1 00:00:05,406 --> 00:00:09,505 Welcome to the NH DNA repair interest group, monthly 2 00:00:09,505 --> 00:00:13,499 video conferences. Today we are very happy to have 3 00:00:13,499 --> 00:00:15,416 a doctor, Nelson Gkara. 4 00:00:15,416 --> 00:00:19,955 To be the guest. Before we proceed into the introduction, 5 00:00:19,955 --> 00:00:24,216 I only like to, encourage everybody to join our young 6 00:00:24,216 --> 00:00:28,396 investigator talk next month in November, the 12.th 7 00:00:28,396 --> 00:00:28,922 Wait, when we, we will have a 2, distinguished award 8 00:00:28,922 --> 00:00:29,397 winning young scientists to share their story. 9 00:00:29,397 --> 00:00:34,402 For today's talk and Dr. Nelson Gera is a distinguished 10 00:00:34,402 --> 00:00:41,765 scientist whose research focus on understanding the 11 00:00:41,765 --> 00:00:49,417 regulation of innate immune responses and DNA repair 12 00:00:49,417 --> 00:00:53,347 Currently, Dr. Idihara held the position of food professor 13 00:00:53,347 --> 00:00:57,247 of microbiology and molecular infection immunology at the 14 00:00:57,247 --> 00:01:00,395 Medical Center University or for Frankenberg. 15 00:01:00,395 --> 00:01:05,097 In Germany. Since, 2,022. Dr. Dakara also serve as 16 00:01:05,097 --> 00:01:09,183 an associated professor at the Winner Green 17 00:01:09,183 --> 00:01:14,409 Institute at the Stockholm University since 2 2 2,019. 18 00:01:14,409 --> 00:01:18,556 Dr. Khakara's academic journey begins with bachelorship in 19 00:01:18,556 --> 00:01:22,681 biochemistry from Jomo Kenyatta University of Agriculture 20 00:01:22,681 --> 00:01:24,419 and Talking Technology. 21 00:01:24,419 --> 00:01:28,827 And after that, he has been, research research shows in 22 00:01:28,827 --> 00:01:31,392 Kenya, Switzerland and Germany. 23 00:01:31,392 --> 00:01:34,755 So he's, So his expertise in infection immunology and 24 00:01:34,755 --> 00:01:42,146 molecular mechanism of horse defense has made him a leader 25 00:01:42,146 --> 00:01:49,410 in the molecular mechanism of horse defense has made him 26 00:01:49,410 --> 00:01:50,994 So before we start, I would like to ask. The audience 27 00:01:50,994 --> 00:01:52,537 to please, in put your questions if you have any in 28 00:01:52,537 --> 00:01:53,414 the chat box and we will go. 29 00:01:53,414 --> 00:02:03,391 Through them after the talk. Dr. Kakara. 30 00:02:03,391 --> 00:02:09,857 So, thank you very much. For the invitation to this. This 31 00:02:09,857 --> 00:02:17,082 delete cloud from I because this is a group on DNA they have to 32 00:02:17,082 --> 00:02:20,408 I have a confession to make. 33 00:02:20,408 --> 00:02:27,047 I actually don't consider myself an expert. And that is 34 00:02:27,047 --> 00:02:34,367 probably the 1st invitation to to. To a seminar series in So 35 00:02:34,367 --> 00:02:38,393 my actually interest in January. 36 00:02:38,393 --> 00:02:45,776 The stems from an interest in understanding. Post 37 00:02:45,776 --> 00:02:52,407 -defense system. And if. Let me talk about, 38 00:02:52,407 --> 00:02:57,048 We can all agree that the net immune system and the 39 00:02:57,048 --> 00:03:01,416 DNA repair system. The primary defense against. 40 00:03:01,416 --> 00:03:05,540 It's external and internal stress. So they needed 41 00:03:05,540 --> 00:03:10,860 new system. No, man, we organize infection, about 42 00:03:10,860 --> 00:03:16,397 what we call the pattern cooperation receptors and 43 00:03:16,397 --> 00:03:20,401 We then mediates pathways and clearance. As well 44 00:03:20,401 --> 00:03:24,405 as the entertainment. Us plus t-shirt in there. 45 00:03:24,405 --> 00:03:28,833 For example, the injuries 2 module infections too mark the 46 00:03:28,833 --> 00:03:33,414 net system also. With us and activations and that pathways. 47 00:03:33,414 --> 00:03:38,419 So as 30 min, as there are said, we are be affected. 48 00:03:38,419 --> 00:03:42,308 And as you all know, the DNA system on the other hand is 49 00:03:42,308 --> 00:03:44,392 a set of signalling pathways. 50 00:03:44,392 --> 00:03:48,380 We're out to get in response to DNA damage. I their 51 00:03:48,380 --> 00:03:52,263 function is of course to the Yeah, but we solving 52 00:03:52,263 --> 00:03:54,402 the integrity of the cell. 53 00:03:54,402 --> 00:03:57,405 And of course the 54 00:03:57,405 --> 00:04:01,409 So there's a lot which is be known about the netting 55 00:04:01,409 --> 00:04:05,685 system on the DNA system. And much of our understanding 56 00:04:05,685 --> 00:04:09,417 of the net immune system but the United system. 57 00:04:09,417 --> 00:04:14,398 Stems from decades or research. Looking at these 58 00:04:14,398 --> 00:04:19,742 systems. Separately. But it's becoming clear from a 59 00:04:19,742 --> 00:04:25,399 can say The last few years that they need new system. 60 00:04:25,399 --> 00:04:31,781 And the DNA system. Highly interdependent. And that 61 00:04:31,781 --> 00:04:38,412 defects in the innate immune system, or DNA systems. 62 00:04:38,412 --> 00:04:42,698 Actually underline many of the health afflictions for 63 00:04:42,698 --> 00:04:47,388 example, infection or immunity, cancer, new regeneration. 64 00:04:47,388 --> 00:04:53,394 And many of the aged, disorders. 65 00:04:53,394 --> 00:04:56,424 And as I said, it's becoming clear that the innate immune 66 00:04:56,424 --> 00:04:59,400 system or the enterprise system are highly independent. 67 00:04:59,400 --> 00:05:03,622 And this will be becoming clear that, regulation of the innate 68 00:05:03,622 --> 00:05:07,481 immune system at the United system involved a developing 69 00:05:07,481 --> 00:05:09,410 set of signaling molecules. 70 00:05:09,410 --> 00:05:12,950 And in this talk, I will be highlighting some of 71 00:05:12,950 --> 00:05:16,417 the key molecules that we've been focusing on. 72 00:05:16,417 --> 00:05:20,866 And these these molecules. Really sit at the intersection 73 00:05:20,866 --> 00:05:25,393 between the net immune system. And the DNA repair system. 74 00:05:25,393 --> 00:05:30,853 And these molecules are what we call the intracellular 75 00:05:30,853 --> 00:05:35,403 DNS sensors. That is C and M link resetters. 76 00:05:35,403 --> 00:05:40,355 And, so that's what I'll be forecasting. So 1st 77 00:05:40,355 --> 00:05:45,413 of all, what I think is Fossil at DNS sends us. 78 00:05:45,413 --> 00:05:49,303 As I says, there are 2 well characters, family members of 79 00:05:49,303 --> 00:05:51,419 the intracellular DNA sensors. 80 00:05:51,419 --> 00:05:57,538 The 1st one is C, which is start a cyclic m. And the other 81 00:05:57,538 --> 00:06:03,090 one is a family of receptors known as, So see GAS is 82 00:06:03,090 --> 00:06:06,400 actually a DNA bonding enzyme. 83 00:06:06,400 --> 00:06:11,072 We are all binding DNL. Catalyzes the secularization 84 00:06:11,072 --> 00:06:13,407 of ATP and GTP into CCOM. 85 00:06:13,407 --> 00:06:17,173 And this sec is a very important activator of the 86 00:06:17,173 --> 00:06:23,365 new system. It triggers downstream events by binding 87 00:06:23,365 --> 00:06:30,391 to an attack on us being and that results in the in the in 88 00:06:30,391 --> 00:06:33,426 The aim like this up is a large family of unique 89 00:06:33,426 --> 00:06:36,397 planning proteins. In human we have 4 members. 90 00:06:36,397 --> 00:06:40,151 In mice we have 13. And the best character as 91 00:06:40,151 --> 00:06:44,405 of this is a DNA banning protocol is known as M 2. 92 00:06:44,405 --> 00:06:48,133 And its function is once its bands with It activates a 93 00:06:48,133 --> 00:06:52,413 complex numbers in Flam. And this influence is important for. 94 00:06:52,413 --> 00:06:58,487 Mediating cell death programs. As well as processing. 95 00:06:58,487 --> 00:07:03,487 Protolithic processing or interlinking one, 96 00:07:03,487 --> 00:07:06,394 farming side of clients. 97 00:07:06,394 --> 00:07:12,829 So now I say my interest in dinner repair really stems 98 00:07:12,829 --> 00:07:16,404 from. A desire to understand. 99 00:07:16,404 --> 00:07:19,943 And when I talk about post -defense, I often start 100 00:07:19,943 --> 00:07:23,411 by these very old time testing military maximum. 101 00:07:23,411 --> 00:07:28,989 But he's to be prepared for work is perhaps the most effective 102 00:07:28,989 --> 00:07:31,419 means of preserving peace. 103 00:07:31,419 --> 00:07:36,390 And that's happened to be true for the new system. 104 00:07:36,390 --> 00:07:42,396 You see the new system. Is constantly wrapped up. 105 00:07:42,396 --> 00:07:46,063 As you all know, you know the new system does not 106 00:07:46,063 --> 00:07:50,404 like I've been waiting to be attacked before it responds. 107 00:07:50,404 --> 00:07:55,863 At any particular time in our bodies. I was, as constantly 108 00:07:55,863 --> 00:08:01,415 produced, even in the absence of infection or engineering. 109 00:08:01,415 --> 00:08:04,958 And this constitute or this background production 110 00:08:04,958 --> 00:08:09,125 of inflammatory cycles or interference. Is very important 111 00:08:09,125 --> 00:08:11,392 for priming the immune system. 112 00:08:11,392 --> 00:08:15,872 Keeping it in a wrap-up mode. So that will be an accountant 113 00:08:15,872 --> 00:08:20,175 section or we're engine and the immune system is able to 114 00:08:20,175 --> 00:08:22,403 react in a very fast moment. 115 00:08:22,403 --> 00:08:26,295 And these, consider production side to clients. It's 116 00:08:26,295 --> 00:08:32,473 very important for the new system because even subtle 117 00:08:32,473 --> 00:08:38,419 changes the production of the cytokines can have a 118 00:08:38,419 --> 00:08:42,215 In response. And that means that if for example If you've 119 00:08:42,215 --> 00:08:48,205 been have a slight decrease. In this base of production of 120 00:08:48,205 --> 00:08:54,402 side What will happen is that your new system will be a big 121 00:08:54,402 --> 00:08:58,648 And you're likely to be grown to be more 122 00:08:58,648 --> 00:09:01,409 acceptable to infections. 123 00:09:01,409 --> 00:09:04,393 But on the flip side, if you have enhanced production, 124 00:09:04,393 --> 00:09:07,573 consider production of cyclone interference. What happens 125 00:09:07,573 --> 00:09:10,418 is your immune system It gets into an older drive. 126 00:09:10,418 --> 00:09:15,404 So which means that if you are infected, your encounter 127 00:09:15,404 --> 00:09:19,393 injury. What happens is you hide, but yeah. 128 00:09:19,393 --> 00:09:23,397 And this can be pathological. 129 00:09:23,397 --> 00:09:28,348 As though one of the fundamental questions that actually when 130 00:09:28,348 --> 00:09:36,314 I started my room meeting as bad is to understand what are 131 00:09:36,314 --> 00:09:44,418 the mechanisms that underline that regulate the expression 132 00:09:44,418 --> 00:09:48,168 And when you talk about what really primes immune system, 133 00:09:48,168 --> 00:09:51,392 I think it's sometimes good to take a step back. 134 00:09:51,392 --> 00:09:55,396 And even us what is the new system? 135 00:09:55,396 --> 00:09:59,900 You know, the leopard definition, the near system 136 00:09:59,900 --> 00:10:04,405 we can say is the ability. To respond to stress. 137 00:10:04,405 --> 00:10:08,337 And what is stress. I mean, stressed many, many things. 138 00:10:08,337 --> 00:10:12,413 I mean, Let's just be micro -gadi rooms as you all know. 139 00:10:12,413 --> 00:10:15,947 Stress could be mechanical stress, you engine your 140 00:10:15,947 --> 00:10:19,670 knee, you have a swelling. And that is inflammation, 141 00:10:19,670 --> 00:10:21,388 that activation system. 142 00:10:21,388 --> 00:10:24,751 Stress could be extreme temperatures. To be 143 00:10:24,751 --> 00:10:26,393 a technical portion. 144 00:10:26,393 --> 00:10:30,226 But for for many years, when people have been looking at 145 00:10:30,226 --> 00:10:34,401 the new system, people have always been focusing on my call. 146 00:10:34,401 --> 00:10:38,166 But if you take a moment and think, my probe 147 00:10:38,166 --> 00:10:42,330 invasion is probably the most reason stressed in 148 00:10:42,330 --> 00:10:44,411 the evolutionary clock. 149 00:10:44,411 --> 00:10:48,096 So that you, but then you can also start it. What is probably 150 00:10:48,096 --> 00:10:51,418 the most preliminary module, the most constant stress. 151 00:10:51,418 --> 00:10:55,486 But our ancestor has to deal with since the beginning 152 00:10:55,486 --> 00:10:59,529 of time. The most concept stress. That, probably has 153 00:10:59,529 --> 00:11:01,395 contributed to shaping. 154 00:11:01,395 --> 00:11:05,803 Our new system to what it is today. And 155 00:11:05,803 --> 00:11:08,402 that brings me to DNN. 156 00:11:08,402 --> 00:11:13,118 So DNA damage as you'll know is probably the most cost of 157 00:11:13,118 --> 00:11:15,639 stress in all live forms. It c 158 00:11:15,639 --> 00:11:18,412 ould be from similar metabolism. 159 00:11:18,412 --> 00:11:20,889 We eat or we generally have to option spaces. We 160 00:11:20,889 --> 00:11:23,417 can cause DNA damage. You could be from UV Live. 161 00:11:23,417 --> 00:11:27,868 Will be ionizing radiation would be environmental chemicals. 162 00:11:27,868 --> 00:11:32,393 You could also be for example because of replication errors. 163 00:11:32,393 --> 00:11:35,705 It could also be my pro -canism. Macro organisms are 164 00:11:35,705 --> 00:11:39,400 not produce. Products that can actually cause DNA damage. 165 00:11:39,400 --> 00:11:44,044 Awesome, for, for example, wires, can also damage the end 166 00:11:44,044 --> 00:11:46,407 by intercolating to the end. 167 00:11:46,407 --> 00:11:49,592 And now, for example, now that our genome has been 168 00:11:49,592 --> 00:11:53,414 sequenced, very clear that our DNS replate filter elements. 169 00:11:53,414 --> 00:11:55,814 W e just really a clear signature. 170 00:11:55,814 --> 00:12:01,439 You know, on Cisco Bust. So based on this reasoning 171 00:12:01,439 --> 00:12:07,394 based on this backstop And then I was asking what the 172 00:12:07,394 --> 00:12:12,785 See that really constantly keeps the immune system. In the 173 00:12:12,785 --> 00:12:17,773 rep. So in in high organism, one of the key companies 174 00:12:17,773 --> 00:12:20,407 would be enterprise system. 175 00:12:20,407 --> 00:12:26,221 Is a kindness known as ATM. A lot of function in ATM 176 00:12:26,221 --> 00:12:32,220 results in a very complex disease known as attacks at 177 00:12:32,220 --> 00:12:35,389 a language does in over 80. 178 00:12:35,389 --> 00:12:40,514 And at that time, more than 14 years ago, I thought maybe 179 00:12:40,514 --> 00:12:45,414 This disease could be modeled. This disease could be a 180 00:12:45,414 --> 00:12:50,404 very good model for starting the impact of DNA repair. 181 00:12:50,404 --> 00:12:55,743 And the immune system. So, 80 attacks it, a, is a, 182 00:12:55,743 --> 00:12:58,412 is a man system disease. 183 00:12:58,412 --> 00:13:02,623 Correct as a bad one has to console. Neural 184 00:13:02,623 --> 00:13:07,421 generation accelerated aging growth retardation. 185 00:13:07,421 --> 00:13:10,459 And at that time, I was it was very curious because when we 186 00:13:10,459 --> 00:13:13,394 have to breathe through the in between the lead feature. 187 00:13:13,394 --> 00:13:17,183 There are reports that this antipation also displayed 188 00:13:17,183 --> 00:13:20,401 a variety of auto neon inflammable diseases. 189 00:13:20,401 --> 00:13:24,210 Or female types whose etiology was unknown. So then 190 00:13:24,210 --> 00:13:28,293 the question is why should defect generate the results 191 00:13:28,293 --> 00:13:30,411 in spontaneous information? 192 00:13:30,411 --> 00:13:34,315 So some of the early experiments that we did was to look at 193 00:13:34,315 --> 00:13:38,419 patients. Take the serial from patients, attack the patients. 194 00:13:38,419 --> 00:13:42,748 I'm looking to see them. And one of the things that we found He's 195 00:13:42,748 --> 00:13:49,693 that in this in this theorem they have very high interferon 196 00:13:49,693 --> 00:13:56,403 and also we've been we take the self in this patient and 197 00:13:56,403 --> 00:14:00,264 And nothing inflammatory cycle points. And when we infect 198 00:14:00,264 --> 00:14:03,834 itself from these patients with virus like bicycular 199 00:14:03,834 --> 00:14:05,412 stomach that is virus. 200 00:14:05,412 --> 00:14:09,384 Then they sales from the stations. What a 201 00:14:09,384 --> 00:14:11,418 system to infection. 202 00:14:11,418 --> 00:14:15,774 And 80 patients are very few. So what we decide to 203 00:14:15,774 --> 00:14:20,365 do to really do make aistic studies. We resorted to, 204 00:14:20,365 --> 00:14:22,396 to my, knock out mice. 205 00:14:22,396 --> 00:14:31,370 And what we also found that if you have sales which lab have 206 00:14:31,370 --> 00:14:35,409 elevated production. Okay. 207 00:14:35,409 --> 00:14:40,643 And that if you change this mice with a and this master 208 00:14:40,643 --> 00:14:47,899 assistant. We is nice, right? But on the other side, if, for 209 00:14:47,899 --> 00:14:55,396 example, also challenge these animals or cell phone this, 80, 210 00:14:55,396 --> 00:14:59,377 What you see you have amplified production of interference 211 00:14:59,377 --> 00:15:03,254 other side accounts and the flip side or the downside of 212 00:15:03,254 --> 00:15:07,408 this is that this animals are highly sensitive to services. 213 00:15:07,408 --> 00:15:12,511 So they tend to die faster. So then we could summarize that. 214 00:15:12,511 --> 00:15:17,755 It appears that defects in DNRIT that are accurate results in 215 00:15:17,755 --> 00:15:20,421 I have a active immune system. 216 00:15:20,421 --> 00:15:24,659 That is protective against viruses. But this technological, 217 00:15:24,659 --> 00:15:28,395 which means that if you have defects in DNA repair. 218 00:15:28,395 --> 00:15:31,479 These days of production of cytokines, which is important 219 00:15:31,479 --> 00:15:35,619 for having up the immune system. All of us suddenly 220 00:15:35,619 --> 00:15:40,407 have, you know, it really, you have elevated, you have the 221 00:15:40,407 --> 00:15:46,413 It really goes out. And then the question was 222 00:15:46,413 --> 00:15:51,618 What causes the spontaneous, innating and triggering 223 00:15:51,618 --> 00:15:53,420 in the absence of 224 00:15:53,420 --> 00:15:57,810 The simple hypothesis then we heard is that This convenience 225 00:15:57,810 --> 00:16:01,395 inflammation we have for example in 80 patients. 226 00:16:01,395 --> 00:16:06,704 Is because of accumulation of DMM in the absence of 227 00:16:06,704 --> 00:16:11,664 the DNA. And this DNA can somehow be recognized 228 00:16:11,664 --> 00:16:14,408 the new system as stress. 229 00:16:14,408 --> 00:16:19,654 Of that country of inflammation. So moving beyond the education 230 00:16:19,654 --> 00:16:26,898 or ATM. Another way of testing this hypothesis is even the 231 00:16:26,898 --> 00:16:33,393 Watt app situation if we use DNA damaging agents we 232 00:16:33,393 --> 00:16:37,282 And indeed what we see if you expose sales to radiation, 233 00:16:37,282 --> 00:16:41,344 you induce interference. We also expose a sales to a Tocco 234 00:16:41,344 --> 00:16:45,405 side, a chemotherapy agents, and which causes DNA damage. 235 00:16:45,405 --> 00:16:50,632 You see you also use But also provide me the Interferon system 236 00:16:50,632 --> 00:16:53,413 when you let them cheleny sales. 237 00:16:53,413 --> 00:16:57,503 With viruses you have an and the consequence of that is 238 00:16:57,503 --> 00:17:02,449 cells which have been exposed in in the dynamic agents 239 00:17:02,449 --> 00:17:07,394 are highly resistant viral infection, which is rather 240 00:17:07,394 --> 00:17:11,398 In sales that are the 241 00:17:11,398 --> 00:17:15,467 So based on this, it's clear that DNA does 242 00:17:15,467 --> 00:17:20,407 problem with the new system to enhance and divide. 243 00:17:20,407 --> 00:17:24,912 Then the mechanisms. So how does Genta make this us in 244 00:17:24,912 --> 00:17:27,414 activation of the new system? 245 00:17:27,414 --> 00:17:31,789 And which innate new pathways are and So, so innately 246 00:17:31,789 --> 00:17:36,219 inactivation. Or at least activation of the Remind me 247 00:17:36,219 --> 00:17:38,392 of cars about 3 families. 248 00:17:38,392 --> 00:17:44,057 Oh, we need to meet receptors that are on the surface. Of 249 00:17:44,057 --> 00:17:49,489 the set. And also intracellular receptors like Variga, 250 00:17:49,489 --> 00:17:52,406 which senses are, are in it. 251 00:17:52,406 --> 00:17:56,833 Or the C gas which I I talked about early. And so what we 252 00:17:56,833 --> 00:18:01,415 did, we screen mice which are defective in these pathways. 253 00:18:01,415 --> 00:18:04,932 And what we found that Mars which are defective in this 254 00:18:04,932 --> 00:18:08,226 adapter for this thing. Who are unresponsive, could 255 00:18:08,226 --> 00:18:11,391 not produce interferon in response to radiation. 256 00:18:11,391 --> 00:18:18,360 Meaning the DNA damage. Up against the new system about 257 00:18:18,360 --> 00:18:21,401 interest in the Sensor. 258 00:18:21,401 --> 00:18:27,142 So, DNED, I might go casting the new that time it was thought 259 00:18:27,142 --> 00:18:32,412 that this intracellular DNS sensors are in the cytosol. 260 00:18:32,412 --> 00:18:37,401 So how does then the stress inside the nucleus results 261 00:18:37,401 --> 00:18:42,389 in a duration of these receptors in to cut the story. 262 00:18:42,389 --> 00:18:46,414 Short, what we found that when you have DNA damage. What do you 263 00:18:46,414 --> 00:18:48,395 have difference in DNA repair? 264 00:18:48,395 --> 00:18:51,808 What happens is that DNA is getting into the cytosol 265 00:18:51,808 --> 00:18:54,805 from the nucleus as we can see for example in 266 00:18:54,805 --> 00:18:56,403 cell phone 80 patients. 267 00:18:56,403 --> 00:19:00,478 And then this DNA is sort of, you know, recognized like a 268 00:19:00,478 --> 00:19:04,411 cell which has been infected by a virus as a bacteria. 269 00:19:04,411 --> 00:19:08,839 And this is what this is what then at least the activation 270 00:19:08,839 --> 00:19:12,260 o f the CEOs. And in collaboration 271 00:19:12,260 --> 00:19:17,391 with the emerald separate if he's 16 and this then 272 00:19:17,391 --> 00:19:22,613 And so this is the model that we propose. to explain how the 273 00:19:22,613 --> 00:19:25,399 inademic and the immune system. 274 00:19:25,399 --> 00:19:30,050 We propose that at any particular time Of course, 275 00:19:30,050 --> 00:19:34,193 ourselves exposed to DNA damaging. It could 276 00:19:34,193 --> 00:19:36,410 be replication stress. 277 00:19:36,410 --> 00:19:40,445 And because of that, we constantly have No, DNS. For 278 00:19:40,445 --> 00:19:44,533 the nuclear to the cytosol and this is essential for 279 00:19:44,533 --> 00:19:46,420 priming the new system. 280 00:19:46,420 --> 00:19:51,096 And that if you have OB exposed to DNA damaging ages like 281 00:19:51,096 --> 00:19:55,743 radiation or chemotherapies. What up as we have an asked 282 00:19:55,743 --> 00:19:58,398 accumulation of being a damage. 283 00:19:58,398 --> 00:20:02,367 And in has release of beginning to the site or so. I then 284 00:20:02,367 --> 00:20:06,406 has activation of the Sega Sting and the AMlet receptors. 285 00:20:06,406 --> 00:20:11,708 And this results in really driving up the new system. I 286 00:20:11,708 --> 00:20:17,272 make us making us hyperactive. To, both, external as well 287 00:20:17,272 --> 00:20:19,419 as internal stresses. 288 00:20:19,419 --> 00:20:24,096 So this this this work is already published in years back 289 00:20:24,096 --> 00:20:28,909 now. And, you know, so since this work has been published, 290 00:20:28,909 --> 00:20:31,398 I think it's, now clear that, 291 00:20:31,398 --> 00:20:35,523 It's accepted that this is probably the principal 292 00:20:35,523 --> 00:20:40,407 mechanism behind the DNA image induced immune activation. 293 00:20:40,407 --> 00:20:44,859 And this is significant because The idea that DNA damage trigos 294 00:20:44,859 --> 00:20:50,079 inflammation is actually not new. probably, you know, when, 295 00:20:50,079 --> 00:20:55,388 radio up to the substance of what is covered, way back more 296 00:20:55,388 --> 00:20:58,191 One of the of the feature which was recognized is 297 00:20:58,191 --> 00:21:01,394 that we put radium on the pocket. You had inflammation. 298 00:21:01,394 --> 00:21:05,634 So inflammation is a whole map of DNA damage. But the mechanism 299 00:21:05,634 --> 00:21:09,402 for how I'm doing it in use inflammation was not clear. 300 00:21:09,402 --> 00:21:14,741 And it is becoming clear that the activation of this 301 00:21:14,741 --> 00:21:21,414 intracillity in a census is the principal mechanism behind this. 302 00:21:21,414 --> 00:21:22,137 And, and so, and so DNA that I'm making this inflammation 303 00:21:22,137 --> 00:21:22,415 is both good and bad. 304 00:21:22,415 --> 00:21:29,233 It has benefit imposed. As I've explained, D and I'm 305 00:21:29,233 --> 00:21:35,395 making this inflammation can boost antimacrob. 306 00:21:35,395 --> 00:21:38,657 And it's also clear that DNA damage use inflammation about 307 00:21:38,657 --> 00:21:40,400 the intracellular DNA sensors. 308 00:21:40,400 --> 00:21:44,317 Underlies the therapeutic efficacy or many of 309 00:21:44,317 --> 00:21:46,406 the anti-Kenser agents. 310 00:21:46,406 --> 00:21:49,409 For example, radiation came up to happen. 311 00:21:49,409 --> 00:21:53,105 And of course, DNA emerging agents, DNA damaging 312 00:21:53,105 --> 00:21:56,416 and use inflammation is also pathological. 313 00:21:56,416 --> 00:22:00,100 Was it drives many of the pathology following accessible 314 00:22:00,100 --> 00:22:03,390 radiation. A key transition syndrome for example. 315 00:22:03,390 --> 00:22:06,624 Oh, also drives many of the pathologies that are 316 00:22:06,624 --> 00:22:10,397 normally found in patients. That love the United there. 317 00:22:10,397 --> 00:22:17,271 I need It's also clear that as we age we lose our we need 318 00:22:17,271 --> 00:22:20,407 to repair the DNA breaks. 319 00:22:20,407 --> 00:22:25,690 And this, accumulation of DNA, damage and activation or C 320 00:22:25,690 --> 00:22:30,417 is what actually contributes to the aging process. 321 00:22:30,417 --> 00:22:34,292 And so, whereas the any damage induced inflammation, 322 00:22:34,292 --> 00:22:38,391 but the CIA scene can also promote anti-tuma immunity. 323 00:22:38,391 --> 00:22:41,725 In other instance, it also been shown. To promote 324 00:22:41,725 --> 00:22:45,398 metaphysics. They can promote, a team of progression. 325 00:22:45,398 --> 00:22:53,406 And it's at the moment it's not really, clear. I did then. 326 00:22:53,406 --> 00:22:57,040 They the conditions, under which CIG has the most 327 00:22:57,040 --> 00:23:01,414 entertainment unity and timber progress is not very clear. 328 00:23:01,414 --> 00:23:05,808 And these are not that many labs are interested in. But 329 00:23:05,808 --> 00:23:10,722 moving forward, the point here, and I wanted to be one of the 330 00:23:10,722 --> 00:23:15,395 techho message is that DNA is a case or intrinsic stress. 331 00:23:15,395 --> 00:23:20,423 We need a new driving. And this priming involve 332 00:23:20,423 --> 00:23:26,161 optimization or int but the DNA that is came from the 333 00:23:26,161 --> 00:23:29,409 nucleus in this side as well. 334 00:23:29,409 --> 00:23:34,002 So when we talk about, you know, so I've been talking about 335 00:23:34,002 --> 00:23:36,416 this intracellity in a census. 336 00:23:36,416 --> 00:23:40,729 Now I'll and they are all in netting in activation. But 337 00:23:40,729 --> 00:23:45,251 now I'll receive the gear and talk about the role of this 338 00:23:45,251 --> 00:23:47,394 introscelled in a sensors. 339 00:23:47,394 --> 00:23:51,898 In that. But before I get into that, I will charge 340 00:23:51,898 --> 00:23:56,403 all a very important aspect of the immune system. 341 00:23:56,403 --> 00:24:00,929 And that is self non self discrimination, the immune 342 00:24:00,929 --> 00:24:06,413 system. How does the new system discriminate itself from self? 343 00:24:06,413 --> 00:24:10,444 So 1st of all, as I've explained, be very clear 344 00:24:10,444 --> 00:24:15,046 from from from the previous slides. The DNN is a very 345 00:24:15,046 --> 00:24:17,390 important you'll use them. 346 00:24:17,390 --> 00:24:22,227 And that. DNA also happened to be the most abundant 347 00:24:22,227 --> 00:24:26,399 macro molecule in the cell. One can say so. 348 00:24:26,399 --> 00:24:29,374 And perhaps one of the things that I did mention this 349 00:24:29,374 --> 00:24:32,405 introcellular DNS sensors CIGS and M blood receptors. 350 00:24:32,405 --> 00:24:37,134 Ultra, it's coagma has DNA, irrespective of the sequence, 351 00:24:37,134 --> 00:24:42,152 which means they can recognize both microbial DNA as well as 352 00:24:42,152 --> 00:24:47,420 No, Oh, DMA is a very important activated on the admin system. 353 00:24:47,420 --> 00:24:52,580 It's very abundant in the cell. I see that's connected. 354 00:24:52,580 --> 00:24:55,395 But under healthy conditions. 355 00:24:55,395 --> 00:24:59,624 The sales does not go up in flame. So then how 356 00:24:59,624 --> 00:25:04,404 how does the new system really discriminate itself? 357 00:25:04,404 --> 00:25:08,625 Another 17. I'm for many years until very recently 358 00:25:08,625 --> 00:25:13,223 actually. One of the key principle of certain and self 359 00:25:13,223 --> 00:25:18,418 -discrimination with the system was based on the assumption. 360 00:25:18,418 --> 00:25:22,532 Does this DNS sense or see here's an emitted 361 00:25:22,532 --> 00:25:27,394 receptors? I exclusively localized inside the zone. 362 00:25:27,394 --> 00:25:32,337 Away from the TN in the nucleus. And that these receptors only 363 00:25:32,337 --> 00:25:36,403 get that theed, following infection with microbes. 364 00:25:36,403 --> 00:25:41,646 Or when we have DNA and the DNE leaks out into the site 365 00:25:41,646 --> 00:25:44,411 and then these receptors are 366 00:25:44,411 --> 00:25:49,057 Another way a very of a simplified way of looking 367 00:25:49,057 --> 00:25:54,129 at this is to imagine that that these receptors which 368 00:25:54,129 --> 00:25:59,392 bind DNE are like us or and the DNA is like explosive. 369 00:25:59,392 --> 00:26:02,472 And the only reason why the sales and is not going 370 00:26:02,472 --> 00:26:05,778 up in Flem is because the gasoline and explosives are 371 00:26:05,778 --> 00:26:07,400 in separate compartments. 372 00:26:07,400 --> 00:26:11,404 At least it was not like that. 373 00:26:11,404 --> 00:26:15,733 But when we started looking very carefully. What we found 374 00:26:15,733 --> 00:26:20,188 is that this intracellular DMS receptors that bind DNA and 375 00:26:20,188 --> 00:26:22,415 we seek us here for example. 376 00:26:22,415 --> 00:26:25,976 This and all the end like receptors. All of them 377 00:26:25,976 --> 00:26:29,586 were actually in the new. For example, see Gauss 378 00:26:29,586 --> 00:26:31,391 was mainly the nucleus. 379 00:26:31,391 --> 00:26:34,757 EFIX teams making the nucleus. The only one which 380 00:26:34,757 --> 00:26:38,398 was in the nucleus and is M 2, 2, so in the nucleus. 381 00:26:38,398 --> 00:26:43,658 So all these receptors Which buying DMA are actually in 382 00:26:43,658 --> 00:26:48,294 the nucleus? So then the question is what really 383 00:26:48,294 --> 00:26:53,413 prevents this new PR, from reacting to economic DNA? 384 00:26:53,413 --> 00:26:57,640 That's 1. The other what is the function of this DNS 385 00:26:57,640 --> 00:27:02,639 sensors in the So this question about the past question, what 386 00:27:02,639 --> 00:27:07,393 prevents nuclear DNA sensor from reacting to genomic DNM? 387 00:27:07,393 --> 00:27:10,984 This has been addressed by recent studies and I'm not 388 00:27:10,984 --> 00:27:14,619 gonna summarize this. So following our demonstration, 389 00:27:14,619 --> 00:27:16,402 the DNS C gas is nucleus. 390 00:27:16,402 --> 00:27:19,216 There are so many papers that came up, for example, 391 00:27:19,216 --> 00:27:21,956 you know, 3 of them in nature that can within one 392 00:27:21,956 --> 00:27:23,409 month of them in science. 393 00:27:23,409 --> 00:27:26,832 But just to summarize, what we found out is that SIGAs 394 00:27:26,832 --> 00:27:31,149 in the nucleus combined with the pro and by binding that 395 00:27:31,149 --> 00:27:35,388 into the chromatin, it's out of trapped in an inactive 396 00:27:35,388 --> 00:27:39,299 And that's why that's not figure information. And that's 397 00:27:39,299 --> 00:27:41,394 all I'm gonna say about this. 398 00:27:41,394 --> 00:27:45,398 No, I'm gonna focus on what is the function. 399 00:27:45,398 --> 00:27:47,400 Oh, this DNS sensors. 400 00:27:47,400 --> 00:27:51,518 In the nucleus. So when we identified that these 401 00:27:51,518 --> 00:27:56,409 receptors are in the nucleus. Our interest at that time. 402 00:27:56,409 --> 00:28:01,078 Was the impact of this receptors. In host response 403 00:28:01,078 --> 00:28:06,650 to Gino's toxic stress. And if we, for example, we analyzed 404 00:28:06,650 --> 00:28:09,389 sales, we will have seek us. 405 00:28:09,389 --> 00:28:16,145 So, What and we look for sell that. What we found that 406 00:28:16,145 --> 00:28:23,403 says that and seek us or aim let receptors What a system. 407 00:28:23,403 --> 00:28:27,599 In other words, that SIGNs and emland receptors are 408 00:28:27,599 --> 00:28:29,409 actually potentiates. 409 00:28:29,409 --> 00:28:33,413 DNA that we do sell it. 410 00:28:33,413 --> 00:28:36,683 And this the prompt had to really look what about 411 00:28:36,683 --> 00:28:40,420 what is the impact of this receptors Indian everywhere. 412 00:28:40,420 --> 00:28:45,754 And then we decide to use a commit and when we compare the 413 00:28:45,754 --> 00:28:51,147 repair of DNA breaks What? I see Ga, we could see that the 414 00:28:51,147 --> 00:28:54,400 S ika's knockout sales peric and a 415 00:28:54,400 --> 00:28:58,197 As I said, SIGNS is an enzyme which symbols a secum and 416 00:28:58,197 --> 00:29:02,408 Cgum 10 signal by the sting partners to reduce inflammation. 417 00:29:02,408 --> 00:29:07,910 And the question was So this results essentially means that C 418 00:29:07,910 --> 00:29:13,563 does. Is an inhibitor of B. But if you don't have it, you have 419 00:29:13,563 --> 00:29:16,389 enhance without your networks. 420 00:29:16,389 --> 00:29:20,582 So therefore we're interested where the seekers in hit the 421 00:29:20,582 --> 00:29:24,737 DNA repair about this thing But when we look at repair of 422 00:29:24,737 --> 00:29:29,402 the DNA breaks, we compare, we found that sting knockout cells. 423 00:29:29,402 --> 00:29:34,998 Can't If he shouldn't like the Walt up sales. Which means this 424 00:29:34,998 --> 00:29:40,413 new function. Oh, SIGNS NGOs in DNA repair was independent. 425 00:29:40,413 --> 00:29:46,419 Of the of the canonical function of the CIA in that immunity. 426 00:29:46,419 --> 00:29:50,628 And now we also look at the aim like receptors. You know, 427 00:29:50,628 --> 00:29:54,394 emland disceptors actually classes in one lockers. 428 00:29:54,394 --> 00:29:58,325 In the human and in mice and they are mice which allow 429 00:29:58,325 --> 00:30:04,591 all the envelope centers. So when we look at the ability 430 00:30:04,591 --> 00:30:10,410 of cell phone, in black, what we see, and this is a 431 00:30:10,410 --> 00:30:14,342 You can see that says that like the am receptors. Could 432 00:30:14,342 --> 00:30:16,416 resolve the DNA breaks fast. 433 00:30:16,416 --> 00:30:20,445 And then you wanted to know to able at receptors 434 00:30:20,445 --> 00:30:24,390 also in P genome repair. Via a bit downstream. 435 00:30:24,390 --> 00:30:30,619 Adopt and only compare the repair from A/C, they prepare 436 00:30:30,619 --> 00:30:36,364 the DNA breaks much like the wild time, which means 437 00:30:36,364 --> 00:30:39,405 again the ample receptors. 438 00:30:39,405 --> 00:30:42,317 Can in pair the Gitome repair independent or the 439 00:30:42,317 --> 00:30:45,411 function of these receptors in the meeting system. 440 00:30:45,411 --> 00:30:48,985 I we went in people. As you're probably born marrow 441 00:30:48,985 --> 00:30:52,418 suppression is is is a major cause of mortality. 442 00:30:52,418 --> 00:30:55,964 For example, following radiation. And so to 443 00:30:55,964 --> 00:31:00,140 really show or determine whether these, Inhibition 444 00:31:00,140 --> 00:31:02,395 of DNA by these receptors. 445 00:31:02,395 --> 00:31:06,346 See, us and, and name like you set us. So it's got 446 00:31:06,346 --> 00:31:08,401 other ones in the people. 447 00:31:08,401 --> 00:31:12,383 We exposed mice to radiation. The Cgas knock out and em blood 448 00:31:12,383 --> 00:31:14,407 the septuna through radiation. 449 00:31:14,407 --> 00:31:18,688 I look for bone marrow and if I see you have one 450 00:31:18,688 --> 00:31:23,416 more operation. 50% within 12 h as you can see here. 451 00:31:23,416 --> 00:31:27,947 But when we carefully type traded, we found that my, 452 00:31:27,947 --> 00:31:32,392 with emerald sectors was significantly the system. 453 00:31:32,392 --> 00:31:37,397 To radiation induced Bonima. 454 00:31:37,397 --> 00:31:41,361 Okay, so from this we could complete that actually 455 00:31:41,361 --> 00:31:45,405 see us and MLAD receptors are negative regulators. 456 00:31:45,405 --> 00:31:49,409 And has accelerated DNA damaging inside. 457 00:31:49,409 --> 00:31:53,010 And then of course then we this also triggers to really 458 00:31:53,010 --> 00:31:56,416 ask what is then is the impact of this DNA sensors. 459 00:31:56,416 --> 00:31:59,658 Oh, the sensitivity of GANSSA. Sales to DNA damaging 460 00:31:59,658 --> 00:32:03,057 agents. And here I show you, for example, and I didn't 461 00:32:03,057 --> 00:32:06,392 show you for the data for the name like Reset Trust. 462 00:32:06,392 --> 00:32:10,282 What we found is that Kancer cells which large the SIGRas 463 00:32:10,282 --> 00:32:12,398 were actually highly assisted. 464 00:32:12,398 --> 00:32:17,069 To a doctor. And here I have to mention that many of the 465 00:32:17,069 --> 00:32:25,093 council says a half down regulation in the expression 466 00:32:25,093 --> 00:32:33,419 of So I'm suggesting that probably lots of SIGNs could 467 00:32:33,419 --> 00:32:36,405 Based on this and we decide to look for example 468 00:32:36,405 --> 00:32:39,392 in publicly available data, data for patients. 469 00:32:39,392 --> 00:32:42,752 Following radiation of chemotherapy. And one of 470 00:32:42,752 --> 00:32:50,486 the things that we found persistently is that, patients 471 00:32:50,486 --> 00:32:55,408 t hat really show lower expression 472 00:32:55,408 --> 00:32:59,579 So they have no explanation of or the M 2 and they 473 00:32:59,579 --> 00:33:04,054 have prognosis. And this I guess that the DNS has a C 474 00:33:04,054 --> 00:33:06,419 does it in black receptors. 475 00:33:06,419 --> 00:33:13,392 Do portation, the the tumour, effects or DNA, 476 00:33:13,392 --> 00:33:16,868 So mechanistically, how do this seek as an emblac? 477 00:33:16,868 --> 00:33:18,397 Is that that in PG G. 478 00:33:18,397 --> 00:33:22,361 Here I will not go into details. I will only 479 00:33:22,361 --> 00:33:27,406 summarize here. As you'll probably know better than me. 480 00:33:27,406 --> 00:33:31,207 One of it, you know. Chromeat instruction is very important 481 00:33:31,207 --> 00:33:35,512 for the timing, you know, the outcome of being and 482 00:33:35,512 --> 00:33:40,419 and one of the early events following the endemic is the 483 00:33:40,419 --> 00:33:45,391 To allow for generic factors to be reproved. 484 00:33:45,391 --> 00:33:48,605 So in somebody what we found is that the end black 485 00:33:48,605 --> 00:33:52,398 receptors and see us by binding directly to the chromatin. 486 00:33:52,398 --> 00:33:57,048 And then that wasn't self-. What these receptors 487 00:33:57,048 --> 00:34:01,407 do is they impede this chromatin relaxation. 488 00:34:01,407 --> 00:34:04,798 Which is important for the regroupment or DNA 489 00:34:04,798 --> 00:34:08,414 factors. And by so doing and by inhibiting DNA. 490 00:34:08,414 --> 00:34:15,421 These receptors. Absolutely. 491 00:34:15,421 --> 00:34:19,630 You know, that was one could also speculate that problem, 492 00:34:19,630 --> 00:34:23,396 this DNA sensors. Could be potential determinants. 493 00:34:23,396 --> 00:34:29,294 Of our marker for predicting the radio sensitivity. Oh, 494 00:34:29,294 --> 00:34:35,679 And as I mentioned before Many of the classes actually have 495 00:34:35,679 --> 00:34:41,414 down regulation in expression of PTDNS, DNS sensors. 496 00:34:41,414 --> 00:34:45,684 And that would be one of the mechanisms of which. 497 00:34:45,684 --> 00:34:50,389 Because I says computer system too. To So in summary. 498 00:34:50,389 --> 00:34:53,392 The message that I wanted to hear is, of message 499 00:34:53,392 --> 00:34:56,395 number 2 is the DNS and SSC does an emblad set. 500 00:34:56,395 --> 00:34:59,691 Have these things subsilla function? In the site also, 501 00:34:59,691 --> 00:35:03,018 the important coordinating in activation in the in the 502 00:35:03,018 --> 00:35:06,405 nucleus, the regulators of chromat instruction repair. 503 00:35:06,405 --> 00:35:10,384 And he's 3 other from many many studies that this you 504 00:35:10,384 --> 00:35:14,249 know defects in this DNA receptors have implication 505 00:35:14,249 --> 00:35:18,417 in many disease in many diseases, including infection. 506 00:35:18,417 --> 00:35:22,592 Vote inflammation class and new regeneration sentences 507 00:35:22,592 --> 00:35:27,284 DTC. And we think that this distinct function In this cycle, 508 00:35:27,284 --> 00:35:29,395 in magnetic in activation. 509 00:35:29,395 --> 00:35:35,401 And in normally there would underline. The 510 00:35:35,401 --> 00:35:39,405 multiple, effect on health. 511 00:35:39,405 --> 00:35:43,394 And so based on this, and again, I want to like the way 512 00:35:43,394 --> 00:35:47,433 I started, I started by, you know, real stating that is 513 00:35:47,433 --> 00:35:49,415 clear that the new system. 514 00:35:49,415 --> 00:35:53,864 The DNA repair system, highly, there's a lot of prostock. 515 00:35:53,864 --> 00:35:58,391 And there are many molecules at the intersection of this. 516 00:35:58,391 --> 00:36:02,573 Some of them we publish on business one ATM one. And 517 00:36:02,573 --> 00:36:07,400 now I've been focusing on the SIGNS and the MLAD receptors. 518 00:36:07,400 --> 00:36:11,085 Yeah, but. These receptors are not only, 1st of all, 519 00:36:11,085 --> 00:36:15,408 they're important for driving DNA damage genes inflammation. 520 00:36:15,408 --> 00:36:18,741 No, I've also shown that these receptors are also 521 00:36:18,741 --> 00:36:22,415 important. Manipulating the repair of the EMM breaks. 522 00:36:22,415 --> 00:36:26,796 And then. The company issue is, you know, to be able, 523 00:36:26,796 --> 00:36:31,053 as I said in the beginning, that the new system and 524 00:36:31,053 --> 00:36:35,394 the dinner repair system or details in this system. 525 00:36:35,394 --> 00:36:39,609 Underline many of the health conditions. And can we find 526 00:36:39,609 --> 00:36:43,650 a way of modulating the new system and being an array 527 00:36:43,650 --> 00:36:45,404 system simultaneously? 528 00:36:45,404 --> 00:36:48,162 And one way would be if we can target some of 529 00:36:48,162 --> 00:36:51,410 the monarchies and the intersection of these fields. 530 00:36:51,410 --> 00:36:54,519 Then the question is because he does and him like receptors 531 00:36:54,519 --> 00:36:57,416 seem to be involved in the regulation of both systems. 532 00:36:57,416 --> 00:37:02,037 What if we can find inhibitors of these figures? And 533 00:37:02,037 --> 00:37:06,392 internet receptors. Can we dump an inflammation? 534 00:37:06,392 --> 00:37:12,362 And, but can we? So following this, line of thought, we 535 00:37:12,362 --> 00:37:15,401 decided to read the screen. 536 00:37:15,401 --> 00:37:21,793 For potential inhibitors of this. And what we did and we 537 00:37:21,793 --> 00:37:28,414 focus on seekers, you know, the inhibitor of the seekers. 538 00:37:28,414 --> 00:37:32,287 And then we found a compound. That when we incubate 539 00:37:32,287 --> 00:37:36,388 themselves, it could in heated induction interferons. 540 00:37:36,388 --> 00:37:40,817 Following activation of CEOs. And that is the structure of 541 00:37:40,817 --> 00:37:45,397 this compound. And for the chemists of you in the audience. 542 00:37:45,397 --> 00:37:48,677 Probably you know what this compound is. But 543 00:37:48,677 --> 00:37:52,404 I'll, I will of course, you know, tell you later. 544 00:37:52,404 --> 00:37:58,410 And so this compound, when we give this we 545 00:37:58,410 --> 00:38:01,814 This is, SAYS with this compound. What we could see 546 00:38:01,814 --> 00:38:05,528 if of course we could reduce the internal induction all 547 00:38:05,528 --> 00:38:07,419 the way in the transaction. 548 00:38:07,419 --> 00:38:11,560 And when we also incubate ourselves with this compound 549 00:38:11,560 --> 00:38:15,394 and do a comment assets, we can see we have Okay. 550 00:38:15,394 --> 00:38:19,378 Which is very nice and this very consistent with what we see when 551 00:38:19,378 --> 00:38:21,400 we don't have CIGS in the cells. 552 00:38:21,400 --> 00:38:26,742 And this is when we go into people and we get this company, 553 00:38:26,742 --> 00:38:32,611 and look for inflammation following radiation, you 554 00:38:32,611 --> 00:38:39,418 could see that drug X would of course reduce interfererow 555 00:38:39,418 --> 00:38:45,089 And with the count the it could actually partially protect 556 00:38:45,089 --> 00:38:50,827 against irrigation. And look at survival, the drug X could 557 00:38:50,827 --> 00:38:53,399 actually extend survival. 558 00:38:53,399 --> 00:39:01,113 So which means that drug apps by a an impeding inflammation, 559 00:39:01,113 --> 00:39:07,413 it can actually promote the survival of animals. 560 00:39:07,413 --> 00:39:12,478 So who are excited? But then we try to do additional experiment 561 00:39:12,478 --> 00:39:16,870 and this was a disappointment because We decide to see 562 00:39:16,870 --> 00:39:19,391 whether is it really specific. 563 00:39:19,391 --> 00:39:24,521 And we found that, when we integrated sales with draft 564 00:39:24,521 --> 00:39:29,712 X, and stimulate the sales at the other is like taller 565 00:39:29,712 --> 00:39:32,404 accepted 2 All except at 3. 566 00:39:32,404 --> 00:39:36,015 Drop X could still in heap it. Activation of 567 00:39:36,015 --> 00:39:40,337 the new system which means This is drug was actually 568 00:39:40,337 --> 00:39:42,414 not really specific for. 569 00:39:42,414 --> 00:39:48,647 We'll see where it is important. And then we also ask what about 570 00:39:48,647 --> 00:39:54,393 repair? People also, just as this had to had 2 9 3D sales. 571 00:39:54,393 --> 00:39:58,278 Don't have seen us and we check what are you know 572 00:39:58,278 --> 00:40:02,401 this is draft can promote the non-repair and visas. 573 00:40:02,401 --> 00:40:06,315 Using this reporter line. And you can see these drug 574 00:40:06,315 --> 00:40:10,582 ads could actually potential genome right there. In this 575 00:40:10,582 --> 00:40:12,411 So it was not specific. 576 00:40:12,411 --> 00:40:20,395 But the most important thing is It's somehow in his inflammation 577 00:40:20,395 --> 00:40:23,389 and it and was about X. 578 00:40:23,389 --> 00:40:28,116 It's asking. The ask me, as you all know, is probably 579 00:40:28,116 --> 00:40:32,398 all the drugs in the history of human medicine. 580 00:40:32,398 --> 00:40:36,819 It's. Is perhaps the most widely used travel inside 581 00:40:36,819 --> 00:40:41,124 Viagra. And is commonly used for the treatment of 582 00:40:41,124 --> 00:40:43,409 pain, inflammation fever. 583 00:40:43,409 --> 00:40:48,961 And cardiovascular diseases. It has also been linked 584 00:40:48,961 --> 00:40:51,417 to. Cancer prevention. 585 00:40:51,417 --> 00:40:55,116 Unless you all know the best mechanism of our 586 00:40:55,116 --> 00:40:59,391 screen. He's inhibition prosta granting production. 587 00:40:59,391 --> 00:41:04,730 Bye blocking the cycloxiness enzymes, box one and box 2. 588 00:41:04,730 --> 00:41:07,399 And this is what was known. 589 00:41:07,399 --> 00:41:12,021 And as I said, it's clear that Aspen, promotes the normal care 590 00:41:12,021 --> 00:41:14,406 and protects against radiation. 591 00:41:14,406 --> 00:41:19,001 And is what I just showed. Now the question is what 592 00:41:19,001 --> 00:41:23,415 are the mechanism? How does asking acceleration? 593 00:41:23,415 --> 00:41:27,858 So, and they can summarize because I don't want to be in 594 00:41:27,858 --> 00:41:32,748 the interest of time. What we found anyway is that One of the 595 00:41:32,748 --> 00:41:35,394 key target of us is the HISTONS. 596 00:41:35,394 --> 00:41:37,726 But us will actually acidulate Eastern. Actually even more 597 00:41:37,726 --> 00:41:41,350 specifically the Houston h 4 k 16. Basicatelating EASTON'S, 598 00:41:41,350 --> 00:41:45,404 what happens is actually promote this competent relaxation, which 599 00:41:45,404 --> 00:41:53,732 Vixam Bracca one. And that's why when we are exposed 600 00:41:53,732 --> 00:41:57,416 to asking. And we eat. 601 00:41:57,416 --> 00:42:01,131 Aspen and you see this in evil as well in vitro. Is 602 00:42:01,131 --> 00:42:03,389 that by-satulating the system? 603 00:42:03,389 --> 00:42:08,082 Askpen really uses the chromatin relaxation. 604 00:42:08,082 --> 00:42:14,024 Promoting improvement in what underlies the protective, 605 00:42:14,024 --> 00:42:16,402 effect of our screen. 606 00:42:16,402 --> 00:42:19,341 And at this and we think that this the ability 607 00:42:19,341 --> 00:42:22,408 to accelerate you number and damp inflammation. 608 00:42:22,408 --> 00:42:26,215 Is a possible explanation for the concept within the Maybe 609 00:42:26,215 --> 00:42:30,416 this is an exaggeration, but at least that's what we are going. 610 00:42:30,416 --> 00:42:32,418 With. 611 00:42:32,418 --> 00:42:36,369 So anyway, in conclusion, as I said, is the new system 612 00:42:36,369 --> 00:42:39,845 and linear repair system are interconnected and 613 00:42:39,845 --> 00:42:43,395 that may be concentrated on on this DNA sensor. 614 00:42:43,395 --> 00:42:48,185 See as an emperor. I'm sure that this malloc is really 615 00:42:48,185 --> 00:42:50,402 sit at the intersection. 616 00:42:50,402 --> 00:42:54,682 Of these defense systems. And many other molecules also are 617 00:42:54,682 --> 00:42:58,576 in the tensor intersection here of course is not only 618 00:42:58,576 --> 00:43:00,412 C and M black receptors. 619 00:43:00,412 --> 00:43:04,677 And we are still persuaded that. That actually targeting 620 00:43:04,677 --> 00:43:08,382 some of the molecules at the intersection of the 621 00:43:08,382 --> 00:43:10,389 mu and DNA repair system. 622 00:43:10,389 --> 00:43:14,209 My providing might provide a means of manipulating 623 00:43:14,209 --> 00:43:18,310 both the new and DNA repair system. In the management 624 00:43:18,310 --> 00:43:20,399 of very complex, diseases. 625 00:43:20,399 --> 00:43:25,859 Our request to find specific inhibitors or C does an em like 626 00:43:25,859 --> 00:43:28,407 receptors. Been turned out. 627 00:43:28,407 --> 00:43:33,770 But, but at least it enable us to find a new mechanism of our 628 00:43:33,770 --> 00:43:39,107 screen. That, and ensure that aspirin actually can modulate, 629 00:43:39,107 --> 00:43:41,420 condemn the inflammation. 630 00:43:41,420 --> 00:43:46,048 And promote and that usspring would be one of 631 00:43:46,048 --> 00:43:51,396 the drugs that could be used. In manipulating this. 632 00:43:51,396 --> 00:43:55,400 To the phone system, to improve that. 633 00:43:55,400 --> 00:44:00,391 And with that, I mean, that's all I had for 634 00:44:00,391 --> 00:44:03,408 you. And, oh, hey, sorry. 635 00:44:03,408 --> 00:44:06,346 I think the last slide for that more argument 636 00:44:06,346 --> 00:44:09,414 I must have deleted by absent. I'm very sorry. 637 00:44:09,414 --> 00:44:19,391 And that's just about it. 638 00:44:19,391 --> 00:44:21,393 I you still there? 639 00:44:21,393 --> 00:44:22,394 Yes. 640 00:44:22,394 --> 00:44:28,924 We are still there. Sorry. Okay, we have questions in 641 00:44:28,924 --> 00:44:35,040 the chat. So I encourage the rest of the audience 642 00:44:35,040 --> 00:44:38,410 to put their questions in. 643 00:44:38,410 --> 00:44:39,411 Okay. 644 00:44:39,411 --> 00:44:41,540 There are 3 questions there, vibrant ski, that I'll just 645 00:44:41,540 --> 00:44:44,893 read the 1st one. And it's from the 1st part of your talk, 646 00:44:44,893 --> 00:44:48,420 which is our DNA damage induced doubts, a DS Dubstone DS DNA 647 00:44:48,420 --> 00:44:57,396 Can you say it again, please? 648 00:44:57,396 --> 00:44:58,397 Yeah. 649 00:44:58,397 --> 00:45:01,018 And I think it's our DNA damage induced. DSDN, I don't 650 00:45:01,018 --> 00:45:03,858 know whether it means double strand breaks in DNA enriched 651 00:45:03,858 --> 00:45:06,405 for retro-transcribe DNA from competitive elements. 652 00:45:06,405 --> 00:45:07,406 No, no, I think. 653 00:45:07,406 --> 00:45:09,521 And it means that. Maybe Whitsky, could you, Banel 654 00:45:09,521 --> 00:45:10,409 could do Lip Ripsky? 655 00:45:10,409 --> 00:45:11,410 So good. 656 00:45:11,410 --> 00:45:16,346 I probably understand. Hey, let me repeat the way I understand 657 00:45:16,346 --> 00:45:18,417 it. The question is what. 658 00:45:18,417 --> 00:45:22,803 The DNA that we find with the cytosol following 659 00:45:22,803 --> 00:45:24,389 DNA damage. From 660 00:45:24,389 --> 00:45:28,393 Yes. Yes. 661 00:45:28,393 --> 00:45:31,691 It's, you know, because we try to analyze this and it's, 662 00:45:31,691 --> 00:45:33,398 it's, completely unspecific. 663 00:45:33,398 --> 00:45:37,363 It's from all over. Because the elements are highly 664 00:45:37,363 --> 00:45:41,406 represented in our genome, we also find them there. 665 00:45:41,406 --> 00:45:45,627 But the other thing I mean this one of the questions 666 00:45:45,627 --> 00:45:50,415 that we asked before He's that when you have inflammation. 667 00:45:50,415 --> 00:45:55,705 And you do have inflammation for One of the things that I have to 668 00:45:55,705 --> 00:45:58,390 be activated is a retro element. 669 00:45:58,390 --> 00:46:02,286 So red elements, if I if you put sales with, for 670 00:46:02,286 --> 00:46:04,396 example, bacteria or LPS. 671 00:46:04,396 --> 00:46:10,351 You see a So you do see an increase expression rate or 672 00:46:10,351 --> 00:46:17,409 elements. But we think that the retro element is a consequence. 673 00:46:17,409 --> 00:46:20,981 Oh, in your I'm not, of us. Of course it contributes 674 00:46:20,981 --> 00:46:24,416 to amplify. But at least we have a issue on that. 675 00:46:24,416 --> 00:46:30,744 Element expression is a consequence of union activation. 676 00:46:30,744 --> 00:46:36,395 And I don't know what I'm answering the question. 677 00:46:36,395 --> 00:46:39,796 Okay, I'll go with the second question from Risky. 678 00:46:39,796 --> 00:46:43,402 Does a C gas binds to a nuclear question from Risky. 679 00:46:43,402 --> 00:46:46,522 Does a C gas binds to a nuclear lamb inbound DNA 680 00:46:46,522 --> 00:46:48,407 and that keep them inactive? 681 00:46:48,407 --> 00:46:52,411 The C does bind to nuclear. 682 00:46:52,411 --> 00:46:57,416 Lamb inbound DNA. 683 00:46:57,416 --> 00:47:00,419 I don't know. 684 00:47:00,419 --> 00:47:05,602 I don't. Because the thing is, What happened is that 685 00:47:05,602 --> 00:47:08,393 in the chromatin, see goes. 686 00:47:08,393 --> 00:47:13,090 Actually, not only binds DNA, but it binds the And that's why 687 00:47:13,090 --> 00:47:15,400 it's inactive in the nucleus. 688 00:47:15,400 --> 00:47:20,906 So if you have promote in SDN name, see guys will 689 00:47:20,906 --> 00:47:26,411 ban it and it even bars with strong alphabetity. 690 00:47:26,411 --> 00:47:30,344 And that's what really drops the CEOs in an inactive, a 691 00:47:30,344 --> 00:47:32,417 confirmation in the nucleus. 692 00:47:32,417 --> 00:47:39,391 So with L, yeah, that's all I can say about this. 693 00:47:39,391 --> 00:47:43,429 Okay, in the interest of letting other people have a. Chance 694 00:47:43,429 --> 00:47:47,399 to answer a question. Because Ritzki has another question. 695 00:47:47,399 --> 00:47:48,400 Yup. 696 00:47:48,400 --> 00:47:48,802 We'll get back to him later. Somebody, I phone 1 9 says 697 00:47:48,802 --> 00:47:49,186 fantastic talk. Do you already have evidence for the 698 00:47:49,186 --> 00:47:49,401 aspirin effect on chromatin? 699 00:47:49,401 --> 00:47:54,102 I think you went through that very quickly. Maybe you 700 00:47:54,102 --> 00:47:56,408 could give a few details. 701 00:47:56,408 --> 00:47:59,993 Do we have heavy deaths? Yes, we have evidence. We had 702 00:47:59,993 --> 00:48:04,830 reporters. Why we could actually when we we were expressing 703 00:48:04,830 --> 00:48:09,421 us and we could we could see that it really impedes for 704 00:48:09,421 --> 00:48:12,528 And will be knock out. See that then you have 705 00:48:12,528 --> 00:48:14,393 more, you know, chromatin. 706 00:48:14,393 --> 00:48:18,397 Oh yeah, so we have everything for this. 707 00:48:18,397 --> 00:48:21,400 And that's in your 2023 paper that you cited. 708 00:48:21,400 --> 00:48:24,403 Yes. 709 00:48:24,403 --> 00:48:30,409 Okay, okay, great. We have a next question from, Suha, 710 00:48:30,409 --> 00:48:35,689 Shaman, does, DNA damage or genotoxin treatment 711 00:48:35,689 --> 00:48:41,420 alter C gas expression in normal and cancer cells. 712 00:48:41,420 --> 00:48:45,839 You know, I think probably good because 1st of all, as I said, 713 00:48:45,839 --> 00:48:50,379 many of the councils, you know, you have, suppression of Ciga's 714 00:48:50,379 --> 00:48:52,397 expression, that's 1 thing. 715 00:48:52,397 --> 00:48:57,140 And also see gas was initially identified as 716 00:48:57,140 --> 00:49:03,248 one of Inferron needs genes which are normally expressed 717 00:49:03,248 --> 00:49:06,411 following immune activation. 718 00:49:06,411 --> 00:49:11,227 So again, because in your activation. Oh, DNA damage 719 00:49:11,227 --> 00:49:18,019 country called near the immune system. And I think the new 720 00:49:18,019 --> 00:49:25,397 immune figure in put in don't figure the expression of So it's 721 00:49:25,397 --> 00:49:29,716 But in many of the cells, you do still have basal 722 00:49:29,716 --> 00:49:34,874 expression of the seagulls, but it could be the expression 723 00:49:34,874 --> 00:49:39,411 could be increased during inflammatory conditions. 724 00:49:39,411 --> 00:49:42,791 Okay, there's a question from Daria Bogdanova. Sorry 725 00:49:42,791 --> 00:49:44,416 about the pronunciation. 726 00:49:44,416 --> 00:49:47,618 Would you please repeat your hypothesis about 727 00:49:47,618 --> 00:49:51,389 how sea gas discriminates self and non self and DNA. 728 00:49:51,389 --> 00:49:55,950 So what happens is that C gas normally is 729 00:49:55,950 --> 00:50:01,399 activated to produce. No, it plans to make a DN. 730 00:50:01,399 --> 00:50:06,344 Then it, But when it advanced to DNN, which is, but you 731 00:50:06,344 --> 00:50:11,425 have systems. What happens is actually there's not bound 732 00:50:11,425 --> 00:50:16,414 to the DNA but it runs very strongly into the histogs. 733 00:50:16,414 --> 00:50:20,599 With a very high. And then by adding to the distance, 734 00:50:20,599 --> 00:50:24,389 it sort of dropped in an inactive confirmation. 735 00:50:24,389 --> 00:50:28,887 So essentially, Sort of, Scarbank is the Cgas in the 736 00:50:28,887 --> 00:50:31,396 nucleus and really drops it. 737 00:50:31,396 --> 00:50:34,012 At least that's 1 of the hypotheses out there. We 738 00:50:34,012 --> 00:50:36,654 do have and this not the only mechanism, at least 739 00:50:36,654 --> 00:50:39,404 that's 1 of the mechanism which has been reported. 740 00:50:39,404 --> 00:50:45,410 That it's because of the competition with the 741 00:50:45,410 --> 00:50:48,883 Great, I think, there is, there are a couple of questions 742 00:50:48,883 --> 00:50:52,417 from the panelists. I see you can raise the hand first.st 743 00:50:52,417 --> 00:50:53,418 Ken, do you want to? Ask a question correctly. 744 00:50:53,418 --> 00:50:54,419 Yes, I'm, I'm, my video is blacked out, but I will talk. 745 00:50:54,419 --> 00:51:06,398 In the mystery. The, this is a wonderful talk. Start my video. 746 00:51:06,398 --> 00:51:10,338 Here we go. Heara, yeah. It's a wonderful talk. You've studied 747 00:51:10,338 --> 00:51:14,406 particularly a taxi at which is a DNA repair deficient disease. 748 00:51:14,406 --> 00:51:18,902 We study a couple of others that where we've been 749 00:51:18,902 --> 00:51:23,369 puzzled for many years how they get inflammatory 750 00:51:23,369 --> 00:51:25,417 and immune reactions. 751 00:51:25,417 --> 00:51:29,688 One is zeroderma pigmentosum. And depending on which 752 00:51:29,688 --> 00:51:34,084 mutation they have. If they have mutations in the XPC 753 00:51:34,084 --> 00:51:38,396 gene that's involved with the global genome repair. 754 00:51:38,396 --> 00:51:42,413 They have normal sun sensitivity. Where is if 755 00:51:42,413 --> 00:51:47,457 they have mutations and other repaired genes like XPA or 756 00:51:47,457 --> 00:51:52,410 XPD that are involved in transcription coupled repair. 757 00:51:52,410 --> 00:51:56,816 They're exquisitely sensitive to the sunlight. And so clearly 758 00:51:56,816 --> 00:52:01,197 there's some role between these particular mutations and the 759 00:52:01,197 --> 00:52:03,388 inflammatory reaction to sun. 760 00:52:03,388 --> 00:52:07,019 And the second disease we study is trico of the xeroderma 761 00:52:07,019 --> 00:52:10,395 patients have a 10,000 fold increase in skin cancer. 762 00:52:10,395 --> 00:52:15,595 All of them do. So that's 1. The other one we look 763 00:52:15,595 --> 00:52:18,403 at is, tricophiodistrophy. 764 00:52:18,403 --> 00:52:22,736 That has a different mutations in the XPD gene. 765 00:52:22,736 --> 00:52:25,410 And then the XP patients do. 766 00:52:25,410 --> 00:52:29,157 But they have a multiple infections. Are they often 767 00:52:29,157 --> 00:52:33,418 die of infection? They have, we publish papers on immune. 768 00:52:33,418 --> 00:52:37,611 The fact that they have immune problems. But we've been 769 00:52:37,611 --> 00:52:41,851 working with them. We try to get the immunologists here 770 00:52:41,851 --> 00:52:44,396 interested in finding the exact. 771 00:52:44,396 --> 00:52:48,501 Issues there and they haven't found it yet. So that's another 772 00:52:48,501 --> 00:52:52,404 area that's Another fertile area for, studies like these. 773 00:52:52,404 --> 00:52:55,407 And I'm really impressed with your study here. Thank you. 774 00:52:55,407 --> 00:52:58,689 Yeah, I guess one, that's thank you very much. I just want to 775 00:52:58,689 --> 00:53:00,412 point out it gets very complex. 776 00:53:00,412 --> 00:53:04,280 When we look at the defects in DNA and the immune system. 777 00:53:04,280 --> 00:53:09,233 Because, we also have to remember the DNA repair 778 00:53:09,233 --> 00:53:14,392 is also very important for the development of the 779 00:53:14,392 --> 00:53:16,805 And so you could also have immune deficiencies because 780 00:53:16,805 --> 00:53:19,397 of the in some of the DNA and it gets very, very complex. 781 00:53:19,397 --> 00:53:27,405 And, yeah. 782 00:53:27,405 --> 00:53:31,409 Okay, we also have a question from Vilbore. Oh? 783 00:53:31,409 --> 00:53:35,518 Yeah, thank you. I also really enjoyed the talk. I 784 00:53:35,518 --> 00:53:39,925 really nice. Overview of this interaction between the 785 00:53:39,925 --> 00:53:42,420 immune system and DNA repair. 786 00:53:42,420 --> 00:53:46,446 I have specific question. Interestingly, these 80 787 00:53:46,446 --> 00:53:50,674 patients very often die from lung disease. Is there 788 00:53:50,674 --> 00:53:55,400 something is a special something special about the long? 789 00:53:55,400 --> 00:54:00,433 And this innate immune system pathway or something. 790 00:54:00,433 --> 00:54:02,407 That explains this. 791 00:54:02,407 --> 00:54:08,003 Yes, so we we did publish a pipeline immunity in 2016 on 792 00:54:08,003 --> 00:54:14,893 this. And one of the things that we found in addition 793 00:54:14,893 --> 00:54:21,392 to defects in DNA there ATM is very important for 794 00:54:21,392 --> 00:54:25,762 And what we found that if you have a lot of oxidative 795 00:54:25,762 --> 00:54:30,584 stress. It oxidizes. Some of these inflammation components 796 00:54:30,584 --> 00:54:35,406 which are also very important for antibacterial immunity. 797 00:54:35,406 --> 00:54:39,165 And this one of them and then this we really did a very I 798 00:54:39,165 --> 00:54:42,758 think we did a very good work we control these I think 799 00:54:42,758 --> 00:54:46,417 that's 1 of the mechanism because of oxidative stress. 800 00:54:46,417 --> 00:54:49,420 Do that is the long. 801 00:54:49,420 --> 00:54:54,353 Because of the alarm. But also I think it gets very complicated 802 00:54:54,353 --> 00:54:58,786 also and I think also what happens because these normals 803 00:54:58,786 --> 00:55:01,399 the poker's new morning is back. 804 00:55:01,399 --> 00:55:05,532 Infection, right? What I think and this is so what 805 00:55:05,532 --> 00:55:10,408 happens when we get old when you go to intensive care unit 806 00:55:10,408 --> 00:55:14,382 What ever even as you have you're more likely to die 807 00:55:14,382 --> 00:55:18,406 of lung but due infection. And this is because of, I 808 00:55:18,406 --> 00:55:20,418 think, neurodegeneration. 809 00:55:20,418 --> 00:55:24,151 Because if you look your plug function that you can 810 00:55:24,151 --> 00:55:29,322 breathe cough and all that you know and you're not able 811 00:55:29,322 --> 00:55:34,399 to constantly expel, for example, the new CAS and all 812 00:55:34,399 --> 00:55:39,404 Over time, you develop this buy of. 813 00:55:39,404 --> 00:55:43,541 And this biofilm, of bacteria, it can hand up 814 00:55:43,541 --> 00:55:48,413 killing. So from, so that's 1 of the aspect I think. 815 00:55:48,413 --> 00:55:52,333 Yeah, very, nice idea. Yeah, thank you. Enjoyed 816 00:55:52,333 --> 00:55:54,419 it. Thank you very much. 817 00:55:54,419 --> 00:55:58,544 All right, so with, with the time restrain, we probably 818 00:55:58,544 --> 00:56:02,496 have to stop here and, for the unanswered questions, 819 00:56:02,496 --> 00:56:04,395 we will reach out to Dr. 820 00:56:04,395 --> 00:56:08,924 Keykara through email and, the, and the later. Again, 821 00:56:08,924 --> 00:56:11,402 please join me to thank, Dr. 822 00:56:11,402 --> 00:56:14,240 Geekara for his wonderful talk. And we're looking 823 00:56:14,240 --> 00:56:17,059 forward for more of your wonderful investigation 824 00:56:17,059 --> 00:56:18,409 and more interactions. 825 00:56:18,409 --> 00:56:21,412 Thank you. 826 00:56:21,412 --> 00:56:24,415 Thank you. 827 00:56:24,415 --> 00:56:25,416 Thank you. 828 00:56:25,416 --> 00:56:26,417 Alright, take care. 829 00:56:26,417 --> 00:56:27,418 Thank you, Thank you. So. 830 00:56:27,418 --> 00:56:30,388 Bye