Pizza's been around for many, many years, and nobody's quite figured out the best way to make it. But what makes things easier and better and faster? That's right, Brian. Power tools. I'm still trying to digest everything you said about pizza in the beginning. Power tools. Brian, what are we doing today? Today, we are using some very powered tools to create some very fine pizza. When you're using power tools, it's all faster. Better than these manual hands. We couldn't do this with our manual hands, right? Yeah, and also, viewers at home, if you don't know this, we're both very Italian, so this is going to work out great. I love Italy. We've got a recipe that we're going to follow for once, and it's going to be quick. It's going to be great, and we've got a plethora of tools to help us out along the way. So, Brian. Brian, would you like to join me in Italy? Sure, I love being inside Italy. Justin, do the Italian transition. And then you make an Italian transition, whatever that may be. First, main course, the dough. Two and a half cups all means course, the dough. That's what it says. Combine one cup of flour, instant yeast, sugar, and salt in a large bowl. Brian, these are mixing bowls, but I don't think they're powerful enough for our power tools. So, we won't be using the mixing bowls today. What will we be using? I don't know, because I actually wasn't told before this video started, so. Oh, bucket from AutoZone. Let me wash it. One cup of flour. Beautiful. Oh, look at the color on that. Good. White is the homeland. Italy. Add olive oil and warm water and use a wooden spoon to stir very well. Wait, it's just half cup of water? Three quarter cup warm water and olive oil. No, hold on. That's literally what it says. Wasn't there more ingredients than just the flour? I think we have to put those in later. It says gradually add another one cup of flour. We maybe should have read the recipe. No, start from the beginning. Half cup of flour. No, one cup of flour. One cup of flour. Then it says add olive oil and warm water. How much olive oil? Ah, Jesus. Two tablespoons of olive oil. And then probably not. Three quarter cup warm water. Three quarter cups warm water, Brian. Three quarters of a cup of warm water, Brian. With a wooden spoon stir well very well. A wooden spoon? Peasants, really. Here is our wooden spoon for today. Oh, God. This will be efficient. Just like grandma used to make. Next step. Now we have to gradually add another one cup of flour. Stirring until the dough is forming into a cohesive elastic ball and is beginning to pull away from the sides of the bowl or bucket. What are we doing? Take all that again. One more cup of flour if it's not pulling away from the sides of the bucket. So, oh, well. Just like Nona. Some extra, it's not really good inside there. Don't worry, that's going to get sanitized. No. Is this going to need more water? Oh, it's really going. That's how you know it's good pizza dough. Such jamming the power tool. Okay. I think that's, I mean that's. It looks mixed. That's some dough. That's dough, baby. Next step. Drizzle a separate large clean bowl generously with olive oil and use a pastry brush to brush up the sides of the bowl. What? We'll actually use a bowl this time and we put olive oil. Olive oil. Drizzle it so it's the sides get all olive oily. Probably that was sure that's a drizzle. And then we have to use our hands to form the dough into a ball. Oh, it is so. Good. Well, well mixed. Yeah. That's real. Oh boy, that is. That's Italy right there, baby. Oh, yay. That's Italy. Come on. There, see. Oh, that's a nice transfer process there. I think we need more water. Can you get more water? We've added too much flour. There's not enough heat. I got this, by the way. No one else got this. It was slowly. Wait. Don't stop. Hold on. We have to do this gently. You're really getting it. Okay, we're getting in there. All right. I need more flour. This is a little more. Just a sprinkle. Yeah, a little bit more. Yeah, okay. Like a Christmas cookie. Okay, now what? Roll it along the ball until it's coated in olive oil and cover the ball tightly with plastic wrap and place it in a warm place. Allow the dough to rise for 30 minutes. Until doubled in size. Do we have 30 minutes? That's fine. How can we? What do you mean do we have 30 minutes? We've got all the time. Time is precious because, as many of you know, there was a channel on YouTube a long time ago where time was very precious and then it disappeared. The holidays are here, folks, and that means it's time to de-stress. It's time to relax. You've got a lot going on. So why not ask Santa for a little special gift this year? Introducing the Enigma Wave by Lilo. This one's more than just a sex toy, folks.  The Enigma Wave brings a new triple stimulation body that caters to both erogenous zones. 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Lilo, they'll have you saying, Ho, ho, ho, yeah, for the holidays. This is what you want. It's gonna look like it. Oh, yeah. That's the sound of good dough. I think we need a little bit more flour. To be honest here. Oh, yeah. This is teamwork. This is real Italian teamwork. This is the Mario Brothers. Chris Pratt, eat your heart out.  And it wasn't good either. And if Chris Pratt comes out and he says, no, that's false. I didn't do that. Yeah, that's right. You didn't do it well. Little more flour. Just a smidge. Just a schmidgeau. A little more. Oh, now that's looking like the dough I'm used to seeing in those pizzerias in Italy. In Italy, where we're going. Where we're from. Going, yeah. And from. And from. And we're from there. So we don't need to put yeast in this. Um, I, because I'm pretty sure we do. I'm pretty sure there was actually other things in the beginning. I'm not saying, seeing anything about yeast. Go to the very beginning. Flour, instant yeast, sugar, and salt. I said all those things and I thought that we had done that. I said multiple times. And I said those things and you weren't listening. No, even correct. I said, what goes in the bucket? I said these things. Justin, play the tape. You play the tape. I asked you what goes in the bucket. And you said flour and water. Well, I, nothing in here says we can't add those things. Now, by the way, this is just Calicalian's dog. It's not even a flak. It's okay. So we need one packet instant yeast mixed in. Okay, I asked you. Yeah, and I told you these things. And then you said. Incorrect. That's so good. Actually incorrect. Oh, what is wrong with your sugar? It's just kind of weird, isn't it? I don't know what's up with it. One and a half. No, no, no, no. Just do it. Just do it. Oh, just by advice.  One and a half teaspoons of sugar on that stuff. Oh, yeah. One and a half teaspoons, baby. And three quarters teaspoons of salt. Ryan, if this pizza turns out bad, I'm blaming it wholly on you. Because of my asking. I don't know. Yeah, just keep doing that. Because of my asking of, is it just flour and water? And you said yes. You know, there's two of us here right now. Because you are the one that's reading the recipe. But there's two of us who were sent the recipe by our known as God rest their souls. You're the one that's reading the recipe, though, on the table. I don't know if that's- It's cool. I was sent the recipe great, but you're the one that's reading the recipe. You're the one that's in the car that has the map. I'm driving car. I don't have the map. GPS exists. I'm asking you to lead me. This is probably fine. This is probably fine, you know. It's probably way too much salt. How much salt was supposed to go in? Three quarter teaspoon. That was definitely fine. That was way more than three quarters of a teaspoon. Who doesn't like a nice salty pizza pie, baby? So now it's time for this to go improved. All right. Let me grab plastic wrap. Plastic wrap. I think this video is going really well so far. And Ryan, all right? I just want to remind the people at home that neurodivergent issues are real, and you should be taking them seriously. This is how 280 HD people typically communicate, but that doesn't mean it has to be that way at home. Communication is an important thing. You and your loved ones can work together.  Thank you. Do we have a recipe for the sauce? Do you have your known as sauce recipe? Oh, I've got it memorized and ready to go. Over low heat, which I mean this is pretty warm in here. It's low heat. Yeah. We need three cloves of garlic minced or finely grated. Three cloves of garlic. Let's finely grate those. Okay. Are you using your hands when we have tools that could do this? Right, you are, Harry. I think that this one would be the best one for the job, Brian. Now put your glasses on for protection. I think first just kind of get the basic chop down. Okay. Oh, I remember that. That actually did most of it. Yeah. That kind of did all of it. That kind of did all of it. How many of these? We need three cloves. Oh, wow. I remember those cool Italian nights where Nona was using a giant mallet to slam the garlic into pulverized little pieces. Three quarter cup of chopped onions. Brian, it's very important that we protect our subs, okay? So true. So you have your glasses. I got this, which connects to a hard hat. Didn't realize that the hard hat didn't come with it. So, just like Nona used to do. Oh, that's so true. We're going to improvise. Just do it around my hat here. Oh, my goodness. Yes. Right into the hair? Please no. Oh, okay. Oh, yeah. No, this is definitely OSHA's safety and regulations being met. Yeah. I'll do some wrapping. Here, I can turn for you. This is pretty sturdy. Is that? Already done? Yeah. All right, cutting onion time. All right. I should put gloves on. Okay, now it's very important. What happened? Here we are. Yeah. Yeah. Oh, yeah, that's definitely doing it. Good. It's probably... Hold on. We're getting there. Oh, yeah. Oh, yeah. Now we're doing it. I think if we do another one of these... Oh, yeah. Now it should be the right size to break down. Oh, yeah. Just... That's good. Perfect. Three quarters of a cup of onion. Very precise. Cover the pot and cook for five minutes. Chopped fresh tomatoes, four cups, five to six medium tomatoes. It's just simply unsafe. How many? What am I doing? Five to six tomatoes should make a good four cups of fresh and chopped tomatoes. Now this is authentic. That's all I gotta say. How many? These aren't as chopped as I would like them to be, Brian. Because, Brian, we didn't drill any pilot holes in the tomatoes. So I think, Brian, if you will, if you could just drill some pilot holes in these tomatoes for me. I think that would be really important. Nice pilot hole. Yeah, just get a few of them. So I don't want to split it. Oh, yeah. That's normal. Yeah, just like Nuno used to do. Her special sauce. See how much better that chops? Oh, yeah. Oh, yeah. If you just drop it on. Perfect. Pretty good. You can do it a couple more times. Oh, yeah.  That's all right. I got 10 of them. Good. A couple more. Oh, nice. Nuno, guide our hands. Brian, now we can go to bashing. And that's why it's also important to keep your face mask on for any accidental splashage. How many do we need? It says five to six. How many did you put in there? I don't know. I know. I put it up in the bath. All right. Sounds like Nuno in the bath. It's looking swell, but I think it needs to be broken down more. I think what you're about to do is probably the equivalent of the 30 minutes of simmering the instructions asked for. Well, because where does heat come from, Brian? We all know this. It comes from God. And friction, right? So if we get enough friction going in here, it will most likely cook up the tomatoes. Good. How's it looking down there, Brian? You know, Nuno would be proud. All right. Going into attack mode. What's a good pizza without a little bit of a topic? We're going classic mode today, Brian. No sicko mode for us. Am I right, Zoomers? Man, Brian, I wish I could get this open. Well, if only you had a tool to do that. I just want to take this moment and say there's other ways to do this, but, you know, we really are sticklers for tradition. We really are, Brian. Hey! How many slices would you like, Brian? You know, as many as you can stomach. I'm thinking this isn't powerful enough, Brian. Boy, yeah. Well, heat will sterilize that. Yeah, that's looking good. I thought of something brilliant, Brian. Oh, of course. How could we have forgotten the classic technique? There it is. Oh, I see. The centrifugal force will pull the sausage apart. It's a much more gentle way to put these pieces of sausage out of their misery. Well, you got that from me. This is looking great. Oh, did it rise? It kind of looks the same as it was before. No, mostly bigger. This is really where this comes into play. Would you like? Oh, absolutely. Yeah, thank you. Oh, yeah. Now, make sure you get it real flat, Brian. Oh, yeah, it's getting real flat. Yeah, that's what we want. Yeah, I think we want it real flat. Oh, that is Mamma Mia. Am I right? Now, make sure you don't go through the whole dough. Right. You don't want it to stay intact. But look how round this is. Look how evenly distributed this dough is coming out. This is looking wonderful. Now, halfway through, you do want to give it a go to all flip and go again. I don't know about you, but that you wouldn't even be able to tell we made that 30 minutes ago. This looks grand, Brian. Yeah. Really, really good. It's time to spread our sauce. Yeah. Now we're going to take it and just let this all come out. Yeah, all come out. A nice, thick, creamy, so out. So glad we made so much. Get it on in there. Well, Nona's pie was known to be really thick. Oh, I just got that. Yeah, Nona's. Really delicious. Really sloppy pie. And she was a sloppy one. For the final portion, Brian, if you please, could transfer the pizza onto the tray. Oh, boy. What are you doing? Nice. Perfect. Perfect transfer. Beautiful. Oh, Brian, we forgot the cheese. How could we? We are so stuck. Oh, that's okay. Because in Italy, you actually put the cheese on top of everything else. Oh, perfect. Nondairy as well, just for me. Just for you, Brian. Now it's time to cook the pizza. Now, ovens are overrated and underpowered. And today we're using power tools, okay? So we will be making this pizza with but a little bit of a flame. This is not a good idea. Oh, that's Italy, baby. Brian, our pizza is done.  We've done it. We've created the pizza just like grandmother used to do. But now it's time for our final thing. I'll cut one side. You cut the other.  Oh, thank you.  Oh, that is just as wet as Luna liked it back in the day. Good. Perfect. So sloppy. Just like Nonna. Come on, Nonna. Come on, Nonna. Come on. We're gripping on there. Just adjust this. Oh, oh, beautiful. You like me to cut you a piece as well? Yes, please. Oh, yeah. Please, here's yours. Oh, thanks. Okay. Okay, I'll get you one from this side. Oh, yeah. Mmm. Oh, looks like a nice Italian man-sized slice. Oh, yeah, I can't wait. We can dig in. Just can't wait. Perfectly cooked all the way through.  Oh, nice big pieces. That's good. Oh, Brian. To Nonna. To Nonna. To Nonna. And to Italy. Oh, that is... It's a perfection. Mmm, wow. I'd say. The taste of Italy. Jokes aside. Kind of, you know. It's not that bad. I've had worse pizza, which is insane to say. The sauce is actually kind of good. It's got a really good spicy, or not spicy, the saltiness. I mean, that's all that salt I added to the dough. Mm-hmm. The sausage. Is cooked relatively. There's ingredients. Some of these bites, it's just so... Italy. Yeah, I just don't even want to swallow them sometimes. I don't mind it. You know? And maybe it's because I don't have any standards or self-respect. But I don't mind it. Does it look bad? I mean, what's on everything? And here's the greatest part. You like it so much, and there's so much more left for you. Well, Brian, I wouldn't want to name poise or something. Look at the flacidity of it. Give it a wave. Look at the twirl. Nice and solid. It's sturdy like an Italian bread job, chef. We really cooked. We really cooked today. Everyone at home, I hope you enjoyed us making our big old pizza pie, just like Arnona used to make back in the day in Italy. You know, we expanded a modern tradition and I believe we went above and beyond with the power tools. I don't think they inhibited us at all. I think that they made us go further, farther, faster. Brian, people wanted to find you on the internet. I hope they don't. Hi, I'm Gervigli, G-I-R-B-E-A. Well, Justin's going to put this in the video. YouTube and Twitch and Twitter and who else cares? Where are they going to find you, Ethan? Right here, unfortunately.  But not as much as this! Yeah, sure, that could be where it ends.


of a suit or other proceeding except where the order if it had been made in favor of the party applied for revolution would have finally disposed of the suit or other proceedings. That means the high court in excess of revolution power will vary or reverse any order only if the condition that the order if it had been the other way about it would have disposed of the suit or other proceedings. Otherwise not of course, crucial power can be exercised in respect of interlocketry proceedings as well, but varying or reversing this is the criteria. Now this was not this was not alone the portion here a portion was deleted by the avenue which is that deleted portion. This order if it had been in favor of the party applying for revolution would have finally disposed of the suit or other proceedings there already in the province that was clause A of the province that there was a clause B which is the order if allowed to stand would occasion a failure of justice or cause irreparable injury to the party, irreparable injury to the party against whom it was made. This was deleted with the result that only if the three conditions are satisfied plus the order if it had been the other way about it would have disposed of the suit or other proceeding that condition also should be fully satisfied. Sorry that is the crux of the amendment that clause B was deleted what is the province and it was subject matter of discussion in Salem-Adukhet bar association is Salem 2 paragraph 40. Salem 2 paragraph 40 and Salem 2 paragraph 40. Let us see what is this paragraph 40 after stating what was contained in what section 115 did contain therefore said clause B stands to be dead. The question is about the constitutional powers of the high court in under article 227 on account of on account of permission made in section 115 of the court. The question stands settled by decision of this court in Surya Dev Raibkar versus Ramchandar Raib that is 2003 6 SCC 675. Holding that the power of the high court under article 206 and 227 of the constitution is always in addition to the constitutional jurisdiction. Confirmed on it curtailment of constitutional jurisdiction of the high court under section 150 does not take away or could not have taken away the constitutional jurisdiction the high court. The power exists untrammeled by the amendment in section 150 and is available to be exercised subject to rules of self discipline and practice which are all well said. What happened after the amendment? The purpose was to reduce the number of litigation. Reduce stagnation and the chance of people rushing to the high court at every stage and getting stay of the proceedings and attracting the trial of the police. That was the purpose laudable purpose. But what happened ultimately is that people started filing original petitions under article 227. So, even an adjelement petition that rejected a stage came people used to float to the high court, rush to the high court. Supreme court has mentioned that rules of self discipline is there and therefore only in exceptional cases the high court will exercise the power of revolution. But this power constitutional power under article 227 is not taken away by the amendment of section 100. And thereafter there is another decision of the Supreme Court which says that a red petition will not lie. That one view was that even a red can be filed to quash an order passed by the subordinate court later that was not accepted and the Supreme Court said that it is original petition not a petition. Now it is being numbered as OPC, OPCL or OTPerminal Water Rights. Now we go to the next portion section 148. What is section 148? 148 is enlargement of the period already grand. Enlargement of time. What are the conditions necessary? Where any period is fixed or granted by the court, granted by the court for doing any act prescribed or allowed by this the court made its discretion from time to time enlarge such period not exceeding 30 days in total even though the period originally fixed or granted may have expired. By the amendment this ceiling of 30 days in total is introduced. Before that it was not there any number of days the court could extend enlarge suppose there is a direction to deposit areas of red that was not deposited say one month's time was granted that time expired even there after what it could apply court could grant in the facts and circumstance of the case in appropriate cases the court could exercise the discretion of granting more time but that is curtailed by the amendment that the maximum period that can be granted under section 148 is 30 days. In total any number of times the court may extend but it should not in total go beyond 30 days. This is the amendment. Now how the court considered it? Salem 2 paragraph 41 to 43 court held that section 151 can be resolved. After that period of 30 days there is no provision that means there is a vacuum the court can exercise the power under section 151 inherent powers and extend the period if necessary in appropriate cases. This is what is held paragraph 41 to 43. Before amendment there was no restriction whether the court has no inherent power to extend the time beyond 30 days is the constitution. We have no doubt that the upper limit fixed in section 148 cannot take away the inherent power of the court to pass orders as may be necessary for the ends of justice or to prevent abuse of the process of the court. The rigid operation of the section would lead to absurdity. Section 151 has therefore to be allowed to operate fully extension beyond the maximum of 30 days thus can be permitted if that could not be performed within 30 days for reasons beyond the control of the party. This is what is held by the Supreme Court further down it is there I rent only the trucks of money. So that in appropriate cases the court can extend time and after this period in total 30 days is over the court retains the power under section 151 of the CPC. Next approach is order 5 rule 9 order 5 rule 9 order 5 is service of summons that underwent drastic change. Now courier service email personal service by the plaintiff against the defendant and all those things were introduced with all good purpose but some apprehensions were raised that courier service how it should be affected and all those things the Supreme Court in Salem 2 discuss the matter in paragraph 27 and 28 27 and 28 27 one sentence I will read the apprehension expressed is that service outside the normal procedure is likely to lead to false reports of service and passing of expatriate decrees this was forced the court said that there is appropriate checks and measures service non-service of summons has been the major causes of delay Supreme Court noticed court shall have to be very careful while dealing with a case where orders for team to service as required to be made on the base of the endorsement of such service or refusal by the courier. High courts can make appropriate rules firing of an affidavit was introduced that the defendant can be the I can be also the affidavit shall be in the language not to the defendant it can also be provided that if an affidavit or an endorsement as to service is found to be false the defendant can be summarily tried and punished for perjury and the courier company can be blacklist all these things were said so that sufficient protection high courts can make rules and some of the states it is working properly nowadays if you have in commercial transactions particularly between two business and or business groups or companies and all those things email and all those things are recognized methods but where the parties are peasants and workers in villages all these things may not work but sufficient safeguards are the otherwise personal services required the court can say that so flexibility is there now next is order 7 rule 11 what is order 7 rule 11 projection of plane salem 1 salem 1 paragraph 16 salem 1 i have mentioned 2003 decision the other is 2005 decision salem 1 paragraph 16 reject the plane there are clauses e and f added by the amendments and where it is not filed in duplicate plane shall be fined duplicate or where the plaintiff fails to comply with the approaches of all rule 9 of order 7 that is producing sufficient number of copies it appears to us that set clauses being procedure would not require the automatic rejection of plane at the first instance sufficient opportunity should be given if there is defect the court should order may be given opportunity of rectifying the defects etc in order 18 rule 4 i am sorry this is what is said order 7 rule now order 8 rule 1 order 8 is written statement order 8 rule 1 what happened in 99 99 it was provided by the 99 amendment it was provided that the written statement shall be filed within 30 days from the date of service of salem and the advocates mentioned i mentioned part one then there was discussion all throughout India and the central government was informed and this matter was considered again by the parliament and certain relaxations were made certain changes were made and reproduced and both these acts came into force on 17 2002 now what is order order 7 rule 11 which i mentioned order 7 rule 14 next order 7 rule 14 we will deal with it next what is order 7 rule 14 salem 2 paragraph 34 salem 2 paragraph 34 order 7 rule 14 order 7 rule 14 says that the plaintiff chart produce all the documents within his power along with the plane or within such time as the court prescribes and the penal consequences if it is not produced cannot be received in evidence all those things are stated in order 7 rule 14 now if you have got the CTC with you please take that order 7 rule 14 order 8 rule 1 i will come to it order 8 rule 1 we have already dealt order 7 rule 14 a document which ought to be produced in court by the plaintiff when the plaintiff is presented that document cannot be produced later nothing in this rule shall apply to documents produced for the cross examination of the plaintiff's witness or handed over to the witness merely to the freshest member this was considered by the supreme court and it is the objection was that there is a mistake in draft instead of the plaintiff's witness it must be defendant's witness and what is sent by the supreme court let us see order 7 rule 14 paragraph 34 and 35 in paragraph 35 last it is mentioned that paragraph 34 last it is evident that the words plaintiff witnesses have been mentioned as a result of a mistake that seems to have been committed by the legislature the words sought to be defendants ought to be the words ought to be defendant's witness there is a similar provision on rate rule 14 1 a 4 which applies to defend after stating so the supreme court said in paragraph 35 to avoid any confusion we direct that till the legislature corrects a mistake the words plaintiff's witness would be read as defendant's witness in order 7 rule 14 4 we however hope that the mistake would be expeditiously corrected by the legislature now I committed a mistake I started ordering rule 1 then I abruptly went to order 7 rule 14 that is because the it is serious area term I have mentioned therefore I had a doubt and confusion now we come to order 8 rule sorry for the difficulty cost to you order 8 rule 1 the amendment in 99 was that the return statement shall be filed within 30 days from the date of service of summits then when this objection was raised by the bar this parliament again considered it and the maximum time limit of 90 days was provided then the question arose what will happen after 90 days let us see what is 7 provided that present a return statement of defense within 30 days that is so that even now it is so provided that where the defendant fails to file the return statement within the set period of 30 days he shall be allowed to file the same on such a day as may be specified by the court for reasons to be recorded and right but which shall not be later than 90 days from the date of service of summits not later than 90 days this created difficulty the question arose whether the court has power in a given case to accept the return statement which is filed beyond 90 days or whether court is bound to pass a decree if it is otherwise grantable taking it that there is no return statement this was the question considered and it is answered in paragraph 14 to 21 of serum 2 serum 2 14 to 21 let us see the relevant portion 14 to 21 very relevant portion otherwise there will be no time yes the question is whether the court has any power or jurisdiction to extend the period beyond 90 days the maximum period of 90 days to file the return statement has been provided but the consequence on failure to file the return statement in set period have not been provided for in orderly to what the point is for concern the point for consideration whether the provisions providing for maximum period of 90 days is mandatory and therefore the court is altogether powerless to extend the time even in exceptionally hard times this was the question considered along with this there is another portion which is to be considered order 8 rule 10 order 8 rule 10 order 8 rule 10 provides that where a party from a return statement is required under rule one or nine fails to present the same within the time permitted or fixed by the court the court shall pronounce the judgment against him or make such an order in relation to the suit as it seems fit so what is the consequence is also mentioned in all way rule 10 supreme court interpreted it meticulously supreme court said that it is not always necessary that when no return statement is filed within time if the plane should be as such decreed as if there is no defects it is not so the court may not appropriate case as such orders therefore there is flexibility and therefore it is only that not managed this is what is said in paragraph 21 in construing this portion support can also be had from order 8 rule 10 then further now in construing the portion of order 8 rule 1 and rule 10 the doctrine of harmonious construction is required to be applied required to be applied the effect would be that under rule 10 of order 8 the court in its discretion would have power to allow the defendant to find the return statement even after the expiry of the period of 90 days provided in order 8 rule 1 there is no restriction order 8 rule 10 that after the expiry of 90 days for that time cannot be granted there is no such restriction the court has wide power to make such an order in relation to the suit as it takes fit clearly therefore the provision of order 8 rule 1 providing for the upper limit of 90 days to find the return statement is directly exceptionally hard case is only in exceptionally hard case the court would grant it supreme court also took precaution and said that the courts will take and in paragraph 20 it is mentioned the word shall in by itself is not confused and the supreme court referred to three decisions of the supreme court in paragraph 17 18 and 19 one is a constitution bench decision the others are not and all these principles in 1965 supreme court 55 supreme court and 2002 supreme court were discussed in other paragraphs earlier paragraphs up to 20 so these are the provisions with respect to order 8 rule 10 rule 1 and I am taking it to some extent possibly because there are other portions also to be covered order 9 rule 5 fresh summons shall be taken if service is not affected fresh summons shall be taken by the plaintiff and it shall be done within seven days that is a portion order 9 rule 5 and that is discussed in Salem 2 paragraph 44 Salem 2 paragraph 44 yes the period of seven days mentioned in order 9 rule 5 is clearly directory conclusion is in one sentence discussion only one sentence the period of seven days in mentioned in order 9 rule 5 is clearly directly this is what is said by supreme therefore it is very clear that the court can always grant time in appropriate case next is order 11 rule 15 order 11 rule 15 serum 2 paragraph 45 the stipulation in order 1 order 11 rule 15 confining the inspection of documents at or before settlement of issues instead of at any time is also nothing but it does not mean that the inspection cannot be allowed after settlement inspection of document discovery and inspection is the heading of order 11 and there the court has power to direct a party to allow the other party to inspect documents and the party can do it and thereby avoid delay in disposal of the matters and there the restriction is which is sort to be introduced by 46 the stipulation that is at or before settlement that is said that it is only directly even after that next approach which is relevant is order 18 rule 2 order 18 rule 2 serum 2 paragraph 32 serum 2 paragraph 38 order 18 rule 2 4 which was inserted by act 104 or 76 has been omitted by act 46 of 99 it was introduced in 1976 by the aforementioned that was taken away in 99 under the said rule the court could direct or permit any party to examine any party or any witness at any stage so by deleting it what the parliament thought that the party is always rushed to the come to the court with a request to examine a party at a related stage and thereby the trial the process of trial is tracked now what the supreme court said before 76 it was not there that provision was not there what were the court doing the courts were allowing it in appropriate cases that position will continue even prior to the insertion of order 18 rule 2 4 such permission could be granted by the court in its discretion the provision was inserted in 1976 by the court the omission of rule 18 order 18 rule 2 4 by the 1999 amendment does not take away the court's inherent power to call for any witness at any stage either so motto or on the prior of a party invoking the inherent powers of the court order 18 rule 2 paragraph 32 order 18 rule 4 next is order 18 rule 4 Salem 1 this is very important order 18 rule 4 Salem 1 paragraph 17 to 19 17 to 19 Salem 2 5 to 12 paragraph 5 to 12 Salem 1 17 to 19 Salem 2 paragraph 5 to 12 I will read the relevant portion in Salem 2 now then thereafter I will go to the other portion this is very important and practical application 5 to 22 5 to 12 and the supreme court considered in Salem 2 not only order 18 rule 4 but considered order 18 rule 19 order 26 rule 4 4 A and certain other provisions because these are all interconnected the amendment provides rule 4 provides that in every case the examination in chief of a witness child beyond affidavit there is no difficulty the court has already been vested with the power to permit affidavits to be filed as evidence as provided in rule 19 of rules order 19 rules one and two of the court it has to be kept in view that the right of process examination pre-examination open court has not been disturbed by order 18 rule 4 inserted by the amendment therefore the court has a discretion affidavit can be insisted then the further the court said an apprehension was expressed by the lawyers that if a witness is summoned not produced by the party calling summoned by the court how can the affidavit be insisted the supreme court said in such cases the court may examine him allow the party to examine him in chief and cross there is nothing wrong and the scope of order 8 rule 4 has been examined by in Salem 1 there is also no question of inadmissible documents being read into evidence merely on account of such documents given as exhibit numbers in W 5 by the examination chief this is another apprehension examination chief practically verbatim reproduction of the plane and the document plus the documents which the plane reproduced an apprehension is raised that there may be inadmissible documents there may be unregistered documents which are inadmissible there are there are documents which are not sufficiently stamped even if registration is not required and such things may be there what will the court do if the affidavit is filed there also the supreme court said provided so to sub rule 2 of order 4 rule 8 clearly suggests that the court has to apply its mind to the facts of the case nature of allegation nature of evidence and importance to the particular witness for determining whether the witness and the examined in court or by the commissioner appointed by it and this it also said that inadmissible document being read nearly on account of such documents being given exhibit numbers in the affidavit file by of examinations further in Salem and to get associated one case it has been held that the trial court in appropriate case can permit the examination chief to be recorded so all these safeguards have been brought then the supreme court considered order 18 rule 5 please see order 18 rule 5 order 18 rule 5 says how evidence shall be taken in applicable cases on reading of rule 5 which was not touched by them and it is retained in the CPC even after of two amendments in 99 and 2002 what it says is that in applicable cases the evidence of each witness shall be taken down the language the court in writing or in the presence or under this personal direction and superintendents of the judge or from the dictation of the judge's directive on the calculator in the judge for reasons to be recorded so directs the record in that kind to be delivered so a judge's presence is always required by rule 5 so it was argued that there is a contradiction between rule 4 and rule 5 then the supreme court answered please see rule 19 of order 18 power to get statements recorded on commission there is such a conclusion order 26 rule 4 a supreme court considered along with this and to accept that in appropriate cases the court can issue commission i will rather read what the supreme court said only the important aspects in paragraph 7 amendment to order 18 rule 5 a and 5 b was read in sentences it is provided that in all appealable cases evidence shall be recorded by the court order 18 rule 4 was amended by the amendment act of 99 and again by amendment act of 2002 order 18 rule 4 3 enables the commissioners to record evidence in all types of cases including appealable cases the convention urge it is that there is a conflict between these provisions and that conflict was resolved by the supreme court that convention was resolved by the supreme court in paragraph 8 and 9 rule 19 was referred to power to get statements recorded on commission and he said in paragraph 8 that the aforesaid portion contains a non-upstanding clause it overrides order 18 rule 5 which provides the court to record evidence in all appealable cases the court is therefore empowered to appoint a commissioner for recording evidence in appealable cases as well further order 26 rule 4 a inserted by amendment act of 99 provides that notwithstanding anything contained in these rules the court may in the interest of justice or for expeditions disposed of the case or for any other reason issue a commission in any soap for the examination of any person resident in the local limits of the court's jurisdiction order 18 rule 19 order 18 rule 19 and order 26 rule 4 a in our view would override order 18 rule 5 a and b therefore these amend provisions which were introduced by the amendment will override rule 5 or 18 there is no conflict it will override then paragraph 10 next question has been raised about the power of the commissioner to declare a witness hostile there the solution is also mentioned paragraph 10 the direction to declare a witness hostile has not been conferred on the commissioner what should be done in such cases also mentioned the court court's order should be taken if a situation has to declaring a hostile witness arises before a commission recording evidence the party concerns shall have to obtain permission from the court under section 154 of the evidence act and it is only after grand or such permission that the commission can allow a party to cross examine this whole witness then in paragraph 12 it is mentioned how the original documents should be dealt with by the commissioner appointed to record what are all the things to be done so order 18 one of the major amendments in 99 and 2002 and the challenge therein not only on the ground of constitutionality but on the ground of inherent contradictions with some of the provisions already existing all resolved by the Supreme Court in Salem 192 order 18 next is order 18 rule 17 a order 18 rule 17 a and it is discussed in Salem 1 at paragraph 20 and 21 and in Salem 2 paragraph 30 let us see Salem 1 para 2021 and what is this amendment of 76 rule 17 a was inserted in order 18 which gave an opportunity to party abuse additional evidence under circumstances mentioned in such a provision was not there it was introduced in 76 by 76 7 supreme court asked what was the circumstances before 19 since what was the court doing before since court in appropriate cases could grant such a request now that is a possession in spite of deletion of that particular rule court still has power to grant it there are many if any is that available to anything and things are to adducing additional evidence prior to 76 would be available now and no more Salem 2 paragraph 13 what does it say reference is made to Salem 1 same thing is said court could had in inbuilt power to permit parties to produce evidence not known to them earlier or which could not be produced in spite of due diligence order 18 rule 17 a did not create a new right but only clarified the position therefore deletion of order 18 rule 17 does not decent title production of evidence at a later stage when a party satisfying the court that after it says some due diligence that evidence was not within the knowledge or could not be produced at the time of party was leading evidence the court may permit leading of such evidence at a later stage therefore the supreme court will solve that problem also next is adjournment order 17 Salem 2 paragraph 29 to 31 paragraph 29 to 31 supreme court said order 17 does not forbid grand of an injection adjournment where the circumstance are beyond the control of the court by the amendment the the court's power was restricted that maximum at the request of a party maximum adjournments can be granted at three only three times not more court said there may arise situations where it is necessary that is considered in paragraph 29 30 and 31 in paragraph 30 it is said so read order 17 does not forbid grand of an adjournment where the circumstance are beyond the control of a party in such a case there is no restriction on the number of adjournments to be granted further down for instance a party may be suddenly hospitalized on account of some serious ailment or there may be serious accident or some act of God leading to devastation if it cannot be said that though the circumstance may be beyond the control of the party further adjournment cannot be granted because of the restriction of three adjournments as provided in the proviso to order 17 one in some extreme cases it may become necessary to grant adjournment despite the fact that three adjournment have already been granted take the example Boppel gas tragedy Gujarat the earthquake and riots and devastation on account of tsunami ultimately it would depend upon the facts and circumstances of each case court has power that is what is it is not ideal to restrict cocktail the power of court should have powers whether it is excited to be exercised in a given case is a different thing it is in the description of the court the court will not go astray court is experienced court is legally trained and it is circumscribed the courts exercise of such power are all regulated by decisions of wonderful supreme court and various icons therefore that danger of the judicial office are going and say saying that I got unbridled powers it is not so court has powers and on the other hand if a registration restricts the powers you shall not do that you have no such power it is not good for the society what cannot be the legislature cannot foresee all the circumstances which may require it to be applied in a given case supreme court ascended paragraph 30 and 31 now corona supreme court extended their period of how many times all these cannot be foreseen therefore don't make a law which takes away the powers of the courts at all times whatever may be the circumstance you have no power beyond 30 days you cannot extend beyond 30 days written statement cannot be accepted after 90 days or a gentleman cannot be granted more than three times these are all such provisions in terror of it is not good for the society and that is why supreme court said while appointing a committee the creases are to be corrected ironed out creases are to be ironed out and that was done by the committee and that was considered by the supreme court in great detail and it was said that these are all directory these are mandatory these are not mandatory it can be applied in extreme cases court retains the power in spite of a particular portion being the it said that after the expiry of that period there is no portion written statement there were 148 extra time therefore the court can exercise the power under 151 who takes away the powers of the court under one civil court has that power criminal court does not have except the high court under 482 the subordinate criminal courts do not have the power which is akin to section 121 cpc many think that the civil courts does not have do not have powers he is not correct civil court has wide powers wide powers and the judgments and decrees of the civil courts will be bound its criminal court will be bound on the other hand civil court will not be bound by the judgment of the criminal court except that what is the result over all the parties what the court did that's all by the committee not the reasoning or other is next is order 41 rule 9 salem 1 paragraph 22 into 1 salem 1 paragraph 22 into 2 registry of memorandum of the old nine provided that of order 41 the court from whose decree and appeal lies shall attain a memorandum of appeal and shall endorse their own the deeper presentation and shall register the appeal in a book kept for that purpose such book called it shall be called the rest of appeal what was the intention of the legislature is nobody is nobody knows it probably the parliament thought that the appropriate portion must be made so that the parties difficulties can be avoided the if he is defeated in the trial court he can present the appeal in that court itself which is to be filed in a far away place maybe that but supreme court said that appeal is to be filed in the court where it is to be filed but all that is meant is that a copy of the appeal memorandum should be kept in the file of the trial court a copy should be provided to the trial that's all required nearly because a memorandum of appeal is not filed under order 41 rule 9 will not in our mind make the appeal filed before the appellate court a defective one only that is required that is that a copy should be that's all all firing in the appellate court otherwise firing in the trial court itself will not do good suppose urgent matter of stay is required what will the trial court do trial court has to transmit their accounts it will take time on the other hand if a trial court's business is rented and after getting copy the party can rush to the appellate court get an emergent order that will be taken away if this rule 9 is strictly compliant the appeal should be filed in the trial court itself but it is optional is all right but it is not so therefore supreme court interpreted like this now with that the complainant of these provisions important evidence and I hope yes five minutes to tell we can type because so thank you very much we'll meet again time permits on some other occasion with some other subject yes thank you as they say that it will continue the knowledge sharing the way you simplify things is just mesmerizing and the way you want to take things forward that is another thing to be understood and there are so many topics and so many things to be learned from you how to maintain balance between an active life how to simplify things and how to maintain that the session which you take forward is actually comes to an end within the time frame to understand the entire gamut of the topic and then bringing it narrowing down in a structured manner is a thing which can always be learned from you but as I say practice makes a man perfect and your heart of perfectionism in that aspect is too fascinating to be understood and followed you have made things so clear at least on the chat we don't have I will just check it out as to whether we have any question on the youtube okay it's only thank you coming forth so we part for the day today and we will have the sessions coming forth we are also starting a service law series with Mr. P. S. Raja Gopal where we will take around 15 sessions on different issues and same way we will be also taking a contract law series by Professor Milima Farfadi we will stay connected with us on the social media and needless to add we have already taken so many sessions with Justice Katie Sankaran and his sessions will continue we will discuss with Justice Katie Sankaran so that rather than taking topics here and there we will try to see that all things go in a chronological manner from now onwards everyone stay safe stay blessed and take precautions as somewhat some numbers of covid has also started increasing and they say the prevention is better than cure so keep on taking preventive measures and we the way we have been able to sail through we are quite sure that we will continue to survive and do betterment for the society and the most positive part of the these testing times were we have been able to connect with people like Justice Katie Sankaran who are full of knowledge and the most interesting part is that they are willing to share everyone stay safe again and stay blessed thank you thank you thank you Mr. Vikas and the buts thank you


All right, well, thank you very much to the organizers for the opportunity to come and talk to you today. What I'm going to tell you about is some work that we've done looking at trying to understand the epigenomic and transcriptional basis, because I think those two things go really hand-in-hand of a very important medical condition that we've been, and my group have been studying for quite some time, which is to say insulin resistance, specifically a complication of obesity and associated with type 2 diabetes. I don't think I need to belabor this point, but I'm sure that most of you are really quite aware of the burden, the medical, psychological, economic burden of type 2 diabetes and obesity in our country. These are just CDC heat maps showing the increase in the prevalence of these conditions in the last several years, and you can see that my maps only go up to 2009. They've been, I didn't put it in the more recent ones, they've had to invoke all new color schemes because they're running out of red. There's only so many deep shades of red you can get. This is not just a major medical and physical burden on people, but it's actually been predicted or been calculated, I should say, to be one of the top three problems economically that the world faces following smoking and armed violence and terrorism is obesity and metabolic diseases. So what my lab studies actually are fat cells. There are many different cells that one could study in obesity, the brain, the liver, the pancreas, et cetera. We're interested in adipocytes. And my lab has already been asking what are the critical transcriptional pathways that underlie these key transitions or differentiations or distinctions in adipose biology?  We're also very interested in how does a fat, a mature fat cell, which is an insulin-sensitive cell, stop listening to insulin? What happens to it to make it stop listening to insulin and a corollary of that is what can we do to make it listen better? And also, how do we turn white fat, which is the energy storing cell type that we're all familiar with, to maybe a brown fat cell type, which many of you may have heard of is a more energy burning and can promote a cell type in which can promote health? So the way that we study these critical questions, actually, the way we approach these things traditionally has been to sort of, you come up with a guess as to what a candidate transcription factor that might be interesting for you to study would be, then you identify its target genes and work on its function in that way.  And then we go and look at the orthologous proteins in mammals. There's another way to approach this problem, which is in a more systematic and comprehensive way, which is if you can identify the cis motifs that are important, which identify regulatory elements that are contributing to the regulation of the process that you're studying, whether it's adipogenesis or insulin sensitivity. And if you can then work backward to computationally predict which transcription factors might be involved based on what the regulatory elements that you see changing in the process that you're studying, then you can go and work on the function in that way. And the way that we do that is essentially by enhancer mapping, using clues from epigenomics. So in this case, you could use DNA methylation status as your predictor. You can use non-coding RNA status in many cases. But what we use in my laboratory primarily are covalent histone modifications through a chip-seq and then identify active enhancers or I should say enhancers that change their activity during a process that we're interested in studying. And then we work backward, as I said, or as I just showed to show to identify and predict factors that might be important in that. And I'll show you some examples of that. We published a study a few years ago in which we looked at adipogenesis. We looked at both mouse cells and human cells that were undergoing differentiation in a dish toward the fat cell pathway. We accumulated various histone-marked chip-seq profiles at different time points of differentiation. And those are shown, for example, here. We have the mouse on the top and the human down below. Sorry, is there a pointer or how do I just use the mouse? Here, right here, I'm sorry, right in front of me. Yep, so the mouse up here, the human down below, and you can see here that there's promoter marks and various enhancer marks, for example, that light up in this region. And we can see that as we move through time, this is in a very early undifferentiated state. And as we move through differentiation, we can see the appearance of new alternate promoters. We can see enhancers that disappear and enhancers that appear. And we can make various predictions. And we can identify literally tens of thousands of regulatory elements that appear to be dynamic during this cell differentiation process. And then what we do is we take these enhancer regions that are interesting to us, that are changing. And we compare the DNA that's under those databases of transcription factor motifs. And we can then predict transcription factors that might be important in this process. And when we did this for adipogenesis, we came up with two lists. One of them was based on motifs, excuse me, one of them was based on enhancer peaks that disappeared during differentiation. So they were high enhancer activity during the preadipocyte stage, and then they disappeared during differentiation. And then the opposite pattern, those that were not present in preadipocytes, but appeared during differentiation. And those all predicted different transcription factors that might be involved. And everything I put a check mark next to here is something that was known from the literature at that time to be involved in differentiation. So you can see this provides an important sanity check then that you shouldn't, with this method, be finding factors that you know are important. But we, of course, wanted to identify new biology. And in this particular study, we focused on these two factors here, serum response factor and PLZF, promylocytic leukemia zinc finger protein, two very well studied transcription factors with a huge amount of literature, but no data whatsoever suggesting that they might be important in adipose tissue biology or adipogenesis specifically. And so we were able to show that when we overexpressed them, we enhanced adipogenesis. And what I'm showing here is that when we knocked down these factors, we could enhance adipogen, sorry, when we overexpressed them, we would press adipogenesis. When we knocked them down, we enhanced adipogenesis. So you can see here, the more red the dish is, the more fat has been accumulated, and various marker genes of adipogenesis are increased in these knocked down cells. And so in this way, we have now identified six novel transcription factor pathways, all of which are published, that we have identified that through this approach that we can use enhancer mapping to sort of tell us what might be important for adipogenesis. I want to shift attention now to insulin resistance. And really, our study on insulin resistance was really focused on trying to answer two different questions that have been bedeviling us for some time clinically. I am a clinical diabetologist, and I do take care of these patients. And something that always struck me was the fact that you can see insulin resistance in a lot of different kinds of patients. So we know that as companies, obesity, for example, but also once these insulin resistance in patients that don't have enough fat. This is a gentleman with a form of congenital lipodystrophy, and you can see his characteristic wasted facies. And people like this gentleman are very, very insulin resistant. People with various hormonal conditions, like the little girl up there on the top who has Cushing syndrome, and she has a tumor that causes the overexpression of glucocorticoid in her body. And the woman down below has acromegaly, a pituitary tumor that causes the overexpression of growth hormone. And both those conditions are associated with quite severe and significant insulin resistance. Also, neurodegeneration, often associated with insulin resistance, as well as even some physiological conditions like pregnancy, also highly associated with insulin resistance. And many other different disease states have insulin resistance as sort of a common phenotype as well. You can model this in a dish, by the way. You can put fat cells, grow them up in a dish, as I've shown, and you can pretty much point to anything in the Sigma catalog and dump it on top of it, and it will cause insulin resistance. And that raised the question, to what extent are the molecular pathways shared in these different conditions? And so you can imagine, then, two different scenarios. One scenario is when you have sort of all these different agents are causing insulin resistance in their own unique way, and then another possibility would be that, in fact, they're all working through some common mediator, some nodal pathway that could be integrating the response to all these different agents. So the approach that we're using, then, is we take culture to dipocytes. These are myriad of dipocytes. It's a well-established cell culture model. They have very high fidelity, and they do almost everything that a real adipocyte does. And we treat them with either TNF-alpha or with dexamethasone, and I'll explain why in just a moment. But those are well known to cause insulin resistance, and so you get this rightward and downward shift, then, in the insulin response curve with respect to glucose uptake. And what we're looking at, then, are changes. They can be transcriptomic changes or epigenomic changes or anything you're interested in that are associated with TNF treatment or dexamethasone treatment, and we're going to focus on what's in this middle set, then. What's in this center piece there, and look, then, to see if that can help direct us toward common pathways. OK, so why dex and TNF? Really, the bottom line is that these are well-established pathways. We know that if you give people or animals or cells dexamethasone or TNF, they cause insulin resistance. If you knock those things out of animals, like the enzymes or the receptors for glucocorticoids, if you knock out TNF or its receptors, you improve insulin sensitivity, et cetera. But really, the reason that we did this is because they're so very different. Remember, we're looking for something in the center of that Venn diagram, and so you really want those two circles to be as pulled apart as far as possible so that you have a very small set in the middle. That makes it a much more tractable experiment. So the really reason is that dex is the prototypical anti-inflammatory agent, TNF is the prototypical pro-inflammatory agent, and so we would expect, on first principles, that they would have a very small number of biological responses that would be overlapping. So that's the first question we wanted to get at. How do so many different things cause insulin resistance? The second question was, are there nuclear mechanisms of insulin resistance? There are literally tens of thousands of papers on the mechanisms of insulin resistance in my lab and many, many, many other labs over decades have contributed to those. And they all focus on cytoplasmic pathways, pathways dealing with signal transduction proteins, mitochondrial pathways, oxidative stress, ER stress, et cetera, et cetera. And yet there is this sort of evidence that, in fact, we should be considering other nuclear aspects to insulin sensitivity. For example, we treat insulin sensitivity in the clinic by giving drugs that activate transcription factors, for example. We also know that these cellular models of insulin resistance, such as I've just described, don't work in hours, it takes days to weeks for them to really fully develop, and that suggests this transcriptional or epigenetic component. And we also know that there is this wealth of data that links chromatin state and epigenetics to obesity and complications, and I'm referring there to things like fetal programming and the developmental origin of adult disease hypotheses where we know that, depending upon conditions that you might experience in utero or nutritional conditions, that your grandparents or great grandparents might have experience, that that has a profound influence on your risk of developing obesity and diabetes, for example. So that suggests, again, to us that there really must be some sort of nuclear component here. So the model is very simple. We take cells, these fat cells in a dish, and we treat them either with dexamethasone or with TNF. We're never treating them together. These are just two separate treatments, and we see that we're causing resistance to insulin. So this is just a measure of glucose uptake and response to added insulin, and these cut that down quite significantly. On the right is just a time course of the effect, and that just illustrates what I showed you, that you don't get full insulin resistance for about a week or so. And then at the bottom here, what I'm showing now is that we are not, with our regimen, affecting traditional signaling pathways. We're also not affecting differentiation of the cells. We're not de-differentiating the cells because this is a very important control in our field because obviously if you cause the cells to revert back to a fibroblastic state, of course they're going to be insulin resistant, and that's a trivial response, and we don't really want to study that.  We looked at the transcriptomics under these two different conditions, and you can see that there are about 1,000 genes that are up-regulated when you add dex or when you add TNF, but there's only about a little less than 300 or so that are coordinated and regulated by these two agents. And that, again, illustrates the point I made earlier that you really want to have a relatively small intersecting set to make that much more tractable to study. If we did TNF-alpha and IL-1, both of those will cause insulin resistance, but we'd imagine that they'd have an almost completely overlapping set, and that would be very difficult to parse apart. And then this just shows that if we compare our genes that are changing here, up-regulation genes here, what we're looking at, and we compare them to genes that are changing in garden variety obesity in an animal that you feed a high-fat diet. In fact, what we see is actually relatively little concordance with the dexamethasone treated genes, a little bit better with the TNF-treated genes, but that intersecting set, those 271 genes, actually are quite similar to the genes that we see when we just look at garden variety obesity. So then what we're focusing on next is epigenomic marks, and we did six different marks, I believe. It may be even a little bit more, but the one I'm going to focus on here is histone-3 lysine-27 acetylation, H3K27AC, which has been shown to be a mark of enhancer activity. And that's really what we're deriving most of our data from here, so we'll focus on that. And specifically, I'm going to focus on the H3K27AC marks that change, that are up-regulated, that are within 400 kilobases or so of genes that are also changing in the same direction. So we're looking at up-regulated genes, and now we're looking in the space around that, and looking for up-regulated K27AC peaks. And we can imagine that there are several different patterns here, you can imagine that there are sometimes you'll find a K27A peak that only changes with dexamethasone, or it might only change with TNF, or it might change co-ordinately with both. And of course those are the ones that we're most interested in. If we look then at those peaks that are changing with dexamethasone only, what we see is the top motifs that we recover under those peaks suggest actions of the glucocorticoid receptor, perhaps a very unsurprising result. And in fact, the AR, the angioreceptor and the PR receptor that you see also in that list, they actually use almost identical motifs. That's the angiogen progesterone receptor, and they're very similar steroid receptor motifs. And so what we can see here is that if we see places where dexamethasone is changing the epigenome, it seems to be doing that perhaps through the glucocorticoid receptor. Similarly, if we look at places where TNF by itself is affecting the epigenome, the top hit there is NFKB, and I think that will surprise absolutely nobody. But what's interesting is if we look at this intersecting set, the ones that were the dex and the TNF are causing similar changes. What we see again is that the top motif is the glucocorticoid receptor, and we know by permuting the labels that this is not just because there's a dex set as part of this, we know that this is truly statistically significant for this intersecting set. We also see some other interesting motifs there, and I'm going to focus on two, the GR and the VDR, which is the vitamin D receptor for the rest of this talk. So what we first of all, we're focused here on the glucocorticoid receptor motif, and we know then that dex works through the glucocorticoid receptor. It is a synthetic glucocorticoid, and that causes insulin resistance, but our work here suggests that TNF also activates enhancer marks that seem to have a GR motif, and it raises the possibility then that TNF could be working through the GR. This is a fairly heretical notion, by the way. Certainly it was very heretical to the inflammatory reviewers. I meant that they study inflammation, not that they were inflammatory, although some of them were, but what we can see is that this pro-inflammatory cytokine could be activating then an anti-inflammatory nuclear receptor. So this is just an example of what those tracks might look like here. I'll just to clue you in, dex's treatment is always going to be in blue, the untreated in black, and TNF always in red, just to make things very simple here, and what we're seeing here is also these tracks show the time course, two hours, 24 hours, and six day treatment, and you can see here that there's this cluster of genes, TMM176A and B. If anyone knows what these do, please let me know. There's really almost no literature on these two genes, but what I can tell you is that they are induced by, or I should say there's an enhancer induced by dex and methanol upstream, and that same enhancer seems to be activated by TNF, and there is a GR motif there. We can show by chip PCR that in these cells when we treat with dex and TNF that we can chip the GR preferentially off that spot. We actually went to an entirely different model, cellular model. This is primary fat cells from animals that we differentiate in a dish, not a cell line, and we treat them with dex and TNF. We also cause insulin resistance, and we also see those same ability to chip GR off that exact spot. Then I think most importantly, if we just go right into an obese animal, take the mouse, isolate its adipocytes, and check out where the GR is binding. In fact, the GR is binding right at that spot as well. Not to belabor the cell biology, but I think this is very interesting. I think it points to the sorts of biological insights one can get from these epigenomic data. We know that the GR normally resides in the cytoplasm. What happens after dex binds to is it moves to the nucleus, so it translocates in response to ligand, and you can see that here that in response to dex, you see an increase in the nuclear amount of GR and a depletion in the cytosol of the GR. This has been shown by many others as well, and what we see here with TNF is that we also can cause nuclear translocation of the GR. This is without adding any exogenous glucocorticoid. We see, in fact, though, that we're not depleting it in the cytosol. We seem to be increasing it in the cytosol as well, suggesting that one of the effects of the GR levels in the cell, and we're looking at this much more closely now in a more rigorous cell biological way. We did chip seek of GR in response to dex and in response to TNF. We can see that TNF causes about tenfold less translocation or tenfold less, I should say, binding of tenfold less spots in the genome than does dex activation of the GR. And so what we can see, though, is that those sites largely are a subset of the GR sites, and we've been looking now and trying to identify what makes those sites special. We think we've identified a co-occurring motif that directs the GR once it's been activated by TNF to those spots. And then this, for us, is really where the rubber meets the road. NR3C1 is the GR gene. We've knocked it down here with four different hairpins. And what we can show is that we can rescue completely dex-induced insulin resistance. So if you get rid of the GR, dex can't work anymore. That's not surprising. But what is surprising here, or what is very hopeful for us is that when we knock down the GR, we get rid of the full ability of TNF to induce insulin resistance. So we still have about, TNF can still do about half of its thing, but it loses about half its potency. And so that does suggest to us, then, that TNF is working, in fact, directly through the GR. And we have a variety of cell biological and biochemical studies going on, phosphor proteomic analysis of the GR and response to TNF. We've identified novel phosphorylation sites, and I won't go into all that, but just to say that all of that is an epigenomic analysis that we did at the beginning to suggest what has been a really heretical hypothesis about activation of an anti-inflammatory factor by a pro-inflammatory cytokine. Another factor that popped up on our list was the vitamin D receptor. This is very interesting to us. There are connotations in the literature that vitamin D might be involved in insulin sensitivity, but in the opposite way. It's something we can discuss later if you want. But the bottom line is that we were wondering that could the VDR be involved here? And in fact, what we can show is that there's a large gene of interest, and here's a, you can see a peak here, K2070C peak that's induced by both dex and by TNF, and it has a VDR motif, and we can chip VDR off that location. I'm not showing it here, but in this other cell model, also we see VDR in the same location, and in obese animals, VDR is also chippable from that location as well. And again, if we over-expest the vitamin D receptor, we cause insulin resistance, and if we knock down the vitamin D receptor, we can prevent the full onset of insulin resistance, and we restore a significant proportion of insulin sensitivity in response to dex and TNF. Interestingly, vitamin D receptor is elevated in the adipose tissue of obese animals, different genetically obese models, high-fat-fed animals. It's also elevated in these cells when we add dex and TNF. VDR is itself one of those 271 genes, and we can also show that it's regulated by the GR, so TNF and dexamethasone both turn on enhancers that regulate the vitamin D receptor. You can see they're different enhancers. The dex is activating through here, TNF through here, but they both have GR motifs. We can chip GR off both those sites in response to dex and TNF, and we can see binding at this site in the animals that are obese. And so what we see then are a network we're beginning to develop about how the epigenomics really can lead us to novel hypotheses about transcription factors and how they may be interrelated. In the last few minutes, what I want to talk about is new data that we've been developing. Everything I just shown you has just recently been published in Nature Cell Biology, but what I want to talk about in the final moments are new data about humans and what we're doing here. So we've tried to take the same paradigm and apply it to humans, if you will. This involves collecting adipose tissue. We are fortunate in that adipose tissue is the one tissue that people are willing to give you an awful lot of. So if we were doing neurobiology, it might be a little more difficult to convince our patients, but we do get between one and 10 kilos of fat at a time from patients. That involves a fair amount of processing. We've had to invest in industrial sausage grinders. I'm not kidding to get through this stuff very quickly. And we can isolate adipocytes. As you know, any tissue in adipose is no exception. It's complex. It's made up of very different cell types. So another advantage that we have built in to the adipose tissue is that mature adipocytes float when dissociated from the rest of their cellular matrix. And so we can use this sort of low-speed centrifugation method after collagen is treated to isolate the mature adipocytes away from the other cells in this heterogeneous tissue. And then we can use the pure adipocyte. Then we isolate the nuclei, cross-link that, and we can then use that for chip-seq. And what we get are these very beautiful profiles. I'm showing one of our profiles up here on the top. And you can see ENCODE data for adipose tissue on the purple line right below it. And one thing you can see is you can see these sort of macrophage markers in the ENCODE data, because, of course, the ENCODE data is a whole tissue and it includes a huge amount. 50% of the cells in a fat pad are not adipocytes and they're made up of immune cells, endothelial cells, and other things. And you can see here that we see the ubiquitous markers. We get a much more robust representation of the adipose tissue marker, the ones that truly belong in the adipocyte, and we basically lose the macrophage markers as well. So we're very pleased that we also lose the pre-adipocyte markers. So we're very pleased with sort of the quality of our data. What we can see is that we can begin to and for a large number of novel biology, amount of novel biology here, we're seeing novel transcripts, alternative start sites, things that are popping up in gene deserts that seem to be important in adipocytes. So what we're going to have very shortly now from literally we've now done dozens and dozens of patients is a much more detailed epigenomic map of what those adipocytes look like. But specifically what we have is now we've collected patients across a spectrum of insulin sensitivity. So we know the patients in the top and the bottom quartiles of insulin action based on a technique that we use called HOMA IR. And what you can see then is that we can already in this sort of small sample that was done a little while ago, you can see that we're already identifying enhancers, for example right here, that are relatively seem to be highly active in insulin sensitive patients, but much less active in insulin resistant patients. There are some opposite ones as well where there seem to be more activity in insulin resistant versus insulin sensitive patients. And we're seeing literally hundreds of such differentially regulated peaks now and many more patients than we have here. The ones I've shown here on the left, these represent biology that is pretty well known, adiponectin, glute 4, other adipocyte genes that we know are involved in insulin action. What we also find are as differentially regulated peaks in genes that some of which have absolutely no known biology in any system, some of them have no known biology in adipocytes, and so we're really trying to put this together now. And we have, I should say in the last week, hot off the presses, we think have identified novel factors that might be involved in insulin resistance in human disease. So to summarize what I've shown you then, DEX and TNF can cause discrete changes in the epigenome of 3T3L1 cells, these are cultured adipocytes and those say with insulin resistance, we can use motif finding in these differentially regulated regions to identify novel pathways that allows us to do a lot of cell biology. Some of what we found is that TNF causes insulin resistance in part through an independent, like an independent activation of the GR, also the vitamin D receptor seems to be important. In data that it didn't show you, we've actually identified some of the downstream target genes of these factors. So we've identified now at least four genes that went overexpressed in fat, seem to cause insulin resistance. DEX and TNF and we have our human studies ongoing which we are actively recruiting for and working on and which appear fingers crossed to be yielding some very interesting data. So with that I want to thank the people who did the work. Most of the work I showed was done by really two talented postdocs, Sona Kang and Linus Sai and Yiming Zhu was our computational biologist. Other people in the lab contributed. We had help from our collaborators and friends at other institutions including the Broad Institute where I'm also a faculty member and I think working from the roadmap was highly elemental in pursuing this and thank you very much for your attention. Great work. A couple of questions. When you looked at your K27AC chip under two conditions, you only had about 50 sites of overlap. When you did the GR chip under the two conditions, you had over 200 sites of overlap. You think there's an issue with a K27 acetylation chip, it's not like sufficient, we need to look at other marks or you think there's a bunch of GR sites that are silent even though they're recruited. Great question. There were about 200 in some odd sites that were together there. Some sites will get recruitment and not change their K27AC very much. Maybe because they're changing trading factors, maybe GR is going on and something else is going off and the overall activity and enhancer as measured by K27AC is not changing. That's one possibility. These are blunt tools. I think that's also a part of it as well. We don't tend to worry about the stuff that is trying to make use of the stuff that we do see and that's a little bit of a cop-out answer but that is how we deal with that. I agree. The second question. How are you taking the genetic heterogeneity into account in the second part of your study, the human focused samples? We are doing that right now. We are integrating the human genetic variants now. From the samples, from the individuals you're getting, are you assessing what's their identity? Do you actually be able to ascribe the one or the other if indeed your patient or your individual is? In the early samples, we were not actually consented to get genotype data from those so we've been doing a little bit with imputation but with that. All the later samples, we have changed our consent form and so we're getting to get that information and we're going to just snip genotype everybody and just figure out what to get that data. Naive question. Are there adipocyte stem cells? Yes. Do you separate them and analyze them? It's a very contentious area of research. What exactly is an adipocyte stem cell? They do exist and in our human studies they're not in the cultured cell studies that the pre-dipocytes that are using the cultured studies are from a later stage of differentiation. They're not stemmy. They sort of have lost all multi-potency and can only become a part of the human studies that gets fractionated out. Remember we collaginase them when we float off the matured dipocytes and all the stuff that goes down to the bottom which includes immune cells, stem cells, pre-dipocytes, endothelial cells, neurons, anything else that's in there is in that. So that is a separate area of investigation and flowing out the specific stem cells is something we save those fractions and we'd like to do that but the field I would say is in disarray about adipose stem cells so we're not sure what markers to use to flow out the actual stem cells.


You saw the thumbnail and the title, and yes, it is true. The original partygoer is back, and I think it's better than ever. If you remember, about five months ago, I made a video called Partygoers Are Back, and that was about the Partygoer entity being taken down and changed into, like, the sanguine Festivus virus. Well, now it's been decided to bring the old Partygoers back, like they used to be here on the Wikidot, but with a few great changes. And in this video, I'm going to be going over these changes and showing you how much this entity has changed for the better. I think this is seriously one of my favorite ones now, and I think that you all will enjoy it. So without further ado, let's get at the explanation and let's talk about the return of a very OG entity. But first, follow my Instagram if you want to see pictures of me and my YouTube friends and real-life friends, and also subscribe to my other channel Spookly if you want more, like, spooky internet horror, ARG, that kind of stuff, self-promoting out of the way. Let's get into the video now. So in this video, I'm going to be going over the Partygoer entity as we now know them, and specifically, I'm going to be pointing out the different things that have changed about their physical appearance, their biology, their minds, and their home level, as well as some of their behaviors. You'll know the differences when you hear them, I'll point them out, but let's go ahead and get into it. Backroom's entity number 67, or the Partygoer, has been classified as a class IETS 5B rating, Chimera. So Chimera is like an entity that is highly intelligent and aggressive, and it poses a threat to anybody who encounters it. The actual word Chimera is a Greek word, and it's pretty much a mishmash of weird, eldritch horror entities and faces.  And that's why the Partygoer entity has been classified as that. Thank you to Raycon for sponsoring this video. Listen man, I'm a YouTuber, so I sit at my desk all day and do nothing. And a way that I've found to counteract this sitting all day and doing nothing is by taking these long, mysterious walks through my neighborhood. And I would never be able to go on one of these walks without having Raycon on me at all times. Raycon is absurdly affordable, which in my opinion is the best part about him. They come in a bunch of cool colors as well, and blue is my favorite color, so that's perfect. They offer that crisp audio quality that we're all looking for at half the price of leading premium brands. They also have a 32-hour battery life and an 8-hour playtime, which means that I can listen to my 10 hours of Backroom's humbuzz three times in a row without the battery dying. Also, I have a confession. My ears are huge. I have massive Dumbo ears. But Raycons have adjustable gel tips, so they're not going to fall out, and they never do. They have great noise isolation as well. And their tap controls makes it super easy to change songs or shuffle playlists on the go without having to yank your phone out. Really, these things are amazing. And if you want to snag yourself a pair and support the channel, you can visit the top link in the description below by raycon.com forward slash brugley to get 20% off in free shipping of your Raycon order. That is 20% off and free shipping too for using the link in the top of the description. Once again, thank you to Raycon for sponsoring the video. And with all that said, let's get back into it, shall we? The new page is decorated with confetti and cakes and party hats. And it's very similar to the first party gore page from a few years ago. It's actually really nostalgic. But the document opens with an excerpt from a MEG operative that says the following. The battle was brief. The closest entity made no noise and never flinched as her best swordsman lopped off both arms. Its eel-like appendages now wiggled on the concrete floor and snapped angrily at the air. Operative Tiger then followed through with a thrust that glanced off as if hitting stone. A hidden chest carapace on each party gore flipped open and a pair of anomalous arms with huge clawed hands shot out. And gouged eyeballs and freed human entrails. The insides of these creatures were a nightmarish conglomeration of human, phobic, centipede, and crustaceans. Our team was divided into two groups, screaming and dying.  The rumors are true. Party gores can turn people into them. Three of us made it out unscathed, but we had to kill six of our own before they transformed completely. Myra Oberlin, Meg team party over. So that was a document describing an attack that party goers recently did on several Meg operatives. And as you can see, a few new interesting things have come out about the biology of the party goer. Specifically, the part about its chest opening up and strange arms coming out of it, which is something to keep in mind. Anyways, overall, the party goer's appearance is very similar to what you're familiar with. But now we know a lot more about the biology and specifics of it. Party goers are conscious and intelligence animates entities. They're able to think and act on their own or in packs of themselves. The hide and tissue of party goers is shockingly similar to woven Kevlar from real life, which is to say it's very tough, very resilient and hard to puncture. It also seems to be fireproof to an extent, especially the skin on the body itself. It's very resistant to stabs, to punches, to cuts, and it's very hard to take them down because of that. Party goers are medium height to tall height, and they're pretty swift, even though they're not the fastest entity. But they use their smartness and their intelligence to hunt in packs and to use pack maneuvers to corner people. They have that yellow skin draped over a decently thin frame, eyes and mouths are slit cut into the skin, and they look like Play-Doh, to be honest. Their arms are long and they're spindly, and at the end of them is what seems to be mouths with teeth on the palms of their hands. The main new thing that you need to take into account is the strange arms that come out of the party goers' chests and the arms of the actual party goer itself. And the mouths on the end of their actual hands is how the party goers transform their prey into other party goers. They latch on, kinda like an octopus suction cup thing, and when they unalive you, they will then start the transformation. But more on the biology later, I will get into the rest of it, but let's talk about where the party goers come from and where their home level seems to be. The party goer origin level and habitat is actually up for debate amongst the people inside the back rooms. They are 100% able to move from level to level, just like wanderers can, using the same entrances and exits, but the actual home level where they come from is a mystery. Of course the level has been named level fun, but what is level fun and why do party goers live and come from there? What we do know is that party decor or decorations and stuff near a door or window is a huge indicator as to an entrance to their home level. If you see balloons or streamers or tables or cakes near a door or an exit, do not open it up because the likelihood is if you do you're gonna walk right into their home. You also might see on any level homemade posters or something like that that advertises their home level as a fun place to go to. These posters typically have arrows and directions that lead to their entrances.  Some say that the entrance is on level one in the ceiling where confetti sprays out of a light fixture and all you have to do is no clip into it to get there. Again, it's unknown if these are true, but they're most likely are not true because there's so many rumors and false information from party goers themselves that have altered the documents about them. We can't even tell what's real and what's fake. Now when party goers began to pop up way back in the day, the leading theory on what was causing this damage and this massacre to the wanderers was that there was some tribe of cannibals or this group of cannibal people that were eating others. People thought there was a cult or something like that lurking in some kind of level and luring people there to consume them, which is a crazy theory. I don't think that'll be my first thought, but most people thought that way until they started seeing the party goer attacked victims begin to turn into party goers themselves. They started to see the people turn yellow and once you start seeing a person turn yellow, yeah, it's over. Anyways, back to the party goer biology. Yellow party goers are not the actual only colors that you might see. You might see a red or blue or green or white one, but those are very rare and typically only on level fun. The only thing consistently the same about all the party goers is that crude smile carved into their leathery skin. The smile is said to be the exact same as a phobic centipede's smile, which you've remember a long time ago. Those are those huge centipede creatures that are very sadistic and they haunt humans and they trick you with nostalgic things and they have a smile just like the party goers one. It's horrifying to think about. The shape of a party goer is roughly humanoid, but their legs are very thick and blocky and they kind of awkwardly wobble around, but are very swift for their awkward size. The transformation process from human to party goer begins the second one of these entities reaches out one of its arms with its hand mouth thing and latches on to you. The only way to stop it is by desponding yourself. If you know what I mean, that's the only way to get out of it. You cannot use almond water. Nothing can stop or slow the transformation from human to party goer. It's impossible. Party goers are downright sadistic hunters. They prey on wanderers for sport and to increase their numbers. They're kind of like Orca whales from real life.  So how does one defeat a large apex predator with thick skin that has knowledge of the back rooms and has other members of its pack hunting you? Now, luckily for you, I know how to do it. So I'm just going to tell you right now a few weaknesses have been found.  You're going to have to take an axe or sword and just cut off the arm. That is the best way to avoid being infected or attacked by one of these entities. If you do that, you'll have a much better chance of actually surviving. The next weakness is once a party goer opens its chest cavity thing where arms come out of it.  It'll weaken it pretty much. Once a human starts to turn into a party goer, their hearing begins to get reduced, their taste and sight and touch, and the ability to feel pain start to decay and all of their sensory things like sighting and sound are turned down. And then eventually they'll turn into the party goer and that's when you'll get adopted into a party goer pack or group. Party goers seem to communicate through some sort of shortwave tilapathy. Again, we're not sure how this happens, but they definitely know what each other are thinking without vocalizing at all. That's how they're so aggressive and how they're so tactile when they're chasing prey. Kind of like Utah Raptors or Velociraptors are when they're hunting in packs. Now party goers, again, have a very strange and unnerving pastime of eating cakes and sweets. But not the sweet kind, the meat kind, if you know what I'm saying. There are alleged videos of these cakes being formed. I can't show them here obviously because it's disgusting, but I'm going to describe them to you. Because now we know how party goers create their sweet meat treats. Fair warning, this is disgusting and disturbing, but stick with it if you want to hear. When party goers end a human, they use their suction-y mouth things on the end of their hands to scrape and mince the sweet meat and tissues off of that individual.  Other party goers will get the rest of the juices and meats and digest them into this frosting consistency liquid. Then they regurgitate that liquid on top of the cake that they just put in the pan. Then they'll bake it in an oven and it's said that the cakes have a sweet red velvet taste. But when you eat it, you'll know that something is very, very, very wrong. Do not eat any cakes you find at all in the back rooms. So now we know a little bit more about the physical description, the motives, the level, and the inner workings of the party goer entity. And we also know that the party goers somehow have the ability to alter information about themselves online, whether it's to make themselves seem better or to lure people closer to their home so they can turn them into cakes. We don't know. But with all the info I just told you, if you encounter a party goer, honestly, you just got to run because that's your best chance to live. They're pretty near-sighted and they're not really that fast and they're sprinting. So if you find yourself cornered, run.  That's sort of the only thing you can do. Never hesitate when you encounter one though because they will attack you with their hands and arms and stuff. Just run away and don't forget to have a little fun along the way, you know what I'm saying? So in summary, that is the new party goer entity. It's the large, yellow, blocky creature that hunts down humans and impacts for sport. Turns them into cupcakes and pastries and with their suction teeth hands, they consume you.  Overall, they're disgusting, they're sadistic, and I freaking love it. I mean, they're amazing. I think this is one of the best rewrites of an entity that I've ever seen. I love how much more horror was plugged into these creatures now. I think it needed that seriousness. I think goers have always been goofy but scary, but now it's even scarier and I really like it. Anyways, I'm done rambling. Hope you enjoyed the new entity or I guess the old entity. If you did, leave a like on the video. Tell me what your favorite thing about it is in the comments. I'm interested to see what you have to say. Let me know if you enjoyed this video too, of course. And let me know what other entities and creatures and levels that I should go over. Like I said, I personally love this creature. I always have liked it, but now I love it even more because I feel like it's been taken more seriously. And I just hope to see more entities be like this. Anyways, thank you for watching and I will see you in the next video.