1 00:00:10,192 --> 00:00:20,636 HE RECEIVED THE ARTHUR S. 2 00:00:11,425 --> 00:00:12,360 FLEMMING AWARD FOR OUTSTANDING 3 00:00:12,360 --> 00:00:13,894 GOVERNMENT SERVICE AND IN 1987 4 00:00:13,894 --> 00:00:15,963 THE YEAR OF HIS UNTIMELY DEATH 5 00:00:15,963 --> 00:00:18,366 AT AGE 43 HE WAS ELECTED TO THE 6 00:00:18,366 --> 00:00:28,809 NATIONAL AKD--SALLY ME OF 7 00:00:29,277 --> 00:00:29,777 SCIENCES. 8 00:00:29,777 --> 00:00:32,380 YOU CAN IT TELL I'M A MAC 9 00:00:32,380 --> 00:00:32,613 PERSON. 10 00:00:32,613 --> 00:00:35,016 AND THIS IS A PHOTO OF GEORGE 11 00:00:35,016 --> 00:00:39,420 KHOURY ON YOUR LEFT WITH A VERY 12 00:00:39,420 --> 00:00:41,022 YOUNG PETER HOWLY AND MALCOM 13 00:00:41,022 --> 00:00:43,557 MARTIN WHO WAS MY OWN Ph.D. 14 00:00:43,557 --> 00:00:45,626 MENTOR -- POST DOCTORAL MENTOR 15 00:00:45,626 --> 00:00:50,031 AND IS HERE IN THE AUDIENCE. 16 00:00:50,031 --> 00:00:52,667 SO DURING HIS SHORT CAREER 17 00:00:52,667 --> 00:00:55,536 GEORGE PUBLISHED OVER 140 PAPERS 18 00:00:55,536 --> 00:00:57,972 DECIPHERING MECHANISMS OF 19 00:00:57,972 --> 00:00:59,940 EUKARYOTIC TRANSCRIPTION. 20 00:00:59,940 --> 00:01:01,942 MANY OF THESE USE VIRUSES AS 21 00:01:01,942 --> 00:01:05,913 MODEL SYSTEMS AND WE HAVE A MAC 22 00:01:05,913 --> 00:01:07,715 TO PC GASHLEING THERE. 23 00:01:07,715 --> 00:01:10,851 GEORGE HAD VERY DISTINGUISHED 24 00:01:10,851 --> 00:01:12,987 TRAINEES AND COLLABORATORS 25 00:01:12,987 --> 00:01:14,121 LISTED HERE. 26 00:01:14,121 --> 00:01:16,624 AND SIMILARLY THE GEORGE KHOURY 27 00:01:16,624 --> 00:01:17,458 MEMORIAL LECTURES HAVE BEEN 28 00:01:17,458 --> 00:01:19,293 GIVEN BY A VERY DISTINGUISHED 29 00:01:19,293 --> 00:01:24,932 GROUP OF SCIENTISTS MOST 30 00:01:24,932 --> 00:01:26,934 RECENTLY JULIE 5ER, SUSAN WEISS, 31 00:01:26,934 --> 00:01:30,037 AND THIS BRINGS US TO TODAY'S 32 00:01:30,037 --> 00:01:32,340 SPEAKER, FOR ILEANA CRISTEA, SHE 33 00:01:32,340 --> 00:01:33,874 DID HER HONOR GRADUATE AND 34 00:01:33,874 --> 00:01:34,709 Ph.D. WORK AT UNIVERSITY OF 35 00:01:34,709 --> 00:01:37,511 MAN THE CHESTER IN THE UK -- 36 00:01:37,511 --> 00:01:39,680 MANCHESTER IN THE UK, IN 37 00:01:39,680 --> 00:01:40,748 PROTEOMICS AND TOXICOLOGY, DID A 38 00:01:40,748 --> 00:01:42,116 POST DOC AT ROCKEFELLER 39 00:01:42,116 --> 00:01:45,920 UNIVERSITY BEFORE BEING 40 00:01:45,920 --> 00:01:47,621 RECRUITED TO PRINCETON 41 00:01:47,621 --> 00:01:51,992 UNIVERSITY WHERE SHE ROSE REALLY 42 00:01:51,992 --> 00:01:53,160 REMARKABLY QUICKLY THROUGH THE 43 00:01:53,160 --> 00:01:56,630 RANKS TO BECOME FULL PROFESSOR 44 00:01:56,630 --> 00:01:57,732 IN 2016. 45 00:01:57,732 --> 00:01:59,633 ILEANA HAS RECEIVED NUMEROUS 46 00:01:59,633 --> 00:02:02,103 AWARDS, TOO MANY TO LIST MERE 47 00:02:02,103 --> 00:02:05,039 BUT THESE INCLUDE AN AVANT GUARD 48 00:02:05,039 --> 00:02:06,707 PILOT PROJECT OR NEAR AWARD, 49 00:02:06,707 --> 00:02:09,110 DISCOVERY AWARD IN PROTEOMIC 50 00:02:09,110 --> 00:02:11,612 SCIENCES, DIRECTOR OF THE 51 00:02:11,612 --> 00:02:14,382 GRADUATE STUDIES AT PRINCETON, 52 00:02:14,382 --> 00:02:15,649 GRADUATE AWARD AT PRINCETON AND 53 00:02:15,649 --> 00:02:19,920 AS OF LAST YEAR, MOLECULAR 54 00:02:19,920 --> 00:02:21,088 CELLULAR PROTEOMICS. 55 00:02:21,088 --> 00:02:22,022 ILEANA MADE REALLY MAJOR 56 00:02:22,022 --> 00:02:24,325 CONTRIBUTIONS TO SEVERAL AREAS 57 00:02:24,325 --> 00:02:26,827 OF RESEARCH INCLUDING DEVELOPING 58 00:02:26,827 --> 00:02:31,832 PROTEOMIC METHODS FOR DISTURBING 59 00:02:31,832 --> 00:02:33,000 VIRUS INTERACTIONS, NUCLEAR 60 00:02:33,000 --> 00:02:36,370 SENSING OF VIRAL DNA, 61 00:02:36,370 --> 00:02:37,071 EVOLUTIONARY CONSERVED ANTIVIRAL 62 00:02:37,071 --> 00:02:39,673 FACTORS AND REGULATION OF 63 00:02:39,673 --> 00:02:40,241 PROTEIN ACETYLATION. 64 00:02:40,241 --> 00:02:42,042 SO I WILL LIKE TO WELCOME ILEANA 65 00:02:42,042 --> 00:02:44,779 TO THE PODIUM FOR HER LECTURE, 66 00:02:44,779 --> 00:02:46,180 THE INTERFACE BETWEEN METABOLISM 67 00:02:46,180 --> 00:02:52,019 AND IMMUNITY WITHIN A VIRUS 68 00:02:52,019 --> 00:02:52,653 MICROENVIRONMENT, WELCOME. 69 00:02:52,653 --> 00:02:52,953 [ APPLAUSE ] 70 00:02:52,953 --> 00:02:55,189 >> THANK YOU SO MUCH FOR THAT 71 00:02:55,189 --> 00:02:56,891 VERY KIND INTRODUCTION, IT IS 72 00:02:56,891 --> 00:02:58,159 JUST SUCH A GREAT HONOR BEING 73 00:02:58,159 --> 00:02:59,460 HERE AND SEEING OLD FRIENDS AND 74 00:02:59,460 --> 00:03:02,863 NEW FRIENDS AND JUST REALLY, I 75 00:03:02,863 --> 00:03:04,565 CANNOT TELL YOU HOW HONORED I AM 76 00:03:04,565 --> 00:03:08,402 TO BE INVITED TO GIVE DR. GEORGE 77 00:03:08,402 --> 00:03:14,842 KHOURY MEMORY MEMORIAL LECTUREI 78 00:03:14,842 --> 00:03:16,944 WANT TO SAY A FEW WORDS ABOUT 79 00:03:16,944 --> 00:03:17,478 THIS. 80 00:03:17,478 --> 00:03:18,412 I THINK ERIC ALREADY TOUCH 81 00:03:18,412 --> 00:03:20,147 OFFICE OF DIVERSITY THIS IN 82 00:03:20,147 --> 00:03:22,316 TERMS OF FUNDAMENT AMILLIO 83 00:03:22,316 --> 00:03:22,883 SCIENTIFIC DISCOVERIES THAT 84 00:03:22,883 --> 00:03:25,619 GEORGE CONTRIBUTED TO THE FIELD 85 00:03:25,619 --> 00:03:26,954 OF MOLECULAR BIOLOGY, HIS WORK 86 00:03:26,954 --> 00:03:29,790 ON ENHANCERS AND ALSO ON 87 00:03:29,790 --> 00:03:30,491 UNDERSTANDING TRANSCRIPTIONAL 88 00:03:30,491 --> 00:03:32,092 CONTROL OF GENE EXPRESSION HAS 89 00:03:32,092 --> 00:03:32,927 BEEN EXTRAORDINARY BUT I WANT TO 90 00:03:32,927 --> 00:03:35,830 SAY ALSO FROM THE PERSPECTIVE OF 91 00:03:35,830 --> 00:03:37,198 PRINCETON, ERIC TOLD YOU THAT 92 00:03:37,198 --> 00:03:39,400 GEORGE ACTUALLY HAD HIS 93 00:03:39,400 --> 00:03:40,201 UNDERGRADUATE DEGREE AT 94 00:03:40,201 --> 00:03:42,169 PRINCETON AND I JUST WANT TO SAY 95 00:03:42,169 --> 00:03:44,438 THAT HE BECAME SUCH A STRONG 96 00:03:44,438 --> 00:03:45,906 SUPPORTER OF PRINCETON 97 00:03:45,906 --> 00:03:47,975 UNIVERSITY AND SO, COMMITTED TO 98 00:03:47,975 --> 00:03:49,944 RECOGNIZING PEOPLE WHO HAVE 99 00:03:49,944 --> 00:03:51,512 CONTRIBUTED TO TRAINING HIM AND 100 00:03:51,512 --> 00:03:55,816 HE HAS BEEN IN CONSTANT KIND OF 101 00:03:55,816 --> 00:03:57,651 TOUCH WITH PRINCETON UNIVERSITY 102 00:03:57,651 --> 00:03:59,253 BECOMING AN ADVISOR TO THE 103 00:03:59,253 --> 00:04:00,654 PRINCETON UNIVERSITY PRESIDENT 104 00:04:00,654 --> 00:04:02,590 AND REALLY HELPING TREMENDOUSLY 105 00:04:02,590 --> 00:04:04,558 TO CREATE THE DEPARTMENT OF 106 00:04:04,558 --> 00:04:06,727 MOLECULAR BIOLOGY AND TO RECRUIT 107 00:04:06,727 --> 00:04:09,296 A NUMBER OF FACULTY AS KIND OF 108 00:04:09,296 --> 00:04:11,065 THE INAUGURAL FACULTY TO START 109 00:04:11,065 --> 00:04:16,604 THIS NEW DEPARTMENT OF MOLECULAR 110 00:04:16,604 --> 00:04:18,939 BIOLOGY FOR PRINCETON AMONGT 111 00:04:18,939 --> 00:04:24,912 THESE ARE DR. LAVINE AND TOM 112 00:04:24,912 --> 00:04:26,113 SHANK, A WONDERFUL VIROLOGIST, 113 00:04:26,113 --> 00:04:29,316 WHO I GOT TO COLLABORATE WITH AT 114 00:04:29,316 --> 00:04:31,085 THE UNIVERSITY WHEN I WAS A POST 115 00:04:31,085 --> 00:04:33,153 DOC AND HE ENCOURAGED ME TO 116 00:04:33,153 --> 00:04:34,822 APPLY AT PRINCETON TO APPLY FOR 117 00:04:34,822 --> 00:04:35,990 A FACULTY POSITION AND I WANT TO 118 00:04:35,990 --> 00:04:37,925 SAY GEORGE HAS IMPACTED MY 119 00:04:37,925 --> 00:04:39,994 CAREER IN ANOTHER WAY EVEN 120 00:04:39,994 --> 00:04:44,932 EARLIER, IN THE 1970S, WHEN HERE 121 00:04:44,932 --> 00:04:48,002 AT THE NIH HE IRPT ACTED WITH 122 00:04:48,002 --> 00:04:53,140 DR. LYNN QUIOF THE AND AT THE 123 00:04:53,140 --> 00:04:55,109 TIME, LYNN WAS CLOSE TO HIS 124 00:04:55,109 --> 00:04:56,977 LABORATORY AND LYNN CREDITS 125 00:04:56,977 --> 00:04:58,913 GEORGE FOR ENCOURAGING HIM AND 126 00:04:58,913 --> 00:05:02,750 SUGGESTING THAT ME MAYBE SHOULD 127 00:05:02,750 --> 00:05:04,552 CHANGE -- USE HIS SKILLS TO 128 00:05:04,552 --> 00:05:06,654 CHANGE SOME OF HIS SCIENTIFIC 129 00:05:06,654 --> 00:05:10,057 FOCUS FROM A COURAGEOUS WAY FROM 130 00:05:10,057 --> 00:05:13,360 BACTERIAL PHAGES AND LUNG PHAGES 131 00:05:13,360 --> 00:05:15,763 TO EUKARYOTIC VIRUSES AND LYNN 132 00:05:15,763 --> 00:05:16,997 LATER ON JOINED PRINCETON 133 00:05:16,997 --> 00:05:18,666 BECOMING THE CHAIR OF THE 134 00:05:18,666 --> 00:05:19,934 DEPARTMENT OF MOLECULAR BIOLOGY 135 00:05:19,934 --> 00:05:21,602 AND BEING THE 1 WHO ENDED UP 136 00:05:21,602 --> 00:05:24,471 RECRUITING ME AND HIRING ME AT 137 00:05:24,471 --> 00:05:24,772 PRINCETON. 138 00:05:24,772 --> 00:05:27,241 SO I MAY NOT BE HERE SPEAKING TO 139 00:05:27,241 --> 00:05:28,709 YOU WITHOUT GEORGE'S 140 00:05:28,709 --> 00:05:29,510 CONTRIBUTION TO MOLEC BAR 141 00:05:29,510 --> 00:05:33,380 BIOLOGY AND TO SPRINS TON. -- 142 00:05:33,380 --> 00:05:33,647 PRINCETON. 143 00:05:33,647 --> 00:05:35,616 SO THANK YOU SO MUCH FOR HAVING 144 00:05:35,616 --> 00:05:35,950 ME HERE. 145 00:05:35,950 --> 00:05:37,318 A LITTLE BIT ABOUT MY TALK TODAY 146 00:05:37,318 --> 00:05:38,185 AS YOU HEARD ISSUES I WOULD LO 147 00:05:38,185 --> 00:05:41,021 OF TO TELL YOU ABOUT HOW SOME 148 00:05:41,021 --> 00:05:42,923 RESEARCH DIRECTIONS IN MY LAB 149 00:05:42,923 --> 00:05:48,762 HAVE EVOLVED TO LOOK INTO THIS 150 00:05:48,762 --> 00:05:50,364 INTERFACE BETWEEN METABOLISM AND 151 00:05:50,364 --> 00:05:52,232 IMPACT ON IMMUNE SIGNALING IN 152 00:05:52,232 --> 00:05:54,201 THIS CONTEXT OF VIRUS 153 00:05:54,201 --> 00:05:55,469 MICROENVIRONMENT AND FIRST I 154 00:05:55,469 --> 00:05:58,872 WILL SAY WHAT MY DISCLOSURES 155 00:05:58,872 --> 00:05:59,406 ARE. 156 00:05:59,406 --> 00:06:02,443 I'M A CONFOUNDER AND MEMBER OF 157 00:06:02,443 --> 00:06:05,145 THIS SCIENTIFIC ADVISORY BOARD 158 00:06:05,145 --> 00:06:11,552 FOR ADVERSE BIOTHAT FOCUSES ON 159 00:06:11,552 --> 00:06:14,421 ANTIVIRAL TREATMENT, TARGETING 160 00:06:14,421 --> 00:06:15,756 CITUANS, AND ALSO DEVICES THAT 161 00:06:15,756 --> 00:06:18,125 ARE FOCUSING ON METHODS FOR 162 00:06:18,125 --> 00:06:20,194 SEPARATING PROTEINS AND OF 163 00:06:20,194 --> 00:06:21,929 COURSE ANALYSIS WITH MASS 164 00:06:21,929 --> 00:06:23,197 SPECTROMETRY, BUT WHEY WILL TELL 165 00:06:23,197 --> 00:06:24,832 YOU IS NOT CONNECTED IN ANY 166 00:06:24,832 --> 00:06:27,134 SHAPE OR FORM WITH THESE 2 167 00:06:27,134 --> 00:06:32,539 POSITIONS THAT I HAVE HELD OR 168 00:06:32,539 --> 00:06:32,873 HOLD. 169 00:06:32,873 --> 00:06:34,441 OKAY, SO, THE STORY THAT I WANT 170 00:06:34,441 --> 00:06:36,210 TO TELL YOU AGAIN AND TO PUT IT 171 00:06:36,210 --> 00:06:39,446 IN CONTEXT STARTED FROM OUR 172 00:06:39,446 --> 00:06:40,247 INTEREST IN UNDERSTANDING 173 00:06:40,247 --> 00:06:43,217 DIFFERENT TYPES OF CELLULAR 174 00:06:43,217 --> 00:06:46,654 COMMUNICATION DURING VIRAL 175 00:06:46,654 --> 00:06:47,721 INFECTION AND OF COURSE THERE 176 00:06:47,721 --> 00:06:50,457 ARE MANY DIFFERENT TYPES OF 177 00:06:50,457 --> 00:06:51,091 COMMUNICATION DURING INFECTION 178 00:06:51,091 --> 00:06:53,427 IN A HOST CELL. 179 00:06:53,427 --> 00:06:56,530 SO AT AN INTRACELLULAR LEVEL, WE 180 00:06:56,530 --> 00:06:58,032 KNOW AN INFECTION TRIGGERS 181 00:06:58,032 --> 00:07:00,100 CHANGES IN THE SE, CHANGES NOT 182 00:07:00,100 --> 00:07:03,971 ONLY THE COMPOSITION OF A CELL 183 00:07:03,971 --> 00:07:06,040 BUT THE ORGANELLE OF THE CELL, 184 00:07:06,040 --> 00:07:07,107 AND THEY MAY LOOK DIFFERENTLY. 185 00:07:07,107 --> 00:07:08,442 AND I WANT TO SPEND THE FIRST 186 00:07:08,442 --> 00:07:10,744 PART OF MY TALK LOOKING AT HOW 187 00:07:10,744 --> 00:07:12,179 WE LOOKED AT INTRACELLULAR 188 00:07:12,179 --> 00:07:13,914 COMMUNICATION THAT IS 189 00:07:13,914 --> 00:07:15,149 FACILITATED BY ORGANIZATION 190 00:07:15,149 --> 00:07:18,519 CHANGES, AND BY CHANGES IN 191 00:07:18,519 --> 00:07:19,353 ORGANELLE-ORGANELLE CONTACTS AND 192 00:07:19,353 --> 00:07:20,254 WHAT THIS MEANS. 193 00:07:20,254 --> 00:07:22,790 AND THEN, I WILL TRANSITION TO 194 00:07:22,790 --> 00:07:24,124 CONSIDERING THIS INFECTED CELL 195 00:07:24,124 --> 00:07:25,926 AS PART OF ITS ENVIRONMENT, AS 196 00:07:25,926 --> 00:07:27,995 PART OF ITS SYSTEM AND LOOKING 197 00:07:27,995 --> 00:07:29,997 AT HOW THIS INFECTED CELL CORN 198 00:07:29,997 --> 00:07:32,466 VEYS THIS INFORMATION AND HOW IT 199 00:07:32,466 --> 00:07:33,634 AFFECTS ITS ENVIRONMENT, THE 200 00:07:33,634 --> 00:07:36,737 CELLS THAT ARE IN THE IMMEDIATE 201 00:07:36,737 --> 00:07:37,905 PROXIMITY OR THOSE THAT ARE 202 00:07:37,905 --> 00:07:39,039 FURTHER AWAY AND NOW WE HAVE 203 00:07:39,039 --> 00:07:42,543 TRIED TO KIND OF CHARACTERIZE 204 00:07:42,543 --> 00:07:44,044 THIS, STILL NOT SUFFICIENTLY 205 00:07:44,044 --> 00:07:45,646 WELL CHARTED ENVIRONMENT OF THE 206 00:07:45,646 --> 00:07:46,680 VIRUS MICROENVIRONMENT. 207 00:07:46,680 --> 00:07:50,384 AND I WILL TRY AS I LOOK AT THIS 208 00:07:50,384 --> 00:07:51,018 INTRACELLULAR AND INTRACELLULAR 209 00:07:51,018 --> 00:07:52,953 STORIES THAT I WILL TELL YOU 210 00:07:52,953 --> 00:07:54,388 ABOUT, WHAT THE RELEVANCE IS IN 211 00:07:54,388 --> 00:07:55,889 TERMS OF INFECTION AND CO 212 00:07:55,889 --> 00:07:57,357 INFECTIONS AND DISEASE AND 213 00:07:57,357 --> 00:07:58,525 INFECTION IN THESE PATHOLOGIES, 214 00:07:58,525 --> 00:08:02,162 SO TO START THE INTRACELLULAR 215 00:08:02,162 --> 00:08:06,400 LEVEL, AS I TOLD YOU VIRUSES -- 216 00:08:06,400 --> 00:08:08,135 INFECTIONS WITH VIRUSES INDUCE 217 00:08:08,135 --> 00:08:09,169 SUCH PROFOUND CHANGES IN 218 00:08:09,169 --> 00:08:12,005 ORGANIZATION OF THE CELL AND 219 00:08:12,005 --> 00:08:13,373 STILL UNDEREXPLORED AREA OF 220 00:08:13,373 --> 00:08:16,877 VIROLOGY IS THAT ORGAN 221 00:08:16,877 --> 00:08:18,445 REMODELING AND THAT IS SO 222 00:08:18,445 --> 00:08:20,147 FUNDAMENTAL TO I HAVE USS YOU 223 00:08:20,147 --> 00:08:23,050 CAN THINK OF, THAT VIRUSES NEED 224 00:08:23,050 --> 00:08:25,152 TO LET ME SEE IF THIS WORKS. 225 00:08:25,152 --> 00:08:27,821 OH, I'M TRYING TO -- OKAY, I'M 226 00:08:27,821 --> 00:08:30,891 LOOKING, IF I HAVE A POINTER, 227 00:08:30,891 --> 00:08:32,593 MAYBE I WILL JUST USE THIS. 228 00:08:32,593 --> 00:08:36,797 CAN YOU SEE MY POINTER? 229 00:08:36,797 --> 00:08:37,464 NO. 230 00:08:37,464 --> 00:08:37,798 OKAY. 231 00:08:37,798 --> 00:08:39,099 IESM GETTING VERY QUICK 232 00:08:39,099 --> 00:08:42,302 TECHNICAL SUPPORT, I SEE. 233 00:08:42,302 --> 00:08:43,137 NO, DOESN'T WORK. 234 00:08:43,137 --> 00:08:44,004 IT'S ALL RIGHT. 235 00:08:44,004 --> 00:08:47,474 I SEE A POINTER ON YOUR 236 00:08:47,474 --> 00:08:48,475 PRESENTATION, THAT APPEARS, SO 237 00:08:48,475 --> 00:08:50,277 SOMEBODY WAS TRYING TO HELP YOU 238 00:08:50,277 --> 00:08:54,648 TO POINT. 239 00:08:54,648 --> 00:08:57,284 OKAY, SO, VIRUSES INDUCE THIS 240 00:08:57,284 --> 00:09:00,788 NUMEROUS CHANGES IN ORGANELLE 241 00:09:00,788 --> 00:09:02,489 SHAPE AND COMPOSITION AND THAT 242 00:09:02,489 --> 00:09:05,859 CAN BE PUT UNDER THE UMBRELLA OF 243 00:09:05,859 --> 00:09:06,660 ORGANELLE REMODELING AND SHE'S 244 00:09:06,660 --> 00:09:08,095 ARE SO IMPORTANT FOR ENTRY OF A 245 00:09:08,095 --> 00:09:09,730 VIRUS INTO HOST CELLS FOR THE 246 00:09:09,730 --> 00:09:11,031 REPLICATION OF THAT VIRUS, 247 00:09:11,031 --> 00:09:13,367 EITHER IF IT'S NUCLEAR OR 248 00:09:13,367 --> 00:09:15,402 CYTOPLASMIC FOR THE ASSEMBLY OF 249 00:09:15,402 --> 00:09:16,436 NEW INFECTIOUS VIRAL PARTICLES 250 00:09:16,436 --> 00:09:19,306 OR FOR THE EGRESS, AND I'M 251 00:09:19,306 --> 00:09:23,310 SHOWING THIS HERE FOR BETTER 252 00:09:23,310 --> 00:09:25,279 HERPES VIRUS, IS REALLY AN 253 00:09:25,279 --> 00:09:26,313 IMPORTANT VIRUS, WIDELY SPREAD 254 00:09:26,313 --> 00:09:28,382 AND CONNECTED TO LOTS OF 255 00:09:28,382 --> 00:09:29,550 DIFFERENT CHRONIC DISEASE, 256 00:09:29,550 --> 00:09:30,484 INCLUDING CARDIAC DISEASE BUT 257 00:09:30,484 --> 00:09:34,254 ALSO THE LEADING CAUSE OF VIRUS 258 00:09:34,254 --> 00:09:35,289 INNED BIRTH DEFECTS BUT WE CAN 259 00:09:35,289 --> 00:09:36,857 LOOK AT MANY OTHER VIRUSES AND 260 00:09:36,857 --> 00:09:38,892 WE WILL FIND SIMILARLY, 261 00:09:38,892 --> 00:09:41,328 DIFFERENT RANGE OF ORGANELLE 262 00:09:41,328 --> 00:09:43,197 REMODELING EVENTS, SO FOR 263 00:09:43,197 --> 00:09:46,433 EXAMPLE, ATMV, THAT I TOLD YOU 264 00:09:46,433 --> 00:09:48,702 EARLIER, INDUCES THIS CHANGES IN 265 00:09:48,702 --> 00:09:50,437 NUCLEAR PERIPHERY AND THE 266 00:09:50,437 --> 00:09:53,173 ASSEMBLY COMPLEX YOU SEE ON THE 267 00:09:53,173 --> 00:09:54,474 RIGHT HAND SIDE, HSV1 ALSO 268 00:09:54,474 --> 00:09:55,876 TARGETS THE NUCLEOTIDES CLER 269 00:09:55,876 --> 00:09:59,646 PERIPHERY, IT ALSO FRAGMENTS 270 00:09:59,646 --> 00:10:01,582 MITOCHONDRIA, INFLUENZA A ALSO 271 00:10:01,582 --> 00:10:03,016 REMODELS MITOCHONDRIA. 272 00:10:03,016 --> 00:10:07,054 CORONA VIRUSES ARE INDUCING THIS 273 00:10:07,054 --> 00:10:08,355 DOUBLE MEMBRANE VESICLES FORMED 274 00:10:08,355 --> 00:10:11,458 OF ER, THAT ARE REALLY IMPORTANT 275 00:10:11,458 --> 00:10:13,060 FOR THE REPLICATION OF THIS 276 00:10:13,060 --> 00:10:16,296 VIRUS, SO ALL THESE CHANGES IN 277 00:10:16,296 --> 00:10:18,131 THE SHAPE AND THE MORPHOLOGY OF 278 00:10:18,131 --> 00:10:20,500 ORGANELLES THAT ARE CAREERICALLY 279 00:10:20,500 --> 00:10:21,902 CONTROLLING AND REGULATING THE 280 00:10:21,902 --> 00:10:23,070 ORGANELLE FUNCTION THAT HAPPENED 281 00:10:23,070 --> 00:10:24,171 DURING INFECTION THAT ARE NEEDED 282 00:10:24,171 --> 00:10:27,774 FOR INFECTION TO PROGRESS. 283 00:10:27,774 --> 00:10:30,310 THIS IS AS I SAID STILL AN 284 00:10:30,310 --> 00:10:31,378 UNDEREXPLORED AREA OF VIROLOGY, 285 00:10:31,378 --> 00:10:34,081 SO FOR MANY OF THESE EVENTS WE 286 00:10:34,081 --> 00:10:35,382 DO NOT UNDERSTAND EXACTLY WHAT 287 00:10:35,382 --> 00:10:36,884 THE FUNCTIONS ARE, OR IF THEY'RE 288 00:10:36,884 --> 00:10:39,453 CONNECT INDEED ANY WAY TO SOME 289 00:10:39,453 --> 00:10:43,056 OF THE LINK, INFECTION INDUCED 290 00:10:43,056 --> 00:10:45,025 PATHOLOGYINGS, ALSO, HOW IT IS 291 00:10:45,025 --> 00:10:45,325 COORDINATED. 292 00:10:45,325 --> 00:10:46,660 OF COURSE IF A SHAPE IS 293 00:10:46,660 --> 00:10:48,428 DIFFERENT, IT WILL AFFECT 294 00:10:48,428 --> 00:10:49,029 IMMEDIATELY ITS ENVIRONMENT, 295 00:10:49,029 --> 00:10:51,331 LIKE IF I SPREAD MY ARMS OR IF 296 00:10:51,331 --> 00:10:52,933 I'M ALTOGETHER, I WILL IMPACT 297 00:10:52,933 --> 00:10:54,968 DIFFERENTLY AND MAKE DIFFERENT 298 00:10:54,968 --> 00:10:55,602 CONNECTIONS WITH MY IMMEDIATE 299 00:10:55,602 --> 00:10:56,370 ENVIRONMENT IN THE CELL. 300 00:10:56,370 --> 00:10:57,938 AT THE SAME TIME HOW ARE THEY 301 00:10:57,938 --> 00:11:01,975 COORDINATED IN SPACE AND TIME. 302 00:11:01,975 --> 00:11:03,277 OR FUNCTIONALLY COORDINATED, SO 303 00:11:03,277 --> 00:11:04,544 WE HAVE INVESTIGATED THIS FOR A 304 00:11:04,544 --> 00:11:09,683 NUMBER OF YEARS IN MY LAB AND I 305 00:11:09,683 --> 00:11:11,952 WANT TO GIVE 1 EXAMPLE FROM SOME 306 00:11:11,952 --> 00:11:13,353 STUDIES THAT WE HAVE DONE SOME 307 00:11:13,353 --> 00:11:14,521 YEARS AGO THAT REALLY HAVE 308 00:11:14,521 --> 00:11:15,956 STARTED TO PUSH US MORE AND MORE 309 00:11:15,956 --> 00:11:18,358 TOWARDS THIS IDEA OF 310 00:11:18,358 --> 00:11:19,760 COORDINATION. 311 00:11:19,760 --> 00:11:20,661 THAT THIS ORGANELLE REMODELING 312 00:11:20,661 --> 00:11:21,528 EVENTS ARE ACTUALLY LINKED TO 313 00:11:21,528 --> 00:11:23,030 EACH OTHER AND THEY ARE 314 00:11:23,030 --> 00:11:24,965 AFFECTING EACH OTHER AND THIS 315 00:11:24,965 --> 00:11:27,801 WAS FROM WORK WE HAVE DONE ON 316 00:11:27,801 --> 00:11:30,037 PEROX DOME WHERE WE WERE 317 00:11:30,037 --> 00:11:32,639 STUDYING THE MEG LA LO VIRUS AND 318 00:11:32,639 --> 00:11:37,010 HSV1, AND WE TART TO SEPARATE 319 00:11:37,010 --> 00:11:38,145 ORGANELLES BY COMPOSITION AND 320 00:11:38,145 --> 00:11:39,446 FIND OUT HOW THEY CHANGE AND 321 00:11:39,446 --> 00:11:41,782 THEN WE COMBINE THIS WITH 322 00:11:41,782 --> 00:11:42,783 STRUCTURAL MICROSCOPY STUDIES 323 00:11:42,783 --> 00:11:44,351 AND ALSO WITH EMILY EDUCATIONAL 324 00:11:44,351 --> 00:11:46,086 ORDER OF MICRONSIC STUDIES AND 325 00:11:46,086 --> 00:11:46,920 MATHEMATICAL MODELS AND MACHINE 326 00:11:46,920 --> 00:11:52,159 LEARNING TO START TO LEARN AND 327 00:11:52,159 --> 00:11:53,593 ASSIGN COMPONENTS, VIRAL HOST 328 00:11:53,593 --> 00:11:54,628 COMPONENTS TO DIFFERENT 329 00:11:54,628 --> 00:11:55,562 ORGANELLES OR UNDERSTAND WHAT 330 00:11:55,562 --> 00:11:57,230 DOES IT MEAN IN TERMS OF THE 331 00:11:57,230 --> 00:11:57,898 STRUCTURE FUNCTION RELATIONSHIPS 332 00:11:57,898 --> 00:12:01,902 AND WHAT WE FOUND IS THAT 333 00:12:01,902 --> 00:12:04,805 PEROXISOMES, I AM STILL HOPING I 334 00:12:04,805 --> 00:12:05,739 CAN GET A POINTER HERE. 335 00:12:05,739 --> 00:12:12,279 LET ME SEE IF I CAN DO THIS. 336 00:12:12,279 --> 00:12:13,080 >> IT'S NOT WORK? 337 00:12:13,080 --> 00:12:14,014 >> NO, IT'S NOT WORKING BUT 338 00:12:14,014 --> 00:12:18,118 MAYBE I NEED TO -- YES. 339 00:12:18,118 --> 00:12:18,685 YEAH, IT'S ALL RIGHT. 340 00:12:18,685 --> 00:12:27,794 SO IN THIS CIRCLE HERE, CAN YOU 341 00:12:27,794 --> 00:12:28,795 SEE PEROXISOMES, ARE CHANGING 342 00:12:28,795 --> 00:12:30,697 IN SHAPE AND NUMBER AND THAT 343 00:12:30,697 --> 00:12:33,367 THESE CHANGE IN MORPHOLOGY 344 00:12:33,367 --> 00:12:34,668 ACTIVATING ENZYMES THAT ARE 345 00:12:34,668 --> 00:12:39,272 RESPONSIBLE FOR INITIATING LIPID 346 00:12:39,272 --> 00:12:46,246 SYNTHESIS, THE AND WE SHOWED HOW 347 00:12:46,246 --> 00:12:48,682 THESE PLACENTAS MALLOW 348 00:12:48,682 --> 00:12:50,584 GENERATEDS AND BECOME INFECTIOUS 349 00:12:50,584 --> 00:12:52,019 PARTICLES SO THE REASON I'M 350 00:12:52,019 --> 00:12:53,820 SAYING COORDINATION IS BECAUSE 351 00:12:53,820 --> 00:12:56,456 THE LIMIT SYNTHESIS STARTS IN 352 00:12:56,456 --> 00:12:57,991 THE PEROXISOME, BUT IT'S BASED 353 00:12:57,991 --> 00:12:59,726 -- THE LIPIDS HAVE TO BE MATURED 354 00:12:59,726 --> 00:13:04,965 IN THE E. R. SO THIS IS BASED ON 355 00:13:04,965 --> 00:13:08,335 THE INTERACTION OF PEROXISOME 356 00:13:08,335 --> 00:13:09,069 AND THE CONTACTS. 357 00:13:09,069 --> 00:13:12,806 SO THE MORE WE INTERROGATE THE 358 00:13:12,806 --> 00:13:15,409 REMODELING EVENTS, THE MORE WE 359 00:13:15,409 --> 00:13:17,044 WERE STRUCK ON HOW THIS IS AND 360 00:13:17,044 --> 00:13:20,380 THE CONTACT, WE DO ALL KNOW THAT 361 00:13:20,380 --> 00:13:21,515 THE THEY HAVE SEPARATION BUT 362 00:13:21,515 --> 00:13:23,717 RATHER THEY FORM THIS INTRICATE 363 00:13:23,717 --> 00:13:24,451 NETWORK OF COMMUNICATION INSIDE 364 00:13:24,451 --> 00:13:25,852 THE CELL THAT ARE SO IMPORTANT 365 00:13:25,852 --> 00:13:28,288 FOR SO MANY FUNDAMENTAL CELLULAR 366 00:13:28,288 --> 00:13:29,489 PROCESSES, AND THESE 367 00:13:29,489 --> 00:13:31,224 INTERACTIONS ARE FACILITATED BY 368 00:13:31,224 --> 00:13:33,160 PROTEINS CALLED MEMBRANE CONTACT 369 00:13:33,160 --> 00:13:33,493 SITES. 370 00:13:33,493 --> 00:13:36,930 I SEE SOME PROMISE. 371 00:13:36,930 --> 00:13:38,098 >> YOU HAVE TO ACTIVATE IT ON 372 00:13:38,098 --> 00:13:38,532 HERE. 373 00:13:38,532 --> 00:13:43,770 IT MIGHT BE THIS LITTLE BUTTON. 374 00:13:43,770 --> 00:13:46,573 >> NO WORRY. 375 00:13:46,573 --> 00:13:48,508 NO WORRIES. 376 00:13:48,508 --> 00:13:50,077 >> AND THEN -- 377 00:13:50,077 --> 00:13:50,544 >> VICTORY. 378 00:13:50,544 --> 00:13:52,145 >> OTHERWISE IT WAS MY POINTING, 379 00:13:52,145 --> 00:13:53,580 I WOULD LOVE TO SEE THAT CHRIS, 380 00:13:53,580 --> 00:13:55,649 I WOULD HOPE FOR THE SECOND 381 00:13:55,649 --> 00:13:55,982 OPTION. 382 00:13:55,982 --> 00:13:59,086 ALL RIGHT, SO THIS INTERACTIONS 383 00:13:59,086 --> 00:14:00,353 BETWEEN ORGANELLES ARE 384 00:14:00,353 --> 00:14:02,355 FACILITATED BY THESE PROTEINS 385 00:14:02,355 --> 00:14:03,623 CALLED MEMBRANE SITES THAT ARE 386 00:14:03,623 --> 00:14:05,792 BRINGING THEM IN CLOSE PROXIMITY 387 00:14:05,792 --> 00:14:07,527 SO THESE ARE NOT FUSION EVENTS 388 00:14:07,527 --> 00:14:10,297 AND THEY CAN FACILITATE DIRECT 389 00:14:10,297 --> 00:14:11,364 TRANSFER OF MOLECULES LIKE 390 00:14:11,364 --> 00:14:12,466 LIPIDS AND CALCIUM AND I'M 391 00:14:12,466 --> 00:14:15,569 SHOWING YOU HERE 1 OF OUR 392 00:14:15,569 --> 00:14:18,305 MICROSCOPY IMAGING WHERE'VE SEEN 393 00:14:18,305 --> 00:14:19,506 RED PEROXISOMES IN THE ER AND 394 00:14:19,506 --> 00:14:21,541 YOU SEE THE DYNAMIC INTERACTION 395 00:14:21,541 --> 00:14:23,443 IS AND I WAS TELLING YOU ON THE 396 00:14:23,443 --> 00:14:27,581 PREVIOUS SLIDE ABOUT THIS ER, 397 00:14:27,581 --> 00:14:28,482 PEROXISOME CONTACT. 398 00:14:28,482 --> 00:14:31,017 SO WE WONDERED WHETHER A LOT OF 399 00:14:31,017 --> 00:14:31,952 THESE ORGANELLE REMODELING 400 00:14:31,952 --> 00:14:34,187 COMPLEXES, OR A LOT OF THESE 401 00:14:34,187 --> 00:14:35,789 AGER ANLE REMODELING EVENTS THAT 402 00:14:35,789 --> 00:14:39,126 I TOLD YOU ABOUT ARE UNDERLYING 403 00:14:39,126 --> 00:14:41,661 SOME OF THIS -- ARE BASED SORRY 404 00:14:41,661 --> 00:14:43,597 ON CHANGES IN MEMBRANE CONTEXT 405 00:14:43,597 --> 00:14:45,332 SIDE AND WHETHER THESE PROTEINS 406 00:14:45,332 --> 00:14:47,100 THAT FORM MEMBRANE CONTACT SITES 407 00:14:47,100 --> 00:14:49,503 ARE FACILITATING OR DRIVING OR 408 00:14:49,503 --> 00:14:52,105 REGULATED BY THIS ORGANELLE 409 00:14:52,105 --> 00:14:55,142 REMODELING EVENTS SO LOOKING AT 410 00:14:55,142 --> 00:14:56,977 THIS DURING INFECTION AND WE HAD 411 00:14:56,977 --> 00:14:57,944 FIRST DEVELOPED A METHOD THAT 412 00:14:57,944 --> 00:15:01,348 WOULD ALLOW US TO DETECT THIS 413 00:15:01,348 --> 00:15:03,817 HARD TO DETECT MEMBRANE CONTEXT 414 00:15:03,817 --> 00:15:05,852 PROTEIN, SOME OF THEM ARE 415 00:15:05,852 --> 00:15:07,120 MEMBRANE BOUND, WE DIDN'T HAVE 416 00:15:07,120 --> 00:15:08,989 ANTIBODIES FOR A LOT OF THIS, SO 417 00:15:08,989 --> 00:15:11,458 CAITLIN IN MY LAB TARGETED THIS 418 00:15:11,458 --> 00:15:12,759 ASSAY THAT ALLOW HER TO DETECT 419 00:15:12,759 --> 00:15:14,895 ALL THE KNOWN MEMBRANE CONTEXT 420 00:15:14,895 --> 00:15:16,163 SIDE PROTEINS, DETECT THEM AND 421 00:15:16,163 --> 00:15:18,198 QUANTIFY THEM AND THEN APPLY 422 00:15:18,198 --> 00:15:19,699 THIS TO THE 4 DIFFERENT VIRUSES 423 00:15:19,699 --> 00:15:23,069 THAT I MENTIONED EARLIER, THIS D 424 00:15:23,069 --> 00:15:25,071 MA VIRUS, AND INFLUENCE AND THIS 425 00:15:25,071 --> 00:15:27,941 BETA CORONA VIRUS, AND LOOK THEA 426 00:15:27,941 --> 00:15:29,876 HOW THESE CONTACTS ARE CHANGING 427 00:15:29,876 --> 00:15:32,279 AS THE INFECTION PROGRESSES AND 428 00:15:32,279 --> 00:15:34,247 THIS KIND OF INITIATED SOME 429 00:15:34,247 --> 00:15:34,881 REALLY INTERESTING RESEARCH 430 00:15:34,881 --> 00:15:35,682 DIRECTIONS IN OUR LAB AND I WANT 431 00:15:35,682 --> 00:15:39,419 TO TELL YOU WHAT WE HAVE LEARNED 432 00:15:39,419 --> 00:15:42,822 FROM HER FINDINGS ON OTHER 433 00:15:42,822 --> 00:15:44,891 MITOCHONDRIA ER CONTACTS 434 00:15:44,891 --> 00:15:45,926 ESPECIALLY DURING HCMV, SO IF 435 00:15:45,926 --> 00:15:47,327 YOU THINK ABOUT MITOCHONDRIA, WE 436 00:15:47,327 --> 00:15:49,162 KNOW THAT MITOCHONDRIA ARE SUCH 437 00:15:49,162 --> 00:15:51,364 A REGULATORY HUB DURING VIRAL 438 00:15:51,364 --> 00:15:53,433 INFECTION, SO MANY VIRUSES ARE 439 00:15:53,433 --> 00:15:55,902 TARGETING MITOCHONDRIA EITHER 440 00:15:55,902 --> 00:15:57,704 INDUCING FUSION OR FRAGMENTATION 441 00:15:57,704 --> 00:16:00,807 OR FISSION, AND THIS IS IN ORDER 442 00:16:00,807 --> 00:16:03,143 TO CONTROL RES PERRATION, SO 443 00:16:03,143 --> 00:16:05,378 ENERGY PRODUCTION, IMMUNE 444 00:16:05,378 --> 00:16:06,146 SIGNALING OR APOPTOSIS. 445 00:16:06,146 --> 00:16:09,816 AND USUALLY WHAT WE KNOW IS THAT 446 00:16:09,816 --> 00:16:11,484 WHEN MITOCHONDRIA ARE BEING 447 00:16:11,484 --> 00:16:13,687 FRAGMENTED THAT'S CONNECTED TO A 448 00:16:13,687 --> 00:16:15,388 DECREASE IN RESPIRATION, 449 00:16:15,388 --> 00:16:16,590 CONNECTED TO DECREASE BIOGENIC 450 00:16:16,590 --> 00:16:17,290 OUTPUT AND HERE YOU SLEEP APNEA 451 00:16:17,290 --> 00:16:23,463 AND OBESITYY SOME VIRUSES THAT 452 00:16:23,463 --> 00:16:25,198 EITHER INDUCE FRAGMENTATION, BUT 453 00:16:25,198 --> 00:16:28,802 SOMETHING'S BEEN PUZZLING IN THE 454 00:16:28,802 --> 00:16:32,005 FIELD OF HMV VIROLOGY IS THAT IT 455 00:16:32,005 --> 00:16:32,806 INDUCES STRIKING FRAGMENTATION 456 00:16:32,806 --> 00:16:34,207 OF MITOCHONDRIA AS YOU SEE HERE. 457 00:16:34,207 --> 00:16:36,676 BUT THIS MITOCHONDRIA IS ALSO 458 00:16:36,676 --> 00:16:43,984 BIOGENETICALLY ENHANCED SO WE 459 00:16:43,984 --> 00:16:45,719 SEE INCREASE IN PRODUCTION. 460 00:16:45,719 --> 00:16:47,754 SO CAITLIN DISCOVERED AT THE 461 00:16:47,754 --> 00:16:49,189 TIME WHEN THIS PHOSPHORYLATION 462 00:16:49,189 --> 00:16:51,057 OCCURS THERE IS ALSO INCREASED 463 00:16:51,057 --> 00:16:52,626 CONTACT BETWEEN MITOCHONDRIA AND 464 00:16:52,626 --> 00:16:55,462 THE ER, THROUGH THOSE MEMBRANE 465 00:16:55,462 --> 00:16:57,497 CONTACT SITE PROTEINS THAT 466 00:16:57,497 --> 00:16:59,332 FACILITATE THE CONTACT, SHE 467 00:16:59,332 --> 00:17:01,735 DELIVER INVESTIGATED THIS 468 00:17:01,735 --> 00:17:02,569 CONTURNING TO MIRROR IMAGE 469 00:17:02,569 --> 00:17:03,737 COSCOPY AND WHAT SHE FOUND IS 470 00:17:03,737 --> 00:17:05,605 THAT THIS CONTACT IS REALLY 471 00:17:05,605 --> 00:17:07,240 CHANGED DURING INFECTION, SO IN 472 00:17:07,240 --> 00:17:09,809 UNINFECTED CELLS AND THESE ARE 473 00:17:09,809 --> 00:17:11,645 PRIMARY HUMAN FIBROBLASTS, SHE 474 00:17:11,645 --> 00:17:14,347 NOTICED THE USUAL AND KNOWN AND 475 00:17:14,347 --> 00:17:15,382 TYPE OF INTERACTION BETWEEN 476 00:17:15,382 --> 00:17:16,650 MITOCHONDRIA AND THE ER WHERE 477 00:17:16,650 --> 00:17:18,285 THERE IS THIS DYNAMIC 478 00:17:18,285 --> 00:17:19,286 INTERACTION, YOU SEE 479 00:17:19,286 --> 00:17:21,621 MITOCHONDRIA IN RED AND THE ER 480 00:17:21,621 --> 00:17:22,789 KIND OF WEAVING,A ROUND THE 481 00:17:22,789 --> 00:17:24,324 MITOCHONDRIA AND HAVING THIS 482 00:17:24,324 --> 00:17:26,059 DYNAMIC INTERACTION, BUT AFTER 483 00:17:26,059 --> 00:17:29,129 INFECTION WITH ACMV, AND AS THE 484 00:17:29,129 --> 00:17:30,964 INFECTION PROGRESSED, THE 485 00:17:30,964 --> 00:17:32,432 FRAGMENTED MITOCHONDRIA BECAME 486 00:17:32,432 --> 00:17:35,535 INCAPSULATED AND STABILIZED IN 487 00:17:35,535 --> 00:17:37,504 ER POCKETS. 488 00:17:37,504 --> 00:17:45,278 SO SHE TURNED THIS NEW SORT OF 489 00:17:45,278 --> 00:17:46,112 CONTACT STRUCTURE MENC AND WENT 490 00:17:46,112 --> 00:17:50,650 AND, HADED AND CONFIRMED THIS 491 00:17:50,650 --> 00:17:53,053 USING USING CRYO MICROSCOPY AND 492 00:17:53,053 --> 00:17:54,587 YOU SEE HERE HOW IT'S SURROUNDED 493 00:17:54,587 --> 00:17:55,889 BY THE ER AND THEN WE 494 00:17:55,889 --> 00:17:56,923 INVESTIGATE TD ITS FUNCTION. 495 00:17:56,923 --> 00:17:59,259 WE FOUND WHAT PROTEINS ARE 496 00:17:59,259 --> 00:18:01,127 NECESSARY FOR THE FORMATION OF 497 00:18:01,127 --> 00:18:03,229 MENC, AND WE SHOW THAT SOMEHOW 498 00:18:03,229 --> 00:18:04,130 THE STRUCTURE FUNCTIONS SOMEHOW 499 00:18:04,130 --> 00:18:06,199 FOR THE BENEFIT OF THE VIRUS AND 500 00:18:06,199 --> 00:18:08,468 SINCE THEN WE INVESTIGATED HOW 501 00:18:08,468 --> 00:18:10,270 THIS HAPPENS AND WHY AND THIS 502 00:18:10,270 --> 00:18:15,475 WAS WORK DONE BY WILL HOFSTAT A 503 00:18:15,475 --> 00:18:17,110 Ph.D. STUDENT IN MY LAB. 504 00:18:17,110 --> 00:18:18,378 IN OTHER WORDS WHY ARE THEY 505 00:18:18,378 --> 00:18:19,579 FORMED AND WHY ARE THEY 506 00:18:19,579 --> 00:18:20,613 FUNCTIONING FOR THE BENEFIT OF 507 00:18:20,613 --> 00:18:22,982 THE VIRUS AND WILL WAS ABLE TO 508 00:18:22,982 --> 00:18:27,120 THOUGH IS FIRST LOOKING AT HOW 509 00:18:27,120 --> 00:18:28,321 MENCs ARE FORMING HE 510 00:18:28,321 --> 00:18:30,223 CONSIDERED 2 THINGS HE 511 00:18:30,223 --> 00:18:31,558 CONSIDERED HOW IT'S FRAGMENTED 512 00:18:31,558 --> 00:18:33,626 AND DURING INFECTION AND HE 513 00:18:33,626 --> 00:18:35,328 FOUND THAT ATMV SUPPRESSES 514 00:18:35,328 --> 00:18:39,833 FUSION OF MITOCHONDRIA BUT 515 00:18:39,833 --> 00:18:41,668 PROMOTES FRAGMENTATION THROUGH 516 00:18:41,668 --> 00:18:43,136 THIS PERIPHERAL FISSION, INSTEAD 517 00:18:43,136 --> 00:18:43,970 OF THE CLATIONZIC MIDZONE 518 00:18:43,970 --> 00:18:47,807 VISION, IT'S THE KIND OF NEWER, 519 00:18:47,807 --> 00:18:51,611 MORE NEWEL DISCOVERED MODE OF 520 00:18:51,611 --> 00:18:52,612 MITOCHONDRIA FRAGMENTATION 521 00:18:52,612 --> 00:18:53,179 THROUGH PERIPHERAL FISSION 522 00:18:53,179 --> 00:18:54,814 OCCURRING IN THE OUTER PART OF 523 00:18:54,814 --> 00:18:55,715 THE MITOCHONDRIA. 524 00:18:55,715 --> 00:18:58,551 AND WHAT IT'S KNOWN IN 525 00:18:58,551 --> 00:19:00,286 UNINFECTED CELLS FROM THE LAB, 526 00:19:00,286 --> 00:19:04,357 IS THAT WHEN MITOCHONDRIA AND 527 00:19:04,357 --> 00:19:05,658 THE PERILERAL FISSION, THIS IS 528 00:19:05,658 --> 00:19:08,395 SUBJECTED TO MIRROR IMAGE TO 529 00:19:08,395 --> 00:19:10,263 HAVAGEY SO IT'S TARGETED FOR 530 00:19:10,263 --> 00:19:12,365 DEGRADATION AND IT HAS DECREASED 531 00:19:12,365 --> 00:19:13,199 MEMBRANE POTENTIAL BUT I JUST 532 00:19:13,199 --> 00:19:15,502 TOLD THAT YOU DURING INFECTION 533 00:19:15,502 --> 00:19:17,904 THE OPPOSITE HAPPENS SO WILL 534 00:19:17,904 --> 00:19:19,439 SHOWED IS THAT THIS FRAGMENT 535 00:19:19,439 --> 00:19:21,574 MITOCHONDRIA ALL OF THIS BY 536 00:19:21,574 --> 00:19:24,377 TRACKING IT, THEY BECOME 537 00:19:24,377 --> 00:19:25,779 INCAPSULATED IN THIS STRUCTURE 538 00:19:25,779 --> 00:19:27,313 IN MENC, AND THEY BECOME 539 00:19:27,313 --> 00:19:31,184 PROTECTED SO HE SAW A DECREASE 540 00:19:31,184 --> 00:19:32,919 IN MITOPHAGEY AND HOW THIS IS 541 00:19:32,919 --> 00:19:35,422 DEPENDENT ON THE FORMATION OF 542 00:19:35,422 --> 00:19:37,524 MENCs AND HE ALSO SHORED THIS 543 00:19:37,524 --> 00:19:41,161 IS CONNECTED TO INCREASING 544 00:19:41,161 --> 00:19:42,495 MEMBRANE POTENTIAL. 545 00:19:42,495 --> 00:19:44,731 SO METHIS, Ys, PROTECTED AGAIN 546 00:19:44,731 --> 00:19:54,874 MIRROR 547 00:19:56,576 --> 00:19:56,843 MITOPHAGEY, OR 548 00:19:56,843 --> 00:19:57,444 INTERRAMITOCHONDRIA CONTEXT 549 00:19:57,444 --> 00:20:01,481 THROUGH THE ER AND YOU CAN SEE 550 00:20:01,481 --> 00:20:03,216 THEM HERE AND THEN THEY FURTHER 551 00:20:03,216 --> 00:20:04,884 COMMUNICATE BY STARTING TO SWAP 552 00:20:04,884 --> 00:20:11,224 MEMBRANE POTENTIAL, YOU CAN SEE 553 00:20:11,224 --> 00:20:14,060 THAT HERE. 554 00:20:14,060 --> 00:20:15,995 THIS MITOCHONDRIA ER INCAP 555 00:20:15,995 --> 00:20:21,801 SUEALATION CALLED MENC, IT WAS 556 00:20:21,801 --> 00:20:22,402 FRAGMENT INDEED A POPULATION. 557 00:20:22,402 --> 00:20:23,770 SO THEN WE WANT TO ASK WHETHER 558 00:20:23,770 --> 00:20:25,171 THIS STRUCTURE COULD HAVE SOME 559 00:20:25,171 --> 00:20:27,040 SORT OF BROADER ROLL VANCE, DID 560 00:20:27,040 --> 00:20:28,875 WE JUST STUMBLE UPON THIS DURING 561 00:20:28,875 --> 00:20:30,176 THE INFEC, IS IT MORE BROADLY 562 00:20:30,176 --> 00:20:32,278 RELEVANT AND WHEN WE THINK ABOUT 563 00:20:32,278 --> 00:20:34,314 ACMV, WE HAVE TO THINK ABOUT 564 00:20:34,314 --> 00:20:36,082 DIFFERENT CELL TYPES, BECAUSE 565 00:20:36,082 --> 00:20:37,817 ACMVs, KNOWN TO INFECT MANY 566 00:20:37,817 --> 00:20:38,885 DEFINITE TYPES OF -- MANY 567 00:20:38,885 --> 00:20:40,487 DIFFERENT CELLS AND OF COURSE 568 00:20:40,487 --> 00:20:41,621 DEPENDING ON WHAT VIRUS TRAINS, 569 00:20:41,621 --> 00:20:43,990 YOU'RE USING IN THE LAB, FOR 570 00:20:43,990 --> 00:20:45,058 STUDYING THIS THEY EITHER HAVE 571 00:20:45,058 --> 00:20:47,260 LOST OR STILL RETAIN THE ABILITY 572 00:20:47,260 --> 00:20:49,662 OF INFECTING DIFFERENT TYPES OF 573 00:20:49,662 --> 00:20:52,966 CELLS, SO WILL TACKLED THESE 574 00:20:52,966 --> 00:20:54,801 QUESTIONS USING DIFFERENT HCMV 575 00:20:54,801 --> 00:20:56,469 STRAIN USING EATER THE 576 00:20:56,469 --> 00:20:57,871 FIBROBLAST OR EPITHELIAL CELLS 577 00:20:57,871 --> 00:21:00,473 AND LOOK AT THEIR CHANGES AND 578 00:21:00,473 --> 00:21:02,642 CHANGES IN MEMBRANE CONTEXT SIZE 579 00:21:02,642 --> 00:21:06,980 AND USING A TARGETED MASS SPECT 580 00:21:06,980 --> 00:21:08,515 TROMETRY ASSAY AS WELL AS DAY 581 00:21:08,515 --> 00:21:12,452 TIME ACQUISITION ON A NEW 582 00:21:12,452 --> 00:21:13,853 INSTRUMENT WE ACQUIRED AT ULTRA. 583 00:21:13,853 --> 00:21:16,556 SO WHAT WE FOUND WAS INTERESTING 584 00:21:16,556 --> 00:21:19,826 BECAUSE HE FOUND THAT EVEN FOR 585 00:21:19,826 --> 00:21:22,428 THE CHANGE -- THE MEMBRANE 586 00:21:22,428 --> 00:21:25,732 CONTEXT SITE, ALTERATION AND 587 00:21:25,732 --> 00:21:26,900 MEMBRANE SITE THAT WERE 588 00:21:26,900 --> 00:21:29,102 DIFFERENT IN EPITHELIAL CELLS OR 589 00:21:29,102 --> 00:21:30,837 FIBROBLAST, THERE SEEM TO BE 590 00:21:30,837 --> 00:21:31,604 SOME CONVERGENCE THERE, LET ME 591 00:21:31,604 --> 00:21:33,206 TELL YOU WHAT I MEAN, SO IF WE 592 00:21:33,206 --> 00:21:35,308 LOOK HERE AT THESE -- THESE ARE 593 00:21:35,308 --> 00:21:37,243 DIFFERENT MEMBRANE CONTEXT SITES 594 00:21:37,243 --> 00:21:38,511 THAT FACILITATE DIFFERENT 595 00:21:38,511 --> 00:21:40,813 CONTEXT, BUT YOU CAN SEE HOW 596 00:21:40,813 --> 00:21:42,415 THEIR ABUNDANCE STARTED AT A 597 00:21:42,415 --> 00:21:44,284 DIFFERENT POINT IN UNAFFECTED 598 00:21:44,284 --> 00:21:45,685 CELL IN EITHER FIBROBLAST OR 599 00:21:45,685 --> 00:21:47,921 EPITHELIAL CELLS BUT THEN AS THE 600 00:21:47,921 --> 00:21:49,556 INFECTION PROGRESSED IN THESE 601 00:21:49,556 --> 00:21:50,623 DIFFERENT CELLS THEY STARTED TO 602 00:21:50,623 --> 00:21:51,224 BECOME MORE SIMILAR TO EERCH 603 00:21:51,224 --> 00:21:53,793 OTHER AND THE SAME HERE, RIGHT? 604 00:21:53,793 --> 00:21:55,929 IT STARTED AS BEING HIGH IF NIEB 605 00:21:55,929 --> 00:21:57,597 ROUGH ATOM BLAST AND LOW IN 606 00:21:57,597 --> 00:21:59,432 EPITHELIAL CELLS BUT AS THE 607 00:21:59,432 --> 00:22:01,834 INFECTION PROGRESSED, EVEN IF 608 00:22:01,834 --> 00:22:03,369 THEY HAD DIFFERENT TRENDS, THEY 609 00:22:03,369 --> 00:22:05,338 KIND OF ENDED UP WITH A SIMILAR 610 00:22:05,338 --> 00:22:06,306 PROTEIN ABUNDANCE IN THESE 611 00:22:06,306 --> 00:22:06,773 CELLS. 612 00:22:06,773 --> 00:22:09,442 SO WHAT TELLS US IS EVEN IF THE 613 00:22:09,442 --> 00:22:10,743 VIRUS IS IN FIBROBLAST AND 614 00:22:10,743 --> 00:22:13,913 EPITHELIAL CELLS, THERE ARE SOME 615 00:22:13,913 --> 00:22:15,048 CONVERGENT CHANGE THAT ARE 616 00:22:15,048 --> 00:22:16,649 ALMOST PUSHING THE CELL TOWARD 617 00:22:16,649 --> 00:22:18,851 SOME SORT OF UNIFIED CELL STATE 618 00:22:18,851 --> 00:22:20,620 THAT IT'S AMENABLE AND SUPPORTS 619 00:22:20,620 --> 00:22:21,554 WELL VIRAL INFECTION, AND THEN 620 00:22:21,554 --> 00:22:23,156 THERE WERE ALSO SHARED CHANGES 621 00:22:23,156 --> 00:22:24,857 THAT WERE THE SAME FOR ANY CELL 622 00:22:24,857 --> 00:22:28,561 THAT WE LOOKED AT AND THESE ALSO 623 00:22:28,561 --> 00:22:30,229 INCLUDED THE FORMATION OF 624 00:22:30,229 --> 00:22:32,599 MENCs, SO AS I SAID EARLIER WE 625 00:22:32,599 --> 00:22:34,701 ALREADY KNEW THAT THIS -- WHAT 626 00:22:34,701 --> 00:22:36,202 MEMBRANE CONTEXT SITES ARE 627 00:22:36,202 --> 00:22:38,371 NEEDED FOR FORMING THAT 628 00:22:38,371 --> 00:22:40,773 STRUCTURE, THE MENC AND IT'S 629 00:22:40,773 --> 00:22:44,677 PP51 ON THE MITOCHONDRIA SIDE 630 00:22:44,677 --> 00:22:46,479 AND THE ON THE ER SIDE AND YOU 631 00:22:46,479 --> 00:22:49,215 SEE HOW THE PROTEIN CHANGES 632 00:22:49,215 --> 00:22:50,750 SIMILARLY IN ABUNDANCE IN 633 00:22:50,750 --> 00:22:51,851 FIBROBLAST OR EPITHELIAL CELLS 634 00:22:51,851 --> 00:22:56,756 AND IT SIMILARLY RECRUITED IN AN 635 00:22:56,756 --> 00:22:58,791 ASYMMETRIC MANNER IN THIS MENC 636 00:22:58,791 --> 00:23:01,561 STRUCTURE AND WE SAW THIS IN 637 00:23:01,561 --> 00:23:02,562 FIBROBLAST, EPITHELIAL CELLS AS 638 00:23:02,562 --> 00:23:05,632 WELL AS IN THE MACROPHAGE CELLS 639 00:23:05,632 --> 00:23:07,567 SO NOW WE UNDERSTAND THAT OKAY, 640 00:23:07,567 --> 00:23:09,135 IS THERE SOME BROAD RELEVANCE 641 00:23:09,135 --> 00:23:12,171 THAT THE FORMATION OF MENCs IS 642 00:23:12,171 --> 00:23:13,740 REALLY BROADLY IMPORTANT FOR THE 643 00:23:13,740 --> 00:23:14,574 INFECTION IN DIFFERENT TYPES OF 644 00:23:14,574 --> 00:23:16,275 CELLS, NOW THE OTHER QUESTION 645 00:23:16,275 --> 00:23:18,144 WAS, WELL, HOW ABOUT MORE 646 00:23:18,144 --> 00:23:19,178 BROADER CONTEXT AND OTHER 647 00:23:19,178 --> 00:23:21,481 CONTEXT WHERE WE DO SEE 648 00:23:21,481 --> 00:23:22,949 MITOCHONDRIA FRAGMENTATION BUT 649 00:23:22,949 --> 00:23:26,285 IN CONJUNCTION WITH THIS HIGH 650 00:23:26,285 --> 00:23:27,620 BIOGENICS AND IMMEDIATELY THAT 651 00:23:27,620 --> 00:23:32,859 MADE US THINK OF CANCER BECAUSE 652 00:23:32,859 --> 00:23:35,028 ACMV IS ALSO A VIRUS, AND WE 653 00:23:35,028 --> 00:23:36,596 WILL SHOW THAT IT IS FORM 654 00:23:36,596 --> 00:23:37,730 NOTHING MELANOMA CELLS AND 655 00:23:37,730 --> 00:23:42,702 CRYSTAL IN MY LAB LOOKED AT HIGH 656 00:23:42,702 --> 00:23:44,303 GRADE VARIANT CANCER AND FOUND 657 00:23:44,303 --> 00:23:46,172 THE FORMATION OF MENCs AND 658 00:23:46,172 --> 00:23:48,107 FURTHER MORE BY LOOKING AT 659 00:23:48,107 --> 00:23:49,542 DIFFERENT MODEL SYSTEMS OF 660 00:23:49,542 --> 00:23:51,778 TIEBAL OVARIAN CANCER AND 661 00:23:51,778 --> 00:23:57,684 LOOKING AT LOOKING AT THOSE 662 00:23:57,684 --> 00:23:58,951 ASSOCIATED WITH POOR PROGNOSIS, 663 00:23:58,951 --> 00:24:01,454 SHE FOUND THESE ARE EXHIBITING 664 00:24:01,454 --> 00:24:03,756 MENC IN CONJUNCTION WITH 665 00:24:03,756 --> 00:24:05,158 DECREASE PHOSPHORYLATION, 666 00:24:05,158 --> 00:24:07,126 DECREASE IMMUNE FACTORS AND 667 00:24:07,126 --> 00:24:09,529 DECREASE IN ATV, SUGGESTS THAT 668 00:24:09,529 --> 00:24:12,598 MENC'S BENEFICIAL FOR VIRAL 669 00:24:12,598 --> 00:24:14,233 INFECTION AND PROMOTING OR OR 670 00:24:14,233 --> 00:24:17,437 MAKING CHANGES IN THE CELLS THAT 671 00:24:17,437 --> 00:24:19,172 ARE AMENABLE TO VIRAL INFECTION. 672 00:24:19,172 --> 00:24:22,008 OKAY, SO WHAT I TOLD YOU SO FAR, 673 00:24:22,008 --> 00:24:27,246 IS HOW OUR STUDIES OF ORGANELLE 674 00:24:27,246 --> 00:24:29,315 REMODELING AND ORGANELLE, 675 00:24:29,315 --> 00:24:30,249 ORGANELLE CONTEXT HAVE ALLOWED 676 00:24:30,249 --> 00:24:31,451 US TO ANSWER THIS SORT OF 677 00:24:31,451 --> 00:24:33,786 MARADOCKS IN THE FIELD OF ATMV 678 00:24:33,786 --> 00:24:36,289 INFECTION, THE FACT THAT HOW 679 00:24:36,289 --> 00:24:38,124 FRAGMENTED MITOCHONDRIA STILL 680 00:24:38,124 --> 00:24:38,991 HAVE INCREASED OXIDATIVE 681 00:24:38,991 --> 00:24:41,994 PHOSPHORYLATION AND IT'S THROUGH 682 00:24:41,994 --> 00:24:44,030 THIS FORMATION OF MITOCHONDRIA 683 00:24:44,030 --> 00:24:46,432 ER INCAP SUEALATION THAT 684 00:24:46,432 --> 00:24:47,066 PROTECTS MITOCHONDRIA FROM 685 00:24:47,066 --> 00:24:50,103 MIRROR IMAGE TO HAVAGEY AND 686 00:24:50,103 --> 00:24:51,237 INCREASES RESPIRATION, BUT 687 00:24:51,237 --> 00:24:54,440 ANOTHER OUTPUT OF THESE 688 00:24:54,440 --> 00:24:55,675 METABOLIC CHANGES DURING 689 00:24:55,675 --> 00:24:57,844 INFECTION AND IS PARTICULAR FOR 690 00:24:57,844 --> 00:25:00,947 THIS FLEX IN GLYCOLYSIS IS AN 691 00:25:00,947 --> 00:25:02,248 INCREASE IN LACTIC ACIDOSEISATE 692 00:25:02,248 --> 00:25:03,950 PRODUCTION AND I WANT TO TELL 693 00:25:03,950 --> 00:25:06,419 YOU HOW WE NOW UNDERSTAND HOW 694 00:25:06,419 --> 00:25:08,621 LACTIC ACIDOSEISATE IS VERY 695 00:25:08,621 --> 00:25:10,690 IMPORTANT IN THE INTRACELLULAR 696 00:25:10,690 --> 00:25:11,524 AND INTRACELLULAR COMMUNICATION 697 00:25:11,524 --> 00:25:13,092 AND PLACING THESE IN THE CONTEXT 698 00:25:13,092 --> 00:25:15,895 OF VIRUS MICROVOIRMT. 699 00:25:15,895 --> 00:25:18,464 SO WE KNOW THAT A NUMBER OF 700 00:25:18,464 --> 00:25:19,866 VIRUSES ARE INDUCING METABOLIC 701 00:25:19,866 --> 00:25:21,634 CHANGES THAT MIRROR WHAT HAPPENS 702 00:25:21,634 --> 00:25:26,773 IN CANCER CELLS, IN PARTICULAR, 703 00:25:26,773 --> 00:25:29,208 THEY INDUCE A WAR LIKE EFFECT 704 00:25:29,208 --> 00:25:32,512 WHERE THERE'S A CHANGE THAT'S 705 00:25:32,512 --> 00:25:41,120 AEROBIC GLYCOLYSIS WHICH IS 706 00:25:41,120 --> 00:25:43,322 INCREASE IN LACTATE ON INFECTED 707 00:25:43,322 --> 00:25:44,724 CELLS BUT OUTSIDE THE CONTEXT OF 708 00:25:44,724 --> 00:25:46,526 INFECTION THERE HAVE BEEN 709 00:25:46,526 --> 00:25:48,561 STUDIES IN CANCER RESEARCH THAT 710 00:25:48,561 --> 00:25:50,530 HAS RECENTLY SHOWN THAT LACTATE 711 00:25:50,530 --> 00:25:52,932 CAN ALSO INHIBIT IMMUNE 712 00:25:52,932 --> 00:25:53,733 RESPONSES. 713 00:25:53,733 --> 00:25:56,102 SO WE WONDER WHETHER ACMV 714 00:25:56,102 --> 00:25:59,539 INFECTION, ALSO LEVERAGES THIS 715 00:25:59,539 --> 00:26:01,674 INCREASE HEARING IN LACTATE FOR 716 00:26:01,674 --> 00:26:03,976 IMMUNE SUPPRESSION AND IN ORDER 717 00:26:03,976 --> 00:26:07,680 TO ADDRESS THIS, MA MATTE A 718 00:26:07,680 --> 00:26:10,950 Ph.D. STUDENT IN MY LAB DID A 719 00:26:10,950 --> 00:26:13,286 EXPERIMENT WHERE HE INFECTED 720 00:26:13,286 --> 00:26:15,588 CELLS WITH A LOW MOI WHERE HE 721 00:26:15,588 --> 00:26:17,690 LOOKED AT SPREAD OF INFECTION 722 00:26:17,690 --> 00:26:19,625 AND IMMUNE SIGNALING AND HE 723 00:26:19,625 --> 00:26:20,793 TREATED THESE CELLS WITH LACTATE 724 00:26:20,793 --> 00:26:24,997 AND HE FOUND THAT IN THIS 725 00:26:24,997 --> 00:26:26,399 CONTEXT OF MOI, LACTATE WAS 726 00:26:26,399 --> 00:26:28,234 FUNCTIONING FOR THE BENEFIT OF 727 00:26:28,234 --> 00:26:30,303 THE VIRUS WAS PROVIRAL FOR 728 00:26:30,303 --> 00:26:31,904 SEQUENTIAL ROUNDS OF REP 729 00:26:31,904 --> 00:26:32,338 WELLICATION. 730 00:26:32,338 --> 00:26:33,739 WHAT DOES THIS MEAN? 731 00:26:33,739 --> 00:26:37,243 WELL, FROM THE LAB OF MING AT 732 00:26:37,243 --> 00:26:40,913 THE UNIVERSITY OF CHICAGO, WE 733 00:26:40,913 --> 00:26:45,251 NOW IT CAN BE ADDED TO LYSINE 734 00:26:45,251 --> 00:26:48,754 RESIDUES MODIFYING THESE 735 00:26:48,754 --> 00:26:49,589 PROTEINS BY LACTATATION, SO 736 00:26:49,589 --> 00:26:53,492 GIVEN THIS, WE KNOW ACMV INDUCES 737 00:26:53,492 --> 00:26:54,093 LACTATE PRODUCTION, WE 738 00:26:54,093 --> 00:26:56,729 ANTICIPATE THAT PROBABLY THERE 739 00:26:56,729 --> 00:26:58,164 ARE EVENTS HAPPENING IN THE 740 00:26:58,164 --> 00:26:58,364 CELL. 741 00:26:58,364 --> 00:27:07,406 SO THEREFORE WE DID THE LACTATE 742 00:27:07,406 --> 00:27:10,009 PURIFICATION, THIS IS ACTIVATED 743 00:27:10,009 --> 00:27:11,978 LYSINE AT DIFFERENT TIME POINTSA 744 00:27:11,978 --> 00:27:15,181 THE TIME OF INFECTION WITH ACMV, 745 00:27:15,181 --> 00:27:18,351 AND THEN WE USE MASS SPEC 746 00:27:18,351 --> 00:27:21,087 TROMETRY TO FIGURE OUT WHICH 1S 747 00:27:21,087 --> 00:27:22,021 BECOME MORE INDUCED BY 748 00:27:22,021 --> 00:27:22,321 MODULATION. 749 00:27:22,321 --> 00:27:24,357 WE FOUND THERE ARE THOUSANDS OF 750 00:27:24,357 --> 00:27:26,092 PROTEINS IN ALMOST EVERY 751 00:27:26,092 --> 00:27:30,129 SUBCELLULAR COMPARTMENT THAT 752 00:27:30,129 --> 00:27:31,264 BECOME LACTATED DURING 753 00:27:31,264 --> 00:27:34,934 INFECTION, AND WHEN WE COMPARE 754 00:27:34,934 --> 00:27:36,702 THIS WITH OTHER MODIFICATIONS WE 755 00:27:36,702 --> 00:27:38,504 FOUND THE MOTIFS WERE DIFFERENT, 756 00:27:38,504 --> 00:27:45,378 THE SITES WERE DIFFERENT AND 757 00:27:45,378 --> 00:27:46,279 FOUND THAT LACTYLOME WAS 758 00:27:46,279 --> 00:27:47,847 DEFINITE IN THESE REGIONS, SO 759 00:27:47,847 --> 00:27:48,881 THEN WE THOUGHT IS THIS 760 00:27:48,881 --> 00:27:50,116 SOMETHING WE NOTICE DURING 761 00:27:50,116 --> 00:27:53,219 INFECTION WHEN WE COMPARE TO 762 00:27:53,219 --> 00:27:55,855 OTHER FIBROBLAST DATA SETS AND 763 00:27:55,855 --> 00:27:57,857 OTHER INFECTED STUDIES DURING 764 00:27:57,857 --> 00:27:59,859 VIRAL INFECTION, OR HOW ABOUT 765 00:27:59,859 --> 00:28:07,066 MORE BROADLY, SO WE DON'T LOAD 766 00:28:07,066 --> 00:28:09,001 IT LACTYALATION, IN E-COLI AND 767 00:28:09,001 --> 00:28:15,608 AGAIN WE FOUND THAT THE LACTATED 768 00:28:15,608 --> 00:28:16,943 WERE ENRICH INDEED REGIONS OF 769 00:28:16,943 --> 00:28:19,211 THE PROTEINS THAT WERE TREATED 770 00:28:19,211 --> 00:28:20,579 TO BE INTRINSICALLY DISORDERS. 771 00:28:20,579 --> 00:28:22,715 WE USE THOSE IN ALPHFOLD AND WE 772 00:28:22,715 --> 00:28:24,317 CONFIRM THIS BY SEEING AN 773 00:28:24,317 --> 00:28:26,419 INCREASE IN THE UNSTRUCTURED 774 00:28:26,419 --> 00:28:29,055 REGIONS AND ALPHA HELIX 775 00:28:29,055 --> 00:28:29,989 REPRESENTATION OF PEPTIDES IN 776 00:28:29,989 --> 00:28:31,691 REGIONS OF THE PROTEINS THAT 777 00:28:31,691 --> 00:28:32,358 CONTAIN THE LYSINE. 778 00:28:32,358 --> 00:28:36,062 SO WHAT DOES THIS MEAN? 779 00:28:36,062 --> 00:28:37,930 HOW IS LACTATATION OF A DISORDER 780 00:28:37,930 --> 00:28:43,102 REGION HOW CAN IT IMPACT THEIR 781 00:28:43,102 --> 00:28:43,469 FUNCTION? 782 00:28:43,469 --> 00:28:45,871 SO WE LOOKEDDA THE FUNCTION OF 783 00:28:45,871 --> 00:28:50,876 PROTEINS AS THE INFECTION 784 00:28:50,876 --> 00:28:52,912 PROGRESSES DIFFERENT HOURS 785 00:28:52,912 --> 00:28:54,213 DURING INFECTION. 786 00:28:54,213 --> 00:28:56,315 SO CYTOKINE RESPONSE, CELLULAR 787 00:28:56,315 --> 00:28:59,518 RESPONSE TO INTERFERON-GAMMA, 788 00:28:59,518 --> 00:29:00,386 ACTIVATION OF INNATE IMMUNE 789 00:29:00,386 --> 00:29:01,354 RESPONSES AND THEN WE ASKED IF 790 00:29:01,354 --> 00:29:05,324 THIS IS JUST THE CASE FOR ACMV. 791 00:29:05,324 --> 00:29:08,527 WE PERFORM SIMILAR LACTATION 792 00:29:08,527 --> 00:29:09,895 STUDIES DURING HSV INFECTION AND 793 00:29:09,895 --> 00:29:11,197 LOOKING AT VIRAL STRAINS THAT 794 00:29:11,197 --> 00:29:12,965 ARE EITHER ABLE TO INHIBIT 795 00:29:12,965 --> 00:29:15,034 IMMUNE RESPONSES OR UNABLE TO 796 00:29:15,034 --> 00:29:16,302 INHIBIT IMMUNE RESPONSES AND 797 00:29:16,302 --> 00:29:23,676 AGAIN, WE FOUND INCREASED 798 00:29:23,676 --> 00:29:26,178 LACTYALATION, SO AGAIN THIS IS A 799 00:29:26,178 --> 00:29:27,046 CONSERVED FEATURE IN INFECTION 800 00:29:27,046 --> 00:29:28,781 EMPLOY SO AMONG THE IMMUNE 801 00:29:28,781 --> 00:29:34,320 FACTORS WE FOUND TO BE MODIFIED 802 00:29:34,320 --> 00:29:38,691 BY LACTYLATION, WHICH IS I5, 803 00:29:38,691 --> 00:29:39,792 CYSTINE, THIS IS INTERFERON THAT 804 00:29:39,792 --> 00:29:41,260 WE HAVE OTHER VS CHARACTERIZED 805 00:29:41,260 --> 00:29:43,262 AS A VIRAL DNA SENSOR THAT CAN 806 00:29:43,262 --> 00:29:44,430 FUNCTION IN THE NUCLEUS AND WE 807 00:29:44,430 --> 00:29:48,734 FOUND THAT THIS PROTEIN BECOMES 808 00:29:48,734 --> 00:29:53,339 DECORATED WITH LACTYLATION IN 809 00:29:53,339 --> 00:29:54,473 ATV INFECTION AND HCMV INFECTION 810 00:29:54,473 --> 00:29:55,908 AND SOME OF THESE ARE IN THE 811 00:29:55,908 --> 00:30:00,579 REGIONS WE PREVIOUSLY 812 00:30:00,579 --> 00:30:01,047 CHARACTERIZED. 813 00:30:01,047 --> 00:30:03,115 SO LOOKING AT 1 OF THESE MUTATED 814 00:30:03,115 --> 00:30:04,050 RESIDUES AND PERFORM MANY 815 00:30:04,050 --> 00:30:05,751 TODAYS BUT I WANT TO FOCUS ON 1 816 00:30:05,751 --> 00:30:06,552 OF THESE. 817 00:30:06,552 --> 00:30:09,155 SO LOOKING AT 1 OF THESE SITES 818 00:30:09,155 --> 00:30:10,790 WE FOUND THIS LACTATED DURING 819 00:30:10,790 --> 00:30:13,025 BOTH OF THESE INFECTIONS WHEN HE 820 00:30:13,025 --> 00:30:14,960 FOUNDS THIS TO A MIMIC HE 821 00:30:14,960 --> 00:30:17,430 ACTUALLY NOTICED THAT THIS 822 00:30:17,430 --> 00:30:19,331 PROTEIN STARTS TO HAVE INHIBITED 823 00:30:19,331 --> 00:30:21,167 ABILITY TO INDUCE IMMUNE 824 00:30:21,167 --> 00:30:22,701 SIGNALING SO THERE'S -- THERE 825 00:30:22,701 --> 00:30:27,306 ARE DECREASES IN INTERFERON BETA 826 00:30:27,306 --> 00:30:29,408 AND CXCL 10 AND IN AGREEMENT HE 827 00:30:29,408 --> 00:30:32,445 SAW A INCREASE IN VIRUS TITER 828 00:30:32,445 --> 00:30:34,513 WHEN THEY WERE EXPRESSING THIS 829 00:30:34,513 --> 00:30:37,616 LACTIC ACIDOSEISILE MIMIC 830 00:30:37,616 --> 00:30:37,983 PROTEIN. 831 00:30:37,983 --> 00:30:39,785 DOWN STREAM ANOTHER IMMUNE 832 00:30:39,785 --> 00:30:43,656 FACTOR DOWN STREAM OF DNA 833 00:30:43,656 --> 00:30:48,160 SENSING RBN14, HERE IS 834 00:30:48,160 --> 00:30:49,228 LACTYLATION THAT HE FOUND AND 835 00:30:49,228 --> 00:30:52,164 AGAIN WHEN HE MUTATED THAT TO A 836 00:30:52,164 --> 00:30:53,566 MIMIC HE FOUND THIS PROTEIN 837 00:30:53,566 --> 00:30:55,801 STARTS TO HAVE INHIBITED ABILITY 838 00:30:55,801 --> 00:30:58,471 TO INDUCE SIGNALING SO REDUCED 839 00:30:58,471 --> 00:31:02,541 INTERFERON BETA AND CXCL-10 840 00:31:02,541 --> 00:31:04,276 WOULD INCREASE VIRUS PRODUCTION 841 00:31:04,276 --> 00:31:04,844 EMPLOY SO ADDRESS BROADER 842 00:31:04,844 --> 00:31:09,415 IMPACTS IT IS HAPPENING, WHY 843 00:31:09,415 --> 00:31:11,283 LACTYLATION OF HOST FACTORS 844 00:31:11,283 --> 00:31:12,251 SEEMS TO SUPPRESS IMMUNE 845 00:31:12,251 --> 00:31:16,122 SIGNALING WE HAD TO TURN BACK TO 846 00:31:16,122 --> 00:31:17,523 PREVIOUS STUDIES IN WHICH WE TRY 847 00:31:17,523 --> 00:31:19,425 TO PUT IN THIS BROADER CONTEXT 848 00:31:19,425 --> 00:31:20,826 TO UNDERSTAND HOW IS IT WORKING 849 00:31:20,826 --> 00:31:23,262 AND WHAT IS NEEDED FOR INDUCING 850 00:31:23,262 --> 00:31:24,363 IMMUNE SIGNALING IN AND OVER THE 851 00:31:24,363 --> 00:31:26,298 YORES WE HAVE DONE IN THIS A 852 00:31:26,298 --> 00:31:27,032 NUMBER OF WAYS. 853 00:31:27,032 --> 00:31:27,933 WE HAVE USED DIFFERENT METHODS 854 00:31:27,933 --> 00:31:30,069 THAT ARE AVAILABLE TO US TO 855 00:31:30,069 --> 00:31:32,471 STUDY LOCAL PROTEIN INTERACTIONS 856 00:31:32,471 --> 00:31:33,973 OR GLOBAL PROTEIN INTERACTION, 857 00:31:33,973 --> 00:31:35,908 AND ACTUALLY MORE RECENTLY, WE 858 00:31:35,908 --> 00:31:38,544 MOVE MORE AND MORE TOWARDS 859 00:31:38,544 --> 00:31:40,179 UNDERSTANDING OR CAPTURING 860 00:31:40,179 --> 00:31:41,914 PROTEIN INTERACTION NETWORKS AT 861 00:31:41,914 --> 00:31:42,882 THE SYSTEMS LEVEL, BECAUSE WE 862 00:31:42,882 --> 00:31:44,884 STARTED TO APPRECIATE IF WE WANT 863 00:31:44,884 --> 00:31:45,551 TO UNDERSTAND ORGANELLE 864 00:31:45,551 --> 00:31:47,253 REMODELING AND HOW THINGS ARE 865 00:31:47,253 --> 00:31:48,988 COORDINATED WE ACTUALLY NEED TO 866 00:31:48,988 --> 00:31:50,322 CAPTURE AN INTERACTION NETWORK 867 00:31:50,322 --> 00:31:51,056 MORE BROADLY. 868 00:31:51,056 --> 00:31:56,495 AND FOR THIS, WE USE METHOD 869 00:31:56,495 --> 00:31:58,664 CALLED THERMAL CO AGGREGATION 870 00:31:58,664 --> 00:32:02,835 PROTILES, OF WHICH SOME CAN BE 871 00:32:02,835 --> 00:32:03,669 CELLS OR TISSUES. 872 00:32:03,669 --> 00:32:05,070 THE SAMPLE IS SUBJECTED TO 873 00:32:05,070 --> 00:32:06,472 INCREASING TURNL AND FOR EACH 874 00:32:06,472 --> 00:32:08,974 TEMPERATURE, YOU TAKE THE 875 00:32:08,974 --> 00:32:10,242 REMAINING SOLUBLE FRACTION AND 876 00:32:10,242 --> 00:32:12,444 ANALYZE IT BY MASS SPECTROMETRY 877 00:32:12,444 --> 00:32:13,746 SO THE DAILY BASIS THEA WOULD 878 00:32:13,746 --> 00:32:16,248 LIKE LIKE THIS, IT WOULD BE 879 00:32:16,248 --> 00:32:16,916 ABNORMALITIES BROIGATION PROFILE 880 00:32:16,916 --> 00:32:17,917 BECAUSE AS THE TEMPERATURE 881 00:32:17,917 --> 00:32:19,084 INCREASES HAVE YOU LESS AND LESS 882 00:32:19,084 --> 00:32:20,853 OF THE PROTEIN, IT BECOMES MORE 883 00:32:20,853 --> 00:32:22,721 AGGREGATED SO HAVE YOU LESS IN 884 00:32:22,721 --> 00:32:23,656 THE SOLUBLE FRACTION, BUT YOU 885 00:32:23,656 --> 00:32:25,925 CAN LOOK AT THE SIMILARITIES OF 886 00:32:25,925 --> 00:32:29,395 THIS CURVE TO START PREDICTING 887 00:32:29,395 --> 00:32:30,429 INTERACTIONS BECAUSE WHEN 888 00:32:30,429 --> 00:32:31,897 PROTEINS ARE TOGETHER AS A 889 00:32:31,897 --> 00:32:33,866 COMPLEX, THEY DON'T BEHAVE AS 890 00:32:33,866 --> 00:32:34,934 SEPARATE ENTITIES BUT RATHER 891 00:32:34,934 --> 00:32:36,235 THEY BECOME THAT UNIT AND THEY 892 00:32:36,235 --> 00:32:38,637 HAVE THE PROPERTIES OF THAT 893 00:32:38,637 --> 00:32:39,805 COMPLEX UNIT. 894 00:32:39,805 --> 00:32:48,647 SO THEREFORE THEY HAVE SIMILAR 895 00:32:48,647 --> 00:32:49,481 ABNORMALITIES BROIGATION 896 00:32:49,481 --> 00:32:50,382 PROTILES. 897 00:32:50,382 --> 00:32:51,984 SO FEDERALLY WE USE IT TO STUDY 898 00:32:51,984 --> 00:32:53,452 INTERN ACTIVITIES AND 899 00:32:53,452 --> 00:32:54,954 PROJECTSIZATION RECEPTOR, WE 900 00:32:54,954 --> 00:32:56,822 USED IT FOR HSV1 AND I WILL COME 901 00:32:56,822 --> 00:33:00,025 BACK TO THAT AND WE MORE 902 00:33:00,025 --> 00:33:03,229 RECENTLY USE IT TO STUDY AN 903 00:33:03,229 --> 00:33:04,296 ASSOCIATED VIRUS BUT THE REASON 904 00:33:04,296 --> 00:33:06,165 WHY THERE ARE LABS THAT 905 00:33:06,165 --> 00:33:09,535 AREOOSING THIS TECHNIQUE IS 906 00:33:09,535 --> 00:33:10,569 BECAUSE THESE AGGREGATION 907 00:33:10,569 --> 00:33:12,037 PROFILES ARE A REALLY A MESS TO 908 00:33:12,037 --> 00:33:13,539 STUDY, THEY ARE COMPLEX, IT'S 909 00:33:13,539 --> 00:33:16,075 VERY HARD TO DECIPHER KIND OF 910 00:33:16,075 --> 00:33:17,843 WHAT THIS MEANS IN TERMS OF 911 00:33:17,843 --> 00:33:19,111 PROTEIN INTERACTIONS AND YOU 912 00:33:19,111 --> 00:33:20,980 NEED REALLY GOOD COMPUTATIONAL 913 00:33:20,980 --> 00:33:25,484 SKILLS AND POWER TO ANALYZE 914 00:33:25,484 --> 00:33:27,586 THIS. 915 00:33:27,586 --> 00:33:33,359 SO TAVIS REED, A Ph.D. IN MY 916 00:33:33,359 --> 00:33:36,228 LAB, HE DEVELOPED A MACHINE 917 00:33:36,228 --> 00:33:38,430 LEARNING COMPUTATIONAL PLATFORM 918 00:33:38,430 --> 00:33:40,633 AND IT'S CALLED TAPIOCA, AND HE 919 00:33:40,633 --> 00:33:42,668 DIDN'T UNDERSTAND WHAT TPCA 920 00:33:42,668 --> 00:33:46,238 MEANS SO HE CALL TODAY TAPIOCA, 921 00:33:46,238 --> 00:33:49,375 AND I SAID OKAY, WE WILL CALL IT 922 00:33:49,375 --> 00:33:53,479 TAPIOCA, SO TO USE LOGISTIC 923 00:33:53,479 --> 00:33:55,914 MODELS TO INTEGRATE SUBSETS OF 924 00:33:55,914 --> 00:33:58,183 DYNAMIC DATA FROM TPCA WITH 925 00:33:58,183 --> 00:33:59,918 DIFFERENT STATIC DATA FROM 926 00:33:59,918 --> 00:34:01,420 TISSUE SPECIFIC FUNCTIONAL 927 00:34:01,420 --> 00:34:03,689 NETWORKS AND DOMAINS OF THE 928 00:34:03,689 --> 00:34:04,623 PROTEINS AND PREDICTED PHYSICAL 929 00:34:04,623 --> 00:34:05,724 PROPERTIES OF THE PROTEINS AND 930 00:34:05,724 --> 00:34:10,396 HE SHOWED HOW USING THIS, YOU 931 00:34:10,396 --> 00:34:11,430 CAN DECONVOLUNTEERSUTE THIS 932 00:34:11,430 --> 00:34:13,032 COMPLEX DATA AND IT DOESN'T 933 00:34:13,032 --> 00:34:14,133 MATTER HOW FULLY ABOUT HAIFED 934 00:34:14,133 --> 00:34:16,168 THE PROTEIN IS AND YOU CAN USE 935 00:34:16,168 --> 00:34:17,603 THIS TO PREDICT DENOVAE 936 00:34:17,603 --> 00:34:18,570 INTERACTIONS AND COMING BACK, 937 00:34:18,570 --> 00:34:24,843 WHY THAT MATTERED TO OUR IL516 938 00:34:24,843 --> 00:34:26,312 STORY AND LACTYALATION STORY, IS 939 00:34:26,312 --> 00:34:27,946 THAT WE USE THAT TO UNDERSTAND 940 00:34:27,946 --> 00:34:30,649 THE UNDERACTION AND IT ALLOWED 941 00:34:30,649 --> 00:34:31,850 US TO CHARACTERIZE IT. 942 00:34:31,850 --> 00:34:34,820 SO TO SUMMARIZE A BIT, WE AND 943 00:34:34,820 --> 00:34:38,090 OTHER VS SHOWN THAT THIS CAN 944 00:34:38,090 --> 00:34:39,725 SENSE NUCLEAR VIRAL DNA AND HE 945 00:34:39,725 --> 00:34:42,194 DOES THAT BY LOCALIZING THE 946 00:34:42,194 --> 00:34:45,030 PERIPHERY HERE, AND INSERTS THE 947 00:34:45,030 --> 00:34:48,901 VIRAL DNA HERE, AS IT LOCALIZES 948 00:34:48,901 --> 00:34:49,134 HERE. 949 00:34:49,134 --> 00:34:51,970 IN MORE RECENT YEARS WE SHOWED 950 00:34:51,970 --> 00:34:56,742 HOW I516 IN THE PERIPHERY 951 00:34:56,742 --> 00:34:59,845 RECRUIT THE DNA DAMAGE WHICH IN 952 00:34:59,845 --> 00:35:01,914 TERMS PHOSPHORYLATES IFI16 IN 953 00:35:01,914 --> 00:35:03,215 THIS DISORDER REGION THAT WE 954 00:35:03,215 --> 00:35:06,018 JUST TALKED ABOUT. 955 00:35:06,018 --> 00:35:06,852 AND THAT PHOSPHORYLATION WAS 956 00:35:06,852 --> 00:35:08,487 SHOWN TO BE NECESSARY FOR THE 957 00:35:08,487 --> 00:35:09,555 ABILITY TO INDUCE IMMUNE 958 00:35:09,555 --> 00:35:12,324 SIGNALING SO IT ADDS TO THIS 959 00:35:12,324 --> 00:35:13,992 GROWING UNDERSTANDS OF ACROSS 960 00:35:13,992 --> 00:35:16,295 TALK BETWEEN DNA SENSING AND DNA 961 00:35:16,295 --> 00:35:18,130 DAMAGE RESPONSE IN IMMUNE 962 00:35:18,130 --> 00:35:18,464 SIGNALING. 963 00:35:18,464 --> 00:35:21,233 SO WE ALREADY KNEW THAT THIS 964 00:35:21,233 --> 00:35:22,267 INTRINSICALLY DISORDER REGION IS 965 00:35:22,267 --> 00:35:25,037 SO IMPORTANT FOR THE ABILITY OF 966 00:35:25,037 --> 00:35:26,472 THIS TO INDUCE IMMUNE SIGNALING 967 00:35:26,472 --> 00:35:28,307 AND THAT IT'S DECORATED WITH 968 00:35:28,307 --> 00:35:31,377 THIS PHOSPHORYLATION SITE AS 969 00:35:31,377 --> 00:35:32,211 WELL AS ADDITIONAL 970 00:35:32,211 --> 00:35:32,911 PHOSPHORYLATION SITE AND THAT 971 00:35:32,911 --> 00:35:34,947 WAY IN MY LAB AND MORE RECENTLY 972 00:35:34,947 --> 00:35:37,383 HAS SHOWN THAT THOSE NUMEROUS 973 00:35:37,383 --> 00:35:39,218 PHOSPHORYLATIONS IN THE 974 00:35:39,218 --> 00:35:39,918 INTRINSICALLY DISORDERED REGION 975 00:35:39,918 --> 00:35:40,886 CAN EXPLAIN SOMETHING WE NOTICE 976 00:35:40,886 --> 00:35:42,421 FOR MANY YEARS FOR THIS PROTEIN, 977 00:35:42,421 --> 00:35:45,057 THAT ONCE IT BINDS TO VIRAL DNA, 978 00:35:45,057 --> 00:35:47,526 IT HAS THESE REALLY STRIKING 3 979 00:35:47,526 --> 00:35:52,231 DYNAMIC BEHAVIOR THAT STARTS TO 980 00:35:52,231 --> 00:35:53,432 FORM THIS STRUCTURE AND WE 981 00:35:53,432 --> 00:35:57,469 COULDN'T UNDERSTAND WHAT THAT 982 00:35:57,469 --> 00:35:59,505 MEANS. 983 00:35:59,505 --> 00:36:01,874 AND DAWEI SHOWED THAT THIS 984 00:36:01,874 --> 00:36:05,711 HAPPENS ON THE LESION, AND IT 985 00:36:05,711 --> 00:36:07,246 UNDERGOES SEPARATION AND THIS 986 00:36:07,246 --> 00:36:08,981 DYNAMIC BEHAVIOR AND HOW THIS IS 987 00:36:08,981 --> 00:36:10,482 IMPORTANT FOR INDUCING SIGNALING 988 00:36:10,482 --> 00:36:12,518 SO WE KNOW IN THAT REGION, THAT 989 00:36:12,518 --> 00:36:14,319 DISORDER REGION IS IMPORTANT AND 990 00:36:14,319 --> 00:36:15,721 REGULATED BY POST TRANSLATIONAL 991 00:36:15,721 --> 00:36:16,922 MODIFICATIONS AND NOW SUDDENLY 992 00:36:16,922 --> 00:36:21,260 WE KNOW THAT IT'S ALSO 993 00:36:21,260 --> 00:36:23,295 LACTYLATATED AND HOW IT CAN 994 00:36:23,295 --> 00:36:24,830 SUPPRESS THE CYSTINE IMMUNE 995 00:36:24,830 --> 00:36:25,097 SIGNALING. 996 00:36:25,097 --> 00:36:27,599 SO THEREFORE WE WENT BACK TO OUR 997 00:36:27,599 --> 00:36:29,501 TPCA DATA SET TO FIND OUT WHAT 998 00:36:29,501 --> 00:36:33,739 INTERACTIONS ARE AFFECTED BY THE 999 00:36:33,739 --> 00:36:34,907 LACTYLATION SITE AND IN LOOKINGA 1000 00:36:34,907 --> 00:36:40,612 THE THIS, IT ACTUALLY WHEN WE 1001 00:36:40,612 --> 00:36:43,348 USE THE LACTY-MIMIC, IFI16 HAS 1002 00:36:43,348 --> 00:36:45,317 IMPEDED ABILITY TO RECRUIT THE 1003 00:36:45,317 --> 00:36:47,319 DNA PK AT THE NUCLEAR PERIPHERY 1004 00:36:47,319 --> 00:36:50,756 AND AS I TOLD YOU THE DNA IS 1005 00:36:50,756 --> 00:36:52,391 NEEDED FOR POSFORALATING IK516, 1006 00:36:52,391 --> 00:36:55,461 SO NOW WE UNDERSTAND THAT 1007 00:36:55,461 --> 00:36:57,663 LACTATE IS VIRAL FOR SEQUENCE 1008 00:36:57,663 --> 00:37:01,600 ROUNDS OF REPLICATION AND IN 1009 00:37:01,600 --> 00:37:03,902 PART, THIS IS THROUGH THE HOST 1010 00:37:03,902 --> 00:37:05,404 IMMUNE FACTOR EXPTION 1011 00:37:05,404 --> 00:37:05,971 SUPPRESSION EVER CYTOKINE 1012 00:37:05,971 --> 00:37:06,905 EXPRESSION AND WE STARTED TO 1013 00:37:06,905 --> 00:37:08,340 LOOK AT WHAT ENZYMES ARE 1014 00:37:08,340 --> 00:37:12,444 REGULATING THIS AND THAT'S KIND 1015 00:37:12,444 --> 00:37:12,945 OF ANOTHER STORY. 1016 00:37:12,945 --> 00:37:15,013 BUT I WANT TO SPEND A BIT OF 1017 00:37:15,013 --> 00:37:16,281 TIME, THE REMAINING PART OF TIME 1018 00:37:16,281 --> 00:37:17,916 TO START TO PUT THESE FINDINGS 1019 00:37:17,916 --> 00:37:18,884 IN THE BROADER PICTURE BECAUSE 1020 00:37:18,884 --> 00:37:21,954 WHAT I TOLD YOU ABOUT LACTATE IT 1021 00:37:21,954 --> 00:37:23,789 BROUGHT A NEW PERSPECTIVE TO OUR 1022 00:37:23,789 --> 00:37:26,358 LONG-TERM INTEREST IN 1023 00:37:26,358 --> 00:37:27,192 UNDERSTANDING HOW ALL THESE 1024 00:37:27,192 --> 00:37:28,160 CHANGES THAT I'M TELLING YOU 1025 00:37:28,160 --> 00:37:30,629 ABOUT IN THE INFECTED CELL, HOW 1026 00:37:30,629 --> 00:37:31,897 ARE THEY CONVAIPED TO THE 1027 00:37:31,897 --> 00:37:32,865 ENVIRONMENT OF THE CELL, TO THE 1028 00:37:32,865 --> 00:37:34,967 CELLS THAT ARE IN THE IMMEDIATE 1029 00:37:34,967 --> 00:37:37,369 PROXIMITY OR THOSE THAT ARE 1030 00:37:37,369 --> 00:37:39,304 FURTHER AWAY, HOW IS THIS 1031 00:37:39,304 --> 00:37:41,440 INFECTED CELL CHANGING ITS 1032 00:37:41,440 --> 00:37:41,907 ENVIRONMENT. 1033 00:37:41,907 --> 00:37:45,477 AND THE LACTATE OF COURSE PLAYS 1034 00:37:45,477 --> 00:37:46,645 A ROLE IN THIS. 1035 00:37:46,645 --> 00:37:48,180 SO A FEW YEARS AGO WE TRY TO 1036 00:37:48,180 --> 00:37:50,215 ADDRESS THIS TO DESIGN A METHOD 1037 00:37:50,215 --> 00:37:52,150 FOR SEPARATING THE CELLS BASED 1038 00:37:52,150 --> 00:37:54,453 ON HOW CLOSE OR FAR THEY ARE 1039 00:37:54,453 --> 00:37:55,888 FROM AN INFECTION SITE TO REALLY 1040 00:37:55,888 --> 00:37:57,856 TART TO TACKLE THIS QUESTION OF 1041 00:37:57,856 --> 00:37:58,957 THE VIRUS MICROENVIRONMENT, TO 1042 00:37:58,957 --> 00:38:00,993 SEPARATE THE CELLS AND START TO 1043 00:38:00,993 --> 00:38:02,060 CHARACTERIZE THEM AND IN ORDER 1044 00:38:02,060 --> 00:38:05,497 TO DO THIS, WE ADAPTED A METHOD 1045 00:38:05,497 --> 00:38:07,366 THAT WAS PREVIOUSLY USED FOR 1046 00:38:07,366 --> 00:38:08,033 STUDYING THE TUMOR 1047 00:38:08,033 --> 00:38:08,667 MICROENVIRONMENT, SO LAWEDDER 1048 00:38:08,667 --> 00:38:11,603 DALE WE DID WAS TO GENERATE 1049 00:38:11,603 --> 00:38:14,773 FIBROBLASTS, THAT EXPRESS AN 1050 00:38:14,773 --> 00:38:16,808 M-CHERRY PROTEIN, SECRETARY 1051 00:38:16,808 --> 00:38:18,243 PEPTIDE AND MAKING THESE RED 1052 00:38:18,243 --> 00:38:19,645 CELLS, WHICH WE THEN INFECTED 1053 00:38:19,645 --> 00:38:24,917 WITH 1 OF OUR GREEN FLUORESCENT 1054 00:38:24,917 --> 00:38:26,618 VIRUS, CREATING THESE DULY 1055 00:38:26,618 --> 00:38:30,155 FORESTIMATE THADENT CELLS, RED 1056 00:38:30,155 --> 00:38:30,656 AND GREEN. 1057 00:38:30,656 --> 00:38:32,758 AND THEN WE CAREFULLY OPTIMIZE 1058 00:38:32,758 --> 00:38:34,293 THE COCULTURES OF WILD-TYPE 1059 00:38:34,293 --> 00:38:38,330 CELLS IN AN ORDER TO ALLOW FOR 1060 00:38:38,330 --> 00:38:39,998 THE SPREAD OF THIS MCHERRY 1061 00:38:39,998 --> 00:38:41,333 SIGNAL PEPTIDE, PRIOR TO THE 1062 00:38:41,333 --> 00:38:43,235 SPREAD OF AN INFECTION, SO IN 1063 00:38:43,235 --> 00:38:44,870 OTHER WORDS, WE WILL HAVE THE 1064 00:38:44,870 --> 00:38:46,505 INFECTED CELLS THAT ARE GREEN 1065 00:38:46,505 --> 00:38:47,873 AND RED, THE NEIGHBORS CELLS 1066 00:38:47,873 --> 00:38:49,641 THAT ARE RED AND THOSE THAT ARE 1067 00:38:49,641 --> 00:38:51,476 FURTHER AWAY, THAT ARE NOT 1068 00:38:51,476 --> 00:38:51,710 LABELED. 1069 00:38:51,710 --> 00:38:55,547 AND THEN WE CAN USE FLUORESCENCE 1070 00:38:55,547 --> 00:38:57,082 ACTIVATED CELL SORTING TO SORT 1071 00:38:57,082 --> 00:38:59,484 THE CELL POPULATION AND THEN USE 1072 00:38:59,484 --> 00:39:01,119 PROTEOMICS THAT USE MASS 1073 00:39:01,119 --> 00:39:02,187 SPECTROMETRY TO CHARACTERIZE THE 1074 00:39:02,187 --> 00:39:03,155 COMPOSITION BUT ALSO DO 1075 00:39:03,155 --> 00:39:06,458 FUNCTIONAL STUDIES ON THE 1076 00:39:06,458 --> 00:39:07,359 SEPARATED CELL POPULATIONS. 1077 00:39:07,359 --> 00:39:10,228 SO WHAT WE DISCOVERED WAS THAT A 1078 00:39:10,228 --> 00:39:11,296 FEW REALLY INTERESTING THINGS, 1079 00:39:11,296 --> 00:39:15,434 SO IN THE INFECTED CELL AS WE 1080 00:39:15,434 --> 00:39:17,536 EXPECTED ACMV HAS MECHANISMS FOR 1081 00:39:17,536 --> 00:39:18,470 SUPPRESSING IMMUNE SIGNALING SO 1082 00:39:18,470 --> 00:39:22,708 WE FOUND THAT IMMUNE FACTORS ARE 1083 00:39:22,708 --> 00:39:24,209 DECREASED HOWEVER, WE FOUND THAT 1084 00:39:24,209 --> 00:39:26,411 THE NEIGHBORING CELLS ALSO HAD 1085 00:39:26,411 --> 00:39:28,447 DAMPENED IMMUNE SIGNALING AND 1086 00:39:28,447 --> 00:39:29,748 THAT THE DISTAL CELLS WERE THE 1087 00:39:29,748 --> 00:39:33,051 1S THAT ACTUALLY HAD ENHANCED 1088 00:39:33,051 --> 00:39:34,119 IMMUNE FACTORS. 1089 00:39:34,119 --> 00:39:34,853 THE MEMBRANE CONTEXT SITES THAT 1090 00:39:34,853 --> 00:39:37,289 I TOLD YOU ABOUT EARLIER, THAT 1091 00:39:37,289 --> 00:39:39,825 REPRESENT ALL THOSE ORGANELLE, 1092 00:39:39,825 --> 00:39:41,026 ORGANELLE CONTACTS, WE FOUND 1093 00:39:41,026 --> 00:39:42,594 THEY WERE REMODELED IN INFECTED 1094 00:39:42,594 --> 00:39:44,830 CELLS BUT WE ALSO FOUND THAT THE 1095 00:39:44,830 --> 00:39:46,331 SPECIFIC SUBSET OF THESE 1096 00:39:46,331 --> 00:39:48,066 MEMBRANE CONTEXT SITES WERE ALSO 1097 00:39:48,066 --> 00:39:49,368 CHANGED IN NEIGHBORING CELLS CAN 1098 00:39:49,368 --> 00:39:53,005 AND THEN THEY WERE NORMAL AND 1099 00:39:53,005 --> 00:39:53,238 DISTAL. 1100 00:39:53,238 --> 00:39:54,573 AND FINALLY PROBABLY THE MOST 1101 00:39:54,573 --> 00:39:56,875 PUZZLING 1 IS YES, WE KNOW THAT 1102 00:39:56,875 --> 00:39:58,377 VIRUSES TARGET THE CELL CYCLE 1103 00:39:58,377 --> 00:40:01,546 AND THAT THEY ARREST ACMV FOR 1104 00:40:01,546 --> 00:40:05,083 EXAMPLE, ARREST CELLS AT G1 AS 1105 00:40:05,083 --> 00:40:07,719 INTERPHASE IN ORDER TO INSURE 1106 00:40:07,719 --> 00:40:09,655 ITS NUCLEAR DNA REPLICATION, BUT 1107 00:40:09,655 --> 00:40:11,990 WE FOUND THAT THE NEIGHBORING 1108 00:40:11,990 --> 00:40:14,660 CELLS GET ARRESTED IN MITOSIS IN 1109 00:40:14,660 --> 00:40:15,427 M-PHASE. 1110 00:40:15,427 --> 00:40:17,896 SO NOW WITH THE STORY I TOLD YOU 1111 00:40:17,896 --> 00:40:19,431 BROUGHT A NEW PERSPECTIVE FROM 1112 00:40:19,431 --> 00:40:20,732 THIS, NOW WE UNDERSTAND THAT IT 1113 00:40:20,732 --> 00:40:23,235 CAN BE ADDED TO IMMUNE SIGNALING 1114 00:40:23,235 --> 00:40:24,369 TO IMMUNE FACTORS AND THAT CAN 1115 00:40:24,369 --> 00:40:26,972 ALSO THE FACT THAT IT'S SECRETED 1116 00:40:26,972 --> 00:40:29,675 THEN PRODUCING SUCH LARGE AMOUNT 1117 00:40:29,675 --> 00:40:31,243 CANS DAMPEN THE IMMUNE RESPONSE 1118 00:40:31,243 --> 00:40:31,910 SO PROBABLY IT CONTRIBUTED TO 1119 00:40:31,910 --> 00:40:35,614 THIS EFFECT THAT WE SEE HERE. 1120 00:40:35,614 --> 00:40:37,816 BUT WE ALSO WONDERED, WELL, WHAT 1121 00:40:37,816 --> 00:40:39,551 ABOUT ALL THESE CHANGES IN 1122 00:40:39,551 --> 00:40:42,054 NEIGHBORING CELLS THAT SEEM TO 1123 00:40:42,054 --> 00:40:44,456 BE SOMEHOW PRIMED WITH ALL THESE 1124 00:40:44,456 --> 00:40:44,790 CHANGES. 1125 00:40:44,790 --> 00:40:46,324 WHAT IS THE RELEVANCE OF THESE 1126 00:40:46,324 --> 00:40:48,460 CHANGES TO CO INFECTIONS SORE TO 1127 00:40:48,460 --> 00:40:49,528 DISEASE PROGRESSION AND THE 1128 00:40:49,528 --> 00:40:51,163 REASON WE ARE INTERESTED IN CO 1129 00:40:51,163 --> 00:40:53,932 INFECTION AS I SAID, ACMV INFECT 1130 00:40:53,932 --> 00:40:55,434 SO MANY DIFFERENT CELL TYPES AND 1131 00:40:55,434 --> 00:40:56,835 SO MANY TISSUES AND IS KNOWN 1132 00:40:56,835 --> 00:40:58,570 THAT THOSE CAN BE INFECT WIDE 1133 00:40:58,570 --> 00:40:59,771 MANY OTHER VIRUSES AND THERE'S A 1134 00:40:59,771 --> 00:41:03,041 LOT OF INTEREST OF COURSE, IN 1135 00:41:03,041 --> 00:41:04,543 THE LINK BETWEEN CO INFECTIONS 1136 00:41:04,543 --> 00:41:06,778 AND MORBIDITY AND DECREASED 1137 00:41:06,778 --> 00:41:07,579 IMMUNITY, CANCER DEVELOPMENT AND 1138 00:41:07,579 --> 00:41:07,946 SO ON. 1139 00:41:07,946 --> 00:41:14,586 SO WHAT WE DID WAS TO GENERATE 1140 00:41:14,586 --> 00:41:15,387 AGAIN, OUR VIRUS, 1141 00:41:15,387 --> 00:41:16,655 MICROENVIRONMENT AND THEN TEST 1142 00:41:16,655 --> 00:41:17,723 THE SUSCEPTIBILITY TO INFECTION. 1143 00:41:17,723 --> 00:41:21,493 SO THIS IS A VIRUS 1144 00:41:21,493 --> 00:41:22,627 MICROENVIRONMENT FROM ACMV, AND 1145 00:41:22,627 --> 00:41:25,163 WHAT WE FOUND IS THAT CELLS 1146 00:41:25,163 --> 00:41:28,033 NEIGHBORING THE SITE OF ACMV 1147 00:41:28,033 --> 00:41:29,668 INFECTION ARE MOSTLY SUSCEPTIBLE 1148 00:41:29,668 --> 00:41:32,771 TO INFECTION NOT ONLY WITH ACMV 1149 00:41:32,771 --> 00:41:34,973 BUT ALSO WITH HSV1, AND ALSO 1150 00:41:34,973 --> 00:41:37,743 WITH INFLUENZA A. 1151 00:41:37,743 --> 00:41:39,244 SO ANOTHER NUCLEAR REPLICATING 1152 00:41:39,244 --> 00:41:41,012 VIRUS BUT AN RNA VIRUS. 1153 00:41:41,012 --> 00:41:43,749 WE INITIALLY DID THIS LOOKING AT 1154 00:41:43,749 --> 00:41:44,950 FIBROBLASTS SURROUNDED BY 1155 00:41:44,950 --> 00:41:46,184 FIBROBLASTS SO AT LEAST THE 1156 00:41:46,184 --> 00:41:47,552 CELLS BACKGROUND IS KEPT 1157 00:41:47,552 --> 00:41:48,620 CONSISTENT BUT THEN WE STARTED 1158 00:41:48,620 --> 00:41:51,256 TO ALSO LOOK AT CELLS SURROUNDED 1159 00:41:51,256 --> 00:41:53,225 DIFFERENCE INTERACTIONS BETWEEN 1160 00:41:53,225 --> 00:41:54,159 FIEBLOBLAST AND EPITHELIAL CELLS 1161 00:41:54,159 --> 00:41:56,261 AND WE FIND AGAIN THAT 1162 00:41:56,261 --> 00:41:58,330 EPITHELIAL CELLS SURROUNDED ARE 1163 00:41:58,330 --> 00:42:00,398 MORE SUSCEPTIBLE TO INFECTION 1164 00:42:00,398 --> 00:42:03,034 WITH VIRUSES AS I'M SHOWING 1165 00:42:03,034 --> 00:42:03,368 HERE. 1166 00:42:03,368 --> 00:42:05,270 SO CLEARLY VIRAL INFECTION 1167 00:42:05,270 --> 00:42:06,638 RESHAPING THE MICROENVIRONMENT 1168 00:42:06,638 --> 00:42:08,073 TO FACILITATE PROGRESSION OF 1169 00:42:08,073 --> 00:42:11,443 INFECTION AND WE START TO HAVE 1170 00:42:11,443 --> 00:42:14,045 EVIDENCE THAT SOME OF THESE 1171 00:42:14,045 --> 00:42:15,413 CHANGES MAY BE LINKED TO 1172 00:42:15,413 --> 00:42:16,481 PROPERTIES BECAUSE WE HAVE 1173 00:42:16,481 --> 00:42:21,186 SCIENCE THAT THERE MAY BE 1174 00:42:21,186 --> 00:42:21,920 GENOMIC INSTABILITY IN THESE 1175 00:42:21,920 --> 00:42:25,023 CELLS AND ALSO THE CELL CYCLE 1176 00:42:25,023 --> 00:42:25,323 DISTURBANCE. 1177 00:42:25,323 --> 00:42:26,625 SO THEREFORE GOING FORWARD, WE 1178 00:42:26,625 --> 00:42:29,561 STARTED NOW TO ADOPT THIS TO 1179 00:42:29,561 --> 00:42:32,063 LOOK AT CELL TO CELL 1180 00:42:32,063 --> 00:42:33,465 COMMUNICATION AS IT OCCURRED IN 1181 00:42:33,465 --> 00:42:35,767 THE TISSUE, SO LOOKING AT DIRECT 1182 00:42:35,767 --> 00:42:39,838 CELL TO CELL CONTACTS SO CRYSTAL 1183 00:42:39,838 --> 00:42:43,175 IN MY LAB, LOOKING FOR RIKE 1184 00:42:43,175 --> 00:42:44,776 ROUGH ATOM ENVIRONMENT, AND 1185 00:42:44,776 --> 00:42:46,945 SHOWING 1 EXAMPLE HERE IN 1186 00:42:46,945 --> 00:42:48,413 PATIENT DERIVED COLORECTAL 1187 00:42:48,413 --> 00:42:49,414 CANCER ORGANOID NCH YOU CAN SEE 1188 00:42:49,414 --> 00:42:51,016 HOW SHE CAN MONITOR DIFFERENT 1189 00:42:51,016 --> 00:42:54,286 STAGES OF AN INFECTION IN THIS 1190 00:42:54,286 --> 00:42:56,388 ORGANOID AS AS IT PROGRESSES AND 1191 00:42:56,388 --> 00:42:57,989 THEN SHE WENT AHEAD TO PROGRESS 1192 00:42:57,989 --> 00:42:59,324 THESE CELLS TO CHARKTIZE THEM. 1193 00:42:59,324 --> 00:43:00,525 SO SINCE I WANT TO LEAVE A LOT 1194 00:43:00,525 --> 00:43:01,860 OF TIME FOR QUESTIONS, I AM 1195 00:43:01,860 --> 00:43:06,665 GOING TO FINISH TO SAY THAT I 1196 00:43:06,665 --> 00:43:09,668 HOPE I SHOWED YOU HOW WE CAN 1197 00:43:09,668 --> 00:43:11,102 INTEGRATE MOTE I DON'T MEANIC 1198 00:43:11,102 --> 00:43:12,437 AND VIROLOGY STUDIES AND 1199 00:43:12,437 --> 00:43:13,705 MICROSCOPY STUDIES TO START TO 1200 00:43:13,705 --> 00:43:14,973 LOOK AT CELLULAR COMMUNICATION 1201 00:43:14,973 --> 00:43:17,275 DURING INFECTION AND THAT WE 1202 00:43:17,275 --> 00:43:19,411 LOOKED AT CELLULAR COMMUNICATION 1203 00:43:19,411 --> 00:43:22,347 EITHER AT THE INTRACELLULAR, OR 1204 00:43:22,347 --> 00:43:24,549 INTRACELLULAR LEVEL, WE LOOKEDDA 1205 00:43:24,549 --> 00:43:25,483 THE ORGANELLE, ORGANELLE 1206 00:43:25,483 --> 00:43:29,087 CONTACTS THAT ARE FACILITATED 1207 00:43:29,087 --> 00:43:29,955 AND/OR FACILITATING ORGANELLE 1208 00:43:29,955 --> 00:43:32,524 REMODELING AND HOW THIS LED TO 1209 00:43:32,524 --> 00:43:37,429 THE DISCOVERY OF THIS 1210 00:43:37,429 --> 00:43:37,963 MITOCHONDRIA HERE INCAPUE 1211 00:43:37,963 --> 00:43:43,001 SUEALATIONS THAT WE CALLED -- 1212 00:43:43,001 --> 00:43:45,470 INCAPUIZATIONS CALLED MENCs, 1213 00:43:45,470 --> 00:43:48,473 AND THEY INCREASE AND MAINTAIN 1214 00:43:48,473 --> 00:43:49,207 PHOSPHORYLATION, I SHOWED YOU 1215 00:43:49,207 --> 00:43:51,810 HOW THE CHANGES THAT HAPPEN IN 1216 00:43:51,810 --> 00:43:54,980 METABOLISM, ARE INDUCING ALSO 1217 00:43:54,980 --> 00:43:55,814 INCREASED LACTATE PRODUCTION AND 1218 00:43:55,814 --> 00:43:57,649 ALSO WHY THIS IS IMPORTANT AT 1219 00:43:57,649 --> 00:43:58,850 THIS INTERFACE BETWEEN 1220 00:43:58,850 --> 00:44:01,152 DISRUPTION OF METABOLISM AND 1221 00:44:01,152 --> 00:44:03,955 IMMUNE SIGNALING BECAUSE THIS 1222 00:44:03,955 --> 00:44:06,024 INCREASED LACTATE PRODUCTION 1223 00:44:06,024 --> 00:44:07,659 DRIVES LACKAATION OF HOST IMMUNE 1224 00:44:07,659 --> 00:44:09,327 FACTORS OF THESE REGIONS AND 1225 00:44:09,327 --> 00:44:11,663 THIS INHIBITS THEIR ABILITY TO 1226 00:44:11,663 --> 00:44:13,999 INDUCE CYTOKINE PRODUCTION, AND 1227 00:44:13,999 --> 00:44:16,201 HOW WE LEARN WHAT SPECIFIC 1228 00:44:16,201 --> 00:44:19,037 PROTEIN INTERACTIONS ARE 1229 00:44:19,037 --> 00:44:20,505 DISRUPTED USING THESE THERMAL 1230 00:44:20,505 --> 00:44:23,708 PROFILING AND INTERACTION 1231 00:44:23,708 --> 00:44:24,776 NETWORKS, FINALLY, I SHOWED YOU 1232 00:44:24,776 --> 00:44:26,711 HOW WE STARTED TO LOOK AT HOW 1233 00:44:26,711 --> 00:44:27,913 THIS INFORMATION IS CONVEYED TO 1234 00:44:27,913 --> 00:44:28,980 THE ENVIRONMENT AND WHAT'S THE 1235 00:44:28,980 --> 00:44:32,317 IMPACT OF AN INFECTED CELL ON 1236 00:44:32,317 --> 00:44:34,352 ITS NEIGHBORHOOD, AND HOW WE 1237 00:44:34,352 --> 00:44:36,788 FOUND THAT NEIGHBORING CELLS, SO 1238 00:44:36,788 --> 00:44:38,290 CELLS NEIGHBORING IN THE 1239 00:44:38,290 --> 00:44:40,458 INFECTED SITE WITH CELLS INFEBT 1240 00:44:40,458 --> 00:44:42,527 WIDE ACMV, BECOME MORE 1241 00:44:42,527 --> 00:44:45,497 SUSCEPTIBLE TO INFECTION WITH 1242 00:44:45,497 --> 00:44:47,832 HSV1 AND SCMV AND EVEN INFLUENZA 1243 00:44:47,832 --> 00:44:49,334 A AND WE ARE ARE PERFOR THE 1244 00:44:49,334 --> 00:44:51,503 PURPOSING QUITE A FEW STUDIES -- 1245 00:44:51,503 --> 00:44:53,872 PERFORMING QUITE A FEW STUDIES 1246 00:44:53,872 --> 00:44:54,973 WITH THESE MECHANISMS NOW. 1247 00:44:54,973 --> 00:44:56,741 SO WITH THAT I WANT TO THANK MY 1248 00:44:56,741 --> 00:44:58,643 LAB FOR ALL THEIR TREMENDOUS 1249 00:44:58,643 --> 00:44:59,844 WORK, THE FUNDING INCLUDING 1250 00:44:59,844 --> 00:45:04,849 FUNDING FROM THE NIH, FROM NIAID 1251 00:45:04,849 --> 00:45:07,852 AND NIGMS, I RECENTLY BECAME AS 1252 00:45:07,852 --> 00:45:11,489 YOU HEARD, LAST YEAR, I BECAME 1253 00:45:11,489 --> 00:45:18,330 THE EDITOR AND CHIEF OF MCP AND 1254 00:45:18,330 --> 00:45:19,531 INVITE YOU TO A SUMMER 1255 00:45:19,531 --> 00:45:20,432 CONFERENCE THAT WILL BE IN 1256 00:45:20,432 --> 00:45:23,635 BOSTON AND I WANT TO FINISH BY 1257 00:45:23,635 --> 00:45:26,638 SAYING THAT ALSO VERY RECENTLY 1258 00:45:26,638 --> 00:45:30,809 WE LOST ANOTHER PHENOMENAL 1259 00:45:30,809 --> 00:45:33,111 VIROLOGIST DR. THOMAS KRISTIE, 1260 00:45:33,111 --> 00:45:34,245 WHO I HAD THE OPPORTUNITY TO 1261 00:45:34,245 --> 00:45:36,147 WORK WITH AND COLLABORATE AND 1262 00:45:36,147 --> 00:45:38,984 CALL MY FREEND AND HE WILL BE 1263 00:45:38,984 --> 00:45:40,018 ABSOLUTELY DEARLY MISS AND I 1264 00:45:40,018 --> 00:45:41,619 JUST WANT TO SEND MY THOUGHTS 1265 00:45:41,619 --> 00:45:42,354 AND MY APPRECIATION FOR 1266 00:45:42,354 --> 00:45:43,955 EVERYTHING HE HAS DONE FOR THIS 1267 00:45:43,955 --> 00:45:44,222 COMMUNITY. 1268 00:45:44,222 --> 00:45:46,725 SO THANK YOU SO MUCH. 1269 00:45:46,725 --> 00:45:56,968 [ APPLAUSE ] 1270 00:45:56,968 --> 00:45:59,170 >> WELL WE HAVE MICs, WE HAVE 1271 00:45:59,170 --> 00:46:00,572 PLENTY OF QUESTIONS ONLINE. 1272 00:46:00,572 --> 00:46:01,906 CAN YOU TRIBUTE THE DIFFERENT 1273 00:46:01,906 --> 00:46:05,143 VIRUS EFFECTS TO THE LEVELS OF 1274 00:46:05,143 --> 00:46:08,446 THE TYPES OF INTERFEREONSS 1275 00:46:08,446 --> 00:46:08,680 INDUCED? 1276 00:46:08,680 --> 00:46:10,548 >> DIFFERENT VIRUS EFFECTS TO 1277 00:46:10,548 --> 00:46:12,684 TYPES OF INTERFERONS, JUST TO 1278 00:46:12,684 --> 00:46:14,753 CLARIFY ABOUT WHICH 1 IS THE 1279 00:46:14,753 --> 00:46:17,522 QUESTION -- WHAT IT REFERS TO. 1280 00:46:17,522 --> 00:46:18,757 >> IT CAME IN RELATIVELY EARLY 1281 00:46:18,757 --> 00:46:23,061 IN YOUR TALK AND IT'S FROM AN 1282 00:46:23,061 --> 00:46:23,428 IMMUNOLOGIST. 1283 00:46:23,428 --> 00:46:25,463 >> YES, SO THE TYPE OF VIRUSES, 1284 00:46:25,463 --> 00:46:28,900 THE TYPE OF VIRUSES, SAY AGAIN. 1285 00:46:28,900 --> 00:46:30,769 NCAN YOU ATTRIBUTE THE DIFFERENT 1286 00:46:30,769 --> 00:46:33,204 VIRUS EFFECTS TO THE LEVELS OF 1287 00:46:33,204 --> 00:46:37,375 TYPES OF INTERFERONS INDUCED? 1288 00:46:37,375 --> 00:46:38,676 >> OKAY, SO, IF IT'S IN THE 1289 00:46:38,676 --> 00:46:42,180 FIRST PART IT'S PROBABLY ABOUT 1290 00:46:42,180 --> 00:46:43,782 ORGANELLE REMODELING AND HOW 1291 00:46:43,782 --> 00:46:45,417 THOSE DIFFERENT CHANGES IN 1292 00:46:45,417 --> 00:46:49,788 ORGANELLE REMODELING CAN ALSO 1293 00:46:49,788 --> 00:46:50,555 IMPACT IMMUNE SIGNALING. 1294 00:46:50,555 --> 00:46:52,257 SOIME GOING TO SPECULATE AND 1295 00:46:52,257 --> 00:46:53,825 ANSWER THIS IN MANY DIFFERENT 1296 00:46:53,825 --> 00:46:55,493 WAYS BECAUSE I CAN ANSWER FROM 1297 00:46:55,493 --> 00:46:56,694 DIFFERENT PARTS. 1298 00:46:56,694 --> 00:46:57,996 >> I KNOW THIS PERSON I KNOW AND 1299 00:46:57,996 --> 00:47:00,565 MAYBE HE WILL WRITE BACK TO 1300 00:47:00,565 --> 00:47:01,066 CLARIFY. 1301 00:47:01,066 --> 00:47:01,433 >> YES, GREAT. 1302 00:47:01,433 --> 00:47:03,435 SO I CAN ALSO MAYBE JUST SAY 1303 00:47:03,435 --> 00:47:05,336 SOMETHING ABOUT IMMUNE SIGNALING 1304 00:47:05,336 --> 00:47:06,037 AND ORGANELLE REMODELING BECAUSE 1305 00:47:06,037 --> 00:47:07,205 THAT'S SOMETHING WE WERE 1306 00:47:07,205 --> 00:47:08,873 THINKING EACH LET'S SAY FROM THE 1307 00:47:08,873 --> 00:47:11,643 FIRST PART ON MITOCHONDRIA 1308 00:47:11,643 --> 00:47:13,845 REMODELING, YOU KNOW, WE WERE 1309 00:47:13,845 --> 00:47:15,180 LOOKING AT THESE MITOCHONDRIA ER 1310 00:47:15,180 --> 00:47:17,782 CONTACTS AND AS YOU KNOW, A 1311 00:47:17,782 --> 00:47:19,717 RESIDENT OF ER IS IMPORTANT 1312 00:47:19,717 --> 00:47:21,619 PROTEIN THAT IS IMPORTANT FOR 1313 00:47:21,619 --> 00:47:25,990 IMMUNE SIGNALING, SO, WE WERE 1314 00:47:25,990 --> 00:47:27,959 THINKING OKAY, THESE METHIS, C 1315 00:47:27,959 --> 00:47:29,494 FORMATIONS ARE ANTIVIRAL BUT IF 1316 00:47:29,494 --> 00:47:32,530 WE -- IF WE INDUCE THIS CONTACT 1317 00:47:32,530 --> 00:47:34,566 BETWEEN MITOCHONDRIA AND THE ER 1318 00:47:34,566 --> 00:47:37,335 EARLY ON, IT'S NOT ANTIVIRAL, 1319 00:47:37,335 --> 00:47:38,870 IT'S ACTUALLY PROVIRAL BECAUSE 1320 00:47:38,870 --> 00:47:39,437 IT ACTIVATES STING. 1321 00:47:39,437 --> 00:47:42,841 SO IF MITOCHONDRIA IS NOT YET 1322 00:47:42,841 --> 00:47:43,975 FRAGMENTED IT'S FILLA 1323 00:47:43,975 --> 00:47:45,243 METROPOLITAN OS ININATE AND YOU 1324 00:47:45,243 --> 00:47:46,444 ARE YOU'RE FEDDERRING ARTIFICIAL 1325 00:47:46,444 --> 00:47:51,483 TO THE ER, IT ACTIVATES STING. 1326 00:47:51,483 --> 00:47:53,651 SO THAT'S YOU KNOW -- SO THAT 1327 00:47:53,651 --> 00:47:55,753 QUESTION IS ABOUT WHETHER 1328 00:47:55,753 --> 00:47:56,721 ORGANELLE REMODELING AND 1329 00:47:56,721 --> 00:47:57,755 MITOCHONDRIA FRAGMENTATION IS 1330 00:47:57,755 --> 00:47:58,790 ALSO TO SUPPRESS IMMUNE 1331 00:47:58,790 --> 00:47:59,057 SIGNALING. 1332 00:47:59,057 --> 00:48:00,325 - IT IS A POSSIBILITY. 1333 00:48:00,325 --> 00:48:02,160 IT'S ALSO POSSIBLE THERE'S JUST 1334 00:48:02,160 --> 00:48:04,295 SOMETHING TO DO WITH MOTILITY 1335 00:48:04,295 --> 00:48:05,296 AND SO ON. 1336 00:48:05,296 --> 00:48:06,531 BUT MY UNDERSTAND SUGGEST THAT 1337 00:48:06,531 --> 00:48:07,532 THE CLARIFICATION WILL COME 1338 00:48:07,532 --> 00:48:10,802 PRETTY SOON. 1339 00:48:10,802 --> 00:48:10,969 YES. 1340 00:48:10,969 --> 00:48:13,138 >> FANTASTIC TALK. 1341 00:48:13,138 --> 00:48:14,472 I'VE ALWAYS LOVED -- YOUR 1342 00:48:14,472 --> 00:48:16,574 GROWING STORY ON LOOKING AT 1343 00:48:16,574 --> 00:48:18,076 INFECTED VERSUS NEIGHBORING 1344 00:48:18,076 --> 00:48:19,911 VERSE US DISTANT CELLS AND 1345 00:48:19,911 --> 00:48:21,446 REALLY FASCINATING SO WITH THE 1346 00:48:21,446 --> 00:48:23,781 NEIGHBORING CELLS YOU ALSO SEE 1347 00:48:23,781 --> 00:48:24,749 THE MENC CHANGES. 1348 00:48:24,749 --> 00:48:25,850 SO IS THAT, YOU TOUCH OFFICE OF 1349 00:48:25,850 --> 00:48:29,287 DIVERSITY THIS A -- YOU TOUCHED 1350 00:48:29,287 --> 00:48:30,989 ON THAT A LITTLE BIT MAYBE BUT 1351 00:48:30,989 --> 00:48:33,825 IS THAT FROM VIRUS UPTAKE, 1352 00:48:33,825 --> 00:48:35,693 METABOLISM, DAMPENING IMMUNE 1353 00:48:35,693 --> 00:48:38,229 RESPONSE, HOW DIFFERENT IS THAT 1354 00:48:38,229 --> 00:48:40,231 UNINFECTED NEIGHBORING CELL FROM 1355 00:48:40,231 --> 00:48:41,132 AN INFEBTED CELL? 1356 00:48:41,132 --> 00:48:41,933 >> SO IT'S QUITE DIFFERENT AND 1357 00:48:41,933 --> 00:48:44,035 THERE SEEM TO BE ONLY A SUBSET 1358 00:48:44,035 --> 00:48:45,436 OF THOSE MEMBRANE CONTEXT SIDES 1359 00:48:45,436 --> 00:48:46,704 THAT ARE CHANGED AND SOME OF 1360 00:48:46,704 --> 00:48:52,076 THEM SEEM TO BE WITH WITH 1361 00:48:52,076 --> 00:48:53,478 REGULATING TRANSFER SO WE SEE 1362 00:48:53,478 --> 00:48:55,847 ONLY SPECIFIC POOLS OF MEMBRANE 1363 00:48:55,847 --> 00:48:58,149 CONTEXT SIZE THAT ARE CHANGED IN 1364 00:48:58,149 --> 00:48:59,884 UNINFECTED CELLS THAT ARE 1365 00:48:59,884 --> 00:49:01,753 NEIGHBORING IN INFECTED CELLS 1366 00:49:01,753 --> 00:49:02,654 THEY LOOK QUITE DIFFERENT SO 1367 00:49:02,654 --> 00:49:03,988 IT'S SOMETHING TO DO EXACTLY AS 1368 00:49:03,988 --> 00:49:06,057 YOU SAY WITH PRIMING THOSE 1369 00:49:06,057 --> 00:49:07,325 NEIGHBORING CELLS FOR INFECTION, 1370 00:49:07,325 --> 00:49:08,793 SO THAT'S WHY WE HAVE OTHER 1371 00:49:08,793 --> 00:49:10,962 PROJECTS IN THE LAB WHERE WE ARE 1372 00:49:10,962 --> 00:49:13,831 LOOKING NOW AT HOW THESE ARE -- 1373 00:49:13,831 --> 00:49:15,166 CONTRIBUTING TO CHANGES IN 1374 00:49:15,166 --> 00:49:15,967 CELLULAR STATE. 1375 00:49:15,967 --> 00:49:18,636 BECAUSE WE KNOW OF COURSE, 1376 00:49:18,636 --> 00:49:19,938 VIRUSES CAN INDUCE MESENCHYMAL, 1377 00:49:19,938 --> 00:49:20,538 TRANSLATION AND SOMETHING WE 1378 00:49:20,538 --> 00:49:24,609 WERE STUDY NOTHING THE CONTEXT 1379 00:49:24,609 --> 00:49:26,744 OF ACMV INFECTION, BUT OR THE 1380 00:49:26,744 --> 00:49:28,046 OPPOSITE EMT, BUT HOW DO THEY 1381 00:49:28,046 --> 00:49:29,847 CHANGE ALSO THE STATE OF THESE 1382 00:49:29,847 --> 00:49:32,584 NEIGHBORING CELLS AND FURTHER 1383 00:49:32,584 --> 00:49:35,253 MORE, AND THAT AS YOU CAN 1384 00:49:35,253 --> 00:49:38,723 IMAGINE CAN BE QUITE HAS THIS 1385 00:49:38,723 --> 00:49:42,393 IMPLICATIONS AND PATHOLOGIES. 1386 00:49:42,393 --> 00:49:42,594 YEAH. 1387 00:49:42,594 --> 00:49:44,596 >> HI, ILEANA, SO WITH REGARDS 1388 00:49:44,596 --> 00:49:48,600 TO THE MENC PART OF THE STORY. 1389 00:49:48,600 --> 00:49:52,170 TWO QUESTIONS, 1, WHEN THEY 1390 00:49:52,170 --> 00:49:53,238 FIZZ, THE 25% FISSION ON THE 1391 00:49:53,238 --> 00:49:57,041 END, DO YOU SEE LOSS OF 1392 00:49:57,041 --> 00:49:58,109 MITOCHONDRIA POTENTIAL BEFORE 1393 00:49:58,109 --> 00:50:00,745 THE FISSION OR IS THE MENC JUST 1394 00:50:00,745 --> 00:50:02,981 HELPING TO MAINTAIN IT INSTEAD 1395 00:50:02,981 --> 00:50:04,282 OF STORE THE MITOCHONDRIA 1396 00:50:04,282 --> 00:50:05,483 POTENTIAL AND ALSO WHAT'S THE 1397 00:50:05,483 --> 00:50:09,787 BENEFIT FOR THE VIRUS IN MAKING 1398 00:50:09,787 --> 00:50:15,026 SMALL BUT HIGHLY BIOENERGETIC 1399 00:50:15,026 --> 00:50:17,662 VERSUS MITOCHONDRIA, VERSUS 1400 00:50:17,662 --> 00:50:18,096 FUSED MITOCHONDRIA. 1401 00:50:18,096 --> 00:50:18,696 >> BEAUTIFUL QUESTION. 1402 00:50:18,696 --> 00:50:19,797 VERY BEAUTIFUL QUESTION. 1403 00:50:19,797 --> 00:50:21,366 YES, WE DO SEE A SLIGHT DECREASE 1404 00:50:21,366 --> 00:50:23,935 IN THIS AND THEN WE SEE THE 1405 00:50:23,935 --> 00:50:24,736 INCREASE THE RESCUE, RIGHT? 1406 00:50:24,736 --> 00:50:26,571 IN TERMS OF -- AND IT'S 1407 00:50:26,571 --> 00:50:27,972 INTERESTING BECAUSE WE'VE BEEN 1408 00:50:27,972 --> 00:50:30,241 MONITORING THIS AND TRYING TO 1409 00:50:30,241 --> 00:50:32,210 LOOK AT TEMPORALITY AND EVEN FOR 1410 00:50:32,210 --> 00:50:33,745 THE SWAPPING OF MEMBRANE 1411 00:50:33,745 --> 00:50:34,646 PROTENTIAL SO IT'S INTERESTING 1412 00:50:34,646 --> 00:50:38,249 HOW IT GOES AWAY AND COMES BACK. 1413 00:50:38,249 --> 00:50:40,351 BUT IN TERMS OF THE RATIONAL FOR 1414 00:50:40,351 --> 00:50:43,221 THIS, I THINK IT'S -- IT'S -- 1415 00:50:43,221 --> 00:50:44,088 THERE ARE MULTIPLE 1416 00:50:44,088 --> 00:50:45,089 POSSIBILITIES, SO OF COURSE, 1417 00:50:45,089 --> 00:50:47,091 SOME OF THIS IS KNOWN TO BE 1418 00:50:47,091 --> 00:50:49,827 CONNECTED TO REGULATION OF 1419 00:50:49,827 --> 00:50:53,231 APOPTOSIS, BUT OTHER CAN BE ALSO 1420 00:50:53,231 --> 00:50:54,832 WITH MOTILITY AND WHERE THIS 1421 00:50:54,832 --> 00:50:55,933 MITOCHONDRIA ARE BEING LOCALIZED 1422 00:50:55,933 --> 00:50:57,502 BECAUSE WE START TO SEA THEM, 1423 00:50:57,502 --> 00:51:01,072 HOW LATER IN INFECTION, THEY GO 1424 00:51:01,072 --> 00:51:02,140 AROUND THE ASSEMBLY COMPLEX 1425 00:51:02,140 --> 00:51:04,075 WHERE YOU GO ALIFE ON EARTH THE 1426 00:51:04,075 --> 00:51:05,410 OF THAT REARRANGEMENT OF GOLGI 1427 00:51:05,410 --> 00:51:07,412 AND THE ENDOSOMES, ALL THAT 1428 00:51:07,412 --> 00:51:08,112 HAPPENS, ORGANIZATION AND 1429 00:51:08,112 --> 00:51:10,315 PRODUCTION OF NEW INFECTIOUS 1430 00:51:10,315 --> 00:51:11,949 VIRAL PARTING, SO MAYBE ENERGIES 1431 00:51:11,949 --> 00:51:14,352 BROUGHT THERE AT THE SITE WHERE 1432 00:51:14,352 --> 00:51:16,854 IT'S NEEDED, IT'S VERY POSSIBLE 1433 00:51:16,854 --> 00:51:21,392 THAT'S 1 LIKELY SCENARIO TO BE 1434 00:51:21,392 --> 00:51:22,160 DEMONSTRATED, YEAH. 1435 00:51:22,160 --> 00:51:23,561 >> I HAD ANOTHER MENC QUESTION, 1436 00:51:23,561 --> 00:51:25,296 SO YOU TALK ABOUT THE FORMATION 1437 00:51:25,296 --> 00:51:27,632 OF THESE STRUCTURES AND HMV 1438 00:51:27,632 --> 00:51:31,002 INFECTION AND IN CANCER, ARE 1439 00:51:31,002 --> 00:51:34,639 THERE NONDISEASE STATES IN WHICH 1440 00:51:34,639 --> 00:51:37,342 THESE STRUCTURES ARE FORMED 1441 00:51:37,342 --> 00:51:43,514 DURING DEVELOPMENT OR SOME OTHER 1442 00:51:43,514 --> 00:51:43,781 SCENARIO? 1443 00:51:43,781 --> 00:51:45,149 >> SO YEAH, REALLY GOOD POINT, 1444 00:51:45,149 --> 00:51:46,884 CONFECTED TO THE EARLIER 1445 00:51:46,884 --> 00:51:49,520 QUESTION AS WELL, I'M GLAD YOU 1446 00:51:49,520 --> 00:51:50,722 ASKED IT, THE REASON WE ARE 1447 00:51:50,722 --> 00:51:52,790 LOOKING AT THOSE IS BECAUSE WE 1448 00:51:52,790 --> 00:51:55,093 SAW MENCs BEING FORMED IN THE 1449 00:51:55,093 --> 00:51:56,627 SMALL LEVEL IN UNINFECTED CELLS 1450 00:51:56,627 --> 00:51:59,897 SO WE KNEW THEY COULD FORMED BUT 1451 00:51:59,897 --> 00:52:01,132 INFECTION PROMOTE THIS IS IS 1452 00:52:01,132 --> 00:52:02,033 PUSHES THIS MITOCHONDRIA INTO 1453 00:52:02,033 --> 00:52:03,334 THIS PARTICULAR STATE BUT THEY 1454 00:52:03,334 --> 00:52:04,702 CAN EXIST. 1455 00:52:04,702 --> 00:52:06,537 SO, THAT'S WHYY WOO THOUGHT, 1456 00:52:06,537 --> 00:52:08,606 OKAY, THEY EXIST ALSO IN 1457 00:52:08,606 --> 00:52:11,542 UNINFECTED CELLS AND THEN NOW WE 1458 00:52:11,542 --> 00:52:15,713 KNOW, AND THAT THEY ARE EVEN 1459 00:52:15,713 --> 00:52:18,783 CONNECTED TO POOR PROGNOSIS AND 1460 00:52:18,783 --> 00:52:20,651 I WOULD SAY THAT YES, IN TERMS 1461 00:52:20,651 --> 00:52:23,621 OF YOUR LAST QUESTION, WE 1462 00:52:23,621 --> 00:52:27,558 STARTED TO LOOK AT SOME OF THE 1463 00:52:27,558 --> 00:52:28,760 NEURAL DEGENERATIVE DISEASES 1464 00:52:28,760 --> 00:52:32,163 LIKE ALZHEIMERS AND HUNTING 1465 00:52:32,163 --> 00:52:35,233 TON'S AND SO ON AND PERHAPS IN 1466 00:52:35,233 --> 00:52:36,968 ALZHEIMER, SO IT'S POSSIBLE, 1467 00:52:36,968 --> 00:52:39,137 IT'S POSSIBLE THIS IS MAY BE A 1468 00:52:39,137 --> 00:52:39,837 MECHANISM TO PROTECT THE 1469 00:52:39,837 --> 00:52:40,805 MITOCHONDRIA THAT NEEDS TO 1470 00:52:40,805 --> 00:52:44,008 PRODUCE A LOT OFOXIDATIVE 1471 00:52:44,008 --> 00:52:45,076 PHOSPHORYLATION, YOU KNOW 1472 00:52:45,076 --> 00:52:46,144 PRODUCE ENERGY, IT'S POSSIBLE, 1473 00:52:46,144 --> 00:52:47,979 IT JUST REMAINS TO BE SEEN. 1474 00:52:47,979 --> 00:52:50,381 WE STARTED TO LOOK INTO THAT A 1475 00:52:50,381 --> 00:52:54,352 LITTLE BIT BUT IT'S JUST VERY 1476 00:52:54,352 --> 00:52:54,652 RECENTLY. 1477 00:52:54,652 --> 00:52:54,852 YEAH. 1478 00:52:54,852 --> 00:52:57,622 ONE THING I WILL MENTION IS 1479 00:52:57,622 --> 00:53:00,024 THAT, AND KIND OF CONNECTED TO 1480 00:53:00,024 --> 00:53:02,326 ACTUALLY -- I WILL ANSWER YOUR 1481 00:53:02,326 --> 00:53:04,328 QUESTION FIRST. 1482 00:53:04,328 --> 00:53:06,097 >> WELL, I HAVE 3. 1483 00:53:06,097 --> 00:53:06,564 >> PERFECT. 1484 00:53:06,564 --> 00:53:08,232 THEN YOU MAY EXACTLY WHAT I WAS 1485 00:53:08,232 --> 00:53:09,700 GOING TO SAY. 1486 00:53:09,700 --> 00:53:11,068 >> TWO TECHNIQUESTIONS TO START 1487 00:53:11,068 --> 00:53:12,170 WITH. 1488 00:53:12,170 --> 00:53:14,906 FOR THE FORMATION OF MENCs, 1489 00:53:14,906 --> 00:53:16,874 HAVE YOU IDENTIFIED ANY RNA 1490 00:53:16,874 --> 00:53:18,910 MARKERS WHERE PEOPLE HAVE LOOK 1491 00:53:18,910 --> 00:53:22,413 AT THE RNA LEVEL TO SEE IF THAT 1492 00:53:22,413 --> 00:53:26,617 SUGGESTS INCREASED FORMATION OF 1493 00:53:26,617 --> 00:53:26,951 MENCs? 1494 00:53:26,951 --> 00:53:32,690 >> NO, SO WE HAVE NOT. 1495 00:53:32,690 --> 00:53:35,760 NO, BUT THE DETECTION OF THE 1496 00:53:35,760 --> 00:53:36,828 MCSs THEMSELVES ISSUES THE 1S 1497 00:53:36,828 --> 00:53:38,796 WE FOUND TO BE LOCALIZED THERE 1498 00:53:38,796 --> 00:53:40,998 IS REALLY, THEY PROVIDE A GREAT 1499 00:53:40,998 --> 00:53:43,701 MARKER BECAUSE THIS IS 1 OF 1500 00:53:43,701 --> 00:53:45,403 THOSE FEW EXAMPLES WHERE A 1501 00:53:45,403 --> 00:53:48,840 CHANGE IN THE ABUNDANCE OF A 1502 00:53:48,840 --> 00:53:49,640 PROTEIN REALLY SIGNIFIES A 1503 00:53:49,640 --> 00:53:52,643 CHANGE IN THE EXTENT OF CONTACT 1504 00:53:52,643 --> 00:53:54,045 BETWEEN 2 ORGANELLES, SO BECAUSE 1505 00:53:54,045 --> 00:53:55,880 USUALLY, YOU KNOW YOU FIND 1506 00:53:55,880 --> 00:53:57,148 CHANGES IN ABUNDANCE AND WHAT 1507 00:53:57,148 --> 00:53:59,150 DOES THAT MEAN, IT CAN MEAN A 1508 00:53:59,150 --> 00:54:00,651 LOT OF DIFFERENT THINGS, BUT 1509 00:54:00,651 --> 00:54:02,386 THEY PROBABLY ARE ALSO OTHER 1510 00:54:02,386 --> 00:54:04,155 MARKERS THAT ARE NOT AT THE RNA 1511 00:54:04,155 --> 00:54:05,690 LEVEL BUT RATHER THE PROTEIN 1512 00:54:05,690 --> 00:54:08,526 LEVEL, I WOULD NOT BE SURPRISED 1513 00:54:08,526 --> 00:54:10,194 IF SOME LET'S SAY POST 1514 00:54:10,194 --> 00:54:11,095 TRANSLATION MODIFICATION ARE AND 1515 00:54:11,095 --> 00:54:12,830 ARE IMPORTANT FOR TARGETING, 1516 00:54:12,830 --> 00:54:15,366 IT'S KNOWN THAT HAPPENS FOR 1517 00:54:15,366 --> 00:54:16,300 CERTAIN MCSs, THAT THEY NEED 1518 00:54:16,300 --> 00:54:17,502 TO BE MODIFIED IN CERTAIN WAYS 1519 00:54:17,502 --> 00:54:19,637 IN ORDER TO BE RECRUIT INDEED A 1520 00:54:19,637 --> 00:54:21,205 CERTAIN CONTACT, FOR PROTEINS 1521 00:54:21,205 --> 00:54:24,108 THAT HAVE MULTIPLE 1522 00:54:24,108 --> 00:54:24,642 LOCALIZATIONS. 1523 00:54:24,642 --> 00:54:24,942 YEAH. 1524 00:54:24,942 --> 00:54:28,813 >> OKAY AND ARE THERE ANTIBODIES 1525 00:54:28,813 --> 00:54:32,149 THAT ARE NOW SPECIFIC TO 1526 00:54:32,149 --> 00:54:33,217 LACTYLIEE, AUDIENCE TION SITES 1527 00:54:33,217 --> 00:54:34,418 IN PROTEINS, ARE THESE REAGENTS 1528 00:54:34,418 --> 00:54:37,755 THAT PEOPLE CAN THINK ABOUT 1529 00:54:37,755 --> 00:54:37,955 USING? 1530 00:54:37,955 --> 00:54:41,993 >> THERE ARE ANTIBODIES THAT ARE 1531 00:54:41,993 --> 00:54:43,828 SPECIFIC TO LACTYLATED LYSINE, 1532 00:54:43,828 --> 00:54:45,396 NOT NECESSARILY TO A SITE IN A 1533 00:54:45,396 --> 00:54:49,066 PROTEIN AND THE INITIAL STUDIES 1534 00:54:49,066 --> 00:54:50,201 ON LACTYALATION, INITIAL STUDIES 1535 00:54:50,201 --> 00:54:51,869 HAVE BEEN DONE ON HISTONE 1536 00:54:51,869 --> 00:54:55,206 MODIIVESS AND HOW, YOU KNOW 1537 00:54:55,206 --> 00:54:55,740 NUCLEAR LACTYALATION IS 1538 00:54:55,740 --> 00:54:56,607 IMPORTANT AND WHY THIS IS 1539 00:54:56,607 --> 00:54:59,110 IMPORTANT JUST IN TERMS OF 1540 00:54:59,110 --> 00:55:01,045 POSSIBLE EVEN CROSS TALK WITH 1541 00:55:01,045 --> 00:55:04,882 OTHER PTMs ON HISTONES AND 1542 00:55:04,882 --> 00:55:05,816 GENE EXPRESSION. 1543 00:55:05,816 --> 00:55:08,286 SO, THIS IS KIND OF HOW THAT 1544 00:55:08,286 --> 00:55:14,425 FIELD OR POST TRANSLATION 1545 00:55:14,425 --> 00:55:16,661 LACTYALATION CAN BE REGULATED 1546 00:55:16,661 --> 00:55:18,329 AND WE HAVE STARTED TO LOOK AT 1547 00:55:18,329 --> 00:55:20,598 WHO ENZYMES IN THE CONTEXT OF 1548 00:55:20,598 --> 00:55:22,466 INFECTION ARE REGULATING THIS 1549 00:55:22,466 --> 00:55:25,169 MODIFICATION, IT'S FASCINATING 1550 00:55:25,169 --> 00:55:28,105 WE FOUND THAT AN ENZYME THAT IS 1551 00:55:28,105 --> 00:55:34,712 INVOLVED IN PLACING ALA9 AND SO 1552 00:55:34,712 --> 00:55:37,014 TRNA, SO ALAN INE, IS THE 1553 00:55:37,014 --> 00:55:40,184 ONESELF THAT BRINGS THE LACTATE 1554 00:55:40,184 --> 00:55:42,253 ON PROTEINS SO YOU CAN PUSH THIS 1555 00:55:42,253 --> 00:55:46,390 ENZYME IF YOU FEED CELLS AA 1556 00:55:46,390 --> 00:55:48,960 NINE, AND IF YOU FEED THEM 1557 00:55:48,960 --> 00:55:51,362 LACTATE SO IT'S CALLED AARS 1 1558 00:55:51,362 --> 00:55:53,197 THAT IT FUNCTIONS AND WORKS IN 1559 00:55:53,197 --> 00:55:55,066 THE NUCLEUS AS WELL AND ARS2 1560 00:55:55,066 --> 00:55:56,968 THAT FUNCTIONS IN THE 1561 00:55:56,968 --> 00:55:58,970 MITOCHONDRIA FOR SOME OF THE 1562 00:55:58,970 --> 00:56:00,371 LACTYALATIONS THAT WE'VE SEEN. 1563 00:56:00,371 --> 00:56:03,574 >> I SEE, 1 MORE QUICK QUESTION. 1564 00:56:03,574 --> 00:56:05,977 IN THE LAST PART OF YOUR TALK, 1565 00:56:05,977 --> 00:56:07,812 YOU MENTIONED THAT THE 1566 00:56:07,812 --> 00:56:09,814 NEIGHBORING CELLS HAD A DAMPEN 1567 00:56:09,814 --> 00:56:11,349 IMMUNE RESPONSE ESTATE BUT THE 1568 00:56:11,349 --> 00:56:13,384 CYSTAL 1S HAD AN INHANSED STATE, 1569 00:56:13,384 --> 00:56:15,219 DO YOU HAVE IDEAS OF THE 1570 00:56:15,219 --> 00:56:16,253 SIGNALING THAT'S HAPPENING 1571 00:56:16,253 --> 00:56:17,421 BETWEEN THE NEIGHBORING CELLS 1572 00:56:17,421 --> 00:56:18,956 AND THE DISTAL CELLS? 1573 00:56:18,956 --> 00:56:21,359 >> NO, BUT WE STARTED TO LOOK AT 1574 00:56:21,359 --> 00:56:23,928 THIS AND ALSO FROM THE 1575 00:56:23,928 --> 00:56:24,895 PERSPECTIVE OF HETEROGENEITY OF 1576 00:56:24,895 --> 00:56:26,263 RESPONSES SO WITHIN EACH OF 1577 00:56:26,263 --> 00:56:28,299 THESE POPULATIONS AS CAN YOU 1578 00:56:28,299 --> 00:56:30,067 IMAGINE, LET'S SAY THE 1579 00:56:30,067 --> 00:56:33,270 NEIGHBORING, THE DISTAL, THERE'S 1580 00:56:33,270 --> 00:56:34,672 STILL SUCH HETEROGENEITY OF 1581 00:56:34,672 --> 00:56:37,308 VIRAL INFECTION AND DIFFERENT 1582 00:56:37,308 --> 00:56:39,810 SUSCEPTIBLE TO INFECTIONS, SO WE 1583 00:56:39,810 --> 00:56:40,511 STARTED NOW TO SEPARATE THESE 1584 00:56:40,511 --> 00:56:43,080 AND A BIT MORE THAN A YEAR AGO, 1585 00:56:43,080 --> 00:56:43,881 WE INSTALLED AN INSTRUMENT IN 1586 00:56:43,881 --> 00:56:46,083 THE LAB THAT CAN DO SINGLE CELL 1587 00:56:46,083 --> 00:56:47,151 PROTEOMICS SO NOW WE'RE 1588 00:56:47,151 --> 00:56:48,653 SEPARATING ALL THESE CELLS AND 1589 00:56:48,653 --> 00:56:52,923 ARE LOOKING AT THE SINGLE CELL 1590 00:56:52,923 --> 00:56:54,925 LEVEL KIND OF WHAT COMPOSITION 1591 00:56:54,925 --> 00:56:56,060 REPRESENTS A CERTAIN RESPONSE OR 1592 00:56:56,060 --> 00:56:57,361 ABILITY AND WE ARE GETTING TO 1593 00:56:57,361 --> 00:56:59,096 THAT QUESTION OF INTERACTIONS 1594 00:56:59,096 --> 00:57:02,066 BETWEEN THE NEIGHBORING AND THE 1595 00:57:02,066 --> 00:57:04,735 DISTAL CELLS. 1596 00:57:04,735 --> 00:57:06,604 >> GREAT, THANKS. 1597 00:57:06,604 --> 00:57:09,407 >> BACK TO THE LACTYALATION, 1598 00:57:09,407 --> 00:57:11,509 THAT IT REVENTS THE RECRUITMENT 1599 00:57:11,509 --> 00:57:11,876 OF KINASES? 1600 00:57:11,876 --> 00:57:14,745 DO YOU KNOW THE MECHANISM FOR 1601 00:57:14,745 --> 00:57:15,079 THAT? 1602 00:57:15,079 --> 00:57:16,347 IS ITSTERRIC HINDRANCE OR 1603 00:57:16,347 --> 00:57:18,916 SOMETHING MORE SUBTLE GOING ON? 1604 00:57:18,916 --> 00:57:20,084 >> THAT DISORDER REGION WE FIND 1605 00:57:20,084 --> 00:57:21,986 TO BE MODIFIED WE FIND THAT MANY 1606 00:57:21,986 --> 00:57:23,688 TIMES WHAT HAPPENS TO THAT AREA 1607 00:57:23,688 --> 00:57:26,791 OF THE REGION HAS A LOT TO DO 1608 00:57:26,791 --> 00:57:27,491 WITH CHARGE, CHARGE-CHARGE 1609 00:57:27,491 --> 00:57:29,860 INTERACTIONS AND MAYBE THAT'S 1610 00:57:29,860 --> 00:57:33,631 WHAT IT'S ABOUT, AND HOW IT'S 1611 00:57:33,631 --> 00:57:38,803 SUDDENLY FOLD IN AND CREATES A 1612 00:57:38,803 --> 00:57:39,603 DIFFERENT FOLD ENVIRONMENT. 1613 00:57:39,603 --> 00:57:40,805 SO WE DO IN THE KNOW MORE, ALL 1614 00:57:40,805 --> 00:57:42,606 WE KNOW FOR THE MOMENT IS THAT 1615 00:57:42,606 --> 00:57:44,675 WHEN THE LACTIC ACIDOSEISERATION 1616 00:57:44,675 --> 00:57:48,679 IS PRESENT ON THE DISORDER 1617 00:57:48,679 --> 00:57:50,514 REGION SUDDENLY IT CAN NO LONGER 1618 00:57:50,514 --> 00:57:53,617 BE RECRUITED TO THE PERIPHERY OF 1619 00:57:53,617 --> 00:57:54,652 SITES OF THE GENOME POSITION, 1620 00:57:54,652 --> 00:57:56,487 THAT'S WHEREY WOO ARE WITH THAT 1621 00:57:56,487 --> 00:57:57,088 FOR THE MOMENT. 1622 00:57:57,088 --> 00:58:00,558 ANY EFFECT ON PROTEIN STABILITY. 1623 00:58:00,558 --> 00:58:01,092 NO. 1624 00:58:01,092 --> 00:58:02,827 WE DID NOT SEE AN EFFECT ON 1625 00:58:02,827 --> 00:58:04,128 PROTEIN STABILITY BUT I WANT TO 1626 00:58:04,128 --> 00:58:05,830 ALSO MENTION SOMETHING ELSE ON 1627 00:58:05,830 --> 00:58:06,864 LACTIC ACIDOSEISALATION BECAUSE 1628 00:58:06,864 --> 00:58:08,499 JUST FOR THE FLOW OF THE TALK 1629 00:58:08,499 --> 00:58:10,568 AND INTEREST OF TIME, I WANTED 1630 00:58:10,568 --> 00:58:13,003 TO GIVE YOU ONLY THE STORY ABOUT 1631 00:58:13,003 --> 00:58:21,512 THE IMMUNE SIGNALING AND THE 1632 00:58:21,512 --> 00:58:22,213 LACTATION ON'MUNE FACTORS, YOU 1633 00:58:22,213 --> 00:58:24,381 CAN'T SAY THAT SOMETHING IS 1634 00:58:24,381 --> 00:58:25,216 ANTIVIRAL PROVIRAL BECAUSE YOU 1635 00:58:25,216 --> 00:58:26,417 ARE GOING TO HAVE THOUSANDS OF 1636 00:58:26,417 --> 00:58:28,052 PROTEINS AND THEY WILL HAVE SO 1637 00:58:28,052 --> 00:58:29,253 MANY FUNCTIONS SO WHAT YOU ARE 1638 00:58:29,253 --> 00:58:30,821 LOOKING AT IS REALLY AN 1639 00:58:30,821 --> 00:58:31,622 AVERAGING OF THAT. 1640 00:58:31,622 --> 00:58:35,893 BUT WE ALSO FOUND VIRAL PROTEINS 1641 00:58:35,893 --> 00:58:37,561 THAT BECOME LACTATED AND SOME OF 1642 00:58:37,561 --> 00:58:39,597 THESE VIRAL PROTEINS WHEN WE DID 1643 00:58:39,597 --> 00:58:41,332 THE SAME EXPERIMENT, I SHOWED 1644 00:58:41,332 --> 00:58:43,734 YOU EARLIER WITH LACTATE 1645 00:58:43,734 --> 00:58:49,140 TREATMENT AND LOW M OY, AND WE 1646 00:58:49,140 --> 00:58:50,908 FOUND THAT IT WAS ANTIVIRAL. 1647 00:58:50,908 --> 00:58:52,209 SO WHEN ALL THE CELLS ARE 1648 00:58:52,209 --> 00:58:53,644 INFECTED AND WE'RE NOT LOOKING 1649 00:58:53,644 --> 00:58:56,747 AT VIRAL CELL TO CELL SPREAD AND 1650 00:58:56,747 --> 00:58:58,649 IMMUNE SIGNALING, WE FOUND THAT 1651 00:58:58,649 --> 00:59:03,954 THEN A LITTLE VIRAL PROTEINS 1652 00:59:03,954 --> 00:59:04,989 BECOME LACTYLATED AND 1 OF THEM 1653 00:59:04,989 --> 00:59:07,558 HAD TO DO WITH IT WAS AGAIN 1654 00:59:07,558 --> 00:59:09,026 INHIBITING THE ABILITY OF THE 1655 00:59:09,026 --> 00:59:12,429 THE IDR OF VIRAL PROTEIN TO GO 1656 00:59:12,429 --> 00:59:14,031 SPONTANEOUS ACTIVITY A LIQUID 1657 00:59:14,031 --> 00:59:18,803 SEPARATION IN THE NUCLEUS TO GO 1658 00:59:18,803 --> 00:59:20,538 INTO REPLICATION COMPARTMENTS SO 1659 00:59:20,538 --> 00:59:23,641 IT CAN INHIBIT THE FUNCTION OF A 1660 00:59:23,641 --> 00:59:26,610 VIRAL PROTEIN. 1661 00:59:26,610 --> 00:59:27,511 SO LACTYALATION CAN AFFAIRS TEAM 1662 00:59:27,511 --> 00:59:28,512 LEADERRER PROTEIN FUNCTION IN 1663 00:59:28,512 --> 00:59:31,482 MANY DIFFERENT WAYS. 1664 00:59:31,482 --> 00:59:34,485 >> DID WE GET A CLARIFICATION. 1665 00:59:34,485 --> 00:59:35,686 >> THAT INDIVIDUAL WAS ALL SET 1666 00:59:35,686 --> 00:59:36,854 WITH THAT RESPONSE. 1667 00:59:36,854 --> 00:59:37,621 , GREAT. 1668 00:59:37,621 --> 00:59:39,790 >> ANY OTHER ONLINE QUESTIONS? 1669 00:59:39,790 --> 00:59:43,027 >> OH LET ME SAY THE CME CODE? 1670 00:59:43,027 --> 00:59:45,963 , THERE IT IS 57688. 1671 00:59:45,963 --> 00:59:49,667 AND ANY -- THERE'S RECEPTION YOU 1672 00:59:49,667 --> 00:59:50,868 CAN MENTION. 1673 00:59:50,868 --> 00:59:52,269 >> YEAH, THERE'S' RECEPTION 1674 00:59:52,269 --> 00:59:53,838 OUTSIDE IMMEDIATELY AFTERWARDS 1675 00:59:53,838 --> 00:59:55,873 AND LET'S THANK ILEANA FOR A 1676 00:59:55,873 --> 00:59:57,174 REALLY BEAUTIFUL TALK. 1677 00:59:57,174 --> 01:00:07,418 [ APPLAUSE ]