34:54,120 --> 02:34:55,320 THE LESS DEFINED GLYCANS MAPPING 3457 02:34:55,320 --> 02:35:03,120 OUT WHAT THEY COULD BE. 3458 02:35:03,120 --> 02:35:05,960 LOOKING FORWARD TO LINKING WITH 3459 02:35:05,960 --> 02:35:07,360 GlyGen AND THESE OTHER 3460 02:35:07,360 --> 02:35:08,360 TOOLS. 3461 02:35:08,360 --> 02:35:11,880 >> WHAT YOU SAID, BRIAN, RAISED 3462 02:35:11,880 --> 02:35:14,080 A QUESTION WITH DEANNE DID YOU 3463 02:35:14,080 --> 02:35:20,760 FIRST A QUESTION FOR REBEKAH. 3464 02:35:20,760 --> 02:35:23,160 SORRY. 3465 02:35:23,160 --> 02:35:25,800 66% OF CELL SURFACE N LINK 3466 02:35:25,800 --> 02:35:28,880 GLYCANS NOT PREDICTED TO BE 3467 02:35:28,880 --> 02:35:29,200 GLYCOSYLATED. 3468 02:35:29,200 --> 02:35:31,800 >> NOT 66%. 3469 02:35:31,800 --> 02:35:37,440 66 TOTAL OUT OF THE 1144. 3470 02:35:37,440 --> 02:35:39,320 >> OKAY. 3471 02:35:39,320 --> 02:35:44,360 THOSE 66, IS THERE A SYSTEMATIC 3472 02:35:44,360 --> 02:35:45,200 REASON, CONSENSUS -- 3473 02:35:45,200 --> 02:35:48,000 >> YEAH. 3474 02:35:48,000 --> 02:35:49,920 YEP, SO THE DATABASES ARE 3475 02:35:49,920 --> 02:35:51,280 WONDERFUL BUT THEY ARE TYPICALLY 3476 02:35:51,280 --> 02:35:53,120 LIMITED IN THE NUMBER OF 3477 02:35:53,120 --> 02:35:55,320 DIFFERENT PREDICTION ALGORITHMS 3478 02:35:55,320 --> 02:35:55,640 THEY USE. 3479 02:35:55,640 --> 02:36:01,960 SO, IF YOU'RE ONLY USING -- 3480 02:36:01,960 --> 02:36:04,320 WELL, UNIPRO WILL HAVE ONE 3481 02:36:04,320 --> 02:36:07,040 TRANSMEMBRANE DOMAIN PREDICTION, 3482 02:36:07,040 --> 02:36:10,240 WHICH PART OF PROTEIN SITS IN 3483 02:36:10,240 --> 02:36:11,360 THE EXTRACELLULAR DOMAIN. 3484 02:36:11,360 --> 02:36:13,840 IF THAT'S WRONG EVEN IF THERE'S 3485 02:36:13,840 --> 02:36:15,400 A SEQUENCE MOTIF IT WON'T 3486 02:36:15,400 --> 02:36:17,440 PREDICT THAT IT'S IN THE CELL 3487 02:36:17,440 --> 02:36:22,320 SURFACE, EXTRACELLULAR, WON'T 3488 02:36:22,320 --> 02:36:23,760 PREDICT IT'S ACTUALLY 3489 02:36:23,760 --> 02:36:24,520 GLYCOPROTEIN. 3490 02:36:24,520 --> 02:36:27,640 TRENDS WE SEE ARE THAT. 3491 02:36:27,640 --> 02:36:30,000 YOU HAVE TO GO BACK TO 3492 02:36:30,000 --> 02:36:32,400 LIMITATION IN THE TRANSMEMBRANE 3493 02:36:32,400 --> 02:36:36,760 PREDICTION ALGORITHM TO START 3494 02:36:36,760 --> 02:36:40,360 WITH, SOME ARE LIMITED BASED ON 3495 02:36:40,360 --> 02:36:41,160 ASSUMPTIONS, SOME REQUIRE A 3496 02:36:41,160 --> 02:36:45,360 CANONICAL SIGNAL PEPTIDE TO GET 3497 02:36:45,360 --> 02:36:46,840 THAT TRANSMEMBRANE PREDICTION. 3498 02:36:46,840 --> 02:36:51,360 IF THE PROTEIN LIKE USUALLY THE 3499 02:36:51,360 --> 02:36:55,160 ONES WE'RE INTERESTED IN DO NOT 3500 02:36:55,160 --> 02:36:56,200 HAVE CANONICAL SIGNAL PEPTIDES, 3501 02:36:56,200 --> 02:36:57,240 IT WILL BE DIFFERENT. 3502 02:36:57,240 --> 02:37:00,080 THEN IF THE ONE THAT UNIPRO IS 3503 02:37:00,080 --> 02:37:03,320 USING IS THE ONE THAT REQUIRED 3504 02:37:03,320 --> 02:37:04,880 US CANONICAL SIGNAL PEPTIDE IT 3505 02:37:04,880 --> 02:37:07,200 WON'T GET THAT RIGHT THEREFORE 3506 02:37:07,200 --> 02:37:08,880 IT WILL NOT ANNOTATE THAT THAT 3507 02:37:08,880 --> 02:37:10,320 SEQUENCE MOTIF IS IN THE 3508 02:37:10,320 --> 02:37:13,080 EXTRACELLULAR DOMAIN. 3509 02:37:13,080 --> 02:37:16,480 SO THAT'S WHY WE EXACTLY THAT 3510 02:37:16,480 --> 02:37:20,080 REASON, WHY WE -- WE STARTED TO 3511 02:37:20,080 --> 02:37:24,400 BECOME CONCERNED SOME DATA WERE 3512 02:37:24,400 --> 02:37:36,920 GIVING PROTEINS BEING 3513 02:37:36,920 --> 02:37:38,120 GLYCOSYLATED. 3514 02:37:38,120 --> 02:37:41,000 AND THEN JUST TAKE MORE OF AN 3515 02:37:41,000 --> 02:37:42,520 APPROACH THAT INCLUDES MORE 3516 02:37:42,520 --> 02:37:44,920 PREDICTIONS AND YOU'LL BUILD 3517 02:37:44,920 --> 02:37:46,680 MORE EVIDENCE. 3518 02:37:46,680 --> 02:37:47,360 >> REGARDING THE CANONICAL 3519 02:37:47,360 --> 02:37:49,720 SIGNAL PEPTIDE ARE YOU SAYING 3520 02:37:49,720 --> 02:37:52,400 THAT FOR THE 66, THE 3521 02:37:52,400 --> 02:37:54,680 CANONICAL -- TALKING ABOUT THE 3522 02:37:54,680 --> 02:37:56,200 SEQUENCE, IF THE SIGNAL PEPTIDE 3523 02:37:56,200 --> 02:37:57,720 IS NOT ANNOTATED FOR THE 3524 02:37:57,720 --> 02:38:00,160 SEQUENCE, IS THAT WHAT YOU'RE 3525 02:38:00,160 --> 02:38:01,000 SAYING? 3526 02:38:01,000 --> 02:38:08,160 >> NOT ALL 66, BUT FOR MANY THAT 3527 02:38:08,160 --> 02:38:10,120 WE'RE INTERESTED IN TRADITIONAL 3528 02:38:10,120 --> 02:38:11,480 SEQUENCE THAT ALGORITHMS WILL 3529 02:38:11,480 --> 02:38:13,040 PREDICT THEY DON'T SEE THAT 3530 02:38:13,040 --> 02:38:13,920 THERE'S A SEQUENCE THERE THAT 3531 02:38:13,920 --> 02:38:23,920 WOULD TAKE IT TO THE CELL 3532 02:38:23,920 --> 02:38:25,200 SURFACE. 3533 02:38:25,200 --> 02:38:29,960 >> CAN WE GO UNTIL 12:37? 3534 02:38:29,960 --> 02:38:30,320 >> YES. 3535 02:38:30,320 --> 02:38:33,160 >> YOU'RE ON THE VERGE OF TAKING 3536 02:38:33,160 --> 02:38:35,320 DEEPER DIVES INTO UNITED WITH 3537 02:38:35,320 --> 02:38:36,720 OTHER DOMAINS THAN PROBABLY 3538 02:38:36,720 --> 02:38:37,360 ANYTHING, IT'S REALLY EXCITING 3539 02:38:37,360 --> 02:38:40,400 TO SEE HOW THAT'S GOING TO 3540 02:38:40,400 --> 02:38:40,720 DEVELOP. 3541 02:38:40,720 --> 02:38:42,720 I HAVE A CONCEPTUAL QUESTION. 3542 02:38:42,720 --> 02:38:45,040 PROBABLY EVERYBODY ON THEM 3543 02:38:45,040 --> 02:38:49,320 SCREEN HAS DONE ANY GLYCOMICS OR 3544 02:38:49,320 --> 02:38:50,600 GLYCOPROTEOMICS WOULD NOT 3545 02:38:50,600 --> 02:38:52,000 ARTICLE WE'RE ONLY SCRATCHING 3546 02:38:52,000 --> 02:38:54,160 THE SURFACE, MAYBE WE HAVE ONLY 3547 02:38:54,160 --> 02:38:55,880 10%, I DON'T KNOW, OF A GLOBAL 3548 02:38:55,880 --> 02:39:05,240 SENSE OF WHAT GLYCOSYLATION 3549 02:39:05,240 --> 02:39:07,400 IS. 3550 02:39:07,400 --> 02:39:08,760 IF YOUR DATABASE IS INCOMPLETE 3551 02:39:08,760 --> 02:39:14,160 HOW MUCH -- WHAT HANDICAP DOES 3552 02:39:14,160 --> 02:39:19,880 THAT PUT YOU AT DRAWING 3553 02:39:19,880 --> 02:39:23,600 KNOWLEDGE THAT REALLY HAS SOME 3554 02:39:23,600 --> 02:39:24,480 CONFIDENCE TO IT? 3555 02:39:24,480 --> 02:39:26,440 >> SO, WE'RE LOOKING FOR THE 3556 02:39:26,440 --> 02:39:29,080 KEYS UNDER THE STREET LIGHT. 3557 02:39:29,080 --> 02:39:30,400 WE ONLY KNOW WHAT WE KNOW, DON'T 3558 02:39:30,400 --> 02:39:32,160 KNOW WHAT WE DON'T KNOW. 3559 02:39:32,160 --> 02:39:33,760 IT'S GOOD FOR UNDERSTANDING 3560 02:39:33,760 --> 02:39:34,720 RELATIONSHIPS YOU DIDN'T EXPECT 3561 02:39:34,720 --> 02:39:37,240 IN THE DATA ALREADY. 3562 02:39:37,240 --> 02:39:44,080 BUT ARE IN LITERATURE OR SOME 3563 02:39:44,080 --> 02:39:45,520 LITERATURES MINED IN UMLS LIKE 3564 02:39:45,520 --> 02:39:46,920 MeSH TERMS, FOR EXAMPLE. 3565 02:39:46,920 --> 02:39:48,960 BUT THERE'S SOME THINGS WE DON'T 3566 02:39:48,960 --> 02:39:49,240 KNOW. 3567 02:39:49,240 --> 02:39:52,400 AND SOME THINGS WE'RE INTERESTED 3568 02:39:52,400 --> 02:39:53,800 IN, WE'RE BUILDING ALGORITHMS, 3569 02:39:53,800 --> 02:39:56,120 HOPEFULLY, AS PART OF THE COMMON 3570 02:39:56,120 --> 02:39:57,720 FUND DATA ECOSYSTEM ON THIS 3571 02:39:57,720 --> 02:39:59,840 LARGE KNOWLEDGE DATA GAP, MORE 3572 02:39:59,840 --> 02:40:02,120 FORMAL INPUT OF PRIMARY DATA, 3573 02:40:02,120 --> 02:40:03,000 PRIMARY DATA IS WHERE THE 3574 02:40:03,000 --> 02:40:04,720 INTERESTING STUFF COMES IN. 3575 02:40:04,720 --> 02:40:07,880 WE HAVE ALL THIS DATA WHICH 3576 02:40:07,880 --> 02:40:13,120 PEOPLE HAVE MINED ON ON OF -- OR 3577 02:40:13,120 --> 02:40:14,920 ASSEMBLED BUT PRIMARY DATA IS 3578 02:40:14,920 --> 02:40:15,640 WHERE DISCOVERIES COME FROM. 3579 02:40:15,640 --> 02:40:17,160 AS LONG AS THE RELATIONSHIPS 3580 02:40:17,160 --> 02:40:20,120 RELATE TO A GENE, RELATE TO A 3581 02:40:20,120 --> 02:40:22,400 SITE OR PROTEIN, YOU CAN TAKE 3582 02:40:22,400 --> 02:40:23,960 TWO DISPARATE POINTS IN THAT 3583 02:40:23,960 --> 02:40:26,120 KNOWLEDGE GRAPH AND FIND 3584 02:40:26,120 --> 02:40:28,640 LINKAGES WHICH MIGHT BE LONG AND 3585 02:40:28,640 --> 02:40:29,640 ALMOST SILLY OR QUITE SHORT AND 3586 02:40:29,640 --> 02:40:32,640 LEAD TO THINGS THAT YOU MAY NOT 3587 02:40:32,640 --> 02:40:33,520 HAVE EXPECTED. 3588 02:40:33,520 --> 02:40:36,000 MORE PRIMARY DATA IS ALWAYS 3589 02:40:36,000 --> 02:40:36,240 WELCOME. 3590 02:40:36,240 --> 02:40:42,640 I CAN TAKE SMALL DATASETS IN. 3591 02:40:42,640 --> 02:40:48,400 AN ANALYSIS ON EMBRYONIC HUMAN 3592 02:40:48,400 --> 02:40:52,440 HEART IN SWEDEN, LUNDBERG LAB, 3593 02:40:52,440 --> 02:40:56,120 6.5 WEEK HUMAN HEARTS AND 3594 02:40:56,120 --> 02:40:58,400 CHARACTERIZE TISSUES IN SINGLE 3595 02:40:58,400 --> 02:41:01,000 CELL LEVEL, THE DETAIL, AS WE 3596 02:41:01,000 --> 02:41:04,040 GET MORE, IT WILL BE HARDER TO 3597 02:41:04,040 --> 02:41:07,480 LINK THAT DATA TOGETHER WITHOUT 3598 02:41:07,480 --> 02:41:10,680 TOOLS LIKE GRAPH DATABASE 3599 02:41:10,680 --> 02:41:16,920 BECAUSE DATA IS TOO 3600 02:41:16,920 --> 02:41:18,360 HETEROGENEOUS. 3601 02:41:18,360 --> 02:41:23,400 WE'RE UNDERPOWERED IN ONE SENSE. 3602 02:41:23,400 --> 02:41:26,760 CERTAINLY DATA THAT'S RAW, GOING 3603 02:41:26,760 --> 02:41:28,560 BACK AND DOING REPREDICTION AND 3604 02:41:28,560 --> 02:41:30,280 FIXING THAT, WE COULD DO, I'M 3605 02:41:30,280 --> 02:41:34,040 HAPPY WITH TRYING TO REPREDICT 3606 02:41:34,040 --> 02:41:35,280 MEMBRANE PROTEINS. 3607 02:41:35,280 --> 02:41:37,920 BUT IT'S STUFF WE SHOULD PUT IN 3608 02:41:37,920 --> 02:41:39,920 AND WE NEED THE BIOLOGY TO 3609 02:41:39,920 --> 02:41:42,960 INFORM OUR CHOICES, THE 3610 02:41:42,960 --> 02:41:43,720 IMPORTANT PART. 3611 02:41:43,720 --> 02:41:45,040 HOW THE DATA RELATES TO EACH 3612 02:41:45,040 --> 02:41:47,400 OTHER IS WHAT WE NEED PEOPLE'S 3613 02:41:47,400 --> 02:41:47,680 INPUT ON. 3614 02:41:47,680 --> 02:41:49,840 AND HOW IT SHOULD RELATE TO EACH 3615 02:41:49,840 --> 02:41:51,680 OTHER AND WHAT REFINEMENTS WE 3616 02:41:51,680 --> 02:41:53,240 SHOULD DO ON THE DATA. 3617 02:41:53,240 --> 02:41:54,240 SO OTHER BIOLOGISTS HAVE TO 3618 02:41:54,240 --> 02:41:58,360 WEIGH IN ON THE CREATIONS. 3619 02:41:58,360 --> 02:42:02,920 >> THAT'S A GREAT COMMENT TO 3620 02:42:02,920 --> 02:42:03,840 WRAP THIS UP. 3621 02:42:03,840 --> 02:42:08,160 WE'VE GOT TO BE ABLE TO GET 3622 02:42:08,160 --> 02:42:10,400 BETTER AT DATA INTEGRATION AND 3623 02:42:10,400 --> 02:42:13,600 WE NEED TO BE DRIVEN BY BIOLOGY 3624 02:42:13,600 --> 02:42:16,480 AND SO WITH THAT I'D LIKE TO 3625 02:42:16,480 --> 02:42:18,480 THANK THE SIX SPEAKERS TODAY FOR 3626 02:42:18,480 --> 02:42:20,520 BEING WILLING TO SHARE THEIR 3627 02:42:20,520 --> 02:42:21,120 TIME. 3628 02:42:21,120 --> 02:42:22,840 ALSO FOR THE SPEAKERS YOU CAN 3629 02:42:22,840 --> 02:42:24,520 SEE QUESTIONS THAT WE DIDN'T GET 3630 02:42:24,520 --> 02:42:26,240 A CHANCE TO GET TO, A LOT OF 3631 02:42:26,240 --> 02:42:31,240 PEOPLE WHEN THEY PUT IN THE 3632 02:42:31,240 --> 02:42:33,920 QUESTION PUT IN THEIR E-MAIL. 3633 02:42:33,920 --> 02:42:35,360 TACK THE TIME TO REPLY, THAT 3634 02:42:35,360 --> 02:42:36,800 WOULD BE FANTASTIC. 3635 02:42:36,800 --> 02:42:37,600 THANKS TO ATTENDEES. 3636 02:42:37,600 --> 02:42:40,160 AND WE WILL START BACK AT 1:30 3637 02:42:40,160 --> 02:42:41,920 SHARP. 3638 02:42:41,920 --> 02:42:45,080 >> WELCOME TO THE AFTERNOON 3639 02:42:45,080 --> 02:42:46,240 SESSION. 3640 02:42:46,240 --> 02:42:50,480 THIS IS THE VIRAL GLYCOBIOLOGY 3641 02:42:50,480 --> 02:42:50,680 SESSION. 3642 02:42:50,680 --> 02:42:53,160 I'M JOHN CIPOLLO FROM CBER FDA. 3643 02:42:53,160 --> 02:42:55,280 WE HAVE AN INTERESTING SERIES OF 3644 02:42:55,280 --> 02:42:58,520 TALKS, BUT FIRST I'D LIKE TO 3645 02:42:58,520 --> 02:43:04,560 REMIND EVERYONE TO SEND TO THE 3646 02:43:04,560 --> 02:43:08,480 LIVE FEEDBACK LINK AT THE NIH 3647 02:43:08,480 --> 02:43:10,520 WEBSITE FOR YOUR QUESTIONS, AND 3648 02:43:10,520 --> 02:43:12,360 FROM THERE THEY WILL ACTUALLY 3649 02:43:12,360 --> 02:43:24,800 PROBABLY MAKE THEIR WAY Y MAKE 3650 02:43:24,800 --> 02:43:28,040 THEIR WAY INTO THE CHAT. 3651 02:43:28,040 --> 02:43:34,480 THIS AFTERNOON WE HAVE AN 3652 02:43:34,480 --> 02:43:44,680 INTERESTING TALK WITH LASSA 3653 02:43:44,680 --> 02:43:48,240 VIRUS AND ALSO WILL BE 3654 02:43:48,240 --> 02:43:50,360 DISCUSSING ARRAYS OF SOME -- 3655 02:43:50,360 --> 02:43:52,640 VARIOUS ARRAYS TO REVEAL SOME 3656 02:43:52,640 --> 02:43:54,760 STRUCTURAL FUNCTIONAL 3657 02:43:54,760 --> 02:43:57,720 RELATIONSHIPS THAT VIRUSES HAVE 3658 02:43:57,720 --> 02:44:01,280 FOUND IN THEIR NICHE. 3659 02:44:01,280 --> 02:44:05,680 LASTLY, AS WE'VE WITNESSED OVER 3660 02:44:05,680 --> 02:44:06,720 THE LAST TWO YEARS THE 3661 02:44:06,720 --> 02:44:09,720 SARS-COV-2 VIRUS HAS BEEN A BIG 3662 02:44:09,720 --> 02:44:15,200 FOCUS, PUTTING EMPHASIS ON 3663 02:44:15,200 --> 02:44:15,720 GLYCOSYLATION AS THE SPIKE 3664 02:44:15,720 --> 02:44:19,080 PROTEIN HAS BEEN OF INTEREST. 3665 02:44:19,080 --> 02:44:22,480 I'D LIKE TO INTRODUCE THE FIRST 3666 02:44:22,480 --> 02:44:30,000 SPEAKER, RON DISKIN, FROM THE 3667 02:44:30,000 --> 02:44:31,800 WEIZMANN INSTITUTE, THE LASSA 3668 02:44:31,800 --> 02:44:32,480 VIRUS. 3669 02:44:32,480 --> 02:44:33,600 WELCOME, RON. 3670 02:44:33,600 --> 02:44:34,000 >> THANKS, JOHN. 3671 02:44:34,000 --> 02:44:37,320 THANK YOU FOR THE ORGANIZERS FOR 3672 02:44:37,320 --> 02:44:55,400 INVITING ME. 3673 02:44:55,400 --> 02:44:57,880 VIRUSES CAN'T REPLICATE ON THEIR 3674 02:44:57,880 --> 02:44:58,520 OWN, THERE'S EVOLUTIONARY 3675 02:44:58,520 --> 02:45:04,160 PRESSURE TO FIND INTERESTING 3676 02:45:04,160 --> 02:45:08,280 WAYS TO PENETRATE CELLS. 3677 02:45:08,280 --> 02:45:09,680 ENVELOPE VIRUSES USE SPECIAL 3678 02:45:09,680 --> 02:45:11,080 PROTEINS ON THE SURFACE TO 3679 02:45:11,080 --> 02:45:13,520 ATTACH TO THE HOST CELL AND TO 3680 02:45:13,520 --> 02:45:17,760 LATER ON FUSE THEIR OWN MEMBRANE 3681 02:45:17,760 --> 02:45:20,400 WITH THE TARGET CELL MEMBRANE. 3682 02:45:20,400 --> 02:45:21,880 AND THESE ARE THE VIRAL 3683 02:45:21,880 --> 02:45:23,880 GLYCOPROTEINS, VIRAL SPIKES. 3684 02:45:23,880 --> 02:45:27,240 I WILL REFER TO THESE AS 3685 02:45:27,240 --> 02:45:28,880 PROTEINS TODAY. 3686 02:45:28,880 --> 02:45:31,520 NOW, OF COURSE, THEY UTILIZE A 3687 02:45:31,520 --> 02:45:33,720 SPECIAL MOIETY, COULD BE 3688 02:45:33,720 --> 02:45:34,280 CHEMICAL MODIFICATION OR 3689 02:45:34,280 --> 02:45:36,120 SPECIFIC PROTEINS, THAT THEY ARE 3690 02:45:36,120 --> 02:45:37,880 FOUND IN THE CELL SURFACE AND 3691 02:45:37,880 --> 02:45:42,720 WE'LL SEE TODAY A VERY NICE OR 3692 02:45:42,720 --> 02:45:44,840 MAYBE UNUSUAL EXAMPLE HOW 3693 02:45:44,840 --> 02:45:46,960 VIRUSES UTILIZE GLYCANS TO ENTER 3694 02:45:46,960 --> 02:45:47,640 CELLS. 3695 02:45:47,640 --> 02:45:50,800 OF COURSE, VIRUSES DON'T DO THAT 3696 02:45:50,800 --> 02:45:51,800 IN VACUUM. 3697 02:45:51,800 --> 02:45:54,080 THERE IS THE HOST RESPONSE, A 3698 02:45:54,080 --> 02:45:57,280 WHOLE COMPLICATED ARENA OF 3699 02:45:57,280 --> 02:46:00,480 INTERACTIONS GOING ON HERE. 3700 02:46:00,480 --> 02:46:01,400 GLYCOBIOLOGY PLAYS A CENTRAL 3701 02:46:01,400 --> 02:46:07,200 ROLE, A LOT OF GLYCANS INVOLVED, 3702 02:46:07,200 --> 02:46:08,560 DEFINITELY INFLUENCES THE MANY 3703 02:46:08,560 --> 02:46:12,480 PROCESSES IN THE CELL ENTRY OF 3704 02:46:12,480 --> 02:46:12,680 VIRUSES. 3705 02:46:12,680 --> 02:46:13,760 I MENTION VIRAL GLYCOPROTEINS, 3706 02:46:13,760 --> 02:46:17,320 WE NEED TO DEFINE THEM. 3707 02:46:17,320 --> 02:46:21,080 AFTER TWO YEARS OR MORE OF THE 3708 02:46:21,080 --> 02:46:24,000 SARS PANDEMIC WE HEARD ABOUT THE 3709 02:46:24,000 --> 02:46:28,880 SPIKE PROTEIN, GAVE THE SARS THE 3710 02:46:28,880 --> 02:46:33,960 NAME, ALL THE CLASS 1 VIRAL 3711 02:46:33,960 --> 02:46:38,800 SPIKES ON SARS, INFLUENZA, AND 3712 02:46:38,800 --> 02:46:41,360 OTHERS, HAVE A SPECIFIC 3713 02:46:41,360 --> 02:46:42,160 ARCHITECTURE, SINGLE PROTEIN 3714 02:46:42,160 --> 02:46:44,760 GETTING CLEAVED IN ORDER TO BE 3715 02:46:44,760 --> 02:46:46,200 ACTIVATED AND THIS POLY PROTEIN 3716 02:46:46,200 --> 02:46:49,520 IS ORGANIZED AS A TRIMER ON THE 3717 02:46:49,520 --> 02:46:50,800 CELL MEMBRANE. 3718 02:46:50,800 --> 02:46:54,080 NOW, THE CLEAVAGE EVENT IS 3719 02:46:54,080 --> 02:46:55,080 ACTIVATING THE PROTEIN AND 3720 02:46:55,080 --> 02:46:56,480 EXPOSED NEW FOLDING SPACE FOR 3721 02:46:56,480 --> 02:46:59,520 THE PROTEINS SO IT EXISTS IN THE 3722 02:46:59,520 --> 02:47:03,480 META STABLE ZONE HIGH ENERGY 3723 02:47:03,480 --> 02:47:06,440 STATE, THAT CAN LATER REFOLD AND 3724 02:47:06,440 --> 02:47:09,200 DRIVE THE MEMBRANE INFUSION. 3725 02:47:09,200 --> 02:47:11,200 THE CLEAVAGE EVENT SEPARATES 3726 02:47:11,200 --> 02:47:12,440 BETWEEN THE N-TERMINAL PART AND 3727 02:47:12,440 --> 02:47:18,840 IN OUR CASE WE CALL IT GP 1, AND 3728 02:47:18,840 --> 02:47:20,640 GP2, THE MEMBRANE PART, GP1 IS 3729 02:47:20,640 --> 02:47:24,720 RESPONSIBLE FOR RECEPTOR AND 3730 02:47:24,720 --> 02:47:35,760 RECOGNITION, IT IT MAKES 3731 02:47:35,760 --> 02:47:39,320 RECEPTOR BINDING DOMAIN, AND GP 3732 02:47:39,320 --> 02:47:39,480 2. 3733 02:47:39,480 --> 02:47:41,680 IT'S A LOADED MOUSE TRAP WITH A 3734 02:47:41,680 --> 02:47:43,200 LOT OF POTENTIAL ENERGY, WAITING 3735 02:47:43,200 --> 02:47:45,360 TO BE RELEASED. 3736 02:47:45,360 --> 02:47:47,640 THIS ENERGY EVENTUALLY IS 3737 02:47:47,640 --> 02:47:48,760 TUNNELED TOWARD THE FUSION OF 3738 02:47:48,760 --> 02:47:52,520 THE MEMBRANE, YOU CAN SEE 3739 02:47:52,520 --> 02:48:01,560 SCHEMATIC DIAGRAM SHOWING THIS 3740 02:48:01,560 --> 02:48:01,800 PROCESS. 3741 02:48:01,800 --> 02:48:04,320 A FEATURE IS THE COAT, ENDING 3742 02:48:04,320 --> 02:48:06,680 GLYCANS THEY USE IN ORDER TO 3743 02:48:06,680 --> 02:48:08,440 CONCEAL THEMSELVES FROM THE 3744 02:48:08,440 --> 02:48:08,800 IMMUNE RESPONSE. 3745 02:48:08,800 --> 02:48:11,920 AND THIS IS A VERY NICE IMAGE, I 3746 02:48:11,920 --> 02:48:14,560 TOOK IT FROM A WRITTEN PAPER 3747 02:48:14,560 --> 02:48:16,680 ABOUT SARS, IT SHOWS THE GLYCANS 3748 02:48:16,680 --> 02:48:19,760 WITH SOME KIND OF MOLECULAR 3749 02:48:19,760 --> 02:48:21,680 DYNAMIC SHOW IT SHOWS REALLY HOW 3750 02:48:21,680 --> 02:48:24,200 MOST OF THE SURFACE OF THE VIRAL 3751 02:48:24,200 --> 02:48:26,800 PROTEIN IS CONCEALED UNDER THESE 3752 02:48:26,800 --> 02:48:27,760 GLYCANS. 3753 02:48:27,760 --> 02:48:32,800 THIS IS WELL-KNOWN EXAMPLES OF A 3754 02:48:32,800 --> 02:48:34,240 GLYCAN FOR VIRUSES, BUT THERE'S 3755 02:48:34,240 --> 02:48:35,640 MORE TO IT. 3756 02:48:35,640 --> 02:48:39,280 TODAY I'M GOING TO SHOW HOW 3757 02:48:39,280 --> 02:48:41,240 LASSA IS ACTUALLY USING A 3758 02:48:41,240 --> 02:48:44,040 SPECIAL KIND OF GLYCAN TO ENTER 3759 02:48:44,040 --> 02:48:44,480 CELLS. 3760 02:48:44,480 --> 02:48:46,080 SO WHAT IS THE LASSA VIRUS? 3761 02:48:46,080 --> 02:48:51,080 THE LASSA VIRUS IS A PATHOGENIC 3762 02:48:51,080 --> 02:48:51,960 VIRUS, CAUSES LASSA HEMORRHAGIC 3763 02:48:51,960 --> 02:48:53,240 FEVER, THE DISEASE. 3764 02:48:53,240 --> 02:48:56,480 IT'S A VIRUS ENDEMIC TO WESTERN 3765 02:48:56,480 --> 02:48:56,720 AFRICA. 3766 02:48:56,720 --> 02:49:03,080 INFECTS THOUSANDS OF PEOPLE 3767 02:49:03,080 --> 02:49:04,160 ANNUALLY. 3768 02:49:04,160 --> 02:49:10,240 SO FAR WE DON'T HAVE ANY 3769 02:49:10,240 --> 02:49:15,240 APPROVED VACCINE FOR THIS VIRUS. 3770 02:49:15,240 --> 02:49:21,680 IT ENTERS USING A GLYCAN, 3771 02:49:21,680 --> 02:49:22,840 MATRIGLYCAN. 3772 02:49:22,840 --> 02:49:26,680 MATRIGLYCAN IS A UNIQUE 3773 02:49:26,680 --> 02:49:33,320 MODIFICATION OF THE UBIQUITOUS 3774 02:49:33,320 --> 02:49:35,000 PRO TOWN ALPHA DYSTROGLYCAN 3775 02:49:35,000 --> 02:49:36,680 FOUND ON MANY CELL TYPES 3776 02:49:36,680 --> 02:49:39,160 MODIFIED BY A SERIES OF ENZYMES. 3777 02:49:39,160 --> 02:49:42,480 THIS IS AN OLINK MODIFICATION, 3778 02:49:42,480 --> 02:49:44,920 SO THERE'S THE FIRST EVENT 3779 02:49:44,920 --> 02:49:47,800 PHOSPHORYLATION, THEN ADDITIONAL 3780 02:49:47,800 --> 02:49:49,640 FEW ENZYMES, MODIFIED, ADDING A 3781 02:49:49,640 --> 02:49:51,600 FEW SUGAR MONOMERS TO CREATE THE 3782 02:49:51,600 --> 02:49:52,480 PRIMER. 3783 02:49:52,480 --> 02:50:03,880 THIS PRIMER IS RECOGNIZED BY 3784 02:50:03,880 --> 02:50:04,480 LARGE1. 3785 02:50:04,480 --> 02:50:06,240 MATRIGLYCAN IS REPEATING LINEAR 3786 02:50:06,240 --> 02:50:23,680 CHAIN OF SUGAR MADE OF XYLOSE 3787 02:50:23,680 --> 02:50:25,320 AND GLUCARONIC ACID. 3788 02:50:25,320 --> 02:50:33,000 NOW SHOULD GIVE CREDIT BECAUSE 3789 02:50:33,000 --> 02:50:36,240 THE DISCOVERY AND FIGURING OUT 3790 02:50:36,240 --> 02:50:37,240 ENZYMES TO GENERATE MATTERY 3791 02:50:37,240 --> 02:50:39,040 GLYCANS WAS DONE IN THE LAB OF 3792 02:50:39,040 --> 02:50:41,160 KEVIN CAMPBELL, UNIVERSITY OF 3793 02:50:41,160 --> 02:50:41,360 IOWA. 3794 02:50:41,360 --> 02:50:44,240 HE'S THE ONE THAT SHOULD GET THE 3795 02:50:44,240 --> 02:50:45,680 CREDIT FOR THAT. 3796 02:50:45,680 --> 02:50:48,840 AND I JUST WANT TO MENTION 3797 02:50:48,840 --> 02:50:52,240 LARGE1 IS A UNIQUE TRANSFERASE, 3798 02:50:52,240 --> 02:50:56,400 DUAL ACTIVITIES, CAN FACILITATE 3799 02:50:56,400 --> 02:50:58,640 IN COOPERATION WITH XYLOSE AND 3800 02:50:58,640 --> 02:51:02,120 GLUCARONIC ACID HAVING TWO 3801 02:51:02,120 --> 02:51:03,920 CATALYTIC DOMAINS, WE STUDIED 3802 02:51:03,920 --> 02:51:04,960 THIS ENZYME, FUNCTIONS AS A 3803 02:51:04,960 --> 02:51:05,640 DIMER. 3804 02:51:05,640 --> 02:51:08,400 WE HAVE TWO CATALYTIC DOMAINS IN 3805 02:51:08,400 --> 02:51:13,680 EACH MONOMER, IN THE MERIC FORM 3806 02:51:13,680 --> 02:51:18,040 HAVE AN INTERESTING ASSEMBLY 3807 02:51:18,040 --> 02:51:21,840 WHICH THE TWO ACTIVE SIDES OF 3808 02:51:21,840 --> 02:51:23,240 THE XYLOSE TRANSFER AND 3809 02:51:23,240 --> 02:51:24,880 GLUCARONIC ACID TRANSFERASE 3810 02:51:24,880 --> 02:51:28,080 POINT TO THE SAME DIRECTION FROM 3811 02:51:28,080 --> 02:51:28,680 TWO OPPOSITE MONOMERS, AN 3812 02:51:28,680 --> 02:51:29,480 INTERESTING FEATURE. 3813 02:51:29,480 --> 02:51:34,240 WE THINK IT MAY RELATE TOED 3814 02:51:34,240 --> 02:51:37,080 PROCESSIVITY OF THE ENZYME AND 3815 02:51:37,080 --> 02:51:39,480 THE MATRIGLYCAN IS LONG, COULD 3816 02:51:39,480 --> 02:51:42,240 REACH UP TO 100, SOMETIMES 3817 02:51:42,240 --> 02:51:49,680 THOUSANDS OF REPEATS, OF THE 3818 02:51:49,680 --> 02:51:51,280 XYLOSE AND GLUCARONIC ACID 3819 02:51:51,280 --> 02:51:53,920 SUBUNITS. 3820 02:51:53,920 --> 02:51:56,400 LASSA VIRUS IS BINDING TO ENTER 3821 02:51:56,400 --> 02:51:58,600 CELLS, FIGURED OUT QUITE SOME 3822 02:51:58,600 --> 02:52:00,320 TIME AGO ACTUALLY. 3823 02:52:00,320 --> 02:52:03,640 IT'S DOING SO WITH ITS VIRAL 3824 02:52:03,640 --> 02:52:04,640 SPIKE COMPLEX, VIRAL 3825 02:52:04,640 --> 02:52:04,960 GLYCOPROTEIN. 3826 02:52:04,960 --> 02:52:06,680 LET'S LOOK AT THIS IN MORE 3827 02:52:06,680 --> 02:52:08,440 DETAIL FOR A SECOND. 3828 02:52:08,440 --> 02:52:11,640 I TELL YOU THERE'S A GENETIC 3829 02:52:11,640 --> 02:52:14,760 STRUCTURE IN WHICH THEY HAVE TWO 3830 02:52:14,760 --> 02:52:17,400 SUBUNITS, GP1 AND GP2, IN THE 3831 02:52:17,400 --> 02:52:19,480 CASE OF LASSA IT'S MORE 3832 02:52:19,480 --> 02:52:20,440 COMPLICATED WITH SIGNAL 3833 02:52:20,440 --> 02:52:20,680 PEPTIDES. 3834 02:52:20,680 --> 02:52:22,280 SIGNAL PEPTIDE OF THE LASSA 3835 02:52:22,280 --> 02:52:24,880 VIRUS AND OF ALL THE OTHER 3836 02:52:24,880 --> 02:52:27,240 ARENAVIRUSES THAT BELONG TO THE 3837 02:52:27,240 --> 02:52:28,960 SAME FAMILY IS QUITE LONG. 3838 02:52:28,960 --> 02:52:33,040 YOU CAN SEE ALMOST 60 RESIDUES 3839 02:52:33,040 --> 02:52:34,440 LONG. 3840 02:52:34,440 --> 02:52:35,480 AND UNLIKE MOST CASES, ACTUALLY 3841 02:52:35,480 --> 02:52:38,840 THIS IS THE ONLY CASE THAT I'M 3842 02:52:38,840 --> 02:52:39,680 FAMILIAR WITH, THE SIGNAL 3843 02:52:39,680 --> 02:52:41,720 PEPTIDE IS START OF THE MATURE 3844 02:52:41,720 --> 02:52:42,800 COMPLEX, VERY IMPORTANT FOR 3845 02:52:42,800 --> 02:52:44,520 FUNCTION OF THE COMPLEX, AND 3846 02:52:44,520 --> 02:52:46,440 THIS IS A KNOWN THING IN THE 3847 02:52:46,440 --> 02:52:48,400 FIELD FOR MANY YEARS. 3848 02:52:48,400 --> 02:52:50,640 SO THE SPIKE OF THE LASSA VIRUS 3849 02:52:50,640 --> 02:52:52,240 WILL LOOK LIKE THAT. 3850 02:52:52,240 --> 02:52:54,440 A SIGNAL PEPTIDE IS INTEGRAL 3851 02:52:54,440 --> 02:52:55,680 PART OF THIS COMPLEX. 3852 02:52:55,680 --> 02:52:58,880 NOW, THE CELL ENTRY OF THE LASSA 3853 02:52:58,880 --> 02:53:03,840 VIRUS IS QUITE COMPLICATED 3854 02:53:03,840 --> 02:53:06,880 PROCESS BECAUSE IT BINDS DISTAL 3855 02:53:06,880 --> 02:53:11,000 GLYCAN TO THE MATRIGLYCAN ON THE 3856 02:53:11,000 --> 02:53:14,800 SURFACE BUT WHEN ENTERS THE 3857 02:53:14,800 --> 02:53:21,920 CELLS IN PH-DRIVEN PASSION 3858 02:53:21,920 --> 02:53:26,080 DISASSOCIATES, REACHES ENDOSOME, 3859 02:53:26,080 --> 02:53:27,640 FINDS SECONDORY RECEPTOR LAMP 1, 3860 02:53:27,640 --> 02:53:28,880 TRIGGER THE SPIKE. 3861 02:53:28,880 --> 02:53:30,480 IT COULD BE A COMPLICATED 3862 02:53:30,480 --> 02:53:32,040 PROCESS AND WE'VE BEEN STUDYING 3863 02:53:32,040 --> 02:53:37,800 THIS PROCESS FOR QUITE SOME 3864 02:53:37,800 --> 02:53:39,680 TIME, INTERESTING INSIGHT BUT 3865 02:53:39,680 --> 02:53:41,520 MANY OPEN QUESTIONS THAT SOME OF 3866 02:53:41,520 --> 02:53:43,280 THEM ARE LISTED HERE. 3867 02:53:43,280 --> 02:53:46,880 AND ONE OF THE MAIN QUESTIONS WE 3868 02:53:46,880 --> 02:53:50,640 HAD WAS HOW LASSA VIRUS BINDS 3869 02:53:50,640 --> 02:53:52,840 AND RECOGNIZES MATTERY GLYCANS. 3870 02:53:52,840 --> 02:53:58,120 FOR THE FIELD OF VIROLOGY, 3871 02:53:58,120 --> 02:53:58,880 FIGURING OUT HOW THE VIRUS 3872 02:53:58,880 --> 02:53:59,360 ACTUALLY ATTACHES TO THE 3873 02:53:59,360 --> 02:53:59,960 RECEPTOR IS A CRITICAL THING 3874 02:53:59,960 --> 02:54:01,320 BECAUSE IF YOU THINK ABOUT 3875 02:54:01,320 --> 02:54:02,800 THERAPEUTICS, IF YOU THINK ABOUT 3876 02:54:02,800 --> 02:54:05,280 THINGS THAT WILL EVENTUALLY 3877 02:54:05,280 --> 02:54:07,600 BLOCK THIS RECOGNITION, THIS IS 3878 02:54:07,600 --> 02:54:10,440 A KEY QUESTION TO ANSWER WHEN 3879 02:54:10,440 --> 02:54:11,800 YOU DEAL WITH VIRUSES. 3880 02:54:11,800 --> 02:54:13,880 WE WERE REALLY BOTHERED WITH 3881 02:54:13,880 --> 02:54:18,800 THIS QUESTION OF HOW LASSA VIRUS 3882 02:54:18,800 --> 02:54:19,680 BINDS MATRIGLYCANS. 3883 02:54:19,680 --> 02:54:21,720 ONE REASON WE HAD SO MANY OPEN 3884 02:54:21,720 --> 02:54:24,800 QUESTIONS WE COULDN'T ANSWER, 3885 02:54:24,800 --> 02:54:26,600 THE PARTICULAR QUESTION OF THE 3886 02:54:26,600 --> 02:54:28,680 MATRIGLYCAN RECOGNITION, WE AND 3887 02:54:28,680 --> 02:54:34,760 OTHERS COULDN'T PRODUCE IN A 3888 02:54:34,760 --> 02:54:36,280 STABLE FASHION THE ECTODOMAIN, 3889 02:54:36,280 --> 02:54:37,600 THE EXTRACELLULAR PORTION OF THE 3890 02:54:37,600 --> 02:54:37,800 SPIKE. 3891 02:54:37,800 --> 02:54:42,600 IF WE LOOK AT OTHER CLASS 1 3892 02:54:42,600 --> 02:54:43,360 SPIKES, LIKE EBOLA VIRUS, FOR 3893 02:54:43,360 --> 02:54:46,440 EXAMPLE, YOU CAN SEE HERE IT WAS 3894 02:54:46,440 --> 02:54:49,280 VERY EASY TO PRODUCE THE 3895 02:54:49,280 --> 02:54:51,720 ECTODOMAIN PORTION AND THAT WAS 3896 02:54:51,720 --> 02:54:52,880 VERY AMENABLE FOR STRUCTURAL 3897 02:54:52,880 --> 02:54:55,200 STUDIES SO WE HAVE A LOT OF 3898 02:54:55,200 --> 02:54:56,400 INFORMATION ABOUT COMPLEX OF 3899 02:54:56,400 --> 02:54:57,080 OTHER VIRUSES. 3900 02:54:57,080 --> 02:55:00,080 BUT THAT WAS NOT THE CASE FOR 3901 02:55:00,080 --> 02:55:02,680 THE LASSA BECAUSE WE DIDN'T -- 3902 02:55:02,680 --> 02:55:04,080 COULDN'T DO THAT PROBABLY 3903 02:55:04,080 --> 02:55:09,240 BECAUSE OF THE UNIQUE STRUCTURAL 3904 02:55:09,240 --> 02:55:09,440 ROLE. 3905 02:55:09,440 --> 02:55:13,680 WE DECIDED TO TAKE A HOLISTIC 3906 02:55:13,680 --> 02:55:15,480 APPROACH AND EXTRACT THE ENTIRE 3907 02:55:15,480 --> 02:55:17,080 SPIKE WITH THE TRANSMEMBRANE 3908 02:55:17,080 --> 02:55:17,320 DOMAIN. 3909 02:55:17,320 --> 02:55:19,640 A BIT MORE INVOLVED TECHNICALLY. 3910 02:55:19,640 --> 02:55:21,840 AND THIS IS DEFINITELY NOT THE 3911 02:55:21,840 --> 02:55:24,560 FIRST APPROACH, WHEN WE START TO 3912 02:55:24,560 --> 02:55:29,760 THINK ABOUT STRUCTURAL 3913 02:55:29,760 --> 02:55:31,320 APPROACHES, STRUCTURAL STUDIES 3914 02:55:31,320 --> 02:55:35,200 BUT WERE ABLE TO PUT THIS SPIKE 3915 02:55:35,200 --> 02:55:38,880 ON, YOU CAN SEE THE INDIVIDUAL 3916 02:55:38,880 --> 02:55:40,480 PARTICLES WHICH GAVE NICELY THE 3917 02:55:40,480 --> 02:55:42,480 CLASSES, ABLE TO RECONSTRUCT THE 3918 02:55:42,480 --> 02:55:43,720 STRUCTURE OFF THE SPIKE SITTING 3919 02:55:43,720 --> 02:55:47,360 IN THE MEMBRANE, WERE ABLE TO 3920 02:55:47,360 --> 02:55:48,200 RESOLVE THIS TRANSMEMBRANE 3921 02:55:48,200 --> 02:55:48,560 REGION. 3922 02:55:48,560 --> 02:55:51,440 THIS IS THE POINT I NEED TO GIVE 3923 02:55:51,440 --> 02:55:53,880 CREDIT, THIS WAS THE WORK DONE 3924 02:55:53,880 --> 02:55:55,800 BY A VERY TALENTED Ph.D. 3925 02:55:55,800 --> 02:56:07,880 STUDENT IN MY LAB, MICHAEL KATZ. 3926 02:56:07,880 --> 02:56:11,720 AND MAAYAN HELPED MICHAEL. 3927 02:56:11,720 --> 02:56:13,760 THIS STRUCTURE INFORMATION WAS 3928 02:56:13,760 --> 02:56:14,920 REALLY UNIQUE AND ANSWERED A LOT 3929 02:56:14,920 --> 02:56:16,040 OF QUESTIONS. 3930 02:56:16,040 --> 02:56:18,640 TODAY I WILL ONLY SHARE A COUPLE 3931 02:56:18,640 --> 02:56:21,200 OF INSIGHTS THAT WE LEARNED FROM 3932 02:56:21,200 --> 02:56:21,800 THIS STRUCTURE. 3933 02:56:21,800 --> 02:56:27,160 AND THE FIRST ONE RELATED TO THE 3934 02:56:27,160 --> 02:56:30,360 FIELD, WE'RE TALKING ABOUT 3935 02:56:30,360 --> 02:56:33,120 GLYCOBIOLOGY, IT'S QUITE UNIQUE 3936 02:56:33,120 --> 02:56:33,480 AND INTERESTING. 3937 02:56:33,480 --> 02:56:37,240 SO IF WE LOOK AT THE MEMBRANE 3938 02:56:37,240 --> 02:56:47,720 AND ORGANIZATION OF 3939 02:56:47,720 --> 02:56:50,720 TRANSMEMBRANE HELICASES, THEY 3940 02:56:50,720 --> 02:56:54,040 BELONG TO THE TRANSMEMBRANE BUT 3941 02:56:54,040 --> 02:56:58,600 HELP WITH FUSION, SSP FITS IN 3942 02:56:58,600 --> 02:57:00,080 THE OUTER PERIPHERY OF THE 3943 02:57:00,080 --> 02:57:05,120 CENTRAL BUNDLE. 3944 02:57:05,120 --> 02:57:08,080 IT'S QUITE INTERESTING, IT 3945 02:57:08,080 --> 02:57:11,240 STARTS WITH THIS TOPOLOGY, SO 3946 02:57:11,240 --> 02:57:13,400 THE HERE IS THE INNER LUMEN, 3947 02:57:13,400 --> 02:57:20,000 HERE IS THE CYTOPLASM. 3948 02:57:20,000 --> 02:57:22,760 THIS IS SSP WHEN PROTEIN IS 3949 02:57:22,760 --> 02:57:27,560 PRODUCED, SIGNAL PEPTIDE IS 3950 02:57:27,560 --> 02:57:30,120 RECOGNIZED, BY SIGNAL 3951 02:57:30,120 --> 02:57:32,560 PEPTIDEASE, CLEAVES, WE SEE A 3952 02:57:32,560 --> 02:57:32,800 SWITCH. 3953 02:57:32,800 --> 02:57:33,880 HELICAL SEGMENT WE CANNOT 3954 02:57:33,880 --> 02:57:35,600 OBSERVE IN DENSITY MAPS WE DON'T 3955 02:57:35,600 --> 02:57:36,720 HAVE A STRUCTURAL DESCRIPTION OF 3956 02:57:36,720 --> 02:57:40,600 THE HELIX BUT IT FLIPS FROM THIS 3957 02:57:40,600 --> 02:57:42,640 STATE TO THIS STATE AND WE HAVE 3958 02:57:42,640 --> 02:57:44,800 A LOT OF BIOCHEMICAL DATA THAT 3959 02:57:44,800 --> 02:57:46,240 WAS ACCUMULATED OVER THE YEARS, 3960 02:57:46,240 --> 02:57:49,880 THAT SUPPORTS THE FACT THAT THIS 3961 02:57:49,880 --> 02:57:52,920 C-TERMINAL REGION OF THE SSP IS 3962 02:57:52,920 --> 02:57:54,200 LOCATED IN THE CYTOPLASM. 3963 02:57:54,200 --> 02:57:57,480 SO THE PART WE ACTUALLY SEE IN 3964 02:57:57,480 --> 02:58:00,480 THE STRUCTURE IS SHOWN HERE, SO 3965 02:58:00,480 --> 02:58:02,240 WE SEE THIS REGION OF SIGNAL 3966 02:58:02,240 --> 02:58:02,800 PEPTIDE. 3967 02:58:02,800 --> 02:58:04,560 AND THIS IS THE SIGNAL PEPTIDE 3968 02:58:04,560 --> 02:58:07,760 IN THE CONTEXT OF THE COMPLETE 3969 02:58:07,760 --> 02:58:07,960 SITE. 3970 02:58:07,960 --> 02:58:11,680 WHAT IS THE ROLE OF THE SIGNAL 3971 02:58:11,680 --> 02:58:12,000 PEPTIDE? 3972 02:58:12,000 --> 02:58:14,160 WELL, I SHOULD ALSO MENTION THE 3973 02:58:14,160 --> 02:58:16,200 TOPOLOGY THAT WE OBSERVED WAS 3974 02:58:16,200 --> 02:58:17,680 NOT PREDICTED, ALTHOUGH MANY 3975 02:58:17,680 --> 02:58:20,200 PEOPLE TRIED TO ADDRESS THAT, I 3976 02:58:20,200 --> 02:58:23,440 THINK ONE OF THE CONFUSING 3977 02:58:23,440 --> 02:58:25,480 THINGS THAT THERE IS A TOPOLOGY 3978 02:58:25,480 --> 02:58:27,160 SWITCH THAT OCCURS WHICH REALLY 3979 02:58:27,160 --> 02:58:28,680 CONFUSED THE PEOPLE THAT TRIED 3980 02:58:28,680 --> 02:58:32,440 TO ADDRESS THE TOPOLOGY BEFORE. 3981 02:58:32,440 --> 02:58:35,400 WHAT IS THE ROLE OF THIS? 3982 02:58:35,400 --> 02:58:37,280 IF WE LOOK AT THE STRUCTURE, 3983 02:58:37,280 --> 02:58:40,680 THESE ARE ONLY THE CENTRAL 3984 02:58:40,680 --> 02:58:42,880 HELICASES, OF GP2, WE TOOK THE 3985 02:58:42,880 --> 02:58:45,680 SINGLE PEPTIDE AWAY, YOU CAN SEE 3986 02:58:45,680 --> 02:58:49,480 THEY ARE TWISTED AROUND EACH 3987 02:58:49,480 --> 02:58:49,680 OTHER. 3988 02:58:49,680 --> 02:58:53,440 THIS IS AN INTERESTING THING. 3989 02:58:53,440 --> 02:58:57,320 AND WE THINK THAT THIS TWIST IS 3990 02:58:57,320 --> 02:59:00,160 NOT STABLE BY ITSELF. 3991 02:59:00,160 --> 02:59:01,840 AND IT'S BEING STUDIED IN THE 3992 02:59:01,840 --> 02:59:03,560 CONTEXT OF NATIVE SPIKE BY THE 3993 02:59:03,560 --> 02:59:04,240 SSP ITSELF. 3994 02:59:04,240 --> 02:59:07,920 YOU CAN SEE HOW THE SSP FITS IN 3995 02:59:07,920 --> 02:59:21,440 THE BETWEEN THE HELICES AND 3996 02:59:21,440 --> 02:59:22,240 HOLDS IN TWISTED CONFIRMATION, 3997 02:59:22,240 --> 02:59:23,520 WE BETWEEN IT'S AN INTEGRAL PART 3998 02:59:23,520 --> 02:59:32,320 OF THE SPIKE THAT KEEPS IT IN 3999 02:59:32,320 --> 02:59:33,920 NATIVE CONFIRMATION. 4000 02:59:33,920 --> 02:59:35,680 WE SEE ANOTHER INTERESTING 4001 02:59:35,680 --> 02:59:36,200 THING. 4002 02:59:36,200 --> 02:59:38,880 YOU CAN SEE DOMAIN SWITCHING, 4003 02:59:38,880 --> 02:59:42,120 TRIPLE DOMAIN SWITCHING BETWEEN 4004 02:59:42,120 --> 02:59:42,760 MONOMERS. 4005 02:59:42,760 --> 02:59:45,680 THIS MONOMER IS A CONTRIBUTING 4006 02:59:45,680 --> 02:59:47,360 THIS PART THAT INTERACTS WITH 4007 02:59:47,360 --> 02:59:48,600 THE TWO ADJACENT MONOMERS. 4008 02:59:48,600 --> 02:59:50,560 YOU CAN SEE EACH ONE IS DOING 4009 02:59:50,560 --> 02:59:52,880 THE SAME THING SO WE HAVE 4010 02:59:52,880 --> 02:59:54,080 THREE-FOLD SYMMETRY HERE, AND 4011 02:59:54,080 --> 02:59:56,760 YOU CAN THINK ABOUT THAT AS A 4012 02:59:56,760 --> 03:00:00,520 COVER OF A CARD BOX, THAT IT WAS 4013 03:00:00,520 --> 03:00:04,440 THE FLAPS ARE ON TOP OF EACH 4014 03:00:04,440 --> 03:00:09,360 OTHER, AND THEY BASICALLY SEAL 4015 03:00:09,360 --> 03:00:13,400 THE SPIKE AND MUTUALLY STABILIZE 4016 03:00:13,400 --> 03:00:14,800 THIS PARTICULAR CONFORMATION. 4017 03:00:14,800 --> 03:00:17,880 THAT'S AN INTERESTING THING TO 4018 03:00:17,880 --> 03:00:18,040 SEE. 4019 03:00:18,040 --> 03:00:19,720 NOW, THIS LITTLE PART, VERY 4020 03:00:19,720 --> 03:00:22,600 IMPORTANT FOR THE SPIKE BECAUSE 4021 03:00:22,600 --> 03:00:27,320 THIS IS THE SKI RECOGNITION 4022 03:00:27,320 --> 03:00:27,600 SITE. 4023 03:00:27,600 --> 03:00:30,440 SKI IS USED TO ACTIVATE 4024 03:00:30,440 --> 03:00:30,880 THEMSELVES. 4025 03:00:30,880 --> 03:00:36,560 AND YOU CAN SEE WE HAVE 2 4026 03:00:36,560 --> 03:00:38,880 ARGININE, 2 LEUCINE, THIS IS THE 4027 03:00:38,880 --> 03:00:41,400 PIECE DONATED BY THE NEIGHBORING 4028 03:00:41,400 --> 03:00:41,840 MONOMER. 4029 03:00:41,840 --> 03:00:43,840 AND YOU CAN SEE IT HERE, THIS IS 4030 03:00:43,840 --> 03:00:46,560 THE CLEAVAGE POINT. 4031 03:00:46,560 --> 03:00:50,600 THIS IS THE SKI RECOGNITION PART 4032 03:00:50,600 --> 03:00:52,080 OF L. 4033 03:00:52,080 --> 03:00:54,520 AND WE SAW A SURPRISE HERE. 4034 03:00:54,520 --> 03:00:56,480 THIS IS QUITE COMMON ACTUALLY 4035 03:00:56,480 --> 03:00:57,280 WHEN WE SOLVE STRUCTURES. 4036 03:00:57,280 --> 03:00:59,040 THERE ARE MANY THINGS WE DIDN'T 4037 03:00:59,040 --> 03:01:01,240 EVEN THINK THAT WE WOULD SEE. 4038 03:01:01,240 --> 03:01:03,880 WE DISCOVERED THEN IN THE 4039 03:01:03,880 --> 03:01:05,520 DENSITY, WE SAW THIS EXTRA 4040 03:01:05,520 --> 03:01:08,560 DENSITY SITTING AT THE TOP OF 4041 03:01:08,560 --> 03:01:10,560 THE SPIKE. 4042 03:01:10,560 --> 03:01:16,200 AND THINGS WE RECONSTRUCTED, THE 4043 03:01:16,200 --> 03:01:17,960 SPIKE, USING THREE-FOLD 4044 03:01:17,960 --> 03:01:19,720 SYMMETRY, C3, FRAGMENTED DENSITY 4045 03:01:19,720 --> 03:01:21,920 BUT NEVERTHELESS WERE ABLE TO 4046 03:01:21,920 --> 03:01:37,880 FIT PIECES OF MATRIDENSITY, WHAT 4047 03:01:37,880 --> 03:01:44,280 WE SEE, YOU CAN SEE IT HERE WE 4048 03:01:44,280 --> 03:01:45,920 HAVE SPECIFIC ANTIBODY THAT 4049 03:01:45,920 --> 03:01:55,760 RECOGNIZES MATTERY GLYCANS -- 4050 03:01:55,760 --> 03:01:58,160 MATRIGLYCANS CARRIED. 4051 03:01:58,160 --> 03:02:01,920 IT'S NOT SURPRISING WE SEE A LOT 4052 03:02:01,920 --> 03:02:03,680 OF HYDROPHILIC INTERACTIONS, 4053 03:02:03,680 --> 03:02:04,760 POLAR INTERACTIONS THAT THOSE 4054 03:02:04,760 --> 03:02:08,920 POLAR RESIDUES MAKE WITH THE 4055 03:02:08,920 --> 03:02:22,000 MATRIGLYCANS, YOU CAN SEE THE 4056 03:02:22,000 --> 03:02:26,720 ARGININE 257 AND 256. 4057 03:02:26,720 --> 03:02:28,240 THERE FEATURES THAT INTERACT 4058 03:02:28,240 --> 03:02:28,640 WITH MATRIGLYCANS. 4059 03:02:28,640 --> 03:02:31,960 WE HAVE A DESCRIPTION FOR THE 4060 03:02:31,960 --> 03:02:34,480 INTERACTION BUT THIS ALSO GIVES 4061 03:02:34,480 --> 03:02:37,880 US A LOT OF INFORMATION ABOUT 4062 03:02:37,880 --> 03:02:42,800 OUR CLUES ABOUT WHY WE SEE 4063 03:02:42,800 --> 03:02:46,000 CERTAIN CONSERVATION IN CERTAIN 4064 03:02:46,000 --> 03:02:47,880 VIRUSES. 4065 03:02:47,880 --> 03:02:48,560 THIS WAS QUITE ENIGMATIC, 4066 03:02:48,560 --> 03:02:50,440 OBSERVES A FEW YEARS AGO THAT 4067 03:02:50,440 --> 03:02:54,840 VIRUSES THAT BELONG TO THIS 4068 03:02:54,840 --> 03:02:57,480 FAMILY OF VIRUSES, ARENA 4069 03:02:57,480 --> 03:03:01,240 VIRIDAE, USE SKI TO ACTIVATE BUT 4070 03:03:01,240 --> 03:03:01,960 DON'T USE MATRIGLYCAN, YOU CAN 4071 03:03:01,960 --> 03:03:04,400 SEE A LIST OF VIRUSES THAT 4072 03:03:04,400 --> 03:03:07,480 BELONG TO THIS GROUP. 4073 03:03:07,480 --> 03:03:10,080 THEY HAVE A VERY CONSERVE THE 4074 03:03:10,080 --> 03:03:11,360 FIRST ARGININE, THIS ARGININE, 4075 03:03:11,360 --> 03:03:15,520 AND THEN ANOTHER SEQUENCE THAT 4076 03:03:15,520 --> 03:03:16,560 IS SEMI CONSERVED BUT RECOGNIZE 4077 03:03:16,560 --> 03:03:17,080 BRIDE SKI. 4078 03:03:17,080 --> 03:03:20,120 IF YOU COMPARE TO VIRUSES THAT 4079 03:03:20,120 --> 03:03:28,800 DO USE MATRIGLYCAN, THE SECOND 4080 03:03:28,800 --> 03:03:30,880 SITE IS HIGHLY CONSERVED. 4081 03:03:30,880 --> 03:03:33,760 THIS PARTICULAR ARGININE MAKES 4082 03:03:33,760 --> 03:03:35,320 CRITICAL CONTACTS WITH 4083 03:03:35,320 --> 03:03:37,000 MATRIGLYCANS, SO IT'S STABILIZED 4084 03:03:37,000 --> 03:03:38,840 ON ONE SIDE WITH MULTIPLE 4085 03:03:38,840 --> 03:03:40,120 INTERACTIONS WITH THE BACKBONE 4086 03:03:40,120 --> 03:03:43,640 OF THE PROTEIN, AND ON THE OTHER 4087 03:03:43,640 --> 03:03:45,400 SIDE IT MAKES MULTIPLE CONTACTS 4088 03:03:45,400 --> 03:03:46,600 WITH MATRIGLYCAN. 4089 03:03:46,600 --> 03:03:49,040 THIS IS A CRITICAL FEATURE FOR 4090 03:03:49,040 --> 03:03:50,720 THE RECOGNITION OF MATRIGLYCAN, 4091 03:03:50,720 --> 03:03:53,680 THAT EXPLAINS THE CONSERVATION 4092 03:03:53,680 --> 03:03:55,440 HERE. 4093 03:03:55,440 --> 03:04:01,680 I TOLD YOU WE RECONSTRUCTED 4094 03:04:01,680 --> 03:04:10,080 DENSITY MAP USING THE SYMMETRY. 4095 03:04:10,080 --> 03:04:14,520 MATRIGLYCAN DOESN'T HAVE 4096 03:04:14,520 --> 03:04:18,160 SYMMETRY, WE RECONSTRUCTED 4097 03:04:18,160 --> 03:04:19,520 WITHOUT IMPOSING ANY SYMMETRY 4098 03:04:19,520 --> 03:04:20,840 CONSTRAINTS. 4099 03:04:20,840 --> 03:04:22,080 C1 MAP. 4100 03:04:22,080 --> 03:04:25,480 NOW WE GOT AN ELONGATED PIECE OF 4101 03:04:25,480 --> 03:04:28,600 DENSITY IN WHICH WE COULD ALSO 4102 03:04:28,600 --> 03:04:30,760 FIT SUGAR RESIDUES IN BETWEEN 4103 03:04:30,760 --> 03:04:34,480 THE INITIAL PIECES THAT WE 4104 03:04:34,480 --> 03:04:41,000 MODELED AND HAVE GLUCARONIC ACID 4105 03:04:41,000 --> 03:04:41,920 AND INTERESTINGLY GLUCARONIC 4106 03:04:41,920 --> 03:04:45,200 ACID IN THIS REGION MAKES 4107 03:04:45,200 --> 03:04:47,720 ADDITIONAL INTERESTING CONTACTS 4108 03:04:47,720 --> 03:04:48,680 WITH THE PROTEIN ITSELF, IN 4109 03:04:48,680 --> 03:04:54,720 PARTICULAR WE CAN SEE HERE THAT 4110 03:04:54,720 --> 03:04:57,920 THE CHARGE GROUP IS SERVING AS 4111 03:04:57,920 --> 03:05:02,160 N-TERMINAL CAP FOR HELIX OF THE 4112 03:05:02,160 --> 03:05:02,680 SPIKE. 4113 03:05:02,680 --> 03:05:03,680 NOW, N-TERMINAL CAPS ARE 4114 03:05:03,680 --> 03:05:05,760 STABILIZERS, SO IT'S NOT ONLY 4115 03:05:05,760 --> 03:05:06,960 BINDING THE SPIKE, IT'S 4116 03:05:06,960 --> 03:05:10,240 STABILIZING THE SPIKE IN THIS 4117 03:05:10,240 --> 03:05:14,160 PARTICULAR NATIVE CONFORMATION 4118 03:05:14,160 --> 03:05:15,160 OF THE SPIKE. 4119 03:05:15,160 --> 03:05:16,080 >> A MINUTE, RON. 4120 03:05:16,080 --> 03:05:20,200 >> I WILL TRY TO BE FAST. 4121 03:05:20,200 --> 03:05:24,200 SO WE WERE WONDERING WHAT THE 4122 03:05:24,200 --> 03:05:27,640 SOURCE OF THIS MATRIGLYCAN IS. 4123 03:05:27,640 --> 03:05:32,600 IT IS HIGHLY SPECIALIZED YOUR 4124 03:05:32,600 --> 03:05:36,240 MEEK MODIFICATION OF ALPHA 4125 03:05:36,240 --> 03:05:38,160 DISTRA GLYCAN. 4126 03:05:38,160 --> 03:05:40,240 ONE POSSIBILITY LASSA GRABBED 4127 03:05:40,240 --> 03:05:44,720 SOME FROM THE CELLS WHILE WE 4128 03:05:44,720 --> 03:05:46,560 WERE PURIFYING BUT WE COULDN'T 4129 03:05:46,560 --> 03:05:48,000 FIND ANY BIOCHEMICAL EVIDENCE SO 4130 03:05:48,000 --> 03:05:57,480 WE CAN SEE IF WE JUST PUT THEM 4131 03:05:57,480 --> 03:06:02,680 ON A MEMBRANE CAN DETECT. 4132 03:06:02,680 --> 03:06:04,560 HOWEVER, IF WE TAKE THE PROTEIN 4133 03:06:04,560 --> 03:06:06,000 SAMPLE WE USED FOR STRUCTURAL 4134 03:06:06,000 --> 03:06:08,000 STUDIES OF THE LASSA VIRUS AND 4135 03:06:08,000 --> 03:06:12,560 PUT IT ON A MEMBRANE, INDICATING 4136 03:06:12,560 --> 03:06:15,680 THE MATRIGLYCAN WAS WASHED AWAY. 4137 03:06:15,680 --> 03:06:19,840 WE CANNOT GET ANY CLUES FOR THE 4138 03:06:19,840 --> 03:06:22,560 EXISTENCE IN THE DATASETS THAT 4139 03:06:22,560 --> 03:06:28,080 WE HAVE, SO WE THINK WE SEE 4140 03:06:28,080 --> 03:06:30,800 SOLUBLE PIECES OF MATRIGLYCAN, 4141 03:06:30,800 --> 03:06:35,280 WE DON'T KNOW WHAT IS THE 4142 03:06:35,280 --> 03:06:37,680 SOURCE, BUT WE CAN SPECULATE 4143 03:06:37,680 --> 03:06:39,440 ABOUT ITS ROLE. 4144 03:06:39,440 --> 03:06:43,480 IF WE TAKE PSEUDOVIRUSES OF THE 4145 03:06:43,480 --> 03:06:45,240 LASSA VIRUS, THE SPIKE THE LASSA 4146 03:06:45,240 --> 03:06:49,520 VIRUS AND SUPPLEMENT ARE 4147 03:06:49,520 --> 03:06:51,680 ARTIFICIALLY MADE SOLUBLE 4148 03:06:51,680 --> 03:06:53,520 MATRIGLYCAN, WE SEE THAT. 4149 03:06:53,520 --> 03:06:54,800 WE SEE STRONG AND SPECIFIC 4150 03:06:54,800 --> 03:06:56,400 INHIBITION OF THE CELL ENTRY. 4151 03:06:56,400 --> 03:07:02,680 WE DON'T SEE THAT WITH VIRUSES 4152 03:07:02,680 --> 03:07:04,240 WITH MATRIGLYCAN, INHIBITING 4153 03:07:04,240 --> 03:07:07,840 CELL ENTRY OF LASSA VIRUS. 4154 03:07:07,840 --> 03:07:10,240 WE PROPOSED THIS MODEL. 4155 03:07:10,240 --> 03:07:14,040 THE SPIKES GENERATED ON CELL 4156 03:07:14,040 --> 03:07:15,960 SURFACE ARE LOADED WITH SOLUBLE 4157 03:07:15,960 --> 03:07:18,680 PIECE OF MATRIGLYCAN AND WE 4158 03:07:18,680 --> 03:07:21,560 THINK IT'S LIKELY TO 4159 03:07:21,560 --> 03:07:22,920 DISASSOCIATE OVER TIME OR 4160 03:07:22,920 --> 03:07:24,160 DISTANCE AS THEY DIFFUSE FROM 4161 03:07:24,160 --> 03:07:26,160 THE CELL THEY BUTTED FROM. 4162 03:07:26,160 --> 03:07:30,680 IF THEY DO SO, IF THE 4163 03:07:30,680 --> 03:07:32,480 MATRIGLYCAN IS DISASSOCIATED 4164 03:07:32,480 --> 03:07:33,680 FROM THE PIKES POTENTIATES 4165 03:07:33,680 --> 03:07:39,640 ABILITY TO ENGAGE WITH THE NEW 4166 03:07:39,640 --> 03:07:41,600 CELL, AND THAT MAKES TWO 4167 03:07:41,600 --> 03:07:42,880 REGIMES, IN ONE THE VIRUS CAN 4168 03:07:42,880 --> 03:07:45,160 ESCAPE A DYING CELL FROM WHICH 4169 03:07:45,160 --> 03:07:47,440 IT WAS FROM AND ON THE OTHER ONE 4170 03:07:47,440 --> 03:07:51,200 CAN ACTUALLY ATTACH TO A NEW 4171 03:07:51,200 --> 03:07:55,400 CELL AFTER IT RELEASED THE 4172 03:07:55,400 --> 03:07:58,840 SOLUBLE MATRIGLYCAN, A MECHANISM 4173 03:07:58,840 --> 03:08:00,880 TO ENSURE PROPER VIRAL EGRESS 4174 03:08:00,880 --> 03:08:02,760 AND IS DOING ADDITIONAL THINGS 4175 03:08:02,760 --> 03:08:04,240 BUT I DON'T HAVE TIME TO 4176 03:08:04,240 --> 03:08:05,560 DESCRIBE THAT. 4177 03:08:05,560 --> 03:08:07,480 JUST TO SUMMARIZE, I SHOWED A 4178 03:08:07,480 --> 03:08:10,240 STRUCTURE OF THE LASSA VIRUS 4179 03:08:10,240 --> 03:08:13,320 SPIKE PROTEIN, WE DISCOVERED AN 4180 03:08:13,320 --> 03:08:16,160 INTERESTING TOPOLOGY AND ROLE 4181 03:08:16,160 --> 03:08:18,440 FOR THIS STRUCTURED SIGNAL 4182 03:08:18,440 --> 03:08:19,480 PEPTIDE. 4183 03:08:19,480 --> 03:08:20,560 WE HAVE A STRUCTURAL MECHANISM 4184 03:08:20,560 --> 03:08:23,280 FOR BINDING BY THE LASSA VIRUS 4185 03:08:23,280 --> 03:08:28,680 AND WE ALSO SUGGEST A ROLE FOR 4186 03:08:28,680 --> 03:08:30,000 EGRESS AND STABILIZING, I WILL 4187 03:08:30,000 --> 03:08:32,680 THANK THE PEOPLE THAT 4188 03:08:32,680 --> 03:08:37,400 CONTRIBUTED TO THIS WORK MAINLY 4189 03:08:37,400 --> 03:08:40,160 FROM MY LAB AND WILL END. 4190 03:08:40,160 --> 03:08:41,680 >> THANK YOU, RON. 4191 03:08:41,680 --> 03:08:43,080 VERY INTERESTING TALK. 4192 03:08:43,080 --> 03:08:46,520 TO THE AUDIENCE, ADDRESS THE 4193 03:08:46,520 --> 03:08:50,320 QUESTIONS BY PLACING THEM IN THE 4194 03:08:50,320 --> 03:08:51,680 DROPBOX AT THE NIH SITE WITH 4195 03:08:51,680 --> 03:08:54,680 PLENTY OF TRIM TIME TO ADDRESS 4196 03:08:54,680 --> 03:08:59,000 IN THE PANEL DISCUSSION. 4197 03:08:59,000 --> 03:09:12,000 NEXT TALK, NEXT SPEAKER IS IEVA 4198 03:09:12,000 --> 03:09:12,280 BAGDONAITE. 4199 03:09:12,280 --> 03:09:14,680 >> THANK YOU FOR THE 4200 03:09:14,680 --> 03:09:15,000 INTRODUCTION. 4201 03:09:15,000 --> 03:09:18,880 THANK YOU FOR THE INVITATION TO 4202 03:09:18,880 --> 03:09:19,640 PRESENT HERE. 4203 03:09:19,640 --> 03:09:24,840 WHAT I'M GOING TO TALK ABOUT IS 4204 03:09:24,840 --> 03:09:26,280 TO GET AN INTRODUCTION AND 4205 03:09:26,280 --> 03:09:27,400 HOST-PATHOGEN INTERACTIONS AND 4206 03:09:27,400 --> 03:09:32,720 PROVIDE A FEW EXAMPLES OF HOW WE 4207 03:09:32,720 --> 03:09:35,560 USE GLYCOPROTEOMICS TO UNCOVER 4208 03:09:35,560 --> 03:09:43,720 FUNCTIONING OF GLYCANS IN VIRAL 4209 03:09:43,720 --> 03:09:43,960 BIOLOGY. 4210 03:09:43,960 --> 03:09:46,920 SO ALL CELLS ARE COVERED WITH 4211 03:09:46,920 --> 03:09:52,720 DENSE LAYER OF GLYCANS, 4212 03:09:52,720 --> 03:09:53,680 COMPRISED OF GLYCOCONJUGATES. 4213 03:09:53,680 --> 03:09:59,880 AND THEY PLAY A CENTRAL FUNCTION 4214 03:09:59,880 --> 03:10:03,440 IN STRUCTURAL INTEGRITY, 4215 03:10:03,440 --> 03:10:04,000 CELL-CELL AND HOST-PATHOGEN 4216 03:10:04,000 --> 03:10:09,040 INTERACTIONS, BUILD UP IN A 4217 03:10:09,040 --> 03:10:10,280 PATHWAY-SPECIFIC MANNER WHERE 4218 03:10:10,280 --> 03:10:13,640 INITIATION STEPS ARE MORE 4219 03:10:13,640 --> 03:10:14,120 DISTINCTS. 4220 03:10:14,120 --> 03:10:17,720 THE FURTHER STEPS ARE LESS 4221 03:10:17,720 --> 03:10:21,200 UNIQUE AND OPEN THE TERMINAL 4222 03:10:21,200 --> 03:10:23,600 STRUCTURES ON DIFFERENT 4223 03:10:23,600 --> 03:10:28,560 GLYCOCONJUGATES IMPORTANT FOR 4224 03:10:28,560 --> 03:10:30,840 INTERACTION WITH VIRUSES. 4225 03:10:30,840 --> 03:10:32,880 GLYCANS ARE IMPORTANT FOR MANY 4226 03:10:32,880 --> 03:10:35,560 STAGES OF LIFE CYCLES OF 4227 03:10:35,560 --> 03:10:36,800 VIRUSES, AND THAT INCLUDES 4228 03:10:36,800 --> 03:10:40,520 ATTACHMENT AS ENTRY TO HOST 4229 03:10:40,520 --> 03:10:43,080 CELLS, VIRAL PARTICLE FORMATION, 4230 03:10:43,080 --> 03:10:47,600 INTERACTION WITH INNATE IMMUNE 4231 03:10:47,600 --> 03:10:50,880 SYSTEM, AND ALSO GLYCANS HELP 4232 03:10:50,880 --> 03:10:52,960 SHAPE ADAPTIVE IMMUNE RESPONSES. 4233 03:10:52,960 --> 03:10:55,360 THE HOST CELL SITE CARBOHYDRATES 4234 03:10:55,360 --> 03:11:03,680 ARE OFTEN RECEPTORS FOR PATHOGENS. 4235 03:11:03,680 --> 03:11:09,320 FOR EXAMPLE, ANTIGENS ARE 4236 03:11:09,320 --> 03:11:17,320 INTERACTED BY H. PYLORI, 4237 03:11:17,320 --> 03:11:18,160 ROTAVIRUSES. 4238 03:11:18,160 --> 03:11:28,080 SIALIC ACIDS ARE OFTEN USED BY 4239 03:11:28,080 --> 03:11:28,320 VIRUSES. 4240 03:11:28,320 --> 03:11:29,040 FLAVIVIRUSES INTERACT FOR 4241 03:11:29,040 --> 03:11:30,160 INITIAL STEPS. 4242 03:11:30,160 --> 03:11:38,800 SUCH INTERACTIONS CAN BE 4243 03:11:38,800 --> 03:11:40,560 EXPLOITED THERAPEUTICALLY. 4244 03:11:40,560 --> 03:11:54,760 ANALOGS ARE WORKING FOR LENTI 4245 03:11:54,760 --> 03:12:04,680 VIRUS BY INHIBITING 4246 03:12:04,680 --> 03:12:05,160 NEURAMINIDASE. 4247 03:12:05,160 --> 03:12:08,080 ON THE VIRUS SIDES, THERE'S ONE 4248 03:12:08,080 --> 03:12:09,880 CLEAR ORIGIN OF THE VIRAL 4249 03:12:09,880 --> 03:12:12,480 GLYCANS FROM THE HOST CELL 4250 03:12:12,480 --> 03:12:14,880 BECAUSE THE VIRALLY ENCODED 4251 03:12:14,880 --> 03:12:20,080 PROTEINS TRAVEL TO THE HOST 4252 03:12:20,080 --> 03:12:21,200 PATHWAY, ACQUIRING HOST-FED 4253 03:12:21,200 --> 03:12:23,880 GLYCANS, OFTEN IT CAN ALSO BE 4254 03:12:23,880 --> 03:12:28,240 ENTRY INTO THE CELL BY 4255 03:12:28,240 --> 03:12:30,840 INTERACTING WITH HOST LECTINS. 4256 03:12:30,840 --> 03:12:36,720 WHEN WE TALK ABOUT THE VIRAL 4257 03:12:36,720 --> 03:12:39,920 PARTICLES, WE USUALLY TALK ABOUT 4258 03:12:39,920 --> 03:12:42,920 GLYCANS THAT ARE MOST 4259 03:12:42,920 --> 03:12:43,240 PREDOMINANT. 4260 03:12:43,240 --> 03:12:48,840 IF WE WERE LOOK AT DIFFERENT 4261 03:12:48,840 --> 03:12:50,640 CLASSES OF VIRUSES, GLYCAN 4262 03:12:50,640 --> 03:12:53,720 DIVERSITY IS SUBSTANTIAL. 4263 03:12:53,720 --> 03:12:55,480 HIV AND FLU HAVE THE HIGH 4264 03:12:55,480 --> 03:13:01,520 CONTENT OF N-GLYCANS, VERY FEW 4265 03:13:01,520 --> 03:13:01,880 O-GLYCANS. 4266 03:13:01,880 --> 03:13:04,240 IN ADDITION, THE TYPES OF GLYCAN 4267 03:13:04,240 --> 03:13:05,600 STRUCTURES CAN VARY 4268 03:13:05,600 --> 03:13:06,760 SUBSTANTIALLY. 4269 03:13:06,760 --> 03:13:11,080 FOR EXAMPLE, HIV SO DENSELY N 4270 03:13:11,080 --> 03:13:19,080 GLYCOSYLATED A GOOD PROPORTION 4271 03:13:19,080 --> 03:13:22,080 ARE IMMATURE, SO-CALLED 4272 03:13:22,080 --> 03:13:22,440 OLIGOMANNOSE. 4273 03:13:22,440 --> 03:13:27,600 EBOLA VIRUS HAS A HUGE AMOUNT OF 4274 03:13:27,600 --> 03:13:29,560 O-GLYCANS, SPECIFIC SITES NOT 4275 03:13:29,560 --> 03:13:36,440 DEFINED, QUITE A BIT OF ANIMAL 4276 03:13:36,440 --> 03:13:37,240 GLYCANS MULTIPLE PROCESS. 4277 03:13:37,240 --> 03:13:39,240 ONE OF THE IMPORTANT FUNCTIONS 4278 03:13:39,240 --> 03:13:42,120 OF GLYCANS AND VIRUS OF COURSE 4279 03:13:42,120 --> 03:13:47,480 IS THE IMMUNE SHIELDING BY 4280 03:13:47,480 --> 03:13:48,680 COVERING DOMINANT EPITOPES. 4281 03:13:48,680 --> 03:13:51,680 AND SOME VIRUSES ARE BETTER THAN 4282 03:13:51,680 --> 03:13:57,520 OTHERS IN PROVIDING THIS SORT OF 4283 03:13:57,520 --> 03:13:57,800 SHIELDING. 4284 03:13:57,800 --> 03:14:00,920 FOR EXAMPLE, HIV AND INFLUENZA, 4285 03:14:00,920 --> 03:14:02,440 LIKE SEASONAL INFLUENZA VIRUSES, 4286 03:14:02,440 --> 03:14:06,760 ARE VERY GOOD AT IMMUNE ESCAPE 4287 03:14:06,760 --> 03:14:13,440 AND ALSO OFTEN CORRELATES ARE 4288 03:14:13,440 --> 03:14:15,680 HIGH OLIGO MINUS. 4289 03:14:15,680 --> 03:14:22,240 IF WE LOOK AT FLU, 4290 03:14:22,240 --> 03:14:25,480 OVERGLYCOSYLATED AS ATTENUATED 4291 03:14:25,480 --> 03:14:27,560 TRYING TO COVER MORE EPITOPES, 4292 03:14:27,560 --> 03:14:31,720 AT THE SAME TIME LOSES SOME OF 4293 03:14:31,720 --> 03:14:32,720 THE VIRULENCE. 4294 03:14:32,720 --> 03:14:47,200 ACTUALLY THIS IS ONE OF THE 4295 03:14:47,200 --> 03:14:54,480 APPROACHES TO IMPROVE, ALTERING 4296 03:14:54,480 --> 03:14:54,760 POSITIONS. 4297 03:14:54,760 --> 03:14:57,240 HIV GLYCANS UNDERPROCESSED, THIS 4298 03:14:57,240 --> 03:15:01,880 CAN BE TARGETED BY SOME 4299 03:15:01,880 --> 03:15:03,040 NATURALLY OCCURRING ANTIBODIESRY 4300 03:15:03,040 --> 03:15:06,800 RECOGNIZE IMMATURE STRUCTURES 4301 03:15:06,800 --> 03:15:10,560 AND CAN CROSS-LINK SPECIFIC 4302 03:15:10,560 --> 03:15:18,960 OLIGOMANNOSE GLYCANS ON THE 4303 03:15:18,960 --> 03:15:22,120 SURFACE. 4304 03:15:22,120 --> 03:15:29,680 AND USED PLANTS AND MICROBIAL 4305 03:15:29,680 --> 03:15:37,800 LECTINS AS ANTI-VIRALS, LECTINS 4306 03:15:37,800 --> 03:15:41,440 FROM BANANA NEUTRALIZES HIV. 4307 03:15:41,440 --> 03:15:43,520 SO WHAT IS REALLY IMPORTANT FOR 4308 03:15:43,520 --> 03:15:46,480 BIOLOGICAL STUDIES TO HAVE A 4309 03:15:46,480 --> 03:15:49,320 GOOD UNDERSTANDING OF THE 4310 03:15:49,320 --> 03:15:52,480 STRUCTURE OF VIRAL PROTEINS, 4311 03:15:52,480 --> 03:15:53,520 MAPPING GLYCOSYLATION SITE IS A 4312 03:15:53,520 --> 03:15:54,760 BIG PART OF THAT. 4313 03:15:54,760 --> 03:15:55,680 DURING THE SARS-COV-2 PANDEMIC 4314 03:15:55,680 --> 03:15:59,400 THERE WAS A HUGE INTEREST IN 4315 03:15:59,400 --> 03:16:01,480 MAPPING N AND O-GLYCOSYLATION 4316 03:16:01,480 --> 03:16:01,920 SITES. 4317 03:16:01,920 --> 03:16:03,480 HERE I'M HIGHLIGHTING ONE OF THE 4318 03:16:03,480 --> 03:16:04,920 STUDIES, THERE HAVE BEEN QUITE A 4319 03:16:04,920 --> 03:16:06,320 FEW OF THOSE. 4320 03:16:06,320 --> 03:16:09,320 PRINCIPALLY SARS-COV-2 IS ONE OF 4321 03:16:09,320 --> 03:16:12,080 THOSE HEAVILY N GLYCOSYLATED 4322 03:16:12,080 --> 03:16:20,120 VIRUSES, WE AMONG OTHERS MAP O 4323 03:16:20,120 --> 03:16:23,960 GLYCOCYTE BUT THIS INFORMATION 4324 03:16:23,960 --> 03:16:25,520 CAN BE TAKEN FORWARD AND USED 4325 03:16:25,520 --> 03:16:28,960 FOR OTHER KIND OF STUDIES LIKE 4326 03:16:28,960 --> 03:16:31,680 STRUCTURAL BIOLOGY OR JUST 4327 03:16:31,680 --> 03:16:33,560 BIOCHEMICAL ASSAYS AND HELP 4328 03:16:33,560 --> 03:16:35,120 DEFINE SOME VERY SPECIFIC 4329 03:16:35,120 --> 03:16:36,640 MOLECULAR FUNCTIONING OF 4330 03:16:36,640 --> 03:16:36,960 GLYCANS. 4331 03:16:36,960 --> 03:16:39,160 FOR EXAMPLE, IT HAS BEEN 4332 03:16:39,160 --> 03:16:41,760 DETERMINED THAT GLYCAN GATE 4333 03:16:41,760 --> 03:16:44,400 CONTROLS OPENING OF SARS-COV-2 4334 03:16:44,400 --> 03:16:48,880 SPIKE PROTEIN AND ALSO 4335 03:16:48,880 --> 03:16:49,720 O-GLYCOSYLATION MODULATES 4336 03:16:49,720 --> 03:16:52,080 CLEAVAGE OF THE PROTEIN. 4337 03:16:52,080 --> 03:16:57,480 SO WHAT WE'RE INTERESTED AT THE 4338 03:16:57,480 --> 03:16:59,440 COPENHAGEN CENTER ARE THE 4339 03:16:59,440 --> 03:16:59,680 O-GLYCANS. 4340 03:16:59,680 --> 03:17:03,720 WHAT WE WISH TO ACHIEVE IS 4341 03:17:03,720 --> 03:17:06,080 GENERATE NOVEL O GLYCOPROTEINS 4342 03:17:06,080 --> 03:17:07,160 AND COMBINE WITH KNOCKOUT 4343 03:17:07,160 --> 03:17:09,400 LIBRARIES TO UNDERSTAND WHAT 4344 03:17:09,400 --> 03:17:11,600 STRUCTURES ARE IMPORTANT BUT 4345 03:17:11,600 --> 03:17:14,840 ALSO LOOK AT SINGLE SITES AND 4346 03:17:14,840 --> 03:17:16,240 CHOOSE SOME OF THE O-GLYCANS 4347 03:17:16,240 --> 03:17:19,280 THAT COULD BE RELATED TO 4348 03:17:19,280 --> 03:17:21,080 STRUCTURAL FEATURES IMPORTANT 4349 03:17:21,080 --> 03:17:23,320 FOR VIRUS BIOLOGY AND COULD 4350 03:17:23,320 --> 03:17:28,560 IMPACT STABILITY FUNCTION AND 4351 03:17:28,560 --> 03:17:29,800 RECOGNITION OF PROTEINS. 4352 03:17:29,800 --> 03:17:34,520 AND TO MANAGE THE SITES WE HAVE 4353 03:17:34,520 --> 03:17:45,840 BEEN USING STRATEGY INVOLVING 4354 03:17:45,840 --> 03:17:46,600 ENRICHMENT, DIGEST PROTEINS AND 4355 03:17:46,600 --> 03:17:51,680 ENRICH WITH LECTINS THAT CAN 4356 03:17:51,680 --> 03:17:52,760 CAPTURE AND TRUNCATED O-GLYCANS. 4357 03:17:52,760 --> 03:18:01,160 WE'VE DONE THAT ON QUITE A FEW 4358 03:18:01,160 --> 03:18:02,720 VIRUSES, IN COLLABORATION WITH 4359 03:18:02,720 --> 03:18:05,680 OTHER LABS, WHAT WE'RE TRYING TO 4360 03:18:05,680 --> 03:18:07,680 DO WITH ASSOCIATE PROFESSORS AT 4361 03:18:07,680 --> 03:18:09,960 THE CENTER IS TO DEVELOP THE WEB 4362 03:18:09,960 --> 03:18:12,240 PAGE WHERE WE COULD DEPOSIT AND 4363 03:18:12,240 --> 03:18:13,880 STORE THIS INFORMATION AND ALSO 4364 03:18:13,880 --> 03:18:16,600 OVERLAY WITH OTHER SOURCE 4365 03:18:16,600 --> 03:18:20,320 INFORMATION OF INFORMATION LIKE 4366 03:18:20,320 --> 03:18:25,080 IMMUNE EPITOPES, BANDS OF 4367 03:18:25,080 --> 03:18:25,720 CONCERN, EVOLUTION CONSERVATION 4368 03:18:25,720 --> 03:18:26,720 FEATURES. 4369 03:18:26,720 --> 03:18:30,720 SO ONE OF THE FIRST VIRUSES WE 4370 03:18:30,720 --> 03:18:33,040 LOOKED AT WAS HERPES SIMPLEX 4371 03:18:33,040 --> 03:18:34,760 TYPE 1 AFFECTING A HUGE PORTION 4372 03:18:34,760 --> 03:18:36,640 OF THE POPULATION, AND THERE ARE 4373 03:18:36,640 --> 03:18:38,160 NO VACCINES AVAILABLE SO FAR, IT 4374 03:18:38,160 --> 03:18:41,800 CAN BE QUITE LIFE-THREATENING 4375 03:18:41,800 --> 03:18:43,160 FOR THE IMMUNOCOMPROMISED 4376 03:18:43,160 --> 03:18:45,280 INDIVIDUALS, ASSOCIATED ALSO 4377 03:18:45,280 --> 03:18:49,320 WITH NEUROLOGICAL DISORDERS SUCH 4378 03:18:49,320 --> 03:18:49,880 AS ALZHEIMER'S. 4379 03:18:49,880 --> 03:18:59,480 AT THE TIME WE MAPPED MORE THAN 4380 03:18:59,480 --> 03:19:04,680 70 O GLYCOSITES, INVESTIGATED 4381 03:19:04,680 --> 03:19:09,120 OTHER MEMBERS, CLOSELY RELATED 4382 03:19:09,120 --> 03:19:12,680 SUCH AS HERPES ZOSTER AND 4383 03:19:12,680 --> 03:19:14,680 DISTANT RELATED BY MEGALOVIRUS, 4384 03:19:14,680 --> 03:19:16,360 THERE WERE SOME QUITE CONSISTENT 4385 03:19:16,360 --> 03:19:19,000 FEATURES IN WHERE WE FIND THE 4386 03:19:19,000 --> 03:19:22,080 O-GLYCANS IN THE HOMOLOGOUS 4387 03:19:22,080 --> 03:19:22,440 PROTEINS. 4388 03:19:22,440 --> 03:19:26,200 THAT PROMPTED US TO ALSO LOOK 4389 03:19:26,200 --> 03:19:27,480 INTO THE FUNCTIONAL RELATIONSHIP 4390 03:19:27,480 --> 03:19:34,560 OF THE VIRAL GLYCANS AND HOST 4391 03:19:34,560 --> 03:19:36,080 CELL. 4392 03:19:36,080 --> 03:19:39,560 WE USED CELLS LACKING TRUNCATED 4393 03:19:39,560 --> 03:19:43,080 GLYCANS BY KNOCKOUT OF 4394 03:19:43,080 --> 03:19:49,200 CHAPERONE, WHICH RESULTED IN 4395 03:19:49,200 --> 03:19:50,960 TREMENDOUS REDUCTION IN THE 4396 03:19:50,960 --> 03:19:55,560 VIRAL TITERS AND SAW MORE 4397 03:19:55,560 --> 03:19:58,680 MODERATE REDUCTION IN TITERS FOR 4398 03:19:58,680 --> 03:20:03,720 A CLOSELY RELATED VIRUS BUT ALSO 4399 03:20:03,720 --> 03:20:06,760 RETARDED TISSUE USING THE VIRUS 4400 03:20:06,760 --> 03:20:08,720 WITH TRUNCATED O-GLYCANS. 4401 03:20:08,720 --> 03:20:13,160 ACTUALLY WE ARE EXPLORING THIS 4402 03:20:13,160 --> 03:20:14,360 FURTHER BY INVESTIGATING BOTH 4403 03:20:14,360 --> 03:20:18,720 DIFFERENT OTHER TYPES OF GLYCAN 4404 03:20:18,720 --> 03:20:20,320 PATHWAYS, ON THE HERPES VIRUS 4405 03:20:20,320 --> 03:20:22,240 BIOLOGY INCLUDING STAGES OF THE 4406 03:20:22,240 --> 03:20:23,520 VIRAL CYCLE BUT ALSO STARTING TO 4407 03:20:23,520 --> 03:20:27,120 CHOOSE SOME OF THE INDIVIDUAL 4408 03:20:27,120 --> 03:20:33,880 SITES THAT ARE PERFORMING 4409 03:20:33,880 --> 03:20:34,200 PROTEIN FOCUS. 4410 03:20:34,200 --> 03:20:40,440 I WOULD LIKE TO TALK ABOUT THE 4411 03:20:40,440 --> 03:20:42,880 EBOLA VIRUS GLYCOSYLATION. 4412 03:20:42,880 --> 03:20:45,680 EBOLA VIRUS NEEDS LITTLE 4413 03:20:45,680 --> 03:20:47,120 INTRODUCTION, ATTENTION VERY 4414 03:20:47,120 --> 03:20:54,240 PATHOGENIC WITH HIGH MORTALITY 4415 03:20:54,240 --> 03:20:55,560 RATES, SURFACE GLYCOPROTEIN 4416 03:20:55,560 --> 03:20:59,880 SPIKE IS HARBORING THIS VERY 4417 03:20:59,880 --> 03:21:03,680 HUGE DOMAIN, STRUCTURE IS NOT 4418 03:21:03,680 --> 03:21:08,080 WELL DETERMINED, USUALLY 4419 03:21:08,080 --> 03:21:13,240 EXCLUDED FROM CRYSTALLOGRAPHIC 4420 03:21:13,240 --> 03:21:13,480 STUDIES. 4421 03:21:13,480 --> 03:21:16,600 RECONSTRUCTION OF SPIKES DERIVED 4422 03:21:16,600 --> 03:21:18,480 FROM VIRUS PARTICLES THEMSELVES, 4423 03:21:18,480 --> 03:21:19,560 EVEN THOUGH PRECISE STRUCTURES 4424 03:21:19,560 --> 03:21:21,320 ARE NOT DETERMINED YOU CAN SEE 4425 03:21:21,320 --> 03:21:23,640 COMPRISES A BIG PART OF THE 4426 03:21:23,640 --> 03:21:24,720 PROTEIN. 4427 03:21:24,720 --> 03:21:26,680 ACTUALLY IT IS NEEDED, IT NEEDS 4428 03:21:26,680 --> 03:21:35,560 TO BE CLEAVED IN ORDER TO 4429 03:21:35,560 --> 03:21:41,080 INTERACT WITH NPC RECEPTOR IN 4430 03:21:41,080 --> 03:21:41,920 THE LYSOSOME. 4431 03:21:41,920 --> 03:21:52,360 THE EARLIER ENTRY INTO THE CELL 4432 03:21:52,360 --> 03:21:56,080 GETTING THE MEMBRANES CLOSER, 4433 03:21:56,080 --> 03:22:01,920 THE DOMAIN ITSELF CAN ACTUALLY 4434 03:22:01,920 --> 03:22:03,880 INTERACT WITH SOME LECTINS, ALSO 4435 03:22:03,880 --> 03:22:07,440 ONE NOT A LECTIN, THAT ALSO 4436 03:22:07,440 --> 03:22:09,200 PLAYS A ROLE. 4437 03:22:09,200 --> 03:22:12,240 THE FUNCTIONS ARE NOT VERY 4438 03:22:12,240 --> 03:22:14,640 PRECISELY DEFINED, AND NEITHER 4439 03:22:14,640 --> 03:22:16,040 IS THE STRUCTURE. 4440 03:22:16,040 --> 03:22:24,000 SO WHAT WE SET OUT TO DO IS MAP 4441 03:22:24,000 --> 03:22:37,160 THE O GLYCOSITES AND USE 4442 03:22:37,160 --> 03:22:38,840 VIRUS-LIKE PARTICLES, USED WITH 4443 03:22:38,840 --> 03:22:50,720 LECTIN ENRICHMENT APPROACH. 4444 03:22:50,720 --> 03:22:51,800 INTERESTING TO INVESTIGATE WHAT 4445 03:22:51,800 --> 03:22:54,640 DO THE DIFFERENT TYPES OF 4446 03:22:54,640 --> 03:22:58,840 STRUCTURES DO FOR THE VIRUS 4447 03:22:58,840 --> 03:23:04,080 INFECTIVITY, ALSO HOW COULD 4448 03:23:04,080 --> 03:23:04,880 ISOFORM-SPECIFIC INITIATION 4449 03:23:04,880 --> 03:23:05,240 AFFECT. 4450 03:23:05,240 --> 03:23:14,560 FOR THAT WE USED CELLS WITH 4451 03:23:14,560 --> 03:23:19,720 KNOCKOUT, AND WE ALSO USED 4452 03:23:19,720 --> 03:23:22,760 KNOCKOUTS OF GALNT 1, 2, 3, 4453 03:23:22,760 --> 03:23:24,600 ELIMINATING THE SITE INITIATION 4454 03:23:24,600 --> 03:23:29,120 GOVERNED BY THE THREE ISOFORMS. 4455 03:23:29,120 --> 03:23:32,320 AND WHEN WE LOOKED AT VIRAL 4456 03:23:32,320 --> 03:23:35,160 PROPAGATION WE SAW BOTH 4457 03:23:35,160 --> 03:23:37,080 DIMINISHED RNA CONTENT, BOTH ON 4458 03:23:37,080 --> 03:23:42,000 THE 1 AND 6 SECTION AND 4459 03:23:42,000 --> 03:23:46,240 IMPORTANTLY ALSO SAW TEN-FOLD 4460 03:23:46,240 --> 03:23:46,880 DIMINISHED TITERS. 4461 03:23:46,880 --> 03:23:50,560 THIS WAS REALLY INTERESTING THAT 4462 03:23:50,560 --> 03:23:53,240 NOT ONLY GLYCAN COMMUNICATION 4463 03:23:53,240 --> 03:23:54,840 BUT SELECTIVE INITIATION BY 4464 03:23:54,840 --> 03:23:57,240 THREE FORMS AFFECTED VIRAL 4465 03:23:57,240 --> 03:23:58,960 TITERS. 4466 03:23:58,960 --> 03:24:00,920 HERE WE WANTED TO INVESTIGATE SO 4467 03:24:00,920 --> 03:24:08,640 WHICH OF THE TYPES WAS INITIATED 4468 03:24:08,640 --> 03:24:12,000 BY ISOFORMS. 4469 03:24:12,000 --> 03:24:14,440 WE USED MASS SPECTROMETRY 4470 03:24:14,440 --> 03:24:15,480 APPROACH EXPRESSED RECOMBINANT 4471 03:24:15,480 --> 03:24:20,520 FULL LENGTH SPIKES IN CELL 4472 03:24:20,520 --> 03:24:25,120 LINES, IN WILDTYPE KNOCKOUTS WE 4473 03:24:25,120 --> 03:24:26,320 THEN PURIFIED PROTEINS, THEN 4474 03:24:26,320 --> 03:24:30,080 DIGESTED PROTEINS AND LABELED 4475 03:24:30,080 --> 03:24:31,680 THEM WITH DIFFERENTIAL MASS SPEC 4476 03:24:31,680 --> 03:24:34,720 WHICH ALLOWED US TO MIX THEM 4477 03:24:34,720 --> 03:24:40,880 TOGETHER AND DISCRIMINATE LATER. 4478 03:24:40,880 --> 03:24:43,400 AFTER LECTIN ENRICHMENT COULD 4479 03:24:43,400 --> 03:24:44,680 QUANTIFY HOW MUCH PEPTIDES 4480 03:24:44,680 --> 03:24:46,240 DERIVED FROM CELLS. 4481 03:24:46,240 --> 03:24:48,400 AND WE COULD UNDERSTAND WHICH 4482 03:24:48,400 --> 03:24:53,200 SITES WERE GOVERNED BY WHICH 4483 03:24:53,200 --> 03:24:53,440 ISOFORM. 4484 03:24:53,440 --> 03:25:01,160 SO WE SAW THE LARGEST EFFECTS 4485 03:25:01,160 --> 03:25:08,760 FROM GALNT1 WITH LARGE NUMBERS 4486 03:25:08,760 --> 03:25:10,560 UPREGULATED, ALSO GLYCOPEPTIDES. 4487 03:25:10,560 --> 03:25:13,200 YOU CAN SEE THAT ON A WESTERN 4488 03:25:13,200 --> 03:25:16,960 BLOT, THERE'S ACTUALLY A VISUAL 4489 03:25:16,960 --> 03:25:20,240 MATCH IN THE PROTEIN WHEN YOU 4490 03:25:20,240 --> 03:25:20,600 KNOCK OUT. 4491 03:25:20,600 --> 03:25:24,720 IF WE OVERLAY THAT WITH THE 4492 03:25:24,720 --> 03:25:28,600 OUTCOME OF PROTEIN WE IS SEE T1 4493 03:25:28,600 --> 03:25:31,320 SITES WERE QUITE EVENLY 4494 03:25:31,320 --> 03:25:34,600 DISTRIBUTED ALONG THE DOMAIN, 4495 03:25:34,600 --> 03:25:38,880 THERE WAS ALSO ONE SPECIFIC SITE 4496 03:25:38,880 --> 03:25:44,840 BY 2 AND 3, MIX THE SITES WHERE 4497 03:25:44,840 --> 03:25:45,960 SEVERAL HAD AN EFFECT. 4498 03:25:45,960 --> 03:25:49,920 WHAT CAN YOU USE THIS SORT OF 4499 03:25:49,920 --> 03:25:51,600 DATA FOR? 4500 03:25:51,600 --> 03:25:55,080 ASIDE FROM THE STRUCTURAL 4501 03:25:55,080 --> 03:25:55,480 CHARACTERIZATION. 4502 03:25:55,480 --> 03:25:59,600 FOR ONCE WE CAN TRY AND DIG 4503 03:25:59,600 --> 03:26:03,120 DEEPER INTO MOLECULAR FUNCTIONS, 4504 03:26:03,120 --> 03:26:06,960 RELATED TO LOSS OR DECREASE IN 4505 03:26:06,960 --> 03:26:12,280 VIRAL TITERS WE WANTED TO SEE 4506 03:26:12,280 --> 03:26:16,200 WHICH IS MOST EFFECTED, USED 4507 03:26:16,200 --> 03:26:17,400 SOME PSEUDOVIRUS EXPERIMENTS, WE 4508 03:26:17,400 --> 03:26:19,920 SAW THERE WAS THE GLYCOSYLATION 4509 03:26:19,920 --> 03:26:22,600 OF HOST CELLS TO WHICH INTEREST 4510 03:26:22,600 --> 03:26:27,120 WAS DIMINISHED ENTRY BY THE 4511 03:26:27,120 --> 03:26:27,680 WILDTYPE SUED VIRUS. 4512 03:26:27,680 --> 03:26:31,600 ANOTHER WAY HOW WE CAN USE THIS 4513 03:26:31,600 --> 03:26:36,880 INFORMATION IS FOR GENERATION OF 4514 03:26:36,880 --> 03:26:40,560 IMMUNOGENS, IMAGINE FROM YOU 4515 03:26:40,560 --> 03:26:49,080 PRODUCE A SPIKE PROTEIN IN THE 4516 03:26:49,080 --> 03:26:50,880 CELL, WOULD GENERATE IMMUNE 4517 03:26:50,880 --> 03:26:55,160 RESPONSES, SO THAT COULD HELP 4518 03:26:55,160 --> 03:26:57,600 UNDERSTAND MECHANISMS. 4519 03:26:57,600 --> 03:27:02,480 BY LOOKING AT SOME KNOWN 4520 03:27:02,480 --> 03:27:04,120 RECOGNITION SITES FOR ZMapp 4521 03:27:04,120 --> 03:27:05,800 AND THERAPEUTIC ANTIBODIES CAN 4522 03:27:05,800 --> 03:27:10,600 SEE THAT OVERLAPS WITH SOME 4523 03:27:10,600 --> 03:27:12,120 SITES WE'VE IDENTIFIED. 4524 03:27:12,120 --> 03:27:19,720 WE WOULD LOOK INTO TAILORED 4525 03:27:19,720 --> 03:27:20,160 THERAPEUTICS, OTHER 4526 03:27:20,160 --> 03:27:23,520 GLYCOSYLATION INHIBITORS. 4527 03:27:23,520 --> 03:27:30,320 THEY LOOKED AT EPITOPES OF 4528 03:27:30,320 --> 03:27:30,920 NATURALLY ACQUIRED AND VACCINE 4529 03:27:30,920 --> 03:27:32,920 INDUCED ANTIBODIES AND THAT JUST 4530 03:27:32,920 --> 03:27:34,360 MAPS IN A SINGLE RESOLUTION 4531 03:27:34,360 --> 03:27:37,760 ALONG THE LENGTH OF THE PROTEIN 4532 03:27:37,760 --> 03:27:41,160 AND BOTH LOOKED AT IgG AND 4533 03:27:41,160 --> 03:27:42,680 IgM SIGNATURES. 4534 03:27:42,680 --> 03:27:45,600 AND WHAT BECOMES EVIDENT THAT IF 4535 03:27:45,600 --> 03:27:48,440 YOU LOOK AT THE DOMAIN THERE ARE 4536 03:27:48,440 --> 03:27:50,720 DIVERGENT SIGNATURES BETWEEN THE 4537 03:27:50,720 --> 03:27:51,080 VACCINATED -- 4538 03:27:51,080 --> 03:27:52,520 >> TWO MINUTES. 4539 03:27:52,520 --> 03:27:55,280 >> ALMOST DONE. 4540 03:27:55,280 --> 03:27:58,080 BETWEEN THE VACCINATED AND 4541 03:27:58,080 --> 03:28:01,400 ACTUAL SURVIVORS. 4542 03:28:01,400 --> 03:28:04,560 AND IF WE OVERLAY, QUITE CLEAR 4543 03:28:04,560 --> 03:28:10,440 YOU SEE SOME SIGNATURES THERE. 4544 03:28:10,440 --> 03:28:11,800 MORE ROBUST DATA SCIENCE WOULD 4545 03:28:11,800 --> 03:28:14,320 COME IN HANDY TO CORRELATE THESE 4546 03:28:14,320 --> 03:28:16,480 SORTS OF DATA. 4547 03:28:16,480 --> 03:28:18,880 THAT'S WHAT WE'RE DOING ON OUR 4548 03:28:18,880 --> 03:28:26,960 PAGE, WE HOPE TO IMPROVE. 4549 03:28:26,960 --> 03:28:30,520 I HOPE I'VE SHOWN GLYCANS PLAY 4550 03:28:30,520 --> 03:28:33,240 MULTIPLE ESSENTIAL ROLES, 4551 03:28:33,240 --> 03:28:38,480 PATHOGEN INTERPLAY, THAT EBOLA 4552 03:28:38,480 --> 03:28:42,480 VIRUS GLYCOPROTEIN IS 4553 03:28:42,480 --> 03:28:44,360 SELECTIVELY GLYCOSYLATED GUY 4554 03:28:44,360 --> 03:28:48,800 GALNAC-T 1, T2, T3, IF WE HAVE 4555 03:28:48,800 --> 03:28:49,440 COMBINED AND ACQUIRED SUCH 4556 03:28:49,440 --> 03:28:54,800 PROTEOMIC YOAMS -- PROTEOMES 4557 03:28:54,800 --> 03:28:57,360 CAN LOOK AT SITES AND ROBUST 4558 03:28:57,360 --> 03:29:01,480 SOLUTIONS WOULD HELP IN 4559 03:29:01,480 --> 03:29:06,000 CORRELATING ALL SORTS OF DATA, 4560 03:29:06,000 --> 03:29:07,240 VACCINOLOGY AND OTHER SORTS OF 4561 03:29:07,240 --> 03:29:08,640 DATA. 4562 03:29:08,640 --> 03:29:12,840 I WOULD LIKE TO THANK YOU FOR 4563 03:29:12,840 --> 03:29:13,600 YOUR ATTENTION. 4564 03:29:13,600 --> 03:29:16,480 SOMETHING IS STUCK. 4565 03:29:16,480 --> 03:29:19,440 AND EVERYBODY INVOLVED. 4566 03:29:19,440 --> 03:29:28,120 MY COLLEAGUES FROM COPENHAGEN 4567 03:29:28,120 --> 03:29:31,680 AND THOSE FROM PUBLIC HEALTH 4568 03:29:31,680 --> 03:29:34,680 AGENCY AND THOSE THAT DID THE 4569 03:29:34,680 --> 03:29:36,600 LIVE AND PSEUDOVIRUS 4570 03:29:36,600 --> 03:29:36,880 EXPERIMENTS. 4571 03:29:36,880 --> 03:29:39,000 >> THANK YOU. 4572 03:29:39,000 --> 03:29:39,920 VERY INTERESTING. 4573 03:29:39,920 --> 03:29:43,920 AGAIN, FOR THE AUDIENCE DROP 4574 03:29:43,920 --> 03:29:46,520 YOUR QUESTIONS IN THE NIH 4575 03:29:46,520 --> 03:29:48,240 DROPBOX, THERE WILL BE PLENTY OF 4576 03:29:48,240 --> 03:29:52,160 TIME AT THE END IN A PANEL 4577 03:29:52,160 --> 03:29:54,560 DISCUSSION FOR YOUR QUESTIONS. 4578 03:29:54,560 --> 03:30:00,920 MOVING TO THE NEXT SPEAKER, YAN 4579 03:30:00,920 --> 03:30:08,880 LIU, IMPERIAL COLLEGE, GLYCAN 4580 03:30:08,880 --> 03:30:13,480 RECEPTORS OF THE POLYOMAVIRIDAE 4581 03:30:13,480 --> 03:30:24,840 REVEALED BY MICRO AWAY. 4582 03:30:24,840 --> 03:30:25,760 >> THANK YOU. 4583 03:30:25,760 --> 03:30:30,680 I'M TRYING TO MINIMIZE MYSELF. 4584 03:30:30,680 --> 03:30:32,360 YES, IT'S A GREAT PLEASURE TO 4585 03:30:32,360 --> 03:30:38,800 ATTEND THIS MEETING AND TO 4586 03:30:38,800 --> 03:30:40,200 REPRESENT THE GLYCOSCIENCE 4587 03:30:40,200 --> 03:30:41,320 LABORATORY AT IMPERIAL COLLEGE 4588 03:30:41,320 --> 03:30:44,960 AND TELL YOU ABOUT THE WORK OF 4589 03:30:44,960 --> 03:30:46,240 THE GROUP MUSING 4590 03:30:46,240 --> 03:30:46,960 GLYCOMICROARRAYS. 4591 03:30:46,960 --> 03:30:52,640 YOU'LL BE HEARING ABOUT SOFTWARE 4592 03:30:52,640 --> 03:30:53,360 USAGE, MANAGING DAY-TO-DAY 4593 03:30:53,360 --> 03:30:55,000 MANAGEMENT OF THE MICROARRAY 4594 03:30:55,000 --> 03:30:58,480 DATA AND ALSO RESEARCH 4595 03:30:58,480 --> 03:30:59,240 HIGHLIGHTS, MICROARRAY ANALYSIS 4596 03:30:59,240 --> 03:31:04,880 OF THE FAMILY OF POLYOMA VIRUSES 4597 03:31:04,880 --> 03:31:11,880 OF HUMAN AND ANIMAL ORIGIN. 4598 03:31:11,880 --> 03:31:16,240 I'D LIKE TO START FROM A 4599 03:31:16,240 --> 03:31:17,800 CELEBRATION OF 20 YEARS 4600 03:31:17,800 --> 03:31:20,520 ANNIVERSARY OF THE EVENT OF THE 4601 03:31:20,520 --> 03:31:21,600 MICROARRAY TECHNOLOGIES. 4602 03:31:21,600 --> 03:31:29,960 SO THE FIRST TWO PLATFORMS 4603 03:31:29,960 --> 03:31:31,240 INTRODUCED BY PROFESSOR FEIZI 4604 03:31:31,240 --> 03:31:38,480 WERE FOLLOWED BY OTHER MAJOR 4605 03:31:38,480 --> 03:31:42,440 PLATFORMS BY NIH, AND THE 4606 03:31:42,440 --> 03:31:45,920 MICROARRAY SYSTEM. 4607 03:31:45,920 --> 03:31:47,680 THERE HAVE BEEN FAST-GROWING 4608 03:31:47,680 --> 03:31:50,920 COMMUNITY AS MENTIONED IN A TALK 4609 03:31:50,920 --> 03:31:52,120 ALSO. 4610 03:31:52,120 --> 03:31:55,440 THERE ARE EMERGING PLATFORMS AND 4611 03:31:55,440 --> 03:31:58,240 TECHNOLOGIES, DIFFERENT FROM THE 4612 03:31:58,240 --> 03:32:00,840 TRADITIONAL MICROARRAY 4613 03:32:00,840 --> 03:32:01,160 TECHNOLOGIES. 4614 03:32:01,160 --> 03:32:02,360 SO, THE GLYCAN MICROARRAY 4615 03:32:02,360 --> 03:32:07,080 REMAINS AS ONE OF THE MOST 4616 03:32:07,080 --> 03:32:12,080 IMPORTANT AND POWERFUL 4617 03:32:12,080 --> 03:32:16,680 TECHNOLOGIES IN GLYCOSCIENCES 4618 03:32:16,680 --> 03:32:18,600 AND GLYCAN BINDING SPECIFICITY. 4619 03:32:18,600 --> 03:32:22,360 WITH THE LAST AMOUNT OF GLYCAN 4620 03:32:22,360 --> 03:32:24,000 MICROARRAYS FROM DIFFERENT 4621 03:32:24,000 --> 03:32:28,360 PLATFORMS THERE'S A NEED FOR 4622 03:32:28,360 --> 03:32:30,720 ENTER NATIONAL GLYCAN REPOSITORY 4623 03:32:30,720 --> 03:32:33,240 FOR SHARING AND MAKING 4624 03:32:33,240 --> 03:32:34,160 MICROARRAY DATA AVAILABLE FOR 4625 03:32:34,160 --> 03:32:36,040 THE BROAD SCIENTIFIC COMMUNITY. 4626 03:32:36,040 --> 03:32:38,880 GLYCOSCIENCE COMMUNITY AND ALSO 4627 03:32:38,880 --> 03:32:40,640 BEYOND. 4628 03:32:40,640 --> 03:32:45,600 SO, THIS IS BEING DEVELOPED 4629 03:32:45,600 --> 03:32:49,000 UNDER THE INITIATIVE WHICH WE'RE 4630 03:32:49,000 --> 03:32:50,800 PART OF. 4631 03:32:50,800 --> 03:32:53,480 THE MAKING THE GLYCAN ARRAY DATA 4632 03:32:53,480 --> 03:32:57,680 AVAILABLE IS ALSO CRUCIAL FOR 4633 03:32:57,680 --> 03:33:04,320 INTRODUCTION OF DATA TO THE 4634 03:33:04,320 --> 03:33:06,920 WIDER RESOURCES. 4635 03:33:06,920 --> 03:33:10,440 THE RECORDING TEAM META DATA 4636 03:33:10,440 --> 03:33:13,920 INFORMATION IS ESSENTIAL FOR THE 4637 03:33:13,920 --> 03:33:15,240 DESIGN OF GLYCAN MICROARRAY 4638 03:33:15,240 --> 03:33:16,600 REPOSITORY. 4639 03:33:16,600 --> 03:33:21,400 I WOULD LIKE TO MENTION THE 4640 03:33:21,400 --> 03:33:22,680 MICROARRAY GUIDELINES TO WHICH I 4641 03:33:22,680 --> 03:33:26,760 CONTRIBUTED TO THE DESIGN OF THE 4642 03:33:26,760 --> 03:33:34,160 FIRST VERSION AS PART OF THE 4643 03:33:34,160 --> 03:33:35,800 INSTITUTE SUPPORTED INITIATIVE. 4644 03:33:35,800 --> 03:33:38,400 MIRAGE STANDS FOR MINIMUM 4645 03:33:38,400 --> 03:33:39,840 INFORMATION REQUIRED FOR A 4646 03:33:39,840 --> 03:33:42,280 GLYCOMIC EXPERIMENT. 4647 03:33:42,280 --> 03:33:44,600 AND WITH THE GROUP OF GLYCAN 4648 03:33:44,600 --> 03:33:50,000 ARRAY EXPERTS, SO WE HAVE 4649 03:33:50,000 --> 03:33:50,480 IDENTIFIED EIGHT AREAS, 4650 03:33:50,480 --> 03:33:55,160 HIGHLIGHTED IN THE WORK FLOW, 4651 03:33:55,160 --> 03:33:56,920 REQUIRED FOR GENERATING GLYCAN 4652 03:33:56,920 --> 03:33:59,600 ARRAY AND OBTAINING BINDING 4653 03:33:59,600 --> 03:34:02,800 DATA, GUIDELINES HAVE BEEN MET, 4654 03:34:02,800 --> 03:34:04,680 FOR EACH OF THE AREA. 4655 03:34:04,680 --> 03:34:07,920 AND THIS AT THE CORE OF THE 4656 03:34:07,920 --> 03:34:12,600 EXPERIMENTAL META DATA IN THE 4657 03:34:12,600 --> 03:34:15,600 GLYCAN REPOSITORY, WHICH WE ARE 4658 03:34:15,600 --> 03:34:17,320 DEVELOPING AT THE MOMENT. 4659 03:34:17,320 --> 03:34:23,560 I'D LIKE TO EMPHASIZE HERE META 4660 03:34:23,560 --> 03:34:26,160 DATA ARE ALSO CRUCIAL FOR 4661 03:34:26,160 --> 03:34:28,600 CURATION AND COMPARISON, THIS IS 4662 03:34:28,600 --> 03:34:29,920 THE DIRECTION THAT WE'RE 4663 03:34:29,920 --> 03:34:36,560 INTERESTED IN THE FUTURE WORK. 4664 03:34:36,560 --> 03:34:44,040 BRIEF INTRODUCTION OF OUR 4665 03:34:44,040 --> 03:34:47,400 TECHNOLOGY BASED ON GLYCOLYTICS, 4666 03:34:47,400 --> 03:34:53,240 DIFFERENT SOURCES CAN BE 4667 03:34:53,240 --> 03:34:57,680 CONJUGATED ON MICROARRAY SLIDES, 4668 03:34:57,680 --> 03:34:58,840 SO THESE CLUSTERS, WITH ELEMENT 4669 03:34:58,840 --> 03:35:04,600 OF MOBILITY THIS TYPE OF 4670 03:35:04,600 --> 03:35:07,840 PRESENTATION FAVORED BY MOST OF 4671 03:35:07,840 --> 03:35:09,720 THE RECOGNITION WE HAVE STARTED 4672 03:35:09,720 --> 03:35:11,880 SO FAR. 4673 03:35:11,880 --> 03:35:14,920 IN PARTICULAR FOR VIRUSES, AND 4674 03:35:14,920 --> 03:35:17,240 VIRAL ADHESIONS, INCLUDING THOSE 4675 03:35:17,240 --> 03:35:19,040 FROM THE REQUIREMENTS FOR THE 4676 03:35:19,040 --> 03:35:21,080 PRESENTATION OF GLYCANS FOR 4677 03:35:21,080 --> 03:35:28,520 BINDING SUCH AS THE PENTAMERIC 4678 03:35:28,520 --> 03:35:34,240 ONES IN THE LATER PART OF MY 4679 03:35:34,240 --> 03:35:34,640 TALK. 4680 03:35:34,640 --> 03:35:37,480 WE SEE MICROARRAY SYSTEMS, LARGE 4681 03:35:37,480 --> 03:35:42,560 GLYCAN, WE HAVE ESTABLISHED 4682 03:35:42,560 --> 03:35:46,640 CARBOHYDRATE MICROARRAY FACILITY 4683 03:35:46,640 --> 03:35:50,840 WITH SUPPORT OF WELLCOME TRUST, 4684 03:35:50,840 --> 03:35:53,800 EVERY TEN YEARS, THIS IS 4685 03:35:53,800 --> 03:35:57,560 BIOMEDICAL RESOURCE FOR THE 4686 03:35:57,560 --> 03:35:58,320 BROAD SCIENTIFIC COMMUNITY. 4687 03:35:58,320 --> 03:36:04,640 I'M CURRENTLY LEAD OF THE 4688 03:36:04,640 --> 03:36:06,840 MICROARRAY FACILITY WITH FUNDING 4689 03:36:06,840 --> 03:36:10,680 SUPPORT, WITH MY COLLEAGUES AND 4690 03:36:10,680 --> 03:36:13,760 ONE OF OUR MAJOR THEMES IN THE 4691 03:36:13,760 --> 03:36:18,360 PERIOD IS TO SHARE OF OUR 4692 03:36:18,360 --> 03:36:19,240 PUBLISHED GLYCAN MICROARRAY 4693 03:36:19,240 --> 03:36:22,640 DATASET TO THE WIDER COMMUNITY 4694 03:36:22,640 --> 03:36:25,000 THROUGH INTERNATIONAL GLYCAN 4695 03:36:25,000 --> 03:36:27,880 MICROARRAY DATA REPOSITORY. 4696 03:36:27,880 --> 03:36:33,800 FROM THE EARLY STAGE, SOFTWARE 4697 03:36:33,800 --> 03:36:36,320 HAS BEEN THE MAINSTAY FOR 4698 03:36:36,320 --> 03:36:37,520 DAY-TO-DAY MICROARRAY DATA 4699 03:36:37,520 --> 03:36:39,480 MANAGEMENT, WE'RE QUITE LUCKY 4700 03:36:39,480 --> 03:36:43,600 BECAUSE WE HAVE RECORDED OVER 4701 03:36:43,600 --> 03:36:47,080 8,000 DATASETS SINCE ALMOST DAY 4702 03:36:47,080 --> 03:36:53,480 ONE OF OUR MICROARRAY RESEARCH. 4703 03:36:53,480 --> 03:36:58,760 INITIALLY USING THIS PROTOTYPE, 4704 03:36:58,760 --> 03:37:00,960 DEVELOPED FOR INHOUSE USE, WITH 4705 03:37:00,960 --> 03:37:04,680 SUPPORT FROM WELLCOME TRUST AND 4706 03:37:04,680 --> 03:37:09,720 ALSO NIH COMMON FUND WE HAVE 4707 03:37:09,720 --> 03:37:22,240 DEVELOPED AND RELEASED NEW 4708 03:37:22,240 --> 03:37:23,240 SOFTWARE, CARBARRAYART. 4709 03:37:23,240 --> 03:37:25,800 THIS SOFTWARE IS BEING DEVELOPED 4710 03:37:25,800 --> 03:37:31,240 AS IT IS BEAUTIFUL GLYCAN ARRAY 4711 03:37:31,240 --> 03:37:32,800 SOFTWARE LINKING WITH 4712 03:37:32,800 --> 03:37:33,560 REPOSITORY. 4713 03:37:33,560 --> 03:37:38,800 TO HIGHLIGHT ADVANTAGES OF THE 4714 03:37:38,800 --> 03:37:51,480 SOFTWARE COMPARED WITH PREVIOUS 4715 03:37:51,480 --> 03:37:54,680 VERSION, USING WINDOWS AND MAC 4716 03:37:54,680 --> 03:37:59,880 SUITS ALL ARRAY FORMATS, LAYS 4717 03:37:59,880 --> 03:38:04,680 OUT ADVANTAGE COMPARED TO OUR 4718 03:38:04,680 --> 03:38:07,120 PROTOTYPES, ALLOWS STORAGE NOT 4719 03:38:07,120 --> 03:38:15,600 ONLY THE SCAN WITH OUR DATA AND 4720 03:38:15,600 --> 03:38:19,640 ALSO RAW DATA IMAGES, AND 4721 03:38:19,640 --> 03:38:27,480 EXPERIMENTAL METADATA 4722 03:38:27,480 --> 03:38:28,040 COMPARABLE WITH MIRAGE 4723 03:38:28,040 --> 03:38:33,920 GUIDELINES, THE AIM TO USE THE 4724 03:38:33,920 --> 03:38:37,760 SOFTWARE FOR DATA DEPOSITION, TO 4725 03:38:37,760 --> 03:38:40,640 AND FROM THE GLYCAN ARRAY 4726 03:38:40,640 --> 03:38:42,800 REPOSITORY. 4727 03:38:42,800 --> 03:38:48,640 THIS IS A COLORFUL WORKFLOW, 4728 03:38:48,640 --> 03:38:50,480 DATA MANAGEMENT WORKFLOW, ON THE 4729 03:38:50,480 --> 03:38:55,960 RIGHT IS EXPERIMENTAL DATA 4730 03:38:55,960 --> 03:38:56,680 WORKFLOW, EXPERIMENTAL WORKFLOW, 4731 03:38:56,680 --> 03:39:01,240 USERS CAN CREATE GLYCAN LIBRARY 4732 03:39:01,240 --> 03:39:06,880 USING THIS ENTIRE, THESE GLYCAN 4733 03:39:06,880 --> 03:39:10,680 SEQUENCING FORMATS AND ARRAY 4734 03:39:10,680 --> 03:39:13,240 LAYOUT, AND THE METADATA FROM 4735 03:39:13,240 --> 03:39:15,960 THE GLYCAN BINDING SAMPLES AND 4736 03:39:15,960 --> 03:39:18,840 FROM EXPERIMENTAL PROTOCOLS CAN 4737 03:39:18,840 --> 03:39:20,840 BE RECORDED. 4738 03:39:20,840 --> 03:39:26,600 TOGETHER WITH THE RAW DATA FROM 4739 03:39:26,600 --> 03:39:27,480 THE SCANNER. 4740 03:39:27,480 --> 03:39:34,640 THE DATA CAN BE PROCESSED WITH 4741 03:39:34,640 --> 03:39:37,080 THIS INFORMATION AND PRESENTED, 4742 03:39:37,080 --> 03:39:40,680 DISPLAYED AS HEAT MAPS WITH 4743 03:39:40,680 --> 03:39:45,680 FILTERING FUNCTIONS AS WELL AS 4744 03:39:45,680 --> 03:39:46,280 REPORTING. 4745 03:39:46,280 --> 03:39:50,800 THESE FUNCTIONS MADE SOFTWARE AS 4746 03:39:50,800 --> 03:39:52,800 DAY-TO-DAY GLYCAN MICROARRAY 4747 03:39:52,800 --> 03:39:54,760 DATA MANAGEMENT IN OUR FACILITY 4748 03:39:54,760 --> 03:39:59,280 AND ALSO CAN BE WIDELY USED IN 4749 03:39:59,280 --> 03:40:03,200 GLYCAN ARRAY LABORATORIES. 4750 03:40:03,200 --> 03:40:13,440 THE DATA, METADATA COMBINED WITH 4751 03:40:13,440 --> 03:40:22,600 MIRAGE DEADLINES GATHER THIS 4752 03:40:22,600 --> 03:40:24,520 INFORMATION THROUGH REPOSITORY. 4753 03:40:24,520 --> 03:40:29,480 I'M GOING TO GO THROUGH THE DATA 4754 03:40:29,480 --> 03:40:34,680 USING OUR GLYCAN ARRAYS ON THE 4755 03:40:34,680 --> 03:40:49,840 STUDIES OF HOST GLYCAN BY 4756 03:40:49,840 --> 03:40:55,920 POLYOMAVIRUSES. 4757 03:40:55,920 --> 03:41:01,480 A BRIEF INTRODUCTION, THEY CAN 4758 03:41:01,480 --> 03:41:06,200 INFECT DIVERSE MAMMALS AND 4759 03:41:06,200 --> 03:41:07,400 BIRDS, FISH AND INVERTEBRATES. 4760 03:41:07,400 --> 03:41:10,360 MORE THAN 100 DISCOVERED SO FAR, 4761 03:41:10,360 --> 03:41:15,000 ONLY 14 HAVE BEEN PROPOSED TO BE 4762 03:41:15,000 --> 03:41:16,240 HUMAN TROPIC. 4763 03:41:16,240 --> 03:41:17,520 INFECTIONS IN HUMANS USUALLY 4764 03:41:17,520 --> 03:41:20,080 GIVE NO SYMPTOMS IN HEALTHY 4765 03:41:20,080 --> 03:41:21,560 INDIVIDUALS, SOME VIRUSES CAN 4766 03:41:21,560 --> 03:41:30,880 CAUSE SEVERE DISEASES IN 4767 03:41:30,880 --> 03:41:35,880 IMMUNOCOMPROMISED INDIVIDUALS. 4768 03:41:35,880 --> 03:41:45,040 IT IS RESPONSIBLE FOR ATTACHMENT 4769 03:41:45,040 --> 03:41:46,800 OF POLYOMAVIRUS, BINDING THROUGH 4770 03:41:46,800 --> 03:41:50,080 GLYCAN RECEPTORS. 4771 03:41:50,080 --> 03:41:53,120 THE NARROW SPECIFICITY SPECIAL 4772 03:41:53,120 --> 03:42:04,720 FEATURE FOR POLYOMA VIRUSES, VP1 4773 03:42:04,720 --> 03:42:09,240 PROTEINS, I'M SHOWING A FEW WELL 4774 03:42:09,240 --> 03:42:38,440 KNOWN HUMAN POLYOMAVIRUSES TO 4775 03:42:38,440 --> 03:42:38,680 HIGHLIGHT. 4776 03:42:38,680 --> 03:42:40,680 THE POLYOMAVIRUS CAUSE SKIN 4777 03:42:40,680 --> 03:42:43,400 DISEASE, SKIN CANCER, SKIN 4778 03:42:43,400 --> 03:42:46,880 DISEASES. 4779 03:42:46,880 --> 03:42:50,880 USING THE GLYCAN MICROARRAYS, WE 4780 03:42:50,880 --> 03:42:52,200 HAVE DISCOVERED THE NARROW 4781 03:42:52,200 --> 03:43:06,080 SPECIFICITY OF MANY OF THE 4782 03:43:06,080 --> 03:43:06,480 VIRUSES. 4783 03:43:06,480 --> 03:43:09,600 WE ARE FOLLOWING UP THE STUDIES 4784 03:43:09,600 --> 03:43:13,240 LOOKING AT MUTANTS OF THE 4785 03:43:13,240 --> 03:43:14,240 VIRUSES ISOLATED FROM PATIENTS. 4786 03:43:14,240 --> 03:43:18,160 TODAY I WOULD LIKE TO FOCUS ON 4787 03:43:18,160 --> 03:43:29,080 THE TWO RECENTLY DISCOVERED 4788 03:43:29,080 --> 03:43:30,400 HUMAN POLYOMAVIRUSES. 4789 03:43:30,400 --> 03:43:33,160 THESE ARE DETECTED IN HUMAN 4790 03:43:33,160 --> 03:43:38,600 LIVER ISSUES, AND THOSE 4791 03:43:38,600 --> 03:43:39,240 IDENTIFIED IN PANCREATIC 4792 03:43:39,240 --> 03:43:42,760 TRANSPLANT PATIENTS. 4793 03:43:42,760 --> 03:43:48,120 USING THE ALIGNMENT OF BINDING 4794 03:43:48,120 --> 03:43:51,000 REGIONS, BC AND DE LOOPS. 4795 03:43:51,000 --> 03:43:55,120 IN BOTH CASES CLOSE RELATIONSHIP 4796 03:43:55,120 --> 03:43:58,680 OF HUMAN VIRUSES WERE FOUND WITH 4797 03:43:58,680 --> 03:44:02,640 THE NUMBER OF ANIMAL VIRUSES. 4798 03:44:02,640 --> 03:44:04,240 RAISING THE QUESTION ABOUT 4799 03:44:04,240 --> 03:44:08,520 ORIGINS AND EVOLUTION OF THE TWO 4800 03:44:08,520 --> 03:44:08,760 VIRUSES. 4801 03:44:08,760 --> 03:44:18,800 I LIKE THIS IMAGE FROM THE A 4802 03:44:18,800 --> 03:44:26,560 PAPER SHOWING OVERVIEW OF VP1 4803 03:44:26,560 --> 03:44:33,200 AMINO ACID, TO THE COMPLEX 4804 03:44:33,200 --> 03:44:37,360 STRUCTURES OF VP1 WITH LACTOSE. 4805 03:44:37,360 --> 03:44:45,360 ON THE LEFT A VIRUS WITH 4806 03:44:45,360 --> 03:44:48,240 CHIMPANZEE, THE RIGHT HUMAN 4807 03:44:48,240 --> 03:44:49,200 POLYOMAVIRUS WITH BIRD 4808 03:44:49,200 --> 03:44:52,440 POLYOMAVIRUS. 4809 03:44:52,440 --> 03:44:57,080 THE MESSAGE HERE IS THAT BINDING 4810 03:44:57,080 --> 03:45:01,960 SITES, YOU CAN SEE SUGARS IN 4811 03:45:01,960 --> 03:45:03,560 GREEN COLOR HERE, HIGHLY 4812 03:45:03,560 --> 03:45:07,560 CONSERVED AS HIGHLIGHTED IN RED 4813 03:45:07,560 --> 03:45:10,080 COLOR HERE. 4814 03:45:10,080 --> 03:45:13,480 THEY ARE HIGHLY CONSERVED ACROSS 4815 03:45:13,480 --> 03:45:16,080 DIFFERENT VIRUSES, DIFFERENT 4816 03:45:16,080 --> 03:45:18,320 SPECIES. 4817 03:45:18,320 --> 03:45:20,520 HOWEVER, THE SURROUNDING 4818 03:45:20,520 --> 03:45:22,360 RESIDUES NEAR THESE SIALIC ACID 4819 03:45:22,360 --> 03:45:25,440 BINDING SITES, YOU CAN SEE THE 4820 03:45:25,440 --> 03:45:33,920 COLORS, THEY DISPLAY MUCH LOWER 4821 03:45:33,920 --> 03:45:34,960 LEVEL OF CONSERVATION SUGGESTING 4822 03:45:34,960 --> 03:45:36,120 DIFFERENT RECEPTOR SPECIFICITY 4823 03:45:36,120 --> 03:45:43,720 MAY BE OBSERVED BY DIFFERENT 4824 03:45:43,720 --> 03:45:43,960 VIRUSES. 4825 03:45:43,960 --> 03:45:47,400 WE CANNOT CONCLUDE FROM 4826 03:45:47,400 --> 03:45:48,840 STRUCTURE STUDIES WITH SIMPLE 4827 03:45:48,840 --> 03:45:50,320 SUGARS. 4828 03:45:50,320 --> 03:45:57,320 WE CAN LOOK IN MICROARRAYS, 4829 03:45:57,320 --> 03:45:59,440 COMPARISON WITH THE CHIMPANZEE 4830 03:45:59,440 --> 03:46:03,880 POLYOMAVIRUS, USING ARRAY OF 4831 03:46:03,880 --> 03:46:09,080 GLYCANS, WE CAN DISPLAY THE 4832 03:46:09,080 --> 03:46:13,080 GLYCANS ACCORDING TO LINKAGE AND 4833 03:46:13,080 --> 03:46:17,080 THESE ARE CLOSELY RELATED, 4834 03:46:17,080 --> 03:46:20,240 HIGHLY CONSERVED, VP1 PROTEINS 4835 03:46:20,240 --> 03:46:55,080 BIND TO TYPE 1 SEQUENCE AND 4836 03:46:55,080 --> 03:46:58,600 NON-SIALYATED SEQUENCE. 4837 03:46:58,600 --> 03:47:10,040 COMPARISON OF THE HUMAN VIRUS, 4838 03:47:10,040 --> 03:47:30,480 CLOSELY RELATED POLYOMAVIRUS 4839 03:47:30,480 --> 03:47:32,640 ALSO SHOWS PREFERENCE. 4840 03:47:32,640 --> 03:47:38,760 AND THIS IS COMPARISON OF HUMAN 4841 03:47:38,760 --> 03:47:41,720 POLYOMAVIRUS WITH SHEEP 4842 03:47:41,720 --> 03:47:42,440 POLYOMAVIRUS. 4843 03:47:42,440 --> 03:47:44,360 THE BINDING SITES IS HIGHLY 4844 03:47:44,360 --> 03:47:48,560 CONSERVED, THE DIFFERENCE IS 4845 03:47:48,560 --> 03:47:52,760 PINK, DISTINCTIVE BINDING HAS 4846 03:47:52,760 --> 03:47:54,480 BEEN OBSERVED. 4847 03:47:54,480 --> 03:48:11,760 WE'RE SEEING BINDING THROUGH THE 4848 03:48:11,760 --> 03:48:12,320 NON-SYLATED. 4849 03:48:12,320 --> 03:48:15,080 THERE WAS ADDITIONAL BINDING IN 4850 03:48:15,080 --> 03:48:25,800 COMPARISON TO HUMAN POLYOMA, SO 4851 03:48:25,800 --> 03:48:28,080 WE CAN OBSERVE BINDING. 4852 03:48:28,080 --> 03:48:36,680 THIS IS QUITE STRIKING WITH THE 4853 03:48:36,680 --> 03:48:42,600 GOOSE POLYOMAVIRUS, ABRUPT 4854 03:48:42,600 --> 03:48:43,840 FINDINGS, THIS PROVIDES SOME 4855 03:48:43,840 --> 03:48:45,680 EXPLANATION, THIS IS ONE OF THE 4856 03:48:45,680 --> 03:48:47,880 FEW KNOWN POLYOMAVIRUSES THAT 4857 03:48:47,880 --> 03:48:53,960 CAN INFECT DIFFERENT AVIAN 4858 03:48:53,960 --> 03:48:54,160 HOSTS. 4859 03:48:54,160 --> 03:48:55,480 I HAVEN'T WHETHER THIS DID CROSS 4860 03:48:55,480 --> 03:48:59,760 TO OTHER SPECIES, BUT IT'S A 4861 03:48:59,760 --> 03:49:04,240 CROSS-SPECIES INFECTIVITY, A 4862 03:49:04,240 --> 03:49:09,160 REAL PATHOGEN CAUSING THE 4863 03:49:09,160 --> 03:49:10,680 DISEASE IN THE GEESE. 4864 03:49:10,680 --> 03:49:11,880 >> TWO MINUTES. 4865 03:49:11,880 --> 03:49:12,240 >> ALMOST DONE. 4866 03:49:12,240 --> 03:49:15,880 I DON'T KNOW IF YOU CAN SEE MY 4867 03:49:15,880 --> 03:49:17,240 TITLE. 4868 03:49:17,240 --> 03:49:18,760 FOOTPRINTS. 4869 03:49:18,760 --> 03:49:23,080 THIS IS A FOOTPRINT, HEAT MAP. 4870 03:49:23,080 --> 03:49:26,720 THE GROUP OF POLYOMAVIRUSES I 4871 03:49:26,720 --> 03:49:29,480 DESCRIBED JUST NOW, GENERATED IN 4872 03:49:29,480 --> 03:49:33,040 OUR MICROAWAY SOFTWARE, HEAT MAP 4873 03:49:33,040 --> 03:49:33,880 SENSATION. 4874 03:49:33,880 --> 03:49:38,680 AND THIS IS A LARGE ARRAY. 4875 03:49:38,680 --> 03:49:41,400 900 PROBES. 4876 03:49:41,400 --> 03:49:44,320 WE CAN SEE THAT THERE IS THE 4877 03:49:44,320 --> 03:49:46,720 CLOSELY RELATED HUMAN AND ANIMAL 4878 03:49:46,720 --> 03:49:48,240 VIRUSES SHARING A LOT OF 4879 03:49:48,240 --> 03:49:58,600 SIMILARITY IN THE GLYCAN 4880 03:49:58,600 --> 03:50:00,640 BINDING, AND SHOWING DIFFERENCE, 4881 03:50:00,640 --> 03:50:02,240 THEY SHARE SIMILARITY BUT HAVE 4882 03:50:02,240 --> 03:50:02,920 DISTINCT DETAILS. 4883 03:50:02,920 --> 03:50:06,080 IT'S SOMETHING I WOULD LIKE TO 4884 03:50:06,080 --> 03:50:10,680 HIGHLIGHT HERE, VERY EXCITING, 4885 03:50:10,680 --> 03:50:11,920 SO THE GLYCAN BINDING OBSERVED 4886 03:50:11,920 --> 03:50:16,160 WITH MANY OF THE VIRUSES, THIS 4887 03:50:16,160 --> 03:50:18,000 HAS BEEN FOLLOWED UP BY 4888 03:50:18,000 --> 03:50:18,440 STRUCTURAL STUDIES. 4889 03:50:18,440 --> 03:50:21,040 I CAN'T SHARE THE DETAILS TODAY, 4890 03:50:21,040 --> 03:50:23,240 OF THE PROBES, THAT HOPEFULLY WE 4891 03:50:23,240 --> 03:50:25,880 WILL BE ABLE TO PRESENT 4892 03:50:25,880 --> 03:50:26,960 STRUCTURAL INSIGHT OF THESE 4893 03:50:26,960 --> 03:50:34,000 INTERACTIONS IN THE NEAR FUTURE. 4894 03:50:34,000 --> 03:50:40,120 IN SUMMARY MICROARRAY DATA, 4895 03:50:40,120 --> 03:50:42,800 CLOSE REVEAL DETAILS OF 4896 03:50:42,800 --> 03:50:44,040 BIPEDDING CHARACTERISTICS, 4897 03:50:44,040 --> 03:50:46,080 HELPING ADVANCE OUR 4898 03:50:46,080 --> 03:50:48,160 UNDERSTANDING OF RECEPTOR-BASED 4899 03:50:48,160 --> 03:50:50,160 CELL TROPISM DIFFERENCES, 4900 03:50:50,160 --> 03:50:51,080 OCCURRENCE OF CROSS-SPECIES 4901 03:50:51,080 --> 03:50:54,800 TRANSMISSION AND ALSO EVOLUTION 4902 03:50:54,800 --> 03:50:56,800 OF POLYOMAVIRUSES, AND ONGOING 4903 03:50:56,800 --> 03:51:06,600 STUDIES WHERE USING MICROARRAYS 4904 03:51:06,600 --> 03:51:09,200 TO MONITOR SPECIFICITY, IN 4905 03:51:09,200 --> 03:51:11,320 TRANSPLANTS, CAN KIDNEY 4906 03:51:11,320 --> 03:51:14,880 TRANSPLANT PATIENTS, SO MUTANTS, 4907 03:51:14,880 --> 03:51:16,760 WE'RE MONITORING MUTANTS OF 4908 03:51:16,760 --> 03:51:21,600 CELLS IN THE KIDNEY TRANSPLANT 4909 03:51:21,600 --> 03:51:22,280 RECIPIENT. 4910 03:51:22,280 --> 03:51:28,520 WE HAVE A LARGE ARMY OF 4911 03:51:28,520 --> 03:51:30,240 MICROARRAY DAY, DIFFERENT 4912 03:51:30,240 --> 03:51:32,040 VIRUSES, INCLUDING HUMAN -- THE 4913 03:51:32,040 --> 03:51:34,680 VIRUS IS DESCRIBED TODAY, ALSO 4914 03:51:34,680 --> 03:51:40,680 OTHER VIRUSES INCLUDING NUMBER 4915 03:51:40,680 --> 03:51:43,880 OF BK MUTANTS AND ADENOVIRUS, 4916 03:51:43,880 --> 03:51:47,280 ROTAVIRUS, ET CETERA. 4917 03:51:47,280 --> 03:51:56,160 THESE ARE STORED IN OUR 4918 03:51:56,160 --> 03:51:59,560 CarbARRAYART, THEY HAVE THE 4919 03:51:59,560 --> 03:52:00,800 GLYCANS, ARRAY INFORMATION 4920 03:52:00,800 --> 03:52:04,400 TOGETHER WITH SIMPLE METADATA, 4921 03:52:04,400 --> 03:52:12,480 EXPERIMENTAL METADATA, WE CAN 4922 03:52:12,480 --> 03:52:14,120 STORE THE PARAMETERS, PROCESS 4923 03:52:14,120 --> 03:52:17,800 DATA TOGETHER WITH RAW DATA FROM 4924 03:52:17,800 --> 03:52:21,040 THE SCANNERS, ALREADY THIS WILL 4925 03:52:21,040 --> 03:52:25,000 BE -- THIS WILL BE READY FOR 4926 03:52:25,000 --> 03:52:26,480 SUBMISSION DEPOSITION INTO THE 4927 03:52:26,480 --> 03:52:29,960 REPOSITORY WHEN THE REPOSITORY 4928 03:52:29,960 --> 03:52:30,280 IS LAUNCHED. 4929 03:52:30,280 --> 03:52:37,440 I'D LIKE TO THANK MY COLLEAGUES 4930 03:52:37,440 --> 03:52:42,880 IN THE LABORATORY, PAST AND 4931 03:52:42,880 --> 03:52:44,760 PRESENT. 4932 03:52:44,760 --> 03:52:53,920 ALSO OUR COLLABORATORS OUR 4933 03:52:53,920 --> 03:52:54,920 ADVISER AND COLLABORATORS. 4934 03:52:54,920 --> 03:52:56,320 THANK YOU FOR YOUR ATTENTION. 4935 03:52:56,320 --> 03:52:57,720 THANK YOU. 4936 03:52:57,720 --> 03:52:58,720 >> THANK YOU, YAN. 4937 03:52:58,720 --> 03:53:00,160 VERY NICE TALK. 4938 03:53:00,160 --> 03:53:01,840 AGAIN, WE CAN ADDRESS QUESTIONS 4939 03:53:01,840 --> 03:53:04,680 AT THE PANEL DISCUSSION. 4940 03:53:04,680 --> 03:53:05,400 >> THANK YOU. 4941 03:53:05,400 --> 03:53:08,240 >> I CAN STOP SHARE. 4942 03:53:08,240 --> 03:53:10,680 THANK YOU. 4943 03:53:10,680 --> 03:53:14,320 >> NEXT SPEAKER IS LARA MAHAL, 4944 03:53:14,320 --> 03:53:16,800 FROM UNIVERSITY OF ALBERTA, 4945 03:53:16,800 --> 03:53:18,040 TITLE IS SYSTEMATICALLY 4946 03:53:18,040 --> 03:53:22,560 UNCOVERING THE ROLES OF 4947 03:53:22,560 --> 03:53:23,240 GLYCOSYLATION IN HOST-PATHOGEN 4948 03:53:23,240 --> 03:53:23,560 INTERACTIONS. 4949 03:53:23,560 --> 03:53:26,200 >> THANK YOU SO MUCH. 4950 03:53:26,200 --> 03:53:28,680 CAN EVERYONE SEE MY SCREEN? 4951 03:53:28,680 --> 03:53:31,200 EVERYTHING GOOD? 4952 03:53:31,200 --> 03:53:32,160 GREAT. 4953 03:53:32,160 --> 03:53:33,880 I FIRST WANT TO THANK YOU FOR 4954 03:53:33,880 --> 03:53:36,400 THE INVITATION TO GIVE OUR TALK 4955 03:53:36,400 --> 03:53:43,360 ON UNPUBLISHED WORK FROM MY LAB. 4956 03:53:43,360 --> 03:53:45,360 THIS IS AN INFORMATICS 4957 03:53:45,360 --> 03:53:49,040 SYMPOSIUM, MY LAB FOCUSES ON 4958 03:53:49,040 --> 03:53:50,760 SYSTEMS BASED UNDERSTANDING, 4959 03:53:50,760 --> 03:53:51,360 SYSTEMS-BASED APPROACHES TO 4960 03:53:51,360 --> 03:53:52,880 UNDERSTANDING GLYCAN, LARGE 4961 03:53:52,880 --> 03:53:55,520 SCALE DATASETS, HOW WE CAN USE 4962 03:53:55,520 --> 03:53:57,480 INFORMATICS TO IDENTIFY HOW 4963 03:53:57,480 --> 03:53:59,080 SUGARS WORK. 4964 03:53:59,080 --> 03:54:02,880 AND SO THE MAIN TOPIC IS I WORK 4965 03:54:02,880 --> 03:54:06,080 IN MICROARRAYS AND DATA 4966 03:54:06,080 --> 03:54:09,320 INTEGRATION, SO MY LAB CREATED 4967 03:54:09,320 --> 03:54:10,720 LECTIN MICROARRAYS, NOW THIS 4968 03:54:10,720 --> 03:54:13,200 TECHNOLOGY IS ALMOST 20 YEARS 4969 03:54:13,200 --> 03:54:14,120 OLD. 4970 03:54:14,120 --> 03:54:16,320 WE-- THE BASIC IDEA OF LECTIN 4971 03:54:16,320 --> 03:54:19,280 MICROARRAY WE CAN TAKE ANYTHING, 4972 03:54:19,280 --> 03:54:22,240 CELL CULTURE, HUMAN TISSUE, YOU 4973 03:54:22,240 --> 03:54:24,120 NAME IT, EXTRACT GLYCOPROTEINS, 4974 03:54:24,120 --> 03:54:25,440 THEY HAVE N AND O-GLYCANS AND 4975 03:54:25,440 --> 03:54:27,920 YOU CAN SOMETIMES LOOK AT 4976 03:54:27,920 --> 03:54:28,680 GLYCOLIPIDS. 4977 03:54:28,680 --> 03:54:32,280 WE LABEL THE SAMPLES WITH ONE 4978 03:54:32,280 --> 03:54:33,400 FLUOROPHORE, HAVE A BIOLOGICAL 4979 03:54:33,400 --> 03:54:37,400 REFERENCE IN MY LAB, A SECOND 4980 03:54:37,400 --> 03:54:38,480 FLUOROPHORE, AND ADD EQUAL 4981 03:54:38,480 --> 03:54:44,920 AMOUNTS TO LECTIN MICROARRAY, 4982 03:54:44,920 --> 03:54:46,680 BINDING OF THESE TWO SAMPLES 4983 03:54:46,680 --> 03:54:49,480 GIVE US AN IDEA BECAUSE WE 4984 03:54:49,480 --> 03:54:51,680 UNDERSTAND THE LECTIN BINDING OF 4985 03:54:51,680 --> 03:54:52,320 VERY SPECIFIC MOLECULAR 4986 03:54:52,320 --> 03:54:54,640 STRUCTURES AND HOW THEY ARE 4987 03:54:54,640 --> 03:54:55,400 CHANGING OVER BIOLOGICAL 4988 03:54:55,400 --> 03:54:55,640 SAMPLES. 4989 03:54:55,640 --> 03:54:58,280 THIS, FOR EXAMPLE, IS AN EXAMPLE 4990 03:54:58,280 --> 03:54:59,680 FROM OUR PANCREATIC CANCER DATA, 4991 03:54:59,680 --> 03:55:03,080 LOOKING AT A MOUSE MODEL, THE 4992 03:55:03,080 --> 03:55:06,880 SUGARS ARE TRAINING AS THE MOUSE 4993 03:55:06,880 --> 03:55:07,880 DEVELOPS PANCREATIC CANCER. 4994 03:55:07,880 --> 03:55:09,760 WHY DOES A LECTIN MICROARRAY 4995 03:55:09,760 --> 03:55:13,480 HAVE ANY ADVANTAGES OVER THE 4996 03:55:13,480 --> 03:55:14,600 OTHER GLYCOMIC METHODS? 4997 03:55:14,600 --> 03:55:15,880 SOME ADVANTAGES WERE DISCUSSED 4998 03:55:15,880 --> 03:55:17,960 BY MY COLLEAGUES WHEN TALKING 4999 03:55:17,960 --> 03:55:19,400 ABOUT THINKING ABOUT HOW YOU 5000 03:55:19,400 --> 03:55:22,120 DISCOVER WHAT LECTIN YOU WOULD 5001 03:55:22,120 --> 03:55:24,880 USE TO LOOK AT GLYCOPROTEINS. 5002 03:55:24,880 --> 03:55:27,120 AND ONE OF THE ADVANTAGES IS 5003 03:55:27,120 --> 03:55:30,200 THAT YOU ARE USING PROBES THAT 5004 03:55:30,200 --> 03:55:32,680 CAN THEN BE USED TO DO MORE 5005 03:55:32,680 --> 03:55:35,920 DISCRETE DISCOVERY. 5006 03:55:35,920 --> 03:55:37,120 YOU CAN DO GLYCOPROTEOMIC 5007 03:55:37,120 --> 03:55:39,560 PULLDOWNS, AN EXAMPLE FROM WORK 5008 03:55:39,560 --> 03:55:45,120 IN CANCER CELL, WHERE WE DID 5009 03:55:45,120 --> 03:55:47,040 GLYCOPROTEOMIC PULLDOWNS TO 5010 03:55:47,040 --> 03:55:49,080 DISCOVER WHY IT IS CORE 5011 03:55:49,080 --> 03:55:50,680 FUCOSYLATION IS CHANGING IN 5012 03:55:50,680 --> 03:55:54,880 MEDICAL MOMENT A METASTASIS, THE 5013 03:55:54,880 --> 03:55:57,400 ROLE IN CELL MIGRATION. 5014 03:55:57,400 --> 03:55:59,360 SAME PROBES CAN BE USED AS A 5015 03:55:59,360 --> 03:56:01,120 PROBE ON, SAY, TISSUE CULTURE OR 5016 03:56:01,120 --> 03:56:02,680 IN THIS PARTICULAR CASE HUMAN 5017 03:56:02,680 --> 03:56:07,320 TISSUES WHERE WE'RE NOW ABLE TO 5018 03:56:07,320 --> 03:56:09,400 LOOK AT LOCALIZATION AND 5019 03:56:09,400 --> 03:56:10,440 EXPRESSION OF SPECIFIC SUGARS ON 5020 03:56:10,440 --> 03:56:12,600 IN THIS CASE CANCER TISSUE. 5021 03:56:12,600 --> 03:56:14,840 AGAIN, THIS IS MELANOMA 5022 03:56:14,840 --> 03:56:16,680 METASTASIS, PRIMARY MELANOMA, 5023 03:56:16,680 --> 03:56:22,560 SEEING A SWITCH FROM 5024 03:56:22,560 --> 03:56:26,680 FUCOSYLATION FROM ONE TWO TO TWO 5025 03:56:26,680 --> 03:56:28,720 SIX IN THE CORE. 5026 03:56:28,720 --> 03:56:32,200 WHAT ELSE CAN IT GO? 5027 03:56:32,200 --> 03:56:33,080 TELLING ABOUT THE BASIC 5028 03:56:33,080 --> 03:56:34,680 TECHNOLOGY, ONE OF THE GREAT 5029 03:56:34,680 --> 03:56:37,480 THINGS IS THAT IT'S REALLY 5030 03:56:37,480 --> 03:56:38,480 HIGH-THROUGHPUT. 5031 03:56:38,480 --> 03:56:40,680 WE HAVE 4 SUBARRAYS PER SLIDE, 5032 03:56:40,680 --> 03:56:43,920 IN TEN SLIDES CAN DO 240 5033 03:56:43,920 --> 03:56:45,120 SAMPLES, STARTING TO APPROACH 5034 03:56:45,120 --> 03:56:47,920 OUR AVERAGE ANALYSIS, TYPICALLY 5035 03:56:47,920 --> 03:56:49,240 DOING AROUND 200 SAMPLES AND 5036 03:56:49,240 --> 03:56:49,800 ANALYSIS. 5037 03:56:49,800 --> 03:56:52,560 WE HAVE A DUAL COLOR APPROACH, 5038 03:56:52,560 --> 03:56:54,520 WHICH I'VE TALKED ABOUT, THIS 5039 03:56:54,520 --> 03:57:08,880 MAKES FOR RAPID AND ROBUST 5040 03:57:08,880 --> 03:57:10,840 QUANTITATION, BECAUSE OF THE 5041 03:57:10,840 --> 03:57:22,960 FACT DATA IS IN THE SAME FORMATS 5042 03:57:22,960 --> 03:57:23,800 IT'S INTEGRATIVE. 5043 03:57:23,800 --> 03:57:30,400 ARRAYS INCLUDE ANTIBODIES. 5044 03:57:30,400 --> 03:57:34,680 WE'RE CONSTANTLY EXPANDING, 5045 03:57:34,680 --> 03:57:35,880 FEEL FREE TO CONTACT US, WE 5046 03:57:35,880 --> 03:57:38,600 WOULD LOVE TO ADD MORE. 5047 03:57:38,600 --> 03:57:40,880 WE'RE USING MACHINE LEARNING 5048 03:57:40,880 --> 03:57:41,160 ANNOTATION. 5049 03:57:41,160 --> 03:57:42,760 AGAIN, THE POINT OF USING A 5050 03:57:42,760 --> 03:57:47,360 LECTIN ARRAY, IF WE LOOK AT 5051 03:57:47,360 --> 03:57:49,920 HYBRID N LINK GLYCAN, IF WE WANT 5052 03:57:49,920 --> 03:57:52,200 TO FIGURE OUT WHETHER IT HAS 5053 03:57:52,200 --> 03:57:54,800 SIALIC ACID THAT'S NOT SO EASY 5054 03:57:54,800 --> 03:57:55,680 USING A TYPICAL MASS 5055 03:57:55,680 --> 03:57:56,880 SPECTROMETRY APPROACH IN A 5056 03:57:56,880 --> 03:57:57,480 HIGH-THROUGHPUT WAY. 5057 03:57:57,480 --> 03:58:01,200 BUT IF YOU WANT TO SEE WHETHER 5058 03:58:01,200 --> 03:58:06,080 OVERALL 2, 6 SIALYATION IS 5059 03:58:06,080 --> 03:58:08,040 INTEREST, IT IS DISCRETE IN 5060 03:58:08,040 --> 03:58:09,600 BINDING FOR THIS PARTICULAR 5061 03:58:09,600 --> 03:58:09,840 GLYCAN. 5062 03:58:09,840 --> 03:58:11,800 INDEED IT DOESN'T BIND IF THIS 5063 03:58:11,800 --> 03:58:14,520 SUGAR IS A SIALIC ACID AT THE 3 5064 03:58:14,520 --> 03:58:14,920 POSITION INSTEAD. 5065 03:58:14,920 --> 03:58:17,680 NOT ONLY THAT, BUT BECAUSE WE 5066 03:58:17,680 --> 03:58:20,240 KNOW THE VERY SPECIFIC LINKAGE 5067 03:58:20,240 --> 03:58:23,480 WE KNOW THE BIOSYNTHETIC ENZYMES 5068 03:58:23,480 --> 03:58:27,360 THAT CAN MAKE IT. 5069 03:58:27,360 --> 03:58:31,440 ST6GAL 2 AND -- 1 AND 2, IN 5070 03:58:31,440 --> 03:58:33,040 TERMS OF BIOLOGICAL PATHWAYS TO 5071 03:58:33,040 --> 03:58:36,760 UNDERLIE SUGARS TO SEE IF WE'RE 5072 03:58:36,760 --> 03:58:38,160 GETTING THROUGH CURRENT DATA. 5073 03:58:38,160 --> 03:58:39,560 TO TALK MORE ABOUT HOW WE 5074 03:58:39,560 --> 03:58:43,720 UNDERSTAND WHAT THESE ARE 5075 03:58:43,720 --> 03:58:46,680 ACTUALLY BINDING, WE HAVE 5076 03:58:46,680 --> 03:58:50,920 PUBLISHED WORK IN ACS CHEMICAL 5077 03:58:50,920 --> 03:58:54,560 BIOLOGY, TUBING THE 611 GLYCAN 5078 03:58:54,560 --> 03:58:55,600 MICROARRAY I A DATASET GENERATED 5079 03:58:55,600 --> 03:58:58,040 A TIME AGO, LOOKED AT 5080 03:58:58,040 --> 03:58:59,360 COMMERCIALLY AVAILABLE LECTINS. 5081 03:58:59,360 --> 03:59:02,840 SO USING THESE DATASETS AS INPUT 5082 03:59:02,840 --> 03:59:07,480 WITH HELP OF DANIEL'S GROUP, WE 5083 03:59:07,480 --> 03:59:08,760 DID MACHINE BASED LEARNING 5084 03:59:08,760 --> 03:59:10,240 ANNOTATION OF THE LECTINS, THIS 5085 03:59:10,240 --> 03:59:14,240 IS A COMBINATION OF BOTH 5086 03:59:14,240 --> 03:59:15,160 MACHINE-BASED LEARNING AND HAND 5087 03:59:15,160 --> 03:59:17,400 ANNOTATION FROM TIME LOOKING AT 5088 03:59:17,400 --> 03:59:17,680 DATASETS. 5089 03:59:17,680 --> 03:59:19,400 WHAT WE HAVE CREATED ARE SERIES 5090 03:59:19,400 --> 03:59:22,480 OF TABLES, THIS IS A GUIDE TO 5091 03:59:22,480 --> 03:59:24,080 ALL THE COMMERCIALLY AVAILABLE 5092 03:59:24,080 --> 03:59:25,600 LECTINS AVAILABLE, AND I MADE IT 5093 03:59:25,600 --> 03:59:27,760 SO IT'S OPEN ACCESS, SO ANYONE 5094 03:59:27,760 --> 03:59:30,840 CAN DOWNLOAD AND PLEASE DO USE 5095 03:59:30,840 --> 03:59:31,000 IT. 5096 03:59:31,000 --> 03:59:32,880 BASICALLY WHAT WE'VE CREATED IS 5097 03:59:32,880 --> 03:59:36,640 A GUIDE TO PREDOMINANT BINDING 5098 03:59:36,640 --> 03:59:43,120 MOTIF, IDEA OF THE RULES. 5099 03:59:43,120 --> 03:59:47,360 WE FOUND SURPRISING THINGS. 5100 03:59:47,360 --> 03:59:48,320 MAACKIA BINDS, WE ALREADY KNEW, 5101 03:59:48,320 --> 03:59:50,200 BUT WHAT I DIDN'T KNOW AND WHAT 5102 03:59:50,200 --> 03:59:54,480 IS NOT OBVIOUS TO THE FIELD IS 5103 03:59:54,480 --> 03:59:58,720 THAT FUCOSYLATION ON THIS 5104 03:59:58,720 --> 04:00:01,280 GlcNAc INHIBITS BINDING. 5105 04:00:01,280 --> 04:00:04,040 THE MOST POPULAR AND FAMOUS 2, 3 5106 04:00:04,040 --> 04:00:08,520 SYLATED GLYCAN IS NOT BOUND BY 5107 04:00:08,520 --> 04:00:08,840 MAA. 5108 04:00:08,840 --> 04:00:10,600 SO THESE SPECIFICITIES ARE 5109 04:00:10,600 --> 04:00:13,600 THINGS THAT WERE REVEALED BY THE 5110 04:00:13,600 --> 04:00:16,080 ANNOTATION WE DID USING MACHINE 5111 04:00:16,080 --> 04:00:16,600 LEARNING. 5112 04:00:16,600 --> 04:00:18,560 SO, AGAIN, IF YOU'RE INTERESTED 5113 04:00:18,560 --> 04:00:19,680 IN SPECIFICITY YOU WANT TO 5114 04:00:19,680 --> 04:00:21,840 FIGURE OUT WHAT MIGHT BIND YOUR 5115 04:00:21,840 --> 04:00:24,720 FAVORITE GLYCANS, THIS IS A GOOD 5116 04:00:24,720 --> 04:00:26,200 NEW RESOURCE TO USE. 5117 04:00:26,200 --> 04:00:28,920 HOW DO WE USE LECTINS TO 5118 04:00:28,920 --> 04:00:30,280 ACTUALLY GET TO BIOLOGICAL DATA? 5119 04:00:30,280 --> 04:00:32,560 THE REAL POINT OF THE TALK IS 5120 04:00:32,560 --> 04:00:35,080 TALKING ABOUT OUR WORK IN 5121 04:00:35,080 --> 04:00:35,680 SARS-COV-2. 5122 04:00:35,680 --> 04:00:37,440 SO WE'VE DONE WORK IN CANCER, I 5123 04:00:37,440 --> 04:00:40,080 WANT TO DO A SHOUT OUT BRIEFLY 5124 04:00:40,080 --> 04:00:44,160 TO WORK IN PANCREATIC CANCER 5125 04:00:44,160 --> 04:00:50,600 RECENTLY PUBLISHED IN MOLECULAR 5126 04:00:50,600 --> 04:00:52,440 CELL PROTEOMICS, WE'VE LOOKED AT 5127 04:00:52,440 --> 04:00:54,080 THE MOUSE MODEL AND HUMAN 5128 04:00:54,080 --> 04:00:55,640 PANCREATIC CANCER TO SEE WHAT 5129 04:00:55,640 --> 04:00:57,080 OVERLAMBS AND WHAT DOES NOT SO 5130 04:00:57,080 --> 04:00:58,760 WHAT CAN YOU MODEL FROM THE 5131 04:00:58,760 --> 04:01:02,000 HUMAN TUMOR IN A MOUSE? 5132 04:01:02,000 --> 04:01:05,480 WE IDENTIFIED IN PARTICULAR 2, 6 5133 04:01:05,480 --> 04:01:07,480 SIALIC ACID, VERY IMPORTANT AND 5134 04:01:07,480 --> 04:01:14,320 CHANGING IN HUMAN AND MOUSE, IN 5135 04:01:14,320 --> 04:01:16,400 THIS PAPER CREATED A GAL 1 5136 04:01:16,400 --> 04:01:18,680 FLOCKOUT KNOCKOUT MOUSE SPECIFIC 5137 04:01:18,680 --> 04:01:19,800 TO PANCREAS AND SHOWED IN THE 5138 04:01:19,800 --> 04:01:22,280 PRESENCE OF THE KNOCKOUT WE 5139 04:01:22,280 --> 04:01:24,080 ACTUALLY DID NOT FORM, IN THE KC 5140 04:01:24,080 --> 04:01:26,840 MOUSE, DID NOT FORM THE KINDS OF 5141 04:01:26,840 --> 04:01:27,880 PANCREATIC LESIONS AND EARLY 5142 04:01:27,880 --> 04:01:31,160 STAGES IN THE KC MOUSE. 5143 04:01:31,160 --> 04:01:32,880 WE RETAINED THE PHENOTYPE OF THE 5144 04:01:32,880 --> 04:01:35,880 PANCREAS THAT ONE WOULD HOPE TO 5145 04:01:35,880 --> 04:01:37,200 HAVE A NORMAL ONE FOR MUCH 5146 04:01:37,200 --> 04:01:38,840 LONGER IN THE KC MOUSE MODEL 5147 04:01:38,840 --> 04:01:45,680 WHEN IT WAS KNOCKED OUT, 5148 04:01:45,680 --> 04:01:50,880 IMPLYING 2, 6 SIALIC ACID AS A 5149 04:01:50,880 --> 04:01:51,440 ROLE. 5150 04:01:51,440 --> 04:01:53,480 THIS HAS BEEN GONE OVER ALREADY, 5151 04:01:53,480 --> 04:01:57,240 MOSTLY WHEN WE TALK ABOUT 5152 04:01:57,240 --> 04:01:59,720 GLYCANS IN CONTEXT OF 5153 04:01:59,720 --> 04:02:00,880 HOST-PATHOGEN INTERACTION, MANY 5154 04:02:00,880 --> 04:02:06,360 TALKS ALREADY HAVE FOCUSED ON 5155 04:02:06,360 --> 04:02:09,840 BINDING OF GLYCANS BY THE VIRUS 5156 04:02:09,840 --> 04:02:12,680 AS HOST ENTRY OR AS LOOKING AT 5157 04:02:12,680 --> 04:02:14,600 THE GLYCOSYLATION OF THE VIRUS 5158 04:02:14,600 --> 04:02:17,080 AS A WAY OF PREVENTING 5159 04:02:17,080 --> 04:02:18,200 RECOGNITION. 5160 04:02:18,200 --> 04:02:20,240 THERE ARE MANY OTHER THINGS THAT 5161 04:02:20,240 --> 04:02:21,640 GLYCOSYLATION PROVIDES IN TERMS 5162 04:02:21,640 --> 04:02:23,040 OF HOST RESPONSE. 5163 04:02:23,040 --> 04:02:29,160 ONE AS WE ALL KNOW MUCINS TRAP 5164 04:02:29,160 --> 04:02:30,480 PATHOGENS, IN THE RESPIRATORY 5165 04:02:30,480 --> 04:02:32,800 TRACT, THE GUNK WE GET WITH 5166 04:02:32,800 --> 04:02:35,080 VIRUSES TENDS TO TRAP AND GET 5167 04:02:35,080 --> 04:02:37,080 RID OF PATHOGENS. 5168 04:02:37,080 --> 04:02:38,840 IN ADDITION ANTIBODY 5169 04:02:38,840 --> 04:02:39,960 GLYCOSYLATION CAN CHANGE 5170 04:02:39,960 --> 04:02:40,560 EFFECTOR FUNCTIONS, THAT HAS 5171 04:02:40,560 --> 04:02:46,520 IMPACT ON HOW WE RESPOND TO 5172 04:02:46,520 --> 04:02:46,800 PATHOGENS. 5173 04:02:46,800 --> 04:02:49,760 WE HAVE LECTIN MEDIATED IMMUNE 5174 04:02:49,760 --> 04:02:52,520 RESPONSES, COMPLEMENT PATHWAY, 5175 04:02:52,520 --> 04:02:53,240 COMPLEMENT RECOGNITION OF 5176 04:02:53,240 --> 04:02:54,840 PATHOGENS TO REMOVE THEM AND 5177 04:02:54,840 --> 04:02:56,800 INFORMATION THAT THIS MAY PLAY A 5178 04:02:56,800 --> 04:02:58,840 ROLE IN SORT OF SOME OF OUR 5179 04:02:58,840 --> 04:03:27,720 REACTIONS TO PATHOGENS AS WELL 5180 04:03:27,720 --> 04:03:32,200 WHEN WE'RE INFECTED. 5181 04:03:32,200 --> 04:03:34,720 WE IDENTIFIED ASSOCIATION WITH 5182 04:03:34,720 --> 04:03:35,480 SEVERITY IN INFLUENZA INFECTION, 5183 04:03:35,480 --> 04:03:40,480 YOU CAN SEE THE STAINING OF AN 5184 04:03:40,480 --> 04:03:45,600 INFECTED LUNG IN THE FERRET. 5185 04:03:45,600 --> 04:03:48,040 IT'S SIGNALING TO ACTIVATE 5186 04:03:48,040 --> 04:03:49,040 COMPLEMENT CASCADE IN 5187 04:03:49,040 --> 04:03:49,360 INFLAMMATIONS. 5188 04:03:49,360 --> 04:03:52,680 I JUST WANT TO POINT THIS OUT AS 5189 04:03:52,680 --> 04:03:53,880 ANOTHER EXAMPLE HOW THESE 5190 04:03:53,880 --> 04:03:56,280 APPROACHES ARE STARTING TO GET 5191 04:03:56,280 --> 04:03:59,040 TO MOLECULAR MECHANISMS THAT MAY 5192 04:03:59,040 --> 04:04:01,200 UNDERSTAND -- HELP US UNDERSTAND 5193 04:04:01,200 --> 04:04:02,760 HOW WE RESPOND TO ILLNESS. 5194 04:04:02,760 --> 04:04:04,400 IN THIS TALK I'M ACTUALLY GOING 5195 04:04:04,400 --> 04:04:10,000 TO FOCUS ON THE THING WE'RE ALL 5196 04:04:10,000 --> 04:04:12,280 FOCUSED ON TO OUR DETRIMENT, 5197 04:04:12,280 --> 04:04:12,480 COVID. 5198 04:04:12,480 --> 04:04:14,880 I'M GOING TO TALK ABOUT SOME 5199 04:04:14,880 --> 04:04:17,360 LATEST UNPUBLISHED WORK ON 5200 04:04:17,360 --> 04:04:18,160 SARS-COV-2. 5201 04:04:18,160 --> 04:04:21,080 I WANT TO POINT OUT STUDENTS WHO 5202 04:04:21,080 --> 04:04:25,680 HAVE DONE THIS WORK. 5203 04:04:25,680 --> 04:04:28,560 SHE IS GRADUATING, AND RIC AND 5204 04:04:28,560 --> 04:04:34,680 EMMA, AND MD/PHD . 5205 04:04:34,680 --> 04:04:42,440 WHAT DO WE KNOW ABOUT GLYCANS IN 5206 04:04:42,440 --> 04:04:43,000 SARS-COV-2 PATHOGENESIS? 5207 04:04:43,000 --> 04:04:45,640 WE FOCUSED ON GLYCOSYLATION OF 5208 04:04:45,640 --> 04:04:47,800 THE PROTEINS, WE KNOW THEY ARE 5209 04:04:47,800 --> 04:04:49,400 GLYCOSYLATED, THIS IS PERSON IN 5210 04:04:49,400 --> 04:04:51,640 TERMS OF BINDING OF ANTIBODIES 5211 04:04:51,640 --> 04:04:54,720 IN RECOGNITION TO THE SPIKE. 5212 04:04:54,720 --> 04:04:59,680 WE KNOW INNATE IMMUNE LECTINS 5213 04:04:59,680 --> 04:05:01,680 CAN RECOGNIZE VIRAL PARTICLES 5214 04:05:01,680 --> 04:05:05,440 AND IN RECENT WORK WE KNOW THAT 5215 04:05:05,440 --> 04:05:13,520 SARS-COV-2 CAN USE SIALIC ACID 5216 04:05:13,520 --> 04:05:18,800 AS A CO-RECEPTOR. 5217 04:05:18,800 --> 04:05:20,480 CAN ALSO USE HEPARIN. 5218 04:05:20,480 --> 04:05:22,720 IF WE THINK ABOUT WHAT'S WRONG 5219 04:05:22,720 --> 04:05:26,800 ABOUT COVID AND WHAT WE'RE 5220 04:05:26,800 --> 04:05:28,120 SCARED ABOUT, IT'S DEATH. 5221 04:05:28,120 --> 04:05:30,120 LOTS OF PEOPLE GET SARS-COV-2 5222 04:05:30,120 --> 04:05:31,440 AND HAVE RELATIVELY LOW LEVEL 5223 04:05:31,440 --> 04:05:31,880 RESPONSES. 5224 04:05:31,880 --> 04:05:34,040 IT'S LIKE A COLD OR NOT LIKE A 5225 04:05:34,040 --> 04:05:36,560 COLD, MORE LIKE A REALLY BAD FLU 5226 04:05:36,560 --> 04:05:38,760 BUT WITH POTENTIAL VERY, VERY 5227 04:05:38,760 --> 04:05:40,080 HORRIBLE LONG-TERM EFFECTS. 5228 04:05:40,080 --> 04:05:41,360 I WON'T DOWNPLAY IT AND SAY IT'S 5229 04:05:41,360 --> 04:05:44,560 NEAR THOSE THINGS BUT I DO THINK 5230 04:05:44,560 --> 04:05:46,720 THE SEVERITY, THE FACT THAT A 5231 04:05:46,720 --> 04:05:48,360 SIGNIFICANT PORTION OF PEOPLE 5232 04:05:48,360 --> 04:05:59,040 DIE IS WE'RE THE MOST CONCERNED 5233 04:05:59,040 --> 04:05:59,600 ABOUT. 5234 04:05:59,600 --> 04:06:02,000 IS INTEREST A WAY TO THINK ABOUT 5235 04:06:02,000 --> 04:06:06,440 PEOPLE WHO ARE DYING AND THOSE 5236 04:06:06,440 --> 04:06:08,680 THAT AREN'T, WE LOOKED AT THE 5237 04:06:08,680 --> 04:06:12,160 PLASMA OF PEOPLE WHO ARE 5238 04:06:12,160 --> 04:06:16,760 NEGATIVE, THIS CAME FROM THE UGA 5239 04:06:16,760 --> 04:06:20,480 COHORT IN GEORGIA, MILD 5240 04:06:20,480 --> 04:06:21,760 SARS-COV-2, CLASSIFIED AS 5241 04:06:21,760 --> 04:06:24,400 UNHOSPITALIZED, PEOPLE WHO ARE 5242 04:06:24,400 --> 04:06:26,120 MODERATE, HOSPITALIZED WITHOUT 5243 04:06:26,120 --> 04:06:28,720 O2 OR SEVERE ON OXYGEN. 5244 04:06:28,720 --> 04:06:32,440 AND WE LOOKED AT THEIR GLYCOMICS 5245 04:06:32,440 --> 04:06:34,800 USING LECTIN MICROARRAY. 5246 04:06:34,800 --> 04:06:38,880 WE SAW CHANGES IN 2, 3 SIALIC 5247 04:06:38,880 --> 04:06:39,200 ACID. 5248 04:06:39,200 --> 04:06:42,080 WE SAW CHANGES IN GLYCANS AND 5249 04:06:42,080 --> 04:06:45,960 SAW CHANGES IN Q 6 SIGH ALEX 5250 04:06:45,960 --> 04:06:46,160 ACID. 5251 04:06:46,160 --> 04:06:50,760 WE SAW 2, 6 BUT NOT 2, 3 WAS 5252 04:06:50,760 --> 04:06:53,720 ACTUALLY RELATED TO THE SEVERITY 5253 04:06:53,720 --> 04:06:54,080 OBSERVED. 5254 04:06:54,080 --> 04:06:58,160 WE SAW THAT IF YOU LOOK AT SNA 5255 04:06:58,160 --> 04:07:02,000 BINDING PEOPLE WHO ARE MILD 5256 04:07:02,000 --> 04:07:03,000 VERSUS MODERATE VERSUS SEVERE, 5257 04:07:03,000 --> 04:07:10,080 WITH SEVERE HAD HIGHER LEVELS OF 5258 04:07:10,080 --> 04:07:11,480 2, 6 SIALIC ACID, HIGHER THAN 5259 04:07:11,480 --> 04:07:12,400 CONTROLS. 5260 04:07:12,400 --> 04:07:16,520 THEY HAD LOWER LEVELS OF 2, 3 5261 04:07:16,520 --> 04:07:18,480 BUT WASN'T SEVERITY DEPENDENT, 5262 04:07:18,480 --> 04:07:22,280 NO REAL DIFFERENCE BETWEEN MILD, 5263 04:07:22,280 --> 04:07:23,280 MODERATE, SEVERE COHORT, SHOWING 5264 04:07:23,280 --> 04:07:30,640 WHY WE HAVE TO CARE ABOUT THE 5265 04:07:30,640 --> 04:07:33,200 EPITOPE, SPECIFIC LINKAGE, 2, 6 5266 04:07:33,200 --> 04:07:36,080 AND 2, 3 ARE NOT THE SAME. 5267 04:07:36,080 --> 04:07:39,040 THIS LECTIN IS SPECIFIC FOR 2, 3 5268 04:07:39,040 --> 04:07:41,760 SIALIC ACID ON O-LINKED CORES, 5269 04:07:41,760 --> 04:07:45,840 WHERE THE UNDERLYING SUGAR IS 5270 04:07:45,840 --> 04:07:49,160 GalNAC, NOT REPRESENTATIVE OF 5271 04:07:49,160 --> 04:07:50,880 2P 3, FINE SPECIFICITY IN HOW 5272 04:07:50,880 --> 04:07:52,480 GLYCOSYLATION IS WORKING IN THE 5273 04:07:52,480 --> 04:07:54,280 BODY. 5274 04:07:54,280 --> 04:07:56,160 WE WANTED TO SEE, WELL, WE SEE 5275 04:07:56,160 --> 04:07:57,360 THIS IN THE PLASMA, IS THERE 5276 04:07:57,360 --> 04:07:58,880 RELATIONSHIP TO WHAT'S GOING ON 5277 04:07:58,880 --> 04:08:00,280 IN TISSUE? 5278 04:08:00,280 --> 04:08:03,480 FOR THAT WE ACTUALLY LOOKED AT A 5279 04:08:03,480 --> 04:08:04,880 COHORT OF PEOPLE FROM NEW YORK 5280 04:08:04,880 --> 04:08:07,440 WHO DIED OF COVID AND COMPARED 5281 04:08:07,440 --> 04:08:09,240 THEM TO PEOPLE WHO HAD DIED OF 5282 04:08:09,240 --> 04:08:10,920 OTHER CAUSES, MANY OF WHICH WERE 5283 04:08:10,920 --> 04:08:12,960 STILL RESPIRATORY IN NATURE. 5284 04:08:12,960 --> 04:08:16,680 WE LOOKED AT THE HARD, KIDNEY, 5285 04:08:16,680 --> 04:08:18,680 UPPER LOBE OF LUNGS OF THESE 5286 04:08:18,680 --> 04:08:18,880 PEOPLE. 5287 04:08:18,880 --> 04:08:21,480 THIS IS JUST TO SHOW TISSUES 5288 04:08:21,480 --> 04:08:22,560 WEREN'T SO HORRIBLY DEGRADED 5289 04:08:22,560 --> 04:08:24,720 THAT WE COULDN'T GET ANYTHING 5290 04:08:24,720 --> 04:08:27,480 OUT OF THEM. 5291 04:08:27,480 --> 04:08:29,480 THIS IS H&E STAINING, YOU CAN 5292 04:08:29,480 --> 04:08:32,760 SEE THAT THE PATIENTS WHO DIED 5293 04:08:32,760 --> 04:08:35,400 OF COVID-19 LUNGS WERE A MESS 5294 04:08:35,400 --> 04:08:37,520 COMPARED TO THOSE, EVEN THOUGH A 5295 04:08:37,520 --> 04:08:44,320 LOT OF PATIENTS HAD RESPIRATORY 5296 04:08:44,320 --> 04:08:46,880 DISORDERS, NOTHING LIKE COVID. 5297 04:08:46,880 --> 04:08:51,200 WE LOOKED AT THE ARRAY. 5298 04:08:51,200 --> 04:08:53,440 ONE THING I LOVE, I HATE THAT 5299 04:08:53,440 --> 04:08:55,360 PEOPLE HAD TO DIE TO SEE THIS 5300 04:08:55,360 --> 04:08:57,600 BUT ONE OF THE THINGS WE OFTEN 5301 04:08:57,600 --> 04:08:59,880 GET IN THE COMMUNITY IS, OH, WHY 5302 04:08:59,880 --> 04:09:02,840 DO YOU CARE ABOUT SUGARS? 5303 04:09:02,840 --> 04:09:06,560 I THINK THIS IS THE PERFECT 5304 04:09:06,560 --> 04:09:06,840 ANTIDOTE. 5305 04:09:06,840 --> 04:09:11,520 PEOPLE WHO DIED OF WIDE VARIETY 5306 04:09:11,520 --> 04:09:13,560 OF CAUSES IN THE NEGATIVE, COVID 5307 04:09:13,560 --> 04:09:15,400 IN THE POSITIVE, HEART, KIDNEY, 5308 04:09:15,400 --> 04:09:17,840 LIVER AND UPPER AND LOWER LOBES 5309 04:09:17,840 --> 04:09:20,280 OF THE LUNGS HAVE DISTINCT 5310 04:09:20,280 --> 04:09:20,600 GLYCANS. 5311 04:09:20,600 --> 04:09:22,760 YOU CAN SEE WHAT TISSUE IS. 5312 04:09:22,760 --> 04:09:23,880 SEPARATE FROM WHETHER OR NOT 5313 04:09:23,880 --> 04:09:24,920 THEY HAD COVID. 5314 04:09:24,920 --> 04:09:27,120 WHAT THAT TELLS ME IS THAT AS 5315 04:09:27,120 --> 04:09:30,680 WE'VE ALWAYS THOUGHT IN THE 5316 04:09:30,680 --> 04:09:31,360 GLYCOCOMMUNITY CARBOHYDRATES ARE 5317 04:09:31,360 --> 04:09:34,520 AN INDICATOR OF TISSUE TYPE AND 5318 04:09:34,520 --> 04:09:35,600 CELL TYPE. 5319 04:09:35,600 --> 04:09:38,280 AT A FUNDAMENTAL LEVEL. 5320 04:09:38,280 --> 04:09:40,240 THAT'S REFLECTED IN GLYCAN OF 5321 04:09:40,240 --> 04:09:40,480 TISSUES. 5322 04:09:40,480 --> 04:09:44,920 TO GET MORE SPECIFIC, WE LOOKED 5323 04:09:44,920 --> 04:09:46,280 AT CHANGES OCCURRING, 5324 04:09:46,280 --> 04:09:47,160 STATISTICALLY DIFFERENT FROM 5325 04:09:47,160 --> 04:09:54,760 THOSE WHO DIED IN COVID AND DID 5326 04:09:54,760 --> 04:09:54,920 NOT. 5327 04:09:54,920 --> 04:09:58,800 I WANT TO POINT OUT WE ACTUALLY 5328 04:09:58,800 --> 04:10:00,880 SAW HIGHER LEVELS OF 2, 3 IN THE 5329 04:10:00,880 --> 04:10:02,880 TISSUE OF OF LIVER AND UPPER AND 5330 04:10:02,880 --> 04:10:06,680 LOWER LOBE OF THE LUNG, AND SAW 5331 04:10:06,680 --> 04:10:08,640 THAT CHANGE IN 2, 6 BUT ONLY IN 5332 04:10:08,640 --> 04:10:12,160 THE LOWER LOBE OF THE LUNG LIE 5333 04:10:12,160 --> 04:10:13,320 LECTIN MICROARRAY. 5334 04:10:13,320 --> 04:10:17,920 WHEN WE LOOK WITH HISTOCHEMISTRY 5335 04:10:17,920 --> 04:10:19,480 WE SEE BEAUTIFUL STAINING WHICH 5336 04:10:19,480 --> 04:10:23,600 A LECTIN THAT WAS CREATED IN MY 5337 04:10:23,600 --> 04:10:25,080 LABORATORY FOR 2P 3 SIALIC ACID. 5338 04:10:25,080 --> 04:10:26,880 IN THE LIVER AND UPPER AND LOWER 5339 04:10:26,880 --> 04:10:28,880 LOBE OF THE LUNG COMPARED TO THE 5340 04:10:28,880 --> 04:10:37,560 COVID NEAPING -- NEGATIVE 5341 04:10:37,560 --> 04:10:38,800 CONTROLS. 5342 04:10:38,800 --> 04:10:39,840 WE DID SEE SOME INCREASED 5343 04:10:39,840 --> 04:10:42,920 STAINING IN THE UPPER LOBE OF 5344 04:10:42,920 --> 04:11:02,680 THE LUNG, WITH SNA. 5345 04:11:02,680 --> 04:11:06,240 WE USED SNA BACK TO OUR PLASMA, 5346 04:11:06,240 --> 04:11:08,440 TO LOOK AT MILD COVID VERSUS 5347 04:11:08,440 --> 04:11:09,800 SEVERE COVID AND TO SEE WHAT IS 5348 04:11:09,800 --> 04:11:14,880 GOING ON IN TERMS OF THE 5349 04:11:14,880 --> 04:11:18,320 GLYCOPROTEINS WE'RE OBSERVING. 5350 04:11:18,320 --> 04:11:19,240 WE DID GLYCOPROTEOMICS AND FOUND 5351 04:11:19,240 --> 04:11:22,800 A LOT OF PROTEINS THAT WERE 5352 04:11:22,800 --> 04:11:24,160 ASSOCIATED WITH COMPLEMENT, 5353 04:11:24,160 --> 04:11:25,920 BEING PULLED DOWN STRONGLY IN 5354 04:11:25,920 --> 04:11:27,280 THE SEVERE COVID COHORT. 5355 04:11:27,280 --> 04:11:30,280 INDEED WHEN WE LOOKED AT 5356 04:11:30,280 --> 04:11:32,320 ENRICHMENT AND LOOKED AT THE 5357 04:11:32,320 --> 04:11:34,120 PATHWAY, WE SAW COMPLEMENT 5358 04:11:34,120 --> 04:11:36,600 ACTIVATION CAME UP VERY HEAVILY. 5359 04:11:36,600 --> 04:11:39,840 AS BEING SOMETHING THAT WAS 5360 04:11:39,840 --> 04:11:41,960 ENRICHED IN 2, 6 SYLATED 5361 04:11:41,960 --> 04:11:45,800 PROTEINS IN THE SEVERE COVID 5362 04:11:45,800 --> 04:11:46,120 COHORT. 5363 04:11:46,120 --> 04:11:55,560 COMPLEMENT HAS BEEN SHOWN TO 5364 04:11:55,560 --> 04:11:57,080 PLAY A ROLE. 5365 04:11:57,080 --> 04:11:59,200 WHAT WE KNOW IS THAT THE 5366 04:11:59,200 --> 04:12:00,880 COMPLEMENT PROTEINS, WE SEE A 5367 04:12:00,880 --> 04:12:05,000 LOT OF COMPLEMENT PROTEINS 5368 04:12:05,000 --> 04:12:06,160 ASSOCIATED WITH DOWNSTREAM 5369 04:12:06,160 --> 04:12:17,880 COMPLEMENT CASCADE AS HIGHLY 5370 04:12:17,880 --> 04:12:18,240 SYLATED. 5371 04:12:18,240 --> 04:12:20,080 WHEN WE LOOK TO SEE WHETHER THIS 5372 04:12:20,080 --> 04:12:21,680 IS BECAUSE COMPLEMENT PROTEINS 5373 04:12:21,680 --> 04:12:24,600 WERE HIGHER OR WHETHER IT WAS 5374 04:12:24,600 --> 04:12:25,880 BECAUSE THE SIALYATION IS 5375 04:12:25,880 --> 04:12:29,440 CHANGING WE SAW THAT ACTUALLY 5376 04:12:29,440 --> 04:12:30,640 IT'S BOTH. 5377 04:12:30,640 --> 04:12:32,440 HERE IT'S NEGATIVE. 5378 04:12:32,440 --> 04:12:34,600 HERE IS THE INPUT VERSUS 5379 04:12:34,600 --> 04:12:34,880 PULLDOWN. 5380 04:12:34,880 --> 04:12:40,560 IN THE C5 WE GET A DEPENDENT 5381 04:12:40,560 --> 04:12:42,000 INCREASE IN 2, 6 SIALYATION, 5382 04:12:42,000 --> 04:12:43,720 DON'T SEE HIGHER LEVELS, WHEN WE 5383 04:12:43,720 --> 04:12:46,160 LOOK AT C 9 IN THE SEVERE WE DO 5384 04:12:46,160 --> 04:12:47,400 SEE SLIGHTLY HIGHER LEVELS OF 5385 04:12:47,400 --> 04:12:53,720 THE C 9 BUT SEE A LOT OF 5386 04:12:53,720 --> 04:12:56,280 INCREASE IN 2, 6 SYLATED PULLED 5387 04:12:56,280 --> 04:13:10,800 DOWN, ARGUING THEY THEY ARE 5388 04:13:10,800 --> 04:13:18,080 DIFFERENTIALLY SYLATED. 5389 04:13:18,080 --> 04:13:20,480 WE STAINED AND FOUND IN THE SAME 5390 04:13:20,480 --> 04:13:24,160 LOCATIONS OBSERVING THE STRONG 5391 04:13:24,160 --> 04:13:29,480 STANDING OF 2, 6 LINING 5392 04:13:29,480 --> 04:13:29,960 AIRWAYS. 5393 04:13:29,960 --> 04:13:33,520 IT'S DRAMATIC IN C 9 AS WELL, 5394 04:13:33,520 --> 04:13:35,200 LINING THE AIRWAYS. 5395 04:13:35,200 --> 04:13:40,160 WHEN WE LOOK AT 2, 6 SIALIC ACID 5396 04:13:40,160 --> 04:13:45,760 VERSUS THE ENZYME THAT CONTROLS 5397 04:13:45,760 --> 04:13:47,600 2, 6 SIALYATION IN PATIENTS THEY 5398 04:13:47,600 --> 04:13:52,040 HAVE MUCH HIGHER LEVELS OF 5399 04:13:52,040 --> 04:14:15,720 STAINING OF 2, 6 OF ST ST6GAL1. 5400 04:14:15,720 --> 04:14:17,640 IT GOES UP ACROSS THE BOARD. 5401 04:14:17,640 --> 04:14:18,800 LIVER LEVELS ARE SO HIGH 5402 04:14:18,800 --> 04:14:21,760 ADDITIONAL INCREASE IS HARD TO 5403 04:14:21,760 --> 04:14:23,440 TELL BY HISTOCHEMISTRY. 5404 04:14:23,440 --> 04:14:26,800 WE SEE 2, 6 SIALYATION GOING UP 5405 04:14:26,800 --> 04:14:29,000 AND SOME EVIDENCE OF RELATIVE 5406 04:14:29,000 --> 04:14:33,680 LEVEL IN TRAN SCRIPT OMICS IN 5407 04:14:33,680 --> 04:14:35,760 WORKS PUBLISHED, RELATIVE LEVEL 5408 04:14:35,760 --> 04:14:40,680 TO C5 TURNS UP IN SARS-COV-2. 5409 04:14:40,680 --> 04:14:42,120 >> ANOTHER MINUTE, LARA. 5410 04:14:42,120 --> 04:14:46,080 >> I'M ON CONCLUSION, GOOD 5411 04:14:46,080 --> 04:14:46,320 TIMING. 5412 04:14:46,320 --> 04:14:49,560 >> WHAT WE OBSERVE IS INCREASES 5413 04:14:49,560 --> 04:14:54,200 IN 2, 6 SIALYATION ARE OBSERVED 5414 04:14:54,200 --> 04:14:56,600 WITH SEVERITY, ENRICHED IN THE 5415 04:14:56,600 --> 04:14:59,960 COMPLEMENT PATHWAY AND 5416 04:14:59,960 --> 04:15:00,560 COMPLEMENT OVERACTIVATION IS 5417 04:15:00,560 --> 04:15:01,480 EMERGING AS A CRITICAL FACTOR. 5418 04:15:01,480 --> 04:15:04,400 WE DON'T KNOW WHAT THE ROLE OF 5419 04:15:04,400 --> 04:15:07,280 THE 2, 6 SIALYATION IS IN 5420 04:15:07,280 --> 04:15:08,560 POTENTIALLY MODULATING THE 5421 04:15:08,560 --> 04:15:09,240 COMPLEMENT CASCADE, IT'S 5422 04:15:09,240 --> 04:15:11,000 POSSIBLE THAT THIS IS PARTLY A 5423 04:15:11,000 --> 04:15:13,440 MECHANISM TO INCREASE THE 5424 04:15:13,440 --> 04:15:15,680 LIFETIME IN SERA WHICH COULD 5425 04:15:15,680 --> 04:15:17,560 CONTRIBUTE TO OVERACTIVATION, 5426 04:15:17,560 --> 04:15:19,880 BUT THERE'S ALSO EMERGING 5427 04:15:19,880 --> 04:15:21,320 EVIDENCE THE GLYCOSYLATION OF 5428 04:15:21,320 --> 04:15:22,160 THESE COMPLEMENT PROTEINS 5429 04:15:22,160 --> 04:15:23,760 THEMSELVES MAY BE CHANGING OUR 5430 04:15:23,760 --> 04:15:25,920 ACTIVITIES IN WAYS THAT HAVE NOT 5431 04:15:25,920 --> 04:15:27,640 BEEN EXPLORED OR DEVELOPED. 5432 04:15:27,640 --> 04:15:32,920 AND SO WITH THAT I WANT TO 5433 04:15:32,920 --> 04:15:33,880 ACKNOWLEDGE THE LAB, ESPECIALLY 5434 04:15:33,880 --> 04:15:36,280 THOSE WHO DID THE DATA, WHO GOT 5435 04:15:36,280 --> 04:15:37,480 ALL OF THIS DATA, AND ARE 5436 04:15:37,480 --> 04:15:44,400 WRITING THE PAPER CURRENTLY WITH 5437 04:15:44,400 --> 04:15:53,320 ME. 5438 04:15:53,320 --> 04:15:56,200 THANK YOU. 5439 04:15:56,200 --> 04:15:56,320 5440 04:15:56,320 --> 04:15:57,080 >> FANTASTIC TALK. 5441 04:15:57,080 --> 04:16:05,120 THE LAST TALK BEFORE PANEL 5442 04:16:05,120 --> 04:16:08,880 DISCUSSION, ELISA FADDA FROM 5443 04:16:08,880 --> 04:16:09,440 MAYNOOTH UNIVERSITY, 5444 04:16:09,440 --> 04:16:10,760 COMPUTATIONAL GLYCOSCIENCE IN 5445 04:16:10,760 --> 04:16:13,760 THE COVID ERA. 5446 04:16:13,760 --> 04:16:18,400 LESSONS LEARNED AND A FEW 5447 04:16:18,400 --> 04:16:18,720 PERSPECTIVES. 5448 04:16:18,720 --> 04:16:20,440 >> CAN YOU HEAR ME? 5449 04:16:20,440 --> 04:16:22,760 >> YEAH. 5450 04:16:22,760 --> 04:16:26,800 >> GOOD MORNING, EVERYBODY, FROM 5451 04:16:26,800 --> 04:16:28,720 BRISBANE. 5452 04:16:28,720 --> 04:16:33,840 I'M SHARING MY SLIDES NOW. 5453 04:16:33,840 --> 04:16:35,880 IT'S VERY EXCITING TO BE HERE. 5454 04:16:35,880 --> 04:16:38,560 THANK YOU FOR THE INVITATION. 5455 04:16:38,560 --> 04:16:40,560 I'M PRETTY EXCITED MY TALK CAME 5456 04:16:40,560 --> 04:16:44,160 AFTER LARA BECAUSE SHE TOUCHED 5457 04:16:44,160 --> 04:16:47,280 ON SO MANY POINTS THAT HELPED ME 5458 04:16:47,280 --> 04:16:51,560 THROUGH MY OWN TALK. 5459 04:16:51,560 --> 04:16:55,600 ESPECIALLY IN HIGHLIGHTING HOW 5460 04:16:55,600 --> 04:16:56,480 OUR APPROACHES IS COMMON, 5461 04:16:56,480 --> 04:16:59,440 COMPLEMENTARY AND WE NEED EACH 5462 04:16:59,440 --> 04:17:01,960 OTHER TO ADVANCE GLYCOSCIENCE. 5463 04:17:01,960 --> 04:17:04,840 I'M GOING TO FOCUS ON 5464 04:17:04,840 --> 04:17:06,840 COMPUTATIONAL GLYCOSCIENCE, MY 5465 04:17:06,840 --> 04:17:09,280 FIELD OF RESEARCH, WHERE YOU USE 5466 04:17:09,280 --> 04:17:13,080 HIGH PERFORMANCE COMPUTING TO 5467 04:17:13,080 --> 04:17:14,480 RECONSTRUCT GLYCOSYLATION, SO 5468 04:17:14,480 --> 04:17:18,320 OFTEN MISSING, AND VERY OFTEN 5469 04:17:18,320 --> 04:17:19,440 NOT EASY TO RECONSTRUCT BECAUSE 5470 04:17:19,440 --> 04:17:21,520 OF LACK OF DATA. 5471 04:17:21,520 --> 04:17:26,880 DATA WE NEED IS MOSTLY LIKE FROM 5472 04:17:26,880 --> 04:17:27,920 GLYCOMICS, GLYCOPROTEOMICS TO 5473 04:17:27,920 --> 04:17:29,160 TELL US WHAT TYPE OF 5474 04:17:29,160 --> 04:17:30,800 GLYCOSYLATION IS THERE, WHERE IT 5475 04:17:30,800 --> 04:17:50,680 IS, WHAT IS THE RELATIVE 5476 04:17:50,680 --> 04:17:52,680 POPULATION. 5477 04:17:52,680 --> 04:18:00,920 WE TAKE THAT INFORMATION AND WE 5478 04:18:00,920 --> 04:18:03,120 REBUILD, COMMONLY REPRESENTED 5479 04:18:03,120 --> 04:18:09,560 WITHIN A CLASSICAL MECHANICS 5480 04:18:09,560 --> 04:18:10,600 FRAMEWORK THROUGH EMPIRICAL AND 5481 04:18:10,600 --> 04:18:13,840 STUDY THROUGH HIGH PERFORMANCE 5482 04:18:13,840 --> 04:18:16,720 COMPUTING, MOST COMMONLY THROUGH 5483 04:18:16,720 --> 04:18:17,880 MOLECULAR DYNAMICS APPROACHES OR 5484 04:18:17,880 --> 04:18:22,720 VARIATION ON THAT FORM TO OBTAIN 5485 04:18:22,720 --> 04:18:27,440 GLYCAN STRUCTURE INFORMATION. 5486 04:18:27,440 --> 04:18:30,360 WHICH THAT IS EXTREMELY 5487 04:18:30,360 --> 04:18:32,080 IMPORTANT TO STUDY MOLECULAR 5488 04:18:32,080 --> 04:18:33,560 RECOGNITION, TO UNDERSTAND THE 5489 04:18:33,560 --> 04:18:36,320 ROLE OF GLYCOSYLATION AND TODAY 5490 04:18:36,320 --> 04:18:38,280 I'M GOING TO FOCUS AGAIN AS LARA 5491 04:18:38,280 --> 04:18:40,080 MENTIONED ON SOMETHING THAT'S 5492 04:18:40,080 --> 04:18:49,280 CONSTANTLY STILL IN OUR MINDS, 5493 04:18:49,280 --> 04:18:49,920 SARS-COV-2. 5494 04:18:49,920 --> 04:18:51,280 AND TO DESIGN GO-TO THERAPEUTICS 5495 04:18:51,280 --> 04:18:55,960 APPROACHES FOR THESE KIND OF 5496 04:18:55,960 --> 04:18:56,480 DISEASES. 5497 04:18:56,480 --> 04:19:01,920 I CHOSE HEAT MAP INSTEAD OF 5498 04:19:01,920 --> 04:19:04,280 CLASSIC 3D STRUCTURE OF GLYCAN 5499 04:19:04,280 --> 04:19:08,560 TO REPRESENT THE STRUCTURAL 5500 04:19:08,560 --> 04:19:10,080 INFORMATION WE OBTAINED. 5501 04:19:10,080 --> 04:19:11,360 THIS IS NOT A CASE. 5502 04:19:11,360 --> 04:19:12,560 NOT AN ACCIDENT. 5503 04:19:12,560 --> 04:19:16,760 THIS IS WHAT WE GET. 5504 04:19:16,760 --> 04:19:20,760 AND THIS IS BECAUSE 5505 04:19:20,760 --> 04:19:21,280 CARBOHYDRATES, COMPLEX 5506 04:19:21,280 --> 04:19:22,760 CARBOHYDRATES, DO NOT OFTEN HAVE 5507 04:19:22,760 --> 04:19:25,360 WHAT WE PERCEIVE AS A STRUCTURE. 5508 04:19:25,360 --> 04:19:27,120 THEY ARE NOT -- "THEY" DON'T 5509 04:19:27,120 --> 04:19:28,960 HAVE AT LEAST ONE STRUCTURE BUT 5510 04:19:28,960 --> 04:19:32,000 OCCUPY A FAMILY OF STRUCTURES 5511 04:19:32,000 --> 04:19:35,520 THAT WE COMMONLY CALL IN THE 5512 04:19:35,520 --> 04:19:40,360 CONFIRMATION ENSEMBLES, LIKE THE 5513 04:19:40,360 --> 04:19:42,800 STRUCTURE OF GLYCANS. 5514 04:19:42,800 --> 04:19:45,040 THIS IS DUE TO ACTUALLY THE 5515 04:19:45,040 --> 04:19:48,440 CHEMICAL NATURE OF THE GLYCAN 5516 04:19:48,440 --> 04:19:50,800 STRUCTURE THAT IS LIKE THE 5517 04:19:50,800 --> 04:19:53,040 LINKAGES BEING A SINGLE BOND AND 5518 04:19:53,040 --> 04:19:55,480 THE STRUCTURE OF THE RING THAT 5519 04:19:55,480 --> 04:19:58,160 OFTEN DEPENDING ON WHAT MONO 5520 04:19:58,160 --> 04:19:59,800 SACCHARIDES WE TALK ABOUT, CAN 5521 04:19:59,800 --> 04:20:01,360 BE QUITE FLEXIBLE AS YOU CAN SEE 5522 04:20:01,360 --> 04:20:06,080 IN THIS CASE THROUGH THIS PATH 5523 04:20:06,080 --> 04:20:08,040 CONNECTING THE STABLE CHAIR TO 5524 04:20:08,040 --> 04:20:11,680 AN ALTERNATIVE CHAIR LESS 5525 04:20:11,680 --> 04:20:12,680 STABLE. 5526 04:20:12,680 --> 04:20:19,200 IN THIS PICTURE HERE 5527 04:20:19,200 --> 04:20:21,880 REPRESENTING A STRUCTURE, IN 5528 04:20:21,880 --> 04:20:24,240 PURPLE, OR DEEP RED, THE FAMILY 5529 04:20:24,240 --> 04:20:27,080 OF ASSOCIATED STRUCTURES IN 5530 04:20:27,080 --> 04:20:27,280 GRAY. 5531 04:20:27,280 --> 04:20:28,040 YOU CAN PROBABLY UNDERSTAND 5532 04:20:28,040 --> 04:20:31,960 WHERE THE ORIGIN OF THE 5533 04:20:31,960 --> 04:20:34,080 DIFFICULTIES OF CHARACTERIZING 5534 04:20:34,080 --> 04:20:34,600 CARBOHYDRATE STRUCTURE BY 5535 04:20:34,600 --> 04:20:35,400 EXPERIMENTAL MEANS. 5536 04:20:35,400 --> 04:20:41,280 IT JUST DOESN'T HAVE A 5537 04:20:41,280 --> 04:20:42,080 STRUCTURE. 5538 04:20:42,080 --> 04:20:46,160 SO, THE REASON WHY GLYCANS CAN 5539 04:20:46,160 --> 04:20:50,160 BE ASSOCIATED LIKE LOOSELY WITH 5540 04:20:50,160 --> 04:20:52,200 INTRINSIC DISORDER LIKE THE TERM 5541 04:20:52,200 --> 04:20:54,080 THAT'S MOSTLY USED FOR PROTEINS 5542 04:20:54,080 --> 04:20:56,800 HOWEVER I THINK IS VERY 5543 04:20:56,800 --> 04:20:58,360 APPROPRIATE IN CASE OF 5544 04:20:58,360 --> 04:21:01,280 CARBOHYDRATES THE FACT THEY ARE 5545 04:21:01,280 --> 04:21:06,280 LINKED BY A SINGLE BOND. 5546 04:21:06,280 --> 04:21:09,680 SINGLE BOND IS CHARACTERIZED BY 5547 04:21:09,680 --> 04:21:13,480 TORSIONS, NOT RANDOM, CANNOT 5548 04:21:13,480 --> 04:21:16,760 LIKE ADOPT ANY VALUE, I'LL 5549 04:21:16,760 --> 04:21:18,760 DISCUSS VERY EXTENSIVELY IN 5550 04:21:18,760 --> 04:21:22,280 GREAT REVIEW BY ROB WOODS 5551 04:21:22,280 --> 04:21:25,400 RECENTLY IN CHEMICAL REVIEWS 5552 04:21:25,400 --> 04:21:29,360 LIKE THESE TORSIONS THEY HAVE 5553 04:21:29,360 --> 04:21:32,160 VERY SPECIFIC MINIMUM. 5554 04:21:32,160 --> 04:21:33,360 TO MINIMIZE ASSOCIATED LIKE A 5555 04:21:33,360 --> 04:21:38,080 GIFT, LET'S SAY LIKE A 5556 04:21:38,080 --> 04:21:40,360 FLEXIBILITY, SEVERAL UP TO THREE 5557 04:21:40,360 --> 04:21:40,960 DEPENDING WHAT TORSION. 5558 04:21:40,960 --> 04:21:49,760 THIS IS A FLEXIBLE LINKAGE, 2, 6 5559 04:21:49,760 --> 04:21:50,800 SIALIC ACID. 5560 04:21:50,800 --> 04:21:56,960 IN TERMS OF DYNAMICS, I TELL YOU 5561 04:21:56,960 --> 04:22:02,760 IT'S PRECISE MINIMUM, IT IS 5562 04:22:02,760 --> 04:22:05,480 QUITE FLEXIBLE. 5563 04:22:05,480 --> 04:22:07,040 THE LINKAGE BETWEEN GAL AND 5564 04:22:07,040 --> 04:22:47,600 GlcNAc DOESN'T MOVE AS MUCH 5565 04:22:47,600 --> 04:22:49,720 BUT IT DOES. 5566 04:22:49,720 --> 04:22:50,760 THIS GETS MORE COMPLICATED AS 5567 04:22:50,760 --> 04:22:55,840 STRUCTURE OF THE GLYCAN ROADS, 5568 04:22:55,840 --> 04:22:59,040 FROM A TRISACCHARIDE, WITHIN THE 5569 04:22:59,040 --> 04:23:00,800 GLYCAN LET'S SAY CONTEXT, IT'S 5570 04:23:00,800 --> 04:23:02,080 NOT A PARTICULARLY DIFFICULT 5571 04:23:02,080 --> 04:23:05,080 GLYCAN TO DEAL WITH OR 5572 04:23:05,080 --> 04:23:06,480 PARTICULARLY SOPHISTICATED 5573 04:23:06,480 --> 04:23:08,120 GLYCAN, JUST VERY COLORFUL IN 5574 04:23:08,120 --> 04:23:14,640 TERMS OF AMOUNT OF MONO 5575 04:23:14,640 --> 04:23:21,560 SACCHARIDE AND HAS A COMPLEX 5576 04:23:21,560 --> 04:23:21,800 DYNAMIC. 5577 04:23:21,800 --> 04:23:23,440 THAT CHANGES, WE DISCOVERED 5578 04:23:23,440 --> 04:23:27,640 THROUGH M.D. BASED ON SEQUENCE 5579 04:23:27,640 --> 04:23:29,680 AND BRANCHING. 5580 04:23:29,680 --> 04:23:38,480 GLYCANS DYNAMICS DEPENDS ON 5581 04:23:38,480 --> 04:23:40,720 SEQUENCE AND BRANCHING. 5582 04:23:40,720 --> 04:23:46,680 REPRESENTED HERE A CLOSE 5583 04:23:46,680 --> 04:23:50,120 CONFIRMATION, THEY HAVE TWO 5584 04:23:50,120 --> 04:23:52,400 ARMS, 3 AND 6 ARM, 3 ARM IS 5585 04:23:52,400 --> 04:23:58,520 ALWAYS EXTENDED BECAUSE OF THE 5586 04:23:58,520 --> 04:24:00,480 RIGIDITY OF THE LINKAGE, THE 5587 04:24:00,480 --> 04:24:03,800 ALPHA 6 ARM IS IN AN EQUILIBRIUM 5588 04:24:03,800 --> 04:24:05,160 BETWEEN OPEN AND CLOSED FORM, 5589 04:24:05,160 --> 04:24:11,280 YOU CAN SEE HERE THE CLOSED FORM 5590 04:24:11,280 --> 04:24:13,240 BECOMES PREDOMINANT, THE SIZE OF 5591 04:24:13,240 --> 04:24:14,920 THE ARM INCREASES, THIS IS THE 5592 04:24:14,920 --> 04:24:16,320 ONE REPRESENTED ON THE 5593 04:24:16,320 --> 04:24:17,480 RIGHT-HAND SIDE. 5594 04:24:17,480 --> 04:24:24,560 HOWEVER, IF I ADD A XYLOSE, 5595 04:24:24,560 --> 04:24:28,400 PRESENT IN PLANTS, THE 5596 04:24:28,400 --> 04:24:32,320 EQUILIBRIUM OF THE ARM IS 5597 04:24:32,320 --> 04:24:42,640 COMPLETELY INVERTED, THE ARM IS 5598 04:24:42,640 --> 04:24:43,120 PREDOMINANTLY OPEN AND 5599 04:24:43,120 --> 04:24:45,480 ACCESSIBLE, LIKE THE REDUCTION. 5600 04:24:45,480 --> 04:24:48,760 SO THIS IS AN IMPORTANT FINDING 5601 04:24:48,760 --> 04:24:51,560 BECAUSE IT GOES DOWN TO 5602 04:24:51,560 --> 04:24:56,240 UNDERSTAND BIOSYNTHESIS OF THE 5603 04:24:56,240 --> 04:24:58,920 GLYCOFORMS, PREDOMINANTLY DUE TO 5604 04:24:58,920 --> 04:24:59,480 INTRAMOLECULAR INTERACTION 5605 04:24:59,480 --> 04:25:02,560 BETWEEN THE ARM AND REST OF THE 5606 04:25:02,560 --> 04:25:04,760 GLYCAN, THE MORE COMPLEX THE 5607 04:25:04,760 --> 04:25:08,680 GLYCAN THE HIGHER THE 5608 04:25:08,680 --> 04:25:10,960 POSSIBILITY THOSE INTERACTIONS 5609 04:25:10,960 --> 04:25:11,880 OCCUR. 5610 04:25:11,880 --> 04:25:12,800 WHAT ABOUT INTRAMOLECULAR 5611 04:25:12,800 --> 04:25:13,120 INTERACTIONS? 5612 04:25:13,120 --> 04:25:17,760 THIS IS WHAT HAPPENS IN 5613 04:25:17,760 --> 04:25:18,280 GLYCOPROTEINS. 5614 04:25:18,280 --> 04:25:21,480 THIS ENSEMBLE OR FAMILY OF 5615 04:25:21,480 --> 04:25:23,120 CONFIRMATION THAT A GLYCAN HAS, 5616 04:25:23,120 --> 04:25:26,800 DUE TO ITS OWN STRUCTURE, THAT 5617 04:25:26,800 --> 04:25:30,800 ARE OBTAINABLE THROUGH M.D., 5618 04:25:30,800 --> 04:25:32,440 SHIFTED BY INTERACTIONS IN 5619 04:25:32,440 --> 04:25:33,080 PROTEINS. 5620 04:25:33,080 --> 04:25:38,240 THIS IS THE CASE, FOR EXAMPLE, 5621 04:25:38,240 --> 04:25:41,360 OF A CD16A WHERE THERE'S LIKE IN 5622 04:25:41,360 --> 04:25:43,400 THIS CASE A MAN 5 BOUND TO 5623 04:25:43,400 --> 04:25:46,200 POSITION N 45, WE FIND IN THIS 5624 04:25:46,200 --> 04:25:53,360 CASE MAN 5 IS LOCKED IN AN OPEN 5625 04:25:53,360 --> 04:25:54,640 CONFIRMATION, BECAUSE OF 5626 04:25:54,640 --> 04:25:56,840 INTERACTION OF THIS ARM WITH 5627 04:25:56,840 --> 04:26:02,880 PROTEIN SO THE ARM IS TRAPPED IN 5628 04:26:02,880 --> 04:26:05,400 THAT CLEFT HERE, STABILIZES OPEN 5629 04:26:05,400 --> 04:26:08,080 CONFIRMATION, THE REASON WHY IN 5630 04:26:08,080 --> 04:26:09,480 THIS PARTICULAR POSITION THERE'S 5631 04:26:09,480 --> 04:26:14,240 A PREDOMINANT OR VERY HIGH 5632 04:26:14,240 --> 04:26:15,600 INCIDENCE OF HYBRID N-GLYCANS 5633 04:26:15,600 --> 04:26:19,000 WHICH HAVE ONLY THREE ARMS THAT 5634 04:26:19,000 --> 04:26:21,480 IS FUNCTIONALIZED BECAUSE 5635 04:26:21,480 --> 04:26:24,960 ACTUALLY ONCE THE GLYCAN BECOMES 5636 04:26:24,960 --> 04:26:31,120 A MAN 3 IS NOT AVAILABLE, 5637 04:26:31,120 --> 04:26:31,920 AFFECTS BIOSYNTHESIS, VERY 5638 04:26:31,920 --> 04:26:36,080 IMPORTANT INFORMATION THAT YOU 5639 04:26:36,080 --> 04:26:38,560 CAN OBTAIN BY OBSERVES WHAT THIS 5640 04:26:38,560 --> 04:26:42,760 CONFIRMATION, SO THE FAMILIES OF 5641 04:26:42,760 --> 04:26:45,640 STRUCTURES THAT M.D. CAN PROVIDE 5642 04:26:45,640 --> 04:26:46,120 MEAN. 5643 04:26:46,120 --> 04:26:52,600 SO THEY LOOK LIKE, WHAT THEY 5644 04:26:52,600 --> 04:26:54,480 LOOK LIKE. 5645 04:26:54,480 --> 04:26:58,880 SO, WE USE THEM RECENTLY TO 5646 04:26:58,880 --> 04:27:00,280 REBUILD GLYCOPROTEINS USING THIS 5647 04:27:00,280 --> 04:27:02,840 STRUCTURE OBTAINED IN SOLUTION 5648 04:27:02,840 --> 04:27:04,880 AND DID IT TO REGLYCOSYLATE 5649 04:27:04,880 --> 04:27:10,440 ALPHA FOLD DATABASE WHICH 5650 04:27:10,440 --> 04:27:12,040 DOESN'T HAVEFULLY GLYCOSYLATION, 5651 04:27:12,040 --> 04:27:15,440 THIS IS PROOF OF PRINCIPLE 5652 04:27:15,440 --> 04:27:16,280 RECENTLY PUBLISHED WITH 5653 04:27:16,280 --> 04:27:18,480 UNIVERSITY OF YORK. 5654 04:27:18,480 --> 04:27:22,040 WHAT WE FOUND IS ALPHA FOLD IS 5655 04:27:22,040 --> 04:27:23,680 ABLE TO REPRODUCE GLYCOSYLATION 5656 04:27:23,680 --> 04:27:25,360 SITE WITH HIGH ACCURACY, WITHOUT 5657 04:27:25,360 --> 04:27:29,920 FLOWING ANYTHING ABOUT 5658 04:27:29,920 --> 04:27:30,800 GLYCOSYLATION BUT LEARNED 5659 04:27:30,800 --> 04:27:31,840 THROUGH ARTIFICIAL INTELLIGENCE 5660 04:27:31,840 --> 04:27:35,160 AND THIS IS THE AMAZING POWERS 5661 04:27:35,160 --> 04:27:48,760 OF ARTIFICIAL INTELLIGENCE THAT 5662 04:27:48,760 --> 04:27:50,800 LARA HIGHLIGHTED. 5663 04:27:50,800 --> 04:27:58,080 IN PURPLE, YOU SEE ENCLOSED 5664 04:27:58,080 --> 04:28:01,200 TRYPTOPHAN, IT IS THERE, 5665 04:28:01,200 --> 04:28:05,080 REPRODUCED VERY WELL BASED ON 5666 04:28:05,080 --> 04:28:06,480 THE LEARNED PDB STRUCTURE AND 5667 04:28:06,480 --> 04:28:12,840 STACKS LIKE THIS VERY HIGHLY 5668 04:28:12,840 --> 04:28:15,640 POPULATED MAN 5 CLOSED 5669 04:28:15,640 --> 04:28:16,440 CONFIRMATION. 5670 04:28:16,440 --> 04:28:19,680 BECAUSE OF THE USEFULNESS OF 5671 04:28:19,680 --> 04:28:21,520 THIS STRUCTURE, WHAT WE'RE DOING 5672 04:28:21,520 --> 04:28:30,400 AS TOOLS BUILDING A DATABASE 5673 04:28:30,400 --> 04:28:32,560 THAT FOR NOW IS STILL IN STAGE 5674 04:28:32,560 --> 04:28:33,880 BECAUSE WE JUST GOT FUNDED FOR 5675 04:28:33,880 --> 04:28:36,080 IT BUT WE HAVE ALL THE 5676 04:28:36,080 --> 04:28:38,320 STRUCTURES THAT WE ACTUALLY GAVE 5677 04:28:38,320 --> 04:28:39,040 TO DIFFERENT RESEARCH GROUPS, 5678 04:28:39,040 --> 04:28:44,920 ESPECIALLY DURING THE COVID 5679 04:28:44,920 --> 04:28:49,440 TIMES TO REGLYCOSYLATE PROTEINS 5680 04:28:49,440 --> 04:28:53,440 FROM THE PDB NON-GLYCOSYLATED OR 5681 04:28:53,440 --> 04:28:54,080 INCOMPLETELY GLYCOSYLATED, WHAT 5682 04:28:54,080 --> 04:28:56,880 WE'RE GOING DO IS IT PUT THEM UP 5683 04:28:56,880 --> 04:28:59,280 LIKE FOR PEOPLE TO USE AND WE 5684 04:28:59,280 --> 04:29:09,360 HAVE A GLYCOBUILDER IN THE 5685 04:29:09,360 --> 04:29:09,600 MAKING. 5686 04:29:09,600 --> 04:29:11,640 THE ADVANTAGE, THEY HAVE 5687 04:29:11,640 --> 04:29:13,400 REPRESENTATIVE -- THEY ARE 5688 04:29:13,400 --> 04:29:21,000 REPRESENTATIVE OF THE ENSEMBLE, 5689 04:29:21,000 --> 04:29:22,560 FOR MANY PEOPLE NOT AWARE OR 5690 04:29:22,560 --> 04:29:23,720 LET'S SAY EXPERIENCED WITH 5691 04:29:23,720 --> 04:29:29,760 GLYCANS THERE WILL BE NO 5692 04:29:29,760 --> 04:29:30,680 MISTAKING ISOMERS, LINKAGES, 5693 04:29:30,680 --> 04:29:36,520 DIFFERENT SPECIES WILL BE 5694 04:29:36,520 --> 04:29:37,440 PRE-BUILT IN APPROPRIATE 5695 04:29:37,440 --> 04:29:37,760 CONFIRMATION. 5696 04:29:37,760 --> 04:29:39,520 GLYCOBUILDER WILL MAKE IT EASIER 5697 04:29:39,520 --> 04:29:41,440 FOR YOU TO REBUILD LOADS OF 5698 04:29:41,440 --> 04:29:43,480 GLYCANS, WE'RE AWARE OF THAT SO 5699 04:29:43,480 --> 04:29:46,080 TRYING TO TROUBLESHOOT THIS 5700 04:29:46,080 --> 04:29:49,600 DENSELY GLYCOSYLATED PROTEIN 5701 04:29:49,600 --> 04:29:53,840 SUCH AS THE SPIKE OF SARS-COV-2. 5702 04:29:53,840 --> 04:29:55,680 SO, LIKE THE GLYCOBUILDER IS 5703 04:29:55,680 --> 04:30:01,320 PRETTY MUCH AN AUTOMATION OF 5704 04:30:01,320 --> 04:30:02,880 THIS STRUCTURE ALIGNMENT OF LIKE 5705 04:30:02,880 --> 04:30:07,760 LET'S SAY ONE OF THE EQUILIBRIUM 5706 04:30:07,760 --> 04:30:08,800 STRUCTURES ONTO THE EXISTING 5707 04:30:08,800 --> 04:30:14,280 GlcNAc OR IN THE ABSENCE OF 5708 04:30:14,280 --> 04:30:18,680 GlcNAc, AND THIS IS WHAT WE 5709 04:30:18,680 --> 04:30:20,600 DID TO REBUILD MANUALLY, AT 5710 04:30:20,600 --> 04:30:24,480 FIRST, OVER TWO YEARS AGO, TO 5711 04:30:24,480 --> 04:30:26,600 REBUILD THE GLYCOSYLATION OF THE 5712 04:30:26,600 --> 04:30:28,800 SARS-COV-2 WHICH AS I'M GOING TO 5713 04:30:28,800 --> 04:30:36,440 PRESENT HERE AS A CASE OF CASE 5714 04:30:36,440 --> 04:30:39,920 EXAMPLE FOR THIS WORK. 5715 04:30:39,920 --> 04:30:42,400 WE RECONSTRUCTED THE GLYCAN 5716 04:30:42,400 --> 04:30:46,000 SHIELD, YOU CAN SEE IN THE IMAGE 5717 04:30:46,000 --> 04:30:51,080 FROM THE STRUCTURES FROM THE 5718 04:30:51,080 --> 04:30:55,560 PAPER IN COLLABORATION PUBLISHED 5719 04:30:55,560 --> 04:30:58,880 IN THE ACS CENTRAL SCIENCE. 5720 04:30:58,880 --> 04:31:02,000 IT COVERS MOST OF THE STRUCTURE 5721 04:31:02,000 --> 04:31:06,680 OF THE SARS-COV-2 SPIKE WITH 5722 04:31:06,680 --> 04:31:07,640 SOME EXCEPTIONS, THERE ARE RBD 5723 04:31:07,640 --> 04:31:12,000 WHEN OPEN AS YOU CAN SEE IN PART 5724 04:31:12,000 --> 04:31:16,720 OF THE NTB, RECOGNIZEDDED BY 5725 04:31:16,720 --> 04:31:21,280 NEUTRALIZING ANTIBODIES. 5726 04:31:21,280 --> 04:31:22,640 SO HOW CAN COMPUTATIONAL 5727 04:31:22,640 --> 04:31:25,840 GLYCOSCIENCE HELP IN THIS CASE? 5728 04:31:25,840 --> 04:31:27,160 IT HELPS A LOT. 5729 04:31:27,160 --> 04:31:32,320 IN MANY AREAS. 5730 04:31:32,320 --> 04:31:35,480 SO, LARA MENTIONED THE GLYCANS 5731 04:31:35,480 --> 04:31:38,800 PLAY AN ESSENTIAL ROLE IN VIRAL 5732 04:31:38,800 --> 04:31:44,280 INFECTION SO THEY ARE HELPING 5733 04:31:44,280 --> 04:31:46,400 IMMUNOGENIC IMMUNE ESCAPE, WE 5734 04:31:46,400 --> 04:31:47,880 AND OTHERS HAVE DETERMINED HOW 5735 04:31:47,880 --> 04:31:49,880 MUCH OF THAT STRUCTURE OF THE 5736 04:31:49,880 --> 04:31:52,000 PROTEIN IS COVERED BY GLYCANS. 5737 04:31:52,000 --> 04:31:57,000 WE ALSO DISCOVERED THAT THE 5738 04:31:57,000 --> 04:31:58,040 GLYCAN SHIELD IS FUNCTIONAL, 5739 04:31:58,040 --> 04:32:01,440 LIKE THIS IS FOR THE FIRST TIME 5740 04:32:01,440 --> 04:32:03,520 IN A VIRAL PROTEIN, THERE IS NOT 5741 04:32:03,520 --> 04:32:07,120 STANDING BACK AND PROTECTING THE 5742 04:32:07,120 --> 04:32:08,320 STRUCTURE FROM IMMUNE CONDITION, 5743 04:32:08,320 --> 04:32:10,640 IT'S JUST A BIG WORD. 5744 04:32:10,640 --> 04:32:12,480 BUT IT'S ALSO PART OF THE 5745 04:32:12,480 --> 04:32:14,600 ARCHITECTURE OF THE SYSTEM, 5746 04:32:14,600 --> 04:32:15,680 INTEGRAL PART. 5747 04:32:15,680 --> 04:32:19,680 THIS POSITION OR THIS GLYCAN IN 5748 04:32:19,680 --> 04:32:22,840 THIS POSITION BEING FUNCTIONAL 5749 04:32:22,840 --> 04:32:25,520 SO THEY HELP THE MECHANISTIC 5750 04:32:25,520 --> 04:32:28,520 PROCESS OF OPENING AND 5751 04:32:28,520 --> 04:32:29,320 RECOGNITION OF THE SPIKE. 5752 04:32:29,320 --> 04:32:31,280 WITHOUT THEM THE SPIKE IS 5753 04:32:31,280 --> 04:32:32,480 USELESS, IT DOESN'T WORK. 5754 04:32:32,480 --> 04:32:34,800 ALSO BECAUSE OF WHAT I SAID, 5755 04:32:34,800 --> 04:32:40,280 BECAUSE OF THE PARTICULAR 5756 04:32:40,280 --> 04:32:41,840 ARCHITECTURAL GLYCANS, DEPENDS 5757 04:32:41,840 --> 04:32:45,120 ON SEQUENCING AND BRANCHING WE 5758 04:32:45,120 --> 04:32:46,480 DISCOVERED POSITIONS ARE EQUALLY 5759 04:32:46,480 --> 04:32:48,440 FUNCTIONAL SO THE PROGRESS OF 5760 04:32:48,440 --> 04:32:49,800 THE PARTICULAR GLYCOSYLATION OF 5761 04:32:49,800 --> 04:32:52,760 THOSE POSITION IS ACTUALLY 5762 04:32:52,760 --> 04:32:56,480 INSTRUMENTAL FOR PERFECT OR 5763 04:32:56,480 --> 04:32:58,240 OPTIMAL FUNCTIONINGOF THE SPIKE. 5764 04:32:58,240 --> 04:32:59,680 WHAT WE'RE LOOKING, ALSO WE'VE 5765 04:32:59,680 --> 04:33:01,600 LOOKED AT, LOOKING INTO, IS THE 5766 04:33:01,600 --> 04:33:04,200 EVOLUTION OF THE GLYCAN SHIELD, 5767 04:33:04,200 --> 04:33:09,960 WE TALK ABOUT -- WE ARE PLAGUED 5768 04:33:09,960 --> 04:33:12,800 BY THE GREEK LETTERS THAT FOCUS 5769 04:33:12,800 --> 04:33:15,480 PARTICULARLY ON PROTEIN 5770 04:33:15,480 --> 04:33:15,760 EVOLUTION. 5771 04:33:15,760 --> 04:33:19,280 SO HOW THAT REGULATES 5772 04:33:19,280 --> 04:33:22,280 INTERACTIONS WITH RECEPTORS. 5773 04:33:22,280 --> 04:33:24,640 HOWEVER, WHAT IS OFTEN OR ALWAYS 5774 04:33:24,640 --> 04:33:27,920 MISSING IS INFORMATION ABOUT HOW 5775 04:33:27,920 --> 04:33:29,520 GLYCAN SHIELD, SUCH A PART OF 5776 04:33:29,520 --> 04:33:32,960 THE SPIKE FUNCTION, IS EVOLVING. 5777 04:33:32,960 --> 04:33:35,480 YOU CAN SEE IN THE VIDEO MAGENTA 5778 04:33:35,480 --> 04:33:38,160 SPOTS ARE ALL THE VARIATION THAT 5779 04:33:38,160 --> 04:33:46,280 WE HAVE NOTED ALONG THE 5780 04:33:46,280 --> 04:33:50,160 PHYLOGENY, THE SHIELD IS 5781 04:33:50,160 --> 04:33:52,720 CHANGING A LOT. 5782 04:33:52,720 --> 04:33:58,800 SOMETHING WE'VE SEEN, IF YOU 5783 04:33:58,800 --> 04:34:02,320 REMEMBER COV 1 EPIDEMIC IN 2003, 5784 04:34:02,320 --> 04:34:08,280 A COUSIN OF THIS VIRUS, HAS LIKE 5785 04:34:08,280 --> 04:34:10,280 THE SPIKE OF THAT VIRUS LIKE 5786 04:34:10,280 --> 04:34:12,880 MUTATED NOW, LIKE ONE OF THE 5787 04:34:12,880 --> 04:34:16,760 GLYCOSYLATION SITES IS LOST. 5788 04:34:16,760 --> 04:34:24,680 THIS IS NOW IN THE POSITION 370, 5789 04:34:24,680 --> 04:34:32,360 SO THERE'S NOT GLYCOSYLATION IN 5790 04:34:32,360 --> 04:34:34,680 COV 2, IT'S ONE OF THE MOST 5791 04:34:34,680 --> 04:34:36,760 IMPORTANT SITES FOR THE 5792 04:34:36,760 --> 04:34:38,840 STABILITY OF THE OPEN SPIKE AND 5793 04:34:38,840 --> 04:34:42,760 WE THINK IT WAS REPLACING THAT 5794 04:34:42,760 --> 04:34:46,360 POSITION ORIGINALLY TO BE LOST 5795 04:34:46,360 --> 04:34:49,280 WHEN 2, 3, 4 CAME UP. 5796 04:34:49,280 --> 04:35:09,560 THE PRESENCE OF N 370 IS 0 IS IN 5797 04:35:09,560 --> 04:35:15,560 MOST CURRENTLY CIRCULATING, IN 5798 04:35:15,560 --> 04:35:18,120 THE PHYLOGENY, YOU CAN SEE IT IS 5799 04:35:18,120 --> 04:35:18,400 CONSERVED. 5800 04:35:18,400 --> 04:35:23,720 WHAT WE DISCOVERED IS THAT N370 5801 04:35:23,720 --> 04:35:27,720 IS ACTUALLY USEFUL TO KEEP THAT 5802 04:35:27,720 --> 04:35:29,880 RBD SHOWN HERE IN ORANGE OPEN 5803 04:35:29,880 --> 04:35:32,120 BUT IS NOT VERY USEFUL WHEN THIS 5804 04:35:32,120 --> 04:35:33,920 SPIKE IS CLOSED BECAUSE IT JUST 5805 04:35:33,920 --> 04:35:37,400 WRAPS AROUND LIKE AS YOU CAN SEE 5806 04:35:37,400 --> 04:35:39,520 HERE, THE CLOSED RBD AND 5807 04:35:39,520 --> 04:35:41,280 ACTUALLY COMING FROM AN IDEATION 5808 04:35:41,280 --> 04:35:46,480 TO RBD BECAUSE IT'S LINKED, IT 5809 04:35:46,480 --> 04:35:48,480 JUST LOCKS DOWN. 5810 04:35:48,480 --> 04:35:51,960 OCCUPYING A CLEFT ON THE RDB, 5811 04:35:51,960 --> 04:35:54,320 YOU CAN SEE VERY STABLE IN THIS 5812 04:35:54,320 --> 04:35:58,120 CASE THROUGH THE 1, 6 ARM OR 1, 5813 04:35:58,120 --> 04:36:00,440 3 ARM FLIES OFF ABOVE PRETTY 5814 04:36:00,440 --> 04:36:09,160 MUCH WHERE THE ACE-2 BINDS. 5815 04:36:09,160 --> 04:36:14,320 LIKE THE RECENT WORK ACTUALLY 5816 04:36:14,320 --> 04:36:18,480 THAT CAME LIKE OUT OF SAME TIME 5817 04:36:18,480 --> 04:36:24,240 AS OURS IN bioRxiv, CAME OUT 5818 04:36:24,240 --> 04:36:28,320 IN JANUARY, PROVED THE REMOVAL 5819 04:36:28,320 --> 04:36:32,440 OF N370 INCREASES REPLICATION, 5820 04:36:32,440 --> 04:36:41,360 SO LIKE IT'S HIGHLY INSTRUMENTAL 5821 04:36:41,360 --> 04:36:42,680 BY REMOVING THIS N370 INCREASED 5822 04:36:42,680 --> 04:36:44,280 VIRULENCE OF THE VIRUS. 5823 04:36:44,280 --> 04:36:48,400 SO GLYCAN SHIELD IS IMPORTANT, 5824 04:36:48,400 --> 04:36:50,280 GLYCAN SHIELD REGULATES 5825 04:36:50,280 --> 04:36:51,720 INFECTION, AND ONE GLYCAN 5826 04:36:51,720 --> 04:36:52,400 MATTERS. 5827 04:36:52,400 --> 04:36:56,280 ALSO THIS GLYCAN IS QUITE 5828 04:36:56,280 --> 04:37:05,640 INTERESTING BECAUSE THE CLEFT IT 5829 04:37:05,640 --> 04:37:06,160 LEAVES IS EVOLUTIONARILY 5830 04:37:06,160 --> 04:37:07,880 DESIGNED TO BIND TO GLYCANS. 5831 04:37:07,880 --> 04:37:10,640 WE'RE SEEING A PAPER THAT LARA 5832 04:37:10,640 --> 04:37:15,200 MENTIONED, SHE WAS INVOLVED IN 5833 04:37:15,200 --> 04:37:18,520 IT, THAT THE RBD BINDS A WHOLE 5834 04:37:18,520 --> 04:37:23,280 LOT OF DIFFERENT GLYCANS WITH 5835 04:37:23,280 --> 04:37:26,480 DIFFERENT AFFINITIES, VERY 5836 04:37:26,480 --> 04:37:27,600 SPECIFICALLY. 5837 04:37:27,600 --> 04:37:29,360 GLYCANS WITH SPECIFIC FEATURES 5838 04:37:29,360 --> 04:37:31,280 ARE BOUND, DIFFERENT FEATURE, 5839 04:37:31,280 --> 04:37:38,200 DIFFERENT AFFINITY. 5840 04:37:38,200 --> 04:37:42,400 THE WORK HAS SHOWN BINDING TO 5841 04:37:42,400 --> 04:37:43,840 RBD WITH THE SAME AFFINITY AS 5842 04:37:43,840 --> 04:37:49,160 GAGS, AS YOU CAN SEE HERE, LOWER 5843 04:37:49,160 --> 04:37:53,000 AFFINITY, THEY ARE MUTUALLY 5844 04:37:53,000 --> 04:37:54,280 EXCLUSIVE. 5845 04:37:54,280 --> 04:37:59,400 ALSO WITH LOWER AFFINITY TYPE 1A 5846 04:37:59,400 --> 04:38:03,400 AND TYPE 1H, AND ALSO LIKE AN 5847 04:38:03,400 --> 04:38:03,680 N-GLYCAN. 5848 04:38:03,680 --> 04:38:09,360 WHICH IS NOT SURPRISING 5849 04:38:09,360 --> 04:38:10,600 CONSIDERING THAT IT IS MISSING, 5850 04:38:10,600 --> 04:38:13,040 LIKELY SOMETHING HAD REPLACED 5851 04:38:13,040 --> 04:38:15,560 THAT IN ITS ABSENCE. 5852 04:38:15,560 --> 04:38:17,520 THIS GIVERS MASSIVE ADVANTAGE TO 5853 04:38:17,520 --> 04:38:21,360 THE VIRUS BY BINDING ALL THE 5854 04:38:21,360 --> 04:38:23,880 GLYCANS EXPRESSED ON CELL 5855 04:38:23,880 --> 04:38:25,360 SURFACE, LIKE FOR LOCALIZATION, 5856 04:38:25,360 --> 04:38:27,760 THAT'S FOR SURE. 5857 04:38:27,760 --> 04:38:36,680 HOW DOES THAT -- HOW TO COMBINE, 5858 04:38:36,680 --> 04:38:37,680 VERY DIFFICULT QUESTION, WE 5859 04:38:37,680 --> 04:38:38,840 CAN'T ANSWER. 5860 04:38:38,840 --> 04:38:45,120 YOU SEE CLEFT HERE BOUND TO THE 5861 04:38:45,120 --> 04:38:47,520 370 FROM CLOSE BY, TURNS AROUND, 5862 04:38:47,520 --> 04:38:51,360 YOU CAN SEE A LOVELY POCKET, 5863 04:38:51,360 --> 04:38:52,760 DESIGNED FOR BINDING CORE FUCOSE 5864 04:38:52,760 --> 04:38:55,000 AND LEFT IS ACTUALLY VERY 5865 04:38:55,000 --> 04:39:02,880 EXTENDED TO BIND THE TWO ARMS. 5866 04:39:02,880 --> 04:39:11,120 THIS IS WORK THAT SHOWED POLYMER 5867 04:39:11,120 --> 04:39:16,080 CAN BIND THAT CLEFT IN PART, 5868 04:39:16,080 --> 04:39:18,160 BECAUSE -- THAT CLEFT CAN BE 5869 04:39:18,160 --> 04:39:25,520 BOUND OR CAN BE -- CAN HELP IN 5870 04:39:25,520 --> 04:39:30,800 THE BINDING OF SULFATED GAG LIKE 5871 04:39:30,800 --> 04:39:33,240 SHOWN BY ROMY'S WORK, AND WE 5872 04:39:33,240 --> 04:39:37,320 FOUND IT BINDS TO TM 1, IN THIS 5873 04:39:37,320 --> 04:39:39,840 CASE SIALIC ACID IN THIS POCKET 5874 04:39:39,840 --> 04:39:42,080 WITH DIFFERENT BINDING SITE OF 5875 04:39:42,080 --> 04:39:46,520 NEUTRAL GLYCANS, THAT'S THE 5876 04:39:46,520 --> 04:39:49,520 LEFT, ACROSS THIS POCKET OF THE 5877 04:39:49,520 --> 04:39:51,680 SIALIC ACID, OCCUPIES THE END OF 5878 04:39:51,680 --> 04:39:55,080 THE 1, 6 ARM OF THE N370 GLYCAN 5879 04:39:55,080 --> 04:40:07,200 THAT WE CAN DESIALITE. 5880 04:40:07,200 --> 04:40:13,440 THEY GINNED -- THEY BIND WITH 5881 04:40:13,440 --> 04:40:18,080 THE SAME AFFINITY, THIS IS LIKE 5882 04:40:18,080 --> 04:40:19,640 A CORROBORATING EVIDENCE THIS IS 5883 04:40:19,640 --> 04:40:26,840 GOOD BINDING SITE FOR IT. 5884 04:40:26,840 --> 04:40:30,840 IN COMPETITIVE BINDINGS WE CAN 5885 04:40:30,840 --> 04:40:34,800 SEE IN COLLABORATION, WITH 5886 04:40:34,800 --> 04:40:38,480 BINDING SITE IN AGREEMENT WITH 5887 04:40:38,480 --> 04:40:45,840 DATA FROM ROMY'S GROUP AND OTHER 5888 04:40:45,840 --> 04:40:50,960 PEOPLE THAT STUDIED HEPARIN 5889 04:40:50,960 --> 04:40:51,760 BINDING. 5890 04:40:51,760 --> 04:40:52,840 THEY ARE MUTUALLY EXCLUSIVE AND 5891 04:40:52,840 --> 04:40:56,800 THIS IS WHAT YOU CAN GET FROM 5892 04:40:56,800 --> 04:40:58,120 DIFFERENT APPROACHES LIKE 5893 04:40:58,120 --> 04:41:04,880 THROUGH DOCKING AND EXTENSIVE 5894 04:41:04,880 --> 04:41:07,320 MOLECULAR DYNAMICS. 5895 04:41:07,320 --> 04:41:12,640 THIS IS NEUTRAL. 5896 04:41:12,640 --> 04:41:14,200 THAT OCCUPIES THE TOP OF THE 5897 04:41:14,200 --> 04:41:17,280 LEFT, NOT THE SAME POSITION AS 5898 04:41:17,280 --> 04:41:18,880 THE GLYCAN, SIALIC ACID, THE 5899 04:41:18,880 --> 04:41:27,080 BOTTOM OF THE CLEFT BUT HERE AT 5900 04:41:27,080 --> 04:41:28,200 THE TOP. 5901 04:41:28,200 --> 04:41:33,760 THE VARIATION OR STRUCTURAL 5902 04:41:33,760 --> 04:41:35,440 COMPLEXITY, THE ARCHITECTURE OF 5903 04:41:35,440 --> 04:41:40,800 THE CLEFT WAS DESIGNED TO 5904 04:41:40,800 --> 04:41:42,800 ACCOMMODATE A DIVERSE IN TERMS 5905 04:41:42,800 --> 04:41:48,080 OF TYPE OF MONO SACCHARIDES, TO 5906 04:41:48,080 --> 04:41:49,840 BIND DIFFERENT GLYCANS IN 5907 04:41:49,840 --> 04:41:51,760 DIFFERENT POSITIONS, THAT'S OF 5908 04:41:51,760 --> 04:41:53,280 THAT CAN -- THAT'S THE REASON 5909 04:41:53,280 --> 04:41:57,480 WHY WE PROBABLY SEE LOTS OF 5910 04:41:57,480 --> 04:42:04,720 GLYCAN BINDING THE SPIKE IN THIS 5911 04:42:04,720 --> 04:42:08,480 POSITION OF DIFFERENT AFFINITY. 5912 04:42:08,480 --> 04:42:09,680 SORRY IF I'M A BIT LATE. 5913 04:42:09,680 --> 04:42:13,200 I'D LIKE TO THANK THE PEOPLE 5914 04:42:13,200 --> 04:42:15,600 THAT MADE THIS WORK POSSIBLE SO 5915 04:42:15,600 --> 04:42:22,200 MY STUDENTS IN MY GROUP, AMERO'S 5916 04:42:22,200 --> 04:42:29,800 GROUP, INSTRUMENTAL FOR INSIGHT 5917 04:42:29,800 --> 04:42:31,760 IN THIS FIELD, ONGOING WORK OF 5918 04:42:31,760 --> 04:42:36,120 THE EVOLUTION OF GLYCAN SHIELD 5919 04:42:36,120 --> 04:42:38,960 AND COLLEAGUES FROM THE BINDING 5920 04:42:38,960 --> 04:42:48,200 ON DIFFERENT GLYCANS THROUGH THE 5921 04:42:48,200 --> 04:42:50,800 RBD, INSTITUTE FOR GLYCOMICS, 5922 04:42:50,800 --> 04:42:51,880 HOSTING ME FOR MY SABBATICAL, 5923 04:42:51,880 --> 04:42:52,920 AND THANK YOU FOR YOUR 5924 04:42:52,920 --> 04:42:55,920 ATTENTION. 5925 04:42:55,920 --> 04:42:57,080 THANK YOU VERY MUCH. 5926 04:42:57,080 --> 04:42:57,800 >> THANK YOU. 5927 04:42:57,800 --> 04:42:59,200 VERY NICE TALKS. 5928 04:42:59,200 --> 04:43:02,000 NOW WE'LL MOVE TO OUR PANEL 5929 04:43:02,000 --> 04:43:04,840 DISCUSSION AND SPEAKERS, PLEASE 5930 04:43:04,840 --> 04:43:06,520 TURN ON YOUR CAMERAS AND UNMUTE 5931 04:43:06,520 --> 04:43:11,040 AND WE CAN MOVE TO SOME 5932 04:43:11,040 --> 04:43:11,560 QUESTIONS. 5933 04:43:11,560 --> 04:43:16,880 I HAVE THE FIRST QUESTION FROM 5934 04:43:16,880 --> 04:43:21,080 LANCE TO RON, DO YOU KNOW WHAT 5935 04:43:21,080 --> 04:43:22,840 IS THE REDUCING END OF THE 5936 04:43:22,840 --> 04:43:24,240 STRUCTURE WITH REGARDS TO WHERE 5937 04:43:24,240 --> 04:43:31,480 IT CAME FROM, WAS IT POSSIBLE TO 5938 04:43:31,480 --> 04:43:34,200 GENERATE SHEDDING GIVEN THE 5939 04:43:34,200 --> 04:43:35,480 BONDS IN THE UNDERLYING M 3 5940 04:43:35,480 --> 04:43:41,640 STRUCTURE, THIS LEADS BACK TO 5941 04:43:41,640 --> 04:43:43,400 WHAT THE ACTUAL -- 5942 04:43:43,400 --> 04:43:44,480 >> YEAH, EXCELLENT QUESTIONS. 5943 04:43:44,480 --> 04:43:48,960 I DON'T HAVE A GOOD ANSWER TO 5944 04:43:48,960 --> 04:43:50,920 PROVIDE. 5945 04:43:50,920 --> 04:43:54,520 WE DON'T HAVE GOOD DENSITY. 5946 04:43:54,520 --> 04:43:55,680 IT'S CLEAR THE MATRIGLYCAN PIECE 5947 04:43:55,680 --> 04:43:58,600 IS LONGER THAN THE ONE WE 5948 04:43:58,600 --> 04:44:02,680 ACTUALLY MODELED BECAUSE THE 5949 04:44:02,680 --> 04:44:06,720 DENSITY PROJECTING, SO WE DON'T 5950 04:44:06,720 --> 04:44:11,560 SEE THE END. 5951 04:44:11,560 --> 04:44:14,840 THE SOURCE, IT COULD BE RELEASED 5952 04:44:14,840 --> 04:44:20,760 BY SOME KIND OF 5953 04:44:20,760 --> 04:44:21,560 PHOSPHODIESTERASE, BUT ANOTHER 5954 04:44:21,560 --> 04:44:24,720 POSSIBILITY ONE OF THE LARGE 5955 04:44:24,720 --> 04:44:28,800 ENZYMES, LARGE 1 OR LARGE 2, 5956 04:44:28,800 --> 04:44:31,080 SEEM TO SYNTHESIZE UNBOUND OR 5957 04:44:31,080 --> 04:44:32,600 UNFREE MATRIGLYCAN BECAUSE WE 5958 04:44:32,600 --> 04:44:35,160 CAN DO THAT IN THE TEST TUBE AND 5959 04:44:35,160 --> 04:44:38,800 THE PRECURSORS ARE AVAILABLE IN 5960 04:44:38,800 --> 04:44:41,720 THE CELLS SO MAYBE A GENERATION 5961 04:44:41,720 --> 04:44:43,760 OF MATTERY GLYCANS. 5962 04:44:43,760 --> 04:44:44,720 >> THAT'S PART OF THE 5963 04:44:44,720 --> 04:44:47,480 HYPOTHESIS, BINDS IN THE POCKET, 5964 04:44:47,480 --> 04:44:52,880 FREE GLYCANS, THAT WOULD MAKE 5965 04:44:52,880 --> 04:44:53,480 SENSE. 5966 04:44:53,480 --> 04:44:56,600 MOVING ON, I HAVE A QUESTION 5967 04:44:56,600 --> 04:45:00,240 DIRECTED TO LEVA. 5968 04:45:00,240 --> 04:45:01,840 HAVE YOU OBSERVED COMPENSATORY 5969 04:45:01,840 --> 04:45:03,480 RESPONSE IN YOUR KNOCKOUTS, 5970 04:45:03,480 --> 04:45:06,800 DERIVED FROM THE VIRAL 5971 04:45:06,800 --> 04:45:10,080 GLYCOPROTEINS, ALSO HAVE YOU 5972 04:45:10,080 --> 04:45:15,400 PERFORMED ANY O GLYCAN RELEASE 5973 04:45:15,400 --> 04:45:18,840 TO FORTIFY YOUR LIBRARY IN CELL 5974 04:45:18,840 --> 04:45:19,080 SYSTEMS? 5975 04:45:19,080 --> 04:45:21,960 >> FIRST QUESTION, WE'RE NOT 5976 04:45:21,960 --> 04:45:28,600 ACTUALLY LOOKING AT N-GLYCANS ON 5977 04:45:28,600 --> 04:45:29,600 PURIFIED PROTEINS BUT WOULD NOT 5978 04:45:29,600 --> 04:45:35,520 EXPECT CHANGES IN GLYCOSYLATED 5979 04:45:35,520 --> 04:45:36,920 POSITION, THE ONLY DIFFERENCE 5980 04:45:36,920 --> 04:45:37,480 COULD BE? 5981 04:45:37,480 --> 04:45:43,520 SITE SPECIFIC STRUCTURES, LEVEL 5982 04:45:43,520 --> 04:45:45,680 OF PROCESSING AND MATURITY. 5983 04:45:45,680 --> 04:45:46,800 >> THAT WAS MY QUESTION, THE 5984 04:45:46,800 --> 04:45:49,080 REASON I ASKED THAT IS BECAUSE 5985 04:45:49,080 --> 04:45:54,800 WORKING WITH A NUMBER OF 5986 04:45:54,800 --> 04:45:56,600 DIFFERENT PROTEASE AND NEMATODES 5987 04:45:56,600 --> 04:45:59,400 WE NOTICED OTHER GLYCOSYLATION 5988 04:45:59,400 --> 04:46:00,880 PROCESSES CAN BE UPREGULATED IN 5989 04:46:00,880 --> 04:46:01,600 COMPENSATION. 5990 04:46:01,600 --> 04:46:01,880 >> OKAY. 5991 04:46:01,880 --> 04:46:03,880 >> IT WAS INTERESTING. 5992 04:46:03,880 --> 04:46:07,920 I THOUGHT IF YOU HAD NOTICED 5993 04:46:07,920 --> 04:46:10,160 ANYTHING IT MIGHT BE 5994 04:46:10,160 --> 04:46:10,840 INTERESTING. 5995 04:46:10,840 --> 04:46:15,880 SECOND PART, O GLYCAN RELEASE. 5996 04:46:15,880 --> 04:46:16,880 >> WE HAVEN'T DONE RELEASED 5997 04:46:16,880 --> 04:46:20,160 ANALYSIS ON PROTEINS THEMSELVES 5998 04:46:20,160 --> 04:46:22,840 BUT HAVE COMPREHENSIVE KNOWLEDGE 5999 04:46:22,840 --> 04:46:27,160 OF CELL LINE WE USED, SO A 6000 04:46:27,160 --> 04:46:31,720 COLLEAGUE FROM THE LAB DEVELOPED 6001 04:46:31,720 --> 04:46:33,480 THIS VERY ROBUST PROFILING 6002 04:46:33,480 --> 04:46:36,400 METHOD, SHE USED FOR THESE 6003 04:46:36,400 --> 04:46:38,760 CELLS, PUBLISHED IN ANALYTICAL 6004 04:46:38,760 --> 04:46:41,080 CHEMISTRY RECENTLY. 6005 04:46:41,080 --> 04:46:45,200 AND WE PRINCIPALLY SEE 60 TO 70% 6006 04:46:45,200 --> 04:46:50,320 O-GLYCANS, UP TO 10% FOR TWO. 6007 04:46:50,320 --> 04:46:51,640 >> I WAS WONDERING ABOUT THE 6008 04:46:51,640 --> 04:46:54,240 INSECT CELL LINES YOU LOOKED AT. 6009 04:46:54,240 --> 04:47:00,360 >> YES, THAT WAS FOR THE 6010 04:47:00,360 --> 04:47:02,840 SARS-COV-2. 6011 04:47:02,840 --> 04:47:10,800 SO THAT'S NS2, WE EXPECT 6012 04:47:10,800 --> 04:47:16,800 STRUCTURES FOR SINGLE GALNIC BUT 6013 04:47:16,800 --> 04:47:17,880 HAVEN'T DONE THE ANALYSIS. 6014 04:47:17,880 --> 04:47:18,560 >> I HAVE A QUESTION. 6015 04:47:18,560 --> 04:47:21,440 DO YOU THINK THE VIRUSES ARE 6016 04:47:21,440 --> 04:47:22,840 ACTUALLY REGULATING THE 6017 04:47:22,840 --> 04:47:23,520 EXPRESSION OF GLYCOSYLATION 6018 04:47:23,520 --> 04:47:26,800 MACHINERY IN THE HOST CELLS? 6019 04:47:26,800 --> 04:47:28,280 IS THERE ANY TRANSCRIPTOMIC 6020 04:47:28,280 --> 04:47:30,680 DATASETS, DATA BASES THAT YOU 6021 04:47:30,680 --> 04:47:33,160 COULD USE TO VALIDATE THAT? 6022 04:47:33,160 --> 04:47:34,720 >> YEAH, THERE ARE. 6023 04:47:34,720 --> 04:47:37,680 WE KNOW SOME ARE. 6024 04:47:37,680 --> 04:47:47,360 WE KNOW, FOR EXAMPLE, THAT VIRUS 6025 04:47:47,360 --> 04:47:48,080 UPREGULATES T3, ENHANCES 6026 04:47:48,080 --> 04:47:48,800 GLYCOSYLATION AND COULD BE THER 6027 04:47:48,800 --> 04:47:57,080 ON THE -- OTHER WAY AROUND BUT 6028 04:47:57,080 --> 04:47:58,520 OTHER VIRUS REGULATES 6029 04:47:58,520 --> 04:47:59,680 TRANSFERASES, YES, IF THERE ARE 6030 04:47:59,680 --> 04:48:02,960 SOME PUBLIC LIP AVAILABLE DATA 6031 04:48:02,960 --> 04:48:08,440 OF INFECTED VERSUS NON-INFECTED 6032 04:48:08,440 --> 04:48:10,560 MATERIALS COULD FISH OUT 6033 04:48:10,560 --> 04:48:10,880 SIGNATURES. 6034 04:48:10,880 --> 04:48:12,400 >> A STUPIDER QUESTION MEASURE, 6035 04:48:12,400 --> 04:48:18,760 DO ANY VIRUSES CARRY THEIR OWN 6036 04:48:18,760 --> 04:48:19,560 ENCODED GLYCOCELE TRANSFERASE OR 6037 04:48:19,560 --> 04:48:22,600 IS IT HOST? 6038 04:48:22,600 --> 04:48:25,120 >> FOR HUMAN VIRAL PROBABLY 6039 04:48:25,120 --> 04:48:26,800 ENTIRE HOST. 6040 04:48:26,800 --> 04:48:28,680 GIANT VIRUSES THAT INFECT LIKE 6041 04:48:28,680 --> 04:48:31,600 THESE ALGAE AND OTHER SMALL 6042 04:48:31,600 --> 04:48:33,920 MICROORGANISMS THAT THEY ENCODE 6043 04:48:33,920 --> 04:48:38,520 A MASTERY OF THEIR OWN AND BUILD 6044 04:48:38,520 --> 04:48:41,880 ALL KIND OF WEIRD N-GLYCANS. 6045 04:48:41,880 --> 04:48:42,840 >> COOL. 6046 04:48:42,840 --> 04:48:45,040 >> ONE MORE QUESTION FOR RON. 6047 04:48:45,040 --> 04:48:49,280 THE SPIKE PROTEIN DOES IT LOOK 6048 04:48:49,280 --> 04:48:52,800 LIKE LAMININ DOMAIN, ARE THESE 6049 04:48:52,800 --> 04:48:53,720 COMPLETELY DIVERGENT EVOLUTION? 6050 04:48:53,720 --> 04:48:56,880 >> YEAH, COMPLETELY DIFFERENT. 6051 04:48:56,880 --> 04:48:58,880 WE DON'T SEE ANY SIMILARITY. 6052 04:48:58,880 --> 04:49:01,680 THERE ARE COMMON FEATURES LIKE 6053 04:49:01,680 --> 04:49:04,480 POLAR INTERACTIONS BUT THIS IS 6054 04:49:04,480 --> 04:49:04,800 VERY GENERAL. 6055 04:49:04,800 --> 04:49:05,280 >> THANKS. 6056 04:49:05,280 --> 04:49:08,280 >> I HAVE A QUESTION THAT MAY BE 6057 04:49:08,280 --> 04:49:22,840 DIRECTED TO BOTH LARA AND ALSO 6058 04:49:22,840 --> 04:49:24,200 ELISA, THE SIALYATION WORK, 6059 04:49:24,200 --> 04:49:30,080 DIFFERENT MODES REALLY, BUT 6060 04:49:30,080 --> 04:49:33,120 WONDERING MERS WAS REPORTED TO 6061 04:49:33,120 --> 04:49:39,440 BIND AT THE N INTERPRET 6062 04:49:39,440 --> 04:49:39,720 N-TERMINUS. 6063 04:49:39,720 --> 04:49:43,680 IF YOU LOOKED AT THE N-TERMINUS 6064 04:49:43,680 --> 04:49:45,400 AND SOME STUFF IN THE RECEPTOR 6065 04:49:45,400 --> 04:49:46,680 BINDING DOMAIN SOME REGIONS ARE 6066 04:49:46,680 --> 04:49:48,880 INTERESTING BUT WONDERING IF 6067 04:49:48,880 --> 04:49:50,560 THERE WAS ANYTHING ON THE 6068 04:49:50,560 --> 04:49:51,680 N-TERMINAL SIDE AND LARA IF 6069 04:49:51,680 --> 04:49:54,680 THERE'S ANYTHING YOU MIGHT 6070 04:49:54,680 --> 04:49:57,880 COMMENT ON AS FAR AS POSSIBILITY 6071 04:49:57,880 --> 04:50:02,840 THAT SARS-COV-2 SPIKE IS BINDING 6072 04:50:02,840 --> 04:50:07,160 SOME OF THESE SIALIC ACIDS. 6073 04:50:07,160 --> 04:50:11,880 >> I THINK IT IS TRUE, I WASN'T 6074 04:50:11,880 --> 04:50:22,840 SURPRISED WHEN IT BOUND BECAUSE 6075 04:50:22,840 --> 04:50:24,040 CORONAVIRUS HAVE A HISTORY OF 6076 04:50:24,040 --> 04:50:25,920 BINDING. 6077 04:50:25,920 --> 04:50:28,840 WHEN IT WAS REVEALED, I WASN'T 6078 04:50:28,840 --> 04:50:34,760 SHOCKED BUT I'LL ALISA TALK 6079 04:50:34,760 --> 04:50:37,160 ABOUT WHERE. 6080 04:50:37,160 --> 04:50:41,600 >> YEAH, THE NTD BINDS IN MERS, 6081 04:50:41,600 --> 04:50:42,480 BINDS SIALIC ACID. 6082 04:50:42,480 --> 04:50:45,480 I THINK ONE OF THE FIRST THINGS 6083 04:50:45,480 --> 04:50:49,160 WE LOOKED AT IN 2020, 6084 04:50:49,160 --> 04:50:50,840 IMMEDIATELY, OH, GALECTIN 6085 04:50:50,840 --> 04:50:55,200 DOMAIN, IS IT CONSERVED FOR NTB 6086 04:50:55,200 --> 04:50:56,800 WHICH IS MOSTLY, HOWEVER THE 6087 04:50:56,800 --> 04:50:58,640 LOOPS THAT ARE RESPONSIBLE FOR 6088 04:50:58,640 --> 04:51:01,840 THE SIALIC ACID BINDING IN MERS 6089 04:51:01,840 --> 04:51:03,600 ARE COMPLETELY CHANGED IN 6090 04:51:03,600 --> 04:51:05,880 SARS-COV-2 SPIKE AND ACTUALLY 6091 04:51:05,880 --> 04:51:08,920 WHAT IS LIKE INTERESTING IS THE 6092 04:51:08,920 --> 04:51:10,840 SARS-COV-2 GROUP 2 GLYCANS, NOT 6093 04:51:10,840 --> 04:51:14,480 ONE, TO COVER THAT SIDE. 6094 04:51:14,480 --> 04:51:18,800 THE PROTEIN CHANGES WERE NOT 6095 04:51:18,800 --> 04:51:22,280 ENOUGH TO DISCOURAGE BINDING 6096 04:51:22,280 --> 04:51:24,600 SIALIC ACID, TWO GLYCANS ON TOP, 6097 04:51:24,600 --> 04:51:26,880 SO IT'S VERY BUSY, LET'S SAY, 6098 04:51:26,880 --> 04:51:28,360 AREA. 6099 04:51:28,360 --> 04:51:30,120 SO IT'S VERY UNLIKELY THAT 6100 04:51:30,120 --> 04:51:31,920 SARS-COV-2 WOULD BIND SIALIC 6101 04:51:31,920 --> 04:51:34,800 ACID IN THE NTV, HOWEVER THERE'S 6102 04:51:34,800 --> 04:51:40,280 EVIDENCE THAT IT BINDS SIALIC 6103 04:51:40,280 --> 04:51:40,480 ACID. 6104 04:51:40,480 --> 04:51:44,920 WHERE IS STILL UP TO THE NTD, UP 6105 04:51:44,920 --> 04:51:46,800 TO LET'S SAY THE DETERMINATION, 6106 04:51:46,800 --> 04:51:49,280 I HAVEN'T SEEN ANYTHING 6107 04:51:49,280 --> 04:51:51,240 PARTICULARLY CONVINCING IN THAT 6108 04:51:51,240 --> 04:51:52,120 REGARD. 6109 04:51:52,120 --> 04:51:53,280 IT'S VERY DIFFICULT TO DETERMINE 6110 04:51:53,280 --> 04:51:55,360 TO BE HONEST BECAUSE ALL THOSE 6111 04:51:55,360 --> 04:51:57,560 PARTS THAT MIGHT BE INVOLVED IN 6112 04:51:57,560 --> 04:51:58,600 BINDING ARE EXTREMELY 6113 04:51:58,600 --> 04:51:59,240 DISORDERED. 6114 04:51:59,240 --> 04:52:04,080 SO THEY ARE ACTUALLY NEVER 6115 04:52:04,080 --> 04:52:08,760 RESOLVED, RARELY RESOLVED IN 6116 04:52:08,760 --> 04:52:09,280 CryoEM STRUCTURES. 6117 04:52:09,280 --> 04:52:13,280 WHAT JOHN ACTUALLY SHOWED, THE 6118 04:52:13,280 --> 04:52:15,880 RBD THAT BINDS SIALIC ACID IN A 6119 04:52:15,880 --> 04:52:17,680 CONTEXT OF A VERY SPECIFIC 6120 04:52:17,680 --> 04:52:19,520 SEQUENCE WHICH IS LIKE, FOR 6121 04:52:19,520 --> 04:52:26,840 EXAMPLE, GIVEN BY GM 1 AND 2, 6122 04:52:26,840 --> 04:52:30,800 DOESN'T BIND POLY SIALIC ACID. 6123 04:52:30,800 --> 04:52:33,200 IT BINDS SPECIFICALLY. 6124 04:52:33,200 --> 04:52:38,440 WITHIN LIKE THE RBD IN THIS 6125 04:52:38,440 --> 04:52:43,640 CASE. 6126 04:52:43,640 --> 04:52:46,520 AGAIN, THE STRUCTURE IS 6127 04:52:46,520 --> 04:52:46,840 DISORDERED. 6128 04:52:46,840 --> 04:52:50,120 A BINDING SITE WE THINK IS 6129 04:52:50,120 --> 04:52:53,240 PROMISING BECAUSE OF ALL LET'S 6130 04:52:53,240 --> 04:52:56,960 SAY DIFFERENT LIKE DATA FROM 6131 04:52:56,960 --> 04:52:58,480 OTHER RESOURCES, BUT LIKE THE 6132 04:52:58,480 --> 04:53:02,240 NAIL IN THE COFFIN WOULD BE A 6133 04:53:02,240 --> 04:53:03,680 STRUCTURE THAT PROBABLY -- 6134 04:53:03,680 --> 04:53:08,680 SOMETHING WE'VE BEEN CHASING 6135 04:53:08,680 --> 04:53:09,280 DOWN. 6136 04:53:09,280 --> 04:53:12,120 WE STILL HAVE CHASING TO DO. 6137 04:53:12,120 --> 04:53:14,800 HOPE THAT ANSWERS YOUR QUESTION. 6138 04:53:14,800 --> 04:53:20,560 >> MAYBE THIS IS A STRETCH, 6139 04:53:20,560 --> 04:53:22,360 GAMMA CORONAVIRUS BIND SIALIC 6140 04:53:22,360 --> 04:53:25,280 RECEPTOR RECEPTOR, WE AND OTHERS 6141 04:53:25,280 --> 04:53:28,560 HAVE LOOKED AT RBD, THEY ARE NOT 6142 04:53:28,560 --> 04:53:29,280 REALLY -- STRUCTURAL RELATED BUT 6143 04:53:29,280 --> 04:53:33,840 NOT SO MUCH AT THE AMINO ACID 6144 04:53:33,840 --> 04:53:37,080 ACID LEVEL, BUT WE HAVE SEEN 6145 04:53:37,080 --> 04:53:38,760 BINDING IN GALECTIN, I WAS 6146 04:53:38,760 --> 04:53:40,280 WONDERING IF THERE'S ANY 6147 04:53:40,280 --> 04:53:41,320 CORRELATION BETWEEN THAT AND 6148 04:53:41,320 --> 04:53:47,920 WHAT YOU MAY BE SEEING AT THE 6149 04:53:47,920 --> 04:53:52,760 RBD IN SARS-COV-2. 6150 04:53:52,760 --> 04:53:53,280 >> I'M HERE. 6151 04:53:53,280 --> 04:53:55,840 YEAH, LIKE THE GAMMA SPIKE IS 6152 04:53:55,840 --> 04:53:56,680 QUITE SIMILAR. 6153 04:53:56,680 --> 04:54:01,680 I WOULD SAY ONE OF THE MAIN 6154 04:54:01,680 --> 04:54:08,080 DIFFERENCES ACTUALLY IS 6155 04:54:08,080 --> 04:54:09,440 N-GLYCOSYLATION, ADDITIONAL SITE 6156 04:54:09,440 --> 04:54:11,840 WE'RE WORKING ON AT THIS POINT. 6157 04:54:11,840 --> 04:54:14,320 SO LIKE THERE IS EVIDENCE THAT 6158 04:54:14,320 --> 04:54:19,320 IT BINDS SIALIC ACID, JUST THE 6159 04:54:19,320 --> 04:54:21,080 POINT IS LIKE WHERE. 6160 04:54:21,080 --> 04:54:23,680 IT'S POTENTIALLY ON THE VERY 6161 04:54:23,680 --> 04:54:25,480 DISORDERED FOLD AT THE TOP OF 6162 04:54:25,480 --> 04:54:27,600 THE VERY BEGINNING OF THE 6163 04:54:27,600 --> 04:54:31,360 N-TERMINUS BUT BECAUSE IT'S SO 6164 04:54:31,360 --> 04:54:33,280 DISORDERED, IT'S VERY DIFFICULT 6165 04:54:33,280 --> 04:54:35,280 TO DETERMINE HOW IT BINDS, WHERE 6166 04:54:35,280 --> 04:54:36,840 IT BINDS. 6167 04:54:36,840 --> 04:54:38,600 IT DOESN'T BIND VERY TIGHTLY 6168 04:54:38,600 --> 04:54:40,280 BECAUSE OTHERWISE WE WOULD HAVE 6169 04:54:40,280 --> 04:54:43,680 A STRUCTURE AT THIS POINT. 6170 04:54:43,680 --> 04:54:46,640 SO I THINK IT'S JUST LIKE WE 6171 04:54:46,640 --> 04:54:49,680 DON'T HAVE ANY -- WE WEREN'T 6172 04:54:49,680 --> 04:54:52,880 SUCCESSFUL AT FINDING A BINDING 6173 04:54:52,880 --> 04:54:54,680 SITE ON THE NTD, WE HAVEN'T 6174 04:54:54,680 --> 04:54:57,760 REALLY FOCUSED ON THAT, TO BE 6175 04:54:57,760 --> 04:54:58,800 HONEST. 6176 04:54:58,800 --> 04:55:02,280 BUT YEAH, OTHER PEOPLE DID AND 6177 04:55:02,280 --> 04:55:04,760 NOTHING PARTICULARLY CONVINCING 6178 04:55:04,760 --> 04:55:06,840 CAME OUT. 6179 04:55:06,840 --> 04:55:08,120 >> SORRY, I WANTED TO ADDRESS 6180 04:55:08,120 --> 04:55:10,080 BOTH -- THE OTHER PART OF THE 6181 04:55:10,080 --> 04:55:11,040 QUESTION, HOW MIGHT THAT BE 6182 04:55:11,040 --> 04:55:13,840 RELATED TO THE FACT THAT WE'RE 6183 04:55:13,840 --> 04:55:14,240 SEEING SHIFTS. 6184 04:55:14,240 --> 04:55:16,960 IT GOES BACK TO SOMETHING THAT 6185 04:55:16,960 --> 04:55:20,600 YOU SAID, MIKE. 6186 04:55:20,600 --> 04:55:21,840 WE DON'T KNOW HOW -- WHAT THE 6187 04:55:21,840 --> 04:55:25,480 RELATIONSHIP IS BETWEEN THE 6188 04:55:25,480 --> 04:55:26,160 CHANGING SIALYATION OF PROTEINS 6189 04:55:26,160 --> 04:55:29,120 AND WHAT WE'RE SEEING ON THE 6190 04:55:29,120 --> 04:55:29,320 LUNG. 6191 04:55:29,320 --> 04:55:31,720 BUT I WOULD SAY THAT I THINK 6192 04:55:31,720 --> 04:55:33,400 IT'S INTERESTING THAT 6193 04:55:33,400 --> 04:55:36,960 CORONAVIRUSES HAVE A TENDENCY TO 6194 04:55:36,960 --> 04:55:38,720 BIND SIALIC ACID IN PARTICULAR, 6195 04:55:38,720 --> 04:55:41,080 COMING UP AS CHANGING UPON 6196 04:55:41,080 --> 04:55:42,800 INFECTION BY CORONAVIRUSES. 6197 04:55:42,800 --> 04:55:43,400 BY SARS-COV-2. 6198 04:55:43,400 --> 04:55:45,600 AND SO I DON'T KNOW IF THERE'S A 6199 04:55:45,600 --> 04:55:47,800 RELATIONSHIP THERE BUT THERE IS 6200 04:55:47,800 --> 04:55:50,720 EVIDENCE THAT VIRUSES DO CHANGE 6201 04:55:50,720 --> 04:55:52,280 GLYCOSYLATION PATTERNS OF 6202 04:55:52,280 --> 04:55:54,040 INFECTION, AND ALSO CAN 6203 04:55:54,040 --> 04:55:55,560 STIMULATE RESPONSES THAT ARE 6204 04:55:55,560 --> 04:55:56,840 BENEFICIAL TO THEMSELVES. 6205 04:55:56,840 --> 04:55:59,120 I WOULDN'T BE SURPRISED IF 6206 04:55:59,120 --> 04:56:00,240 THERE'S SOME SORT OF CORRELATION 6207 04:56:00,240 --> 04:56:03,280 BETWEEN THE FACT THAT WE'RE 6208 04:56:03,280 --> 04:56:04,440 SEEING SIALIC ACID IN PARTICULAR 6209 04:56:04,440 --> 04:56:09,120 COME UP AND THE FACT THAT THESE 6210 04:56:09,120 --> 04:56:10,280 IN GENERAL ARE BINDERS. 6211 04:56:10,280 --> 04:56:12,160 IT COULD ALSO PARTLY BE BECAUSE 6212 04:56:12,160 --> 04:56:14,440 IT HAS A HUGE ROLE IN 6213 04:56:14,440 --> 04:56:15,200 SUPPRESSION OF IMMUNITY, AND 6214 04:56:15,200 --> 04:56:19,560 THAT COULD ALSO BE PART AS WELL. 6215 04:56:19,560 --> 04:56:22,840 >> OR THE VIRUSES ARE TAKING 6216 04:56:22,840 --> 04:56:25,840 ADVANTAGE OF THE SHIFT. 6217 04:56:25,840 --> 04:56:26,320 >> EXACTLY. 6218 04:56:26,320 --> 04:56:32,080 >> I WAS INTRIGUED BY THE NEW 6219 04:56:32,080 --> 04:56:33,560 JERSEY VARIANT, A LOT OF STRANGE 6220 04:56:33,560 --> 04:56:35,280 THINGS COME OUT OF NEW JERSEY, I 6221 04:56:35,280 --> 04:56:37,960 WENT TO HIGH SCHOOL IN NEW 6222 04:56:37,960 --> 04:56:38,280 JERSEY. 6223 04:56:38,280 --> 04:56:40,760 THAT'S OKAY. 6224 04:56:40,760 --> 04:56:44,280 BUT THE SHIFT FROM RECOGNIZING 6225 04:56:44,280 --> 04:56:46,760 ASYLATED MOTIFS SEEMS LIKE A BIG 6226 04:56:46,760 --> 04:56:49,120 SHIFT FROM CHARGE TO UNCHARGED. 6227 04:56:49,120 --> 04:56:50,920 ARE THERE EXAMPLES OF THAT 6228 04:56:50,920 --> 04:56:58,240 REALLY SIGNIFICANT SHIFT IN 6229 04:56:58,240 --> 04:56:58,840 RECOGNITION? 6230 04:56:58,840 --> 04:57:03,480 >> THIS IS VERY NOBLE FINDING, I 6231 04:57:03,480 --> 04:57:08,520 THINK THE STRUCTURE STUDIES 6232 04:57:08,520 --> 04:57:09,880 STILL ONGOING, I'M NOT QUITE 6233 04:57:09,880 --> 04:57:11,680 SURE IF I CAN DISCUSS TOO MUCH 6234 04:57:11,680 --> 04:57:17,800 DETAIL AT THE MOMENT BUT THIS IS 6235 04:57:17,800 --> 04:57:22,120 NOT KNOWN BEFORE FOR OTHER 6236 04:57:22,120 --> 04:57:24,720 POLEYOMA VIRUSES, FOR THE ONCE 6237 04:57:24,720 --> 04:57:25,040 WE ANALYZED. 6238 04:57:25,040 --> 04:57:29,240 THIS IS THE FIRST TIME. 6239 04:57:29,240 --> 04:57:32,280 SO WE'RE OBSERVING BY THIS GROUP 6240 04:57:32,280 --> 04:57:32,560 OF VIRUS. 6241 04:57:32,560 --> 04:57:33,960 >> FARMING ARRAY DATA IN THE 6242 04:57:33,960 --> 04:57:35,360 FUTURE IS GOING TO BE OUR WAY TO 6243 04:57:35,360 --> 04:57:35,720 UNDERSTAND THAT. 6244 04:57:35,720 --> 04:57:39,640 THAT'S WHERE WE'RE GOING TO SEE 6245 04:57:39,640 --> 04:57:41,640 IT FIRST. 6246 04:57:41,640 --> 04:57:43,800 THERE'S ONE OTHER SIALIC RELATED 6247 04:57:43,800 --> 04:57:46,240 QUESTION, THAT MIGHT BE A GOOD 6248 04:57:46,240 --> 04:57:46,440 ONE. 6249 04:57:46,440 --> 04:57:50,160 >> I BELIEVE THAT WAS TO ME. 6250 04:57:50,160 --> 04:57:51,880 SO, NANCY, IT'S AN EXCELLENT 6251 04:57:51,880 --> 04:57:53,800 QUESTION, NOBODY KNOWS. 6252 04:57:53,800 --> 04:57:55,160 >> REPEAT THE QUESTION. 6253 04:57:55,160 --> 04:57:56,960 >> THE QUESTION, IS THERE ANY 6254 04:57:56,960 --> 04:57:57,600 CORRELATION BETWEEN DISEASE 6255 04:57:57,600 --> 04:58:09,680 SEVER SEVERITY OF 6256 04:58:09,680 --> 04:58:10,280 NEUROAMINIDASE. 6257 04:58:10,280 --> 04:58:10,920 WE SEE NEURAMINIDASE EXPRESSION 6258 04:58:10,920 --> 04:58:12,720 IN THE SERA, WE DON'T KNOW. 6259 04:58:12,720 --> 04:58:14,320 HONESTLY AT THE MOMENT IT'S NOT 6260 04:58:14,320 --> 04:58:22,320 SOMETHING PEOPLE HAVE LOOKED 6261 04:58:22,320 --> 04:58:22,480 FOR. 6262 04:58:22,480 --> 04:58:22,800 >> GREAT. 6263 04:58:22,800 --> 04:58:24,760 WE'VE REACHED ALMOST 15 MINUTES 6264 04:58:24,760 --> 04:58:28,280 PAST OUR ORIGINAL STOP TIME SO 6265 04:58:28,280 --> 04:58:28,880 -- 6266 04:58:28,880 --> 04:58:30,440 >> A QUICK QUESTION. 6267 04:58:30,440 --> 04:58:36,680 THE SLIDE THAT YOU SHOWED, I WAS 6268 04:58:36,680 --> 04:58:39,160 TRYING TO UNDERSTAND, I HAVEN'T 6269 04:58:39,160 --> 04:58:42,280 READ THE PAPER, BUT IT LOOKS 6270 04:58:42,280 --> 04:58:46,680 LIKE YOU CAN USE ALPHA 4 DATA TO 6271 04:58:46,680 --> 04:58:49,560 PREDICT WHICH SITES ARE 6272 04:58:49,560 --> 04:58:50,840 GLYCOSYLATED BASED ON THE 6273 04:58:50,840 --> 04:58:52,800 FORMATION OF THE MODEL. 6274 04:58:52,800 --> 04:58:55,080 AND IF THAT IS TRUE, IS THAT 6275 04:58:55,080 --> 04:58:57,760 TRUE? THAT'S WHAT I'M TRYING TO 6276 04:58:57,760 --> 04:58:58,280 UNDERSTAND. 6277 04:58:58,280 --> 04:59:02,640 >> PREDICT IS A BIG WORD. 6278 04:59:02,640 --> 04:59:06,400 OUR ARGUMENT WAS SITE IS 6279 04:59:06,400 --> 04:59:08,680 ACTUALLY -- THE SITE'S 6280 04:59:08,680 --> 04:59:13,280 ARCHITECTURE IS PRESERVED, ALPHA 6281 04:59:13,280 --> 04:59:17,400 FOLD MODEL REPRODUCES 6282 04:59:17,400 --> 04:59:21,680 ARCHITECTURAL FEATURES SUCH AS 6283 04:59:21,680 --> 04:59:22,280 STACKING RESIDUES, HYDROPHOBIC 6284 04:59:22,280 --> 04:59:24,760 WITHOUT KNOWING A THING ABOUT 6285 04:59:24,760 --> 04:59:27,600 GLYCOSYLATION BECAUSE IT DOESN'T 6286 04:59:27,600 --> 04:59:29,880 DO MODIFICATION AS WELL AS 6287 04:59:29,880 --> 04:59:31,880 REPRODUCES VERY WELL CAVITIES 6288 04:59:31,880 --> 04:59:36,280 THAT SHOULD CONTAIN CO-FACTORS, 6289 04:59:36,280 --> 04:59:38,440 LIPIDS, THE EXAMPLE WE CHOSE 6290 04:59:38,440 --> 04:59:39,920 CONTAINS A MASSIVE LIPID IN THE 6291 04:59:39,920 --> 04:59:42,360 PDB BUT NOT THE ALPHA FOLD 6292 04:59:42,360 --> 04:59:45,760 MODEL, THE POCKET IS PERFECTLY 6293 04:59:45,760 --> 04:59:46,080 REPRODUCED. 6294 04:59:46,080 --> 04:59:48,120 IT LEARNED FEATURES THAT FROM 6295 04:59:48,120 --> 04:59:52,360 THE PDB BUT IT IS ENRICHED BY 6296 04:59:52,360 --> 04:59:54,600 LIKE THE BIOLOGY THAT GOES 6297 04:59:54,600 --> 04:59:56,320 AROUND THE STRUCTURE AND DOESN'T 6298 04:59:56,320 --> 04:59:58,040 KNOW THAT, IT LEARNS THINGS THAT 6299 04:59:58,040 --> 05:00:02,840 ARE DUE TO DIFFERENT REASONS BUT 6300 05:00:02,840 --> 05:00:05,520 TO DIFFERENT -- HASN'T REALLY 6301 05:00:05,520 --> 05:00:07,000 PROCESSED WHY. 6302 05:00:07,000 --> 05:00:08,040 THAT'S MACHINE LEARNING PROBLEM 6303 05:00:08,040 --> 05:00:12,680 IN A WAY, IN THE SENSE THAT IT 6304 05:00:12,680 --> 05:00:13,640 DERIVES INFORMATION WITHOUT 6305 05:00:13,640 --> 05:00:17,880 LET'S SAY NEEDING TO KNOW WHY 6306 05:00:17,880 --> 05:00:20,920 THAT INFORMATION. 6307 05:00:20,920 --> 05:00:23,120 THE POINT WAS ALPHA 4 MODELS ARE 6308 05:00:23,120 --> 05:00:26,040 USEFUL IF YOU WANT TO USE THEM 6309 05:00:26,040 --> 05:00:28,440 TO REBUILD COMPLETELY FULL MODEL 6310 05:00:28,440 --> 05:00:31,440 OF PROTEIN BECAUSE THEY DO 6311 05:00:31,440 --> 05:00:32,080 REPRODUCE THE STRUCTURAL 6312 05:00:32,080 --> 05:00:37,280 FEATURES OF STABLE GLYCOSYLATION 6313 05:00:37,280 --> 05:00:38,800 SITES IF THAT ANSWERS YOUR 6314 05:00:38,800 --> 05:00:39,080 QUESTION. 6315 05:00:39,080 --> 05:00:40,440 >> THAT DOES. 6316 05:00:40,440 --> 05:00:40,680 VERY GOOD. 6317 05:00:40,680 --> 05:00:42,800 THANK YOU. 6318 05:00:42,800 --> 05:00:44,120 >> THANK YOU. 6319 05:00:44,120 --> 05:00:52,360 A QUICK NOTE ABOUT WHAT MIKE WAS 6320 05:00:52,360 --> 05:00:52,960 SAYING, QUESTION, THIS FEATURE 6321 05:00:52,960 --> 05:00:58,320 OF IF I UNDERSTAND CORRECTLY OF 6322 05:00:58,320 --> 05:01:00,880 THE BINDING EPITOPES, IF YOU 6323 05:01:00,880 --> 05:01:03,240 THINK ABOUT THE LOSS OF 6324 05:01:03,240 --> 05:01:10,040 GLYCOSYLATION SITE ON RBD, AS 6325 05:01:10,040 --> 05:01:11,360 DISCUSSED EARLIER, COMPLEX 6326 05:01:11,360 --> 05:01:15,280 N-GLYCAN, THOSE ARMS CAN BE SIGH 6327 05:01:15,280 --> 05:01:18,680 AL LATED OR NOT, BOUND BY 6328 05:01:18,680 --> 05:01:21,520 INTERACTIONS, THE WHOLE ARM IS 6329 05:01:21,520 --> 05:01:23,280 TIGHTLY BOUND, IT DOESN'T HINGE 6330 05:01:23,280 --> 05:01:25,120 ON THE SIALIC ACID. 6331 05:01:25,120 --> 05:01:27,080 IT HINGES ON THE OLD SEQUENCE 6332 05:01:27,080 --> 05:01:28,560 THAT HOLDS THAT SIALIC ACID SO 6333 05:01:28,560 --> 05:01:38,480 THE FACT SIGH ALEX -- SIALIC 6334 05:01:38,480 --> 05:01:40,040 ACID IS THERE OR NOT, THE CLEFT 6335 05:01:40,040 --> 05:01:44,360 IS SO DEEP AND LINED WITH 6336 05:01:44,360 --> 05:01:46,680 HYDROPHOBIC RESIDUES THAT FORM 6337 05:01:46,680 --> 05:01:56,600 INTERACTION WITH GALACTOSE, 6338 05:01:56,600 --> 05:01:57,880 GLUCOSE, MONO SACCHARIDES ARE 6339 05:01:57,880 --> 05:01:58,080 BOUND. 6340 05:01:58,080 --> 05:02:09,200 IT CAN BE BOUND ANYWAY ANYWAY, 6341 05:02:09,200 --> 05:02:10,840 DUE TO EVOLUTION, LOSS OF 6342 05:02:10,840 --> 05:02:13,680 GLYCOSYLATION HAS GIVEN THIS 6343 05:02:13,680 --> 05:02:16,280 VIRUS THE ABILITY OF BINDENING, 6344 05:02:16,280 --> 05:02:17,880 VARIETY OF GLYCANS. 6345 05:02:17,880 --> 05:02:20,480 AS LONG AS THEY REPRODUCE BITS 6346 05:02:20,480 --> 05:02:37,240 OF THAT N-GLYCAN, THEY CAN BE 6347 05:02:37,240 --> 05:02:39,120 BOUND. 6348 05:02:39,120 --> 05:02:41,800 THAT'S NOT SUPER SURPRISING. 6349 05:02:41,800 --> 05:02:43,920 THAT'S PROBABLY MY READING INTO 6350 05:02:43,920 --> 05:02:44,800 IT. 6351 05:02:44,800 --> 05:02:50,160 ONE REASON WHY THIS VIRUS DOES 6352 05:02:50,160 --> 05:02:51,280 THIS FEATURE. 6353 05:02:51,280 --> 05:02:53,800 >> AN INFORMATIC QUESTION, 6354 05:02:53,800 --> 05:02:56,040 FRONTIER OF INFORMATICS, WE'RE 6355 05:02:56,040 --> 05:02:56,640 IGNORING THE FACT THAT 6356 05:02:56,640 --> 05:03:12,320 GLYCOPROTEIN IS A MIX OF THINGS. 6357 05:03:12,320 --> 05:03:16,160 ARE THERE TOOLS TO SKIM THROUGH 6358 05:03:16,160 --> 05:03:25,840 TO SEE IF SOME ARE BETTER, TO 6359 05:03:25,840 --> 05:04:06,840 SPIN THE WHEEL AND SEE THE 6360 05:04:06,840 --> 05:04:08,080 GLYCAN STRUCTURES? 6361 05:04:08,080 --> 05:04:12,240 >> HOW THE GLYCANS CAN CHANGE 6362 05:04:12,240 --> 05:04:18,800 THE STRUCTURE, THAT'S I THINK A 6363 05:04:18,800 --> 05:04:22,520 MATTER, VERY EXTENSIVE, A GREAT 6364 05:04:22,520 --> 05:04:25,680 QUESTION AND, YEAH, SO IF I CAN 6365 05:04:25,680 --> 05:04:30,240 ANTICIPATE WITH THAT TYPE OF 6366 05:04:30,240 --> 05:04:32,680 GLYCAN AT 370 MATTERS FOR THE 6367 05:04:32,680 --> 05:04:35,160 STRUCTURE OF THE RBD. 6368 05:04:35,160 --> 05:04:36,840 WHICH IS GREAT BECAUSE IT'S JUST 6369 05:04:36,840 --> 05:04:39,760 WHAT WE ALL EXPECT, THE GLYCAN 6370 05:04:39,760 --> 05:04:42,400 MODULATES THE STRUCTURE OF A 6371 05:04:42,400 --> 05:04:42,800 PROTEIN. 6372 05:04:42,800 --> 05:04:45,080 THAT WOULD BE LET'S SAY LIKE 6373 05:04:45,080 --> 05:04:48,440 REALLY GOOD NEWS TO TELL THE 6374 05:04:48,440 --> 05:04:50,800 PEOPLE THAT ONLY DO PROTEINS. 6375 05:04:50,800 --> 05:04:56,080 YOU NEED TO HAVE THEM TO KEEP 6376 05:04:56,080 --> 05:04:58,400 YOUR STRUCTURE PRESERVED. 6377 05:04:58,400 --> 05:05:01,760 THAT'S MY TWO CENTS. 6378 05:05:01,760 --> 05:05:02,080 >> THANKS. 6379 05:05:02,080 --> 05:05:06,560 DO YOU WANT TO CLOSE US UP? 6380 05:05:06,560 --> 05:05:07,520 >> YEAH, WELL, IT WAS REALLY 6381 05:05:07,520 --> 05:05:07,880 GREAT. 6382 05:05:07,880 --> 05:05:11,360 THANK YOU TO ALL THE SPEAKERS. 6383 05:05:11,360 --> 05:05:12,720 IT WAS ENLIGHTENING. 6384 05:05:12,720 --> 05:05:14,480 AND I THINK WE PROBABLY HAVE 6385 05:05:14,480 --> 05:05:16,480 MORE QUESTIONS THAN WHEN WE 6386 05:05:16,480 --> 05:05:18,320 STARTED, WHICH IS GREAT BECAUSE 6387 05:05:18,320 --> 05:05:20,440 ALL THIS DATA IS REALLY GIVING 6388 05:05:20,440 --> 05:05:23,160 US MORE TO DRIVE ON. 6389 05:05:23,160 --> 05:05:26,800 SO WITH THAT I WANT TO THANK THE 6390 05:05:26,800 --> 05:05:29,280 ORGANIZERS FOR INVOLVING ME WITH 6391 05:05:29,280 --> 05:05:31,880 ALL THESE GREAT SPEAKERS, RAJA 6392 05:05:31,880 --> 05:05:34,640 AND MIKE, YOU PUT TOGETHER A 6393 05:05:34,640 --> 05:05:37,480 GREAT DAY HERE. 6394 05:05:37,480 --> 05:05:40,040 WITH THAT, TRYING TO HOLD BACK 6395 05:05:40,040 --> 05:05:43,680 MY OWN QUESTIONS, THANK YOU, 6396 05:05:43,680 --> 05:05:43,960 EVERYONE. 6397 05:05:43,960 --> 05:05:45,880 WE'LL SEE SOME OF YOU TOMORROW 6398 05:05:45,880 --> 05:05:51,080 FOR THE NEXT DAY SESSION. 6399 05:05:51,080 --> 00:00:00,000 >> THANKS, EVERYBODY.