All right, what's up internet? So we're filming this during the time of corona and kaya tayo nakamas ngayon. Focus on positive news, especially para sa mga mahiilin sa computer, mga gamers. There is actually good news coming. AMD is scheduled to release its fourth gen CPUs and this is the Zen 3 architecture. It looks like AMD is still on a roll. The performance increases will be just as dramatic as what we saw from Ryzen 1 to Ryzen 2 and then Ryzen 2 to Ryzen 3. So AMD is on track to deliver the same performance increases. And considering a lot of people are quite happy with R2, Ryzen 2, Ryzen 3, we expect to be happy as well when the Ryzen 4 comes out this year. Rumor has it they will be announced officially September this year and then they will probably be released around October and because the Philippines is not a major market, we might start seeing them locally around November or December. But definitely the Ryzen 4 will be faster and will supposedly consume less wattage as well. The bad news is they won't support DDR5 so if you're looking to upgrade to DDR5, you might need to wait for the motherboard manufacturers to come up with new boards because you will need new boards for DDR5. And the good news is it's still AM4 so the socket is still AM4 just as AMD promised so it is backward compatible with the Ryzen 1 and onward motherboards. Although they're not all backwards compatible because some motherboard manufacturers are having a hard time fitting all of the instructions onto the BIOS chipset. It's a bit technical but the socket itself AM4 is backward compatible but some boards because of the limitations of storage won't be backward compatible with the Ryzen 4. But this is the last time we're going to be seeing an AMD release with AM4 because they have confirmed that Ryzen 5 will be using a different socket. So this is the swan song of the AM4 but who knows to AMD that they have kept the same that they have kept it at AM4 for their entire run of Ryzen so far. Ryzen 1 all the way up to 4 have used the AM4 socket and this is in contrast to Intel which basically changes sockets a lot more and of course this is harder for people who want to upgrade just the CPU instead. And of course every time a socket changes it's that much harder to upgrade it gets more expensive so who knows really to AMD for getting performance as well as managing to keep the same socket. Team Red is on a roll and it looks like it will continue its impressive performance later on in the year with Ryzen 4. Still keeping with AMD news they are also scheduled to announce and release the update to their graphics card. It's called NaVy 2 or Big NaVy or RDNA2 and just a side note on the naming conventions actually I think this is one area where AMD can improve because their naming structure is really confusing. It's not like NVIDIA NVIDIA does a good job there's the NVIDIA 1000 line so that's the 1660, the 1080, 1070, 960 and things like that and you know what you're getting AMD for graphics cards has a very convoluted naming system and you know again they can't figure it out the latest upcoming is called Big NaVy, NaVy 2 unlike their CPU line which is super easy there's a Ryzen 1 followed by the 2, 3 and 4 and I wish AMD would adopt something like that instead of flip flopping with the names because the names are important the lines or what you call the lines make it a lot easier for consumers to understand that yes I want this NaVy 2 because it's faster than NaVy is NaVy 2 different from Big NaVy what's RDNA2 the more terms you file on the consumer the harder it is for him to figure out that this is the card that I need don't make the consumer think anymore because if you have to think too much he's just gonna go run to NVIDIA where everything is a lot more straightforward but that aside yes NaVy 2 looks to be better for AMD finally NaVy 2 will allow them to have 4k gaming which currently only NVIDIA is capable of doing the performance as well is supposed to be a lot faster 50-75% is the leaks or the news that is circulating so at least and most importantly it will finally have ray tracing or basically RTX on something that NVIDIA popularized and really jumped on with the 2000 line, the RTX 2000 line so finally AMD is playing catch up but at least with the NaVy 2 it looks like they will be at par with NVIDIA but that won't be for long because as I'll talk about NVIDIA's 3000 line looks set to blow it looks set to surpass all of the performance specs now it's gonna leapfrog over everything else so AMD might tie NVIDIA's 2000 line but when the ampere 3000 line of NVIDIA comes along that's gonna be a different story and we're gonna talk about that later NaVy 2 is set to launch sometime around October so again maybe around December we can expect the cards to reach us here in the Philippines and interestingly enough around October is when the PS5 is coming out and the Xbox Series X again, I don't know why they made these names so complicated but what's nice about or what's interesting about the next gen consoles the PS5 and the Xbox Series X is that they also make use of the NaVy 2 for their graphics processing and if the architectures are basically the same then it might be easier for console games to be ported to the PC so we might be seeing a lot more of porting from console exclusive items maybe they'll make their way to the PC faster so we PS in particular has a lot of nice exclusives like Horizon Zero Dawn which only recently got ported to the PC and since now the next gen consoles will be sharing a lot of graphical architecture with NaVy 2 it might be easier for game makers to port them to the PC assuming that a lot of people do buy NaVy 2 GPUs so those will be the ones to port them okay, shifting over to the Intel side of things Intel is set to release the 10th gen Comet Lake desktop we've already seen some of them being used in laptops so there are 10 gen Intel CPUs in laptops already this is slated the desktop CPUs are slated to be on hand around 2nd quarter so we're thinking actually next month may perhaps Intel will start releasing them so as I mentioned Intel likes changing the socket so this is not LGA 1151 it's LGA 1200 and the motherboards that you need will be the Z490 line actually the motherboard manufacturers have been all set to go based on the news they've been ready with the Z490 line however Intel has held back this particular chipset the 10th gen because they have been trying to get better performance with less power because all of the early reports have indicated that the 10th gen Intel generate a lot of heat and they use a lot of power and so Intel has been trying to cut that down but apparently they've been unsuccessful because now what we're hearing is that they are just simply going to release the 10th gen CPUs very soon and just to put it in perspective the Intel 10th gen are supposedly use as much power as an RTX 2080 that's around 220 watts and that's a lot of power and actually you're going to have a 10th gen and then you're going to have a 2080 that's basically 440-480 watts so you're going to need a good PSU and you're going to need a good cooler if you're going to be upgrading to the 10th gen Intel disappointingly performance is sort of lackluster at this scene some early leaks and again this is all rumor this is not official but it seems to tie in to what everybody else is saying they had an i9 10900K versus and Ryzen 9300X so they are 9300X is available now it's from the current line of Ryzen it's not the 4th gen Ryzen so a CPU that AMD has available now stacked up versus a future Intel CPU the AMD actually won it's actually 7% faster or roughly than the Intel 10th gen so the comet lake 10th gen Intel looks to be a bit disappointing and yes there are people who super love Intel and they might be a reason to upgrade to it but on its own all things considered the 10th gen line will not be the one to convince people to go back to Intel so Intel is still playing catch up with the comet lake line someone not playing catch up though is NVIDIA and they are set to release their third or their 3000 series it's a new graphics architecture they call it ampere versus the touring architecture of the 2000 line my promises is much much faster graphics at a lower much much faster graphics for less power the rumor is or the early numbers are showing that we will get a 50-75% increase in performance with a decrease in power consumption of around 50% so that's really across the board those are great numbers and you really might want to wait if you're looking to upgrade your graphics card you might want to wait for the NVIDIA 3000 line because the numbers really are looking quite good how long will you have to wait? the rumor is that they will be officially announced in August and then they will be available commercially sometime around the end of the year and and in fairness to NVIDIA they really do take care of the gamer segment and pushing to the performance if you're curious the gaming segment makes up 50% of NVIDIA's revenue so they know who butters their toast and they really actively try to push the envelope when it comes to graphics cards so who does so NVIDIA and you might want to wait for their 3000 series if you're thinking of upgrading lastly we're going to end with memory with RAM DDR5 we've been hearing about this for a long time around 2018 that's what people started saying that DDR5 is actually a reality 2019, bit of news and finally in 2020 there has been news that it will be finally in 2020 it has been announced that yes, DDR5 will be mass manufactured this year so that's going to slowly start rolling out the server side builds and then more slowly to consumer and PCs and DDR5 will require you to buy a new motherboard current motherboard do not support DDR5 but what you get basically DDR5 is offering double the speed so it's roughly DDR4's around 3200MHz yes there are faster but on the average 3200MHz DDR5 is promising 6400MHz and that is not yet overclocked so there is significant performance gains associated with DDR5 but you will need to upgrade your motherboard and no word yet as to pricing this should benefit AMD builds because the Ryzen architecture has taken advantage of faster RAMs and RAM size so generally the faster your RAM the better your Ryzen builds and so that can only get better with the upcoming DDR5 so that's it a lot of interesting things coming for PC later on in the year we just need to get through the first part of 2020 and you know a lot of people are suffering health wise a lot of people are suffering economic wise business wise so the best thing we can do is to follow health protocols we will beat this thing and hopefully once we come out on the other side there are a lot of interesting hardware to splurge on or that we can experiment with or that we can have fun with so in the meantime everyone stay safe and things to look forward later on and these were the things to look forward to after we get out of lockdown so I hope that these basic tips helped you if you found this video helpful please drop a like and hit the subscribe button for your PC needs consider buying from us hardware sugar at Lazada or on our website you can find links in the description below and thank you for watching see you next video


This is Think Tech Hawaii, Community Matters here. Guys, and we're live back here in Think Tech Studios, Hawaii, with the Prince of Investing show. Live here, and let's shoot a broadcast live on how we were live. If you guys know, I'm here in River, Colorado, but thank you guys for tuning in, guys. Don't forget to hit that like, subscribe, comment, and share button, and all the other great stuff. As you guys can already see, we have a very, very special guest with us here today in 12-year NFL veteran, live backer, Jared Johnson. He called us all the way from Florida. We're going to sit down with him. We're going to talk about his NFL career, life before the NFL, life during the NFL, you know, financial literacy, all the other great stuff, time in the league, and life after the league. Thank you to all of that. But you guys stay tuned. You guys stay, keep it locked right here. And as always, I don't have a lot of time, and I definitely, you guys don't have a lot of time, but we're going to jump straight into it. So, what I've heard to do, I know you guys are tuning in to hear my MindFall Day. I've got to bring in our special guest, Mr. Jared Johnson. How you doing today, sir? I'm doing great. How are you? I'm doing outstanding. First of all, I want to say thank you for stopping by and spending a little time with a peon like myself. I greatly appreciate it. Oh, no. Ain't nobody saying, man, I don't know about that peon thing.  That's right. You guys are going to the college football league. I'm a college football championship against Georgia here. And with that being said, me being originally from Georgia, you already know I'm rooting for the Bulldogs. I just want to say, man, you guys already got no championships. Let us get one. Okay. That's the thing about being an Alabama fan is just watching how mad everybody else gets. But we have something in common, something in common is half the country, more than half the country. H-D-S-E-C, and it just makes me happy that it's an all S-E-C championship game. So, uh, we get to enjoy that in the build up to the game, and it will be, uh, it will be enemies today, uh, but until then, I'm going to enjoy making everybody else mad. I knew they were going to get Alabama, and that's some type of way. But with that being said, for people out there who don't know who Jerry Johnson is, who is Jerry Johnson? Who am I? Now I'm a retired, uh, NFL linebacker, um, and I'm a family man, I do some radio on the side, um, I run a fishing charter on the side, but my, uh, everyday job is I'm a stay-at-home dad, um, I'm around the house a lot when I'm not traveling on the water or something like that, but, um, you know, I, uh, I pride myself on, on being a good husband and a good father. Oh, awesome, awesome.  How was that feeling of getting drafted into the NFL? It was good. I didn't, I didn't so much enjoy the draft process, uh, the combine and senior ball and stuff like that. I mean, it's a, it's a straight up meat market. So I, I think it was very stressful. Um, you get a lot of people pulling at you.  It's not real healthy. Um, I didn't, I don't really enjoy the attention or limelight or anything like that. Um, so once I did get draft day, I thought I was just like everybody else. So I was going on the first day, ended up going on the second day. Um, but it could, I could have got drafted in a better place, you know, better spot. I was a fourth round draft pick, but ended up being a perfect spot for me. Um, and then to a team that I played for for nine years, um, had a great career in Baltimore. I was a perfect team that fit my personality and my style of play. And then I went on to, uh, San Diego and finished down my career with 30 years of San Diego. Okay, now looking back on that, you know, so you got to play with some of the, some pretty, um, big names from Hall of Famer's day.   Right. No, it was awesome.  He and Charles Suggs were, uh, in the same draft class. He's still one of my closest friends. Um, but the guy there is, is Ray Lewis. You know, he's a standard maker. He's, he's, uh, the bar. He's set the bar for the rest of the players to live up to. Um, but, uh, I was definitely fortunate to have, um, a lot of really good players around me. It also, a lot of really good coaches, like for Chuck Gano and Rick Ryan and MPs and I can go down the list and the number of good coaches that, uh, that opportunity to play for. Okay. Now you say, you know, when you go through this, I thought that's kind of funny when you said that a little meat market process going through the end of, uh, when you're going through this and you know, you finally get drafted, how, you know, who at your NFL career, since you had a pretty long career, 12 years, if you don't mind saying it here, how much money do you think you probably accumulated throughout that time? Um, I don't, I don't know. Um, yeah, I, I, I signed a three year deal. My rookie deal was a three year deal. Um, and then I signed a one year tender. Um, and then I signed, uh, a five year deal. That was my first, that was my three contracts with Baltimore. And then I signed a four year deal with San Diego, in which I played three of it. Um, but I don't, I don't know the, the, uh, the exact number. Um, but it was, you know, I had a, uh, fortunate career. I played a lot longer than I, than I, that I even anticipated me playing. Um, you know, and it was, uh, you know, it was, um, it was definitely, I had the opportunity to live a dream. Um, but fine in my money wise, you know, uh, she doesn't have to add it up. Okay. Well, you know, since you know, when you make that type of money, you don't even know what you're made. You probably, you know, I got a couple million, pretty sure it was a couple of millions, right?  Yeah, I did. I've, I've, uh, I learned a lot in my financial career. What I call you take your, uh, your, your, uh, focus outside of football and family, you know, um, there definitely become, you definitely take on a lot of responsibility. Once you start making money in the NFL, um, things definitely change.  I was, you know, I'm from the country, very small town, and I remember I was going through the draft process and I was visiting with my uncle and he started asking me questions about, um, uh, he was wanting to refinance his house and he was asking my opinion on how he should refinance his house and I was like, why are you asking me this? I mean, you know, the point is, is that just because he knew I was going to get drafted and start making money, he automatically thought that I was like this financial guru that I knew the things that he needed to be doing with, with his financial life and I hadn't even, first of all, I didn't know what he was talking about at the time and I hadn't signed my contract yet. So I was still basically living like a college kid. Now that was my first indicator of how, you know, people's view of huge changes wants to associate you with the NFL. Wow. Okay. So, so you go into, what are some other examples of how people treat you a little different?  I'm sorry, can you repeat the question? Like, what are some other examples, like you had the example of your uncle about refinancing his house? What are some other examples? Yeah, well, I mean, yeah, you could be out socially, yeah, you could be out socially being a bar or social event or whatever and, you know, I dress normal. I'm a bigger guy, but I don't, you know, I'm not going to, you know, you're not going to automatically know that I'm playing the NFL.  And all of a sudden, the minute they find out that, that you play in the NFL, their attitude changes, they're the way they look at you, the way they, the questions they get, like, automatically.  They're always either going to go in a negative way or an overly positive way. And a lot of times I'm like, hold on, now, you were just talking to me normal, second ago, before you found out I play and also the final you play, they got treated in a different way. But you just, you got to learn to deal with that. One thing I always try to do is treat everybody the same, no matter if it's, you know, if it's a bomb on the street or a fear of a company, everybody's the same, you know, we're all created by God and are equals. The only way, the only thing that's different is the way you treat people, the way people treat you.  What do you drive?  So people kind of, that's kind of funny that you say some people go over the top with bragging about themselves or measure up or they become intimidated. So but, but now the question that, you know, financially seems like you did pretty well with planning to leave for 12 years and now you just, you know, hanging out fishing and just being dead and husband. No, I was always, you know, I think the best thing that I did financially is that I kept it simple. I understood I made a budget every year based off of my lifestyle and my income and the things I wanted to get out of whatever I was making that year. I started my rookie contract. You know, as rookie, I'm making there's much money and I remember my first game check I was making like, like 7,000 a week. And that's only that's for the games you play. So 16 games plus a buy. We see 17 checks and I would take 5,000 of that and I put it in the savings and I'd take two and I would go to my bills and, you know, my basically went into my checking account.  That obviously changes, you know, that number changes. But the philosophy that the majority of it is going to go to savings and a portion of it goes into your checking and kind of your lifestyle. It goes up as your salary goes as you get to be a veteran and you start making more money. But I never, I never, I never deviated from that from that plan. You know, I never change from, you know, I didn't look at my salary is what they had slotted in my contract. I looked at it is no. What what am I paying myself to live off of and arrest of it is all going to whether I have a real estate plan or just my say most of it just go straight and save it or my portfolio. And I did that for my entire of your career. OK, now when you say you made investments, what type of investments did you make? If you don't mind me asking?  You know, I had a financial advisor that was trying to give me into some outside stuff outside of just my portfolio. And you know, one of them was a product that they use for it was a product of the instruction to spray this formula or the solution on the frame of houses and I was supposed to termize kidney and all this junk. You know, luckily, I didn't invest that much money in it. I ended up getting that getting the money out of it. But I did that and then but as my career went on, I mainly just real estate. You know, I did a couple of real estate deals. Just bought some dirt in some areas in Ballin County and have a buddy that owns a company in Texas. I'm a silent partner with him. But outside that, I mean, the vast majority of my stuff is just, you know, I would call it not, not sexy, not some fun to talk about it. I'm a bottom ladder. No, that's that's actually pretty good to hear, you know, as far as, you know, getting involved with real estate because, you know, so often we have stories of NFL, you know, veterans that are not doing too well with. Yeah. Go ahead. Go ahead. Go ahead. Yeah, you know, everybody wants to talk about the bad stories. Everybody wants to talk about the stories of the guys that, you know, that boil their money and they buy all these crazy cars or houses and travelers. Yeah, I would say that obviously those are the fun ones to talk about.  But I mean, I'd be willing to say that the majority of the teammates I've had over the years have been there's been just as many of them who have been either have every dime they've made since they played or have made more. There's just as many as those guys is our guys that are that are they're struggling and blew their money. But nobody wants to talk about the guys that have gone on and and either just live off their savings and live a modest lifestyle or they got into outside deals started companies. They went on and got a job or went into coaching or whatever in there and do and do really well with it financially. But that's a little different. You know, I'm different. I like to highlight you guys to say, hey, you know what? You've done some good stuff, you know, not everybody because what happened is the outside world is we're not in the league. We're nowhere near close to being in the league. All we know is what the media push out there in the media usually jumps onto the stories of, oh, look, this guy blew everything he has. Nothing in blah, blah.  It's that you don't see the good ones.  Right. So yeah, that's exactly right.  I'm going to tell you how much money they have. They don't dress or act in a way.  And saved every penny. They've started gyms and other outside companies.  But yeah, those guys are not real fun to talk about.  Jay, are you just describing yourself without telling us?   I keep everything within my means.  You know, I I set aside enough money to where if my wife wants to go out to a nice dinner, I'm not going to complain about the price of the steak or, you know, she wants to go somewhere for a weekend and we're going to get to I'm not going to complain about it. You know, we're just going to talk that up. Is is a life experience and and and we're going to enjoy life.  OK, well, that's good. You know, I'm very glad to hear that.   Yeah, yeah, I married, got two little girls, OK, been married to my wife for. You know, I've been there for 13 years again. I don't think about it there for a second. But now the question I have now is is there anything that you look back over your NFL career and say, man, I wish I would have done this different or I wish somebody would have told me this for somebody who's listening to this that maybe you're ready to go to the league or that maybe, you know, get ready to play in the national championship, college football, national championship, that's going to that meat market. Like you said, what advice would you give? Financially, yeah, financially, financially, and personal to. I don't know. I really wouldn't change a whole lot about my career. I think. I think personally, as an athlete, I would have. I wish I would know about nutrition and things, you know, know how to take care of my body earlier in my career. You know, you know, I didn't learn that stuff till four or five years in the league.  And then once I got once I got in the NFL and you got a personal trainer for that eat properly and nutrition and all this stuff, you know, it made me a better player. I wish I'd learn that earlier in my career.  I mean, I can't tell you the amount of ideas and get rich themes.  I'll walk away. Good advice. Yeah, but the vast majority of them I never followed through with, you know, and I'm thankful for that, you know, but so financially, I wouldn't I wouldn't change a whole lot.  I don't I don't have any debt.  And because of that, I can live debt free forever. So, you know, I would I wouldn't change a whole lot about my my financial career. Well, that's very good advice that you gave out, keeping it simple, invest it into things that you possibly know about.  Getting a franchise? Yeah, like a franchise. I don't know, Dare Queen, the subway, McDonald's or something like that.  You know, I don't I don't really I don't really look into them personally, but, you know, there are some some good franchises out there that are that are sound investments for investor, and you can get a pretty safe return on your dollar. You know, like a lot of McDonald's if they're run correctly, you know, are are can be super good investments. But, you know, I would say that the main saying that you need to do as far as investing is, is have a good CPA, you know, have a good financial advisor, somebody that you can trust, and they don't have to be a sports specific investor. You know, the minute you start going through the draft process, all these guys are going to come out of the wood work, and they're going to start recruiting these players to come and invest their money with them. And a lot of them are saying, you know, I'm going to pay your bills for you. I'm going to handle your taxes for you. I'm going to do all this stuff. And it's going to be at a super inflated rate. Don't ever let anybody pay your bills. Always pay your own bills. So you know what's going out every day. And then don't ever sign a power of attorney that's going to let somebody say, look, sign this power of attorney, and I'm going to take your money, I'm going to handle it for you. Always know where every penny is gone. It doesn't have to be anything super glamorous. You know, like me, I had a sport specific advisor. I fired him before I got a dime because I saw the right if they're going to charge like 30 grand just to do my taxes.  I was going to he was going to pay me. I had to pay him like 30 grand. I found out about plus he was going to charge like two and three percent to invest my I realized this is a racket.  And I was like, who's your dad? He used to use this guy with Morgan Keegan. I went and met him. And he's just just a good old guy. Just a real smart investor, very conservative, didn't say anything super sexy, never told me he was going to make me rich. And he ended up being my financial advisor for a long time until he retired. And when I left him, I went and got another guy that was very similar, you know, but you've got to be careful of anybody that's out hunting you without pursuing you because they're not doing it for nothing. They're they're being that aggressive and taking you to dinner and going to do all this stuff because they're going to make money on the back end. OK, so it was a sports agent. So like he was going on this sports advisor, so like he was going to hook you right on up. Yeah, yeah. Yeah, well, I mean, there's an agent totally different. An agent he's going to make his three percent. He handles your contract. You know, I'm talking about I'm talking about the financial advisor. Yeah.  No, no, no. Now, the question is now after football, life after football, what is life after football for Jared Johnson?   Like, would you get into anything in detail? You just like just keep it simple, just do a little fishing and, you know, right. All right, retirement is tough for everybody, especially the longer you play in the NFL, the harder it's going to be when you get out because, you know, when you're in, it's not reality. I mean, you your whole life, the best example or the best analogy I've heard grabbing life in the NFL or retirement in general, is that life in the NFL is like a road.   Retirement is like traveling in an open field, there's nothing but time, opportunity and resources to go any direction you want. But there's nothing in your past that has trained you to know which way to go. I mean, you could it's it's it's really paralyzing your first couple months out. When you realize that I could go work out, but I don't have to go work out, you know, I could, I could, I could start a business, you know, but I know how to run this business. You know, you could you could start a restaurant, you could go get a job, you could get into coaching, you could get into personnel. You can I mean, the resources or the opportunities are endless and you can afford essentially to do anything.  Oh, that sounds good.  You know, let's go this. Let's go. And so it's paralyzing on knowing which way to go. So I stuck with what I know and what I'm passionate about at a radio show when I was in Baltimore, I got into doing radio again. And that's been trying to travel a little bit against staying in contact with the team, watch a little film. You know, it's great. I grew up fishing. Fishing is a passion of mine. So I started the charter company. I don't make a lot of money on it. But the fishing and having a boat is expensive and I get to run enough trips to where all that all my activities are tax deductible. I can write all off under the business. So that became an advantage of mine to basically fund my hobby. And then the other thing is my family. I'm passionate about hanging out with my girls and getting involved in their sports and different things. And basically what I'm saying, when you get out, if you don't have the same passion about something else in life other than football, as if you're not as passionate about that as you were about football, you're going to struggle when you get out of the NFL. It's going to be tough for you. So I kind of figured out what you want to do.  I don't have to go work out and, you know, just kind of. But that's good. So tell us about your radio. So what got you in the radio? I had a show when I was in Baltimore. I had a show for three years on our flagship station for the Ravens WBWDAL 98 Rock. And I had a show there for a while. It was a lot of fun. They wanted to ask me to come back and continue the show. And I've been doing that ever since. And now I've recently moved into the booth with our with the play by play guy on WDAL and I'm the analyst at the booth. So I've been doing that the last four games of the season. So it's it's been good. It's I don't get paid a lot of money, but I get paid a little bit. It's fun to travel.  And the radio has just added another thing in my day that that I get to get up and have something to get out and accomplish. Now, with that being said, what made you what happened to the Ravens this season? Well, it was a pretty lucky season. I mean, they started out, even played pretty good early, had a pretty bad three or four game stretch, got behind and they had a bunch of injuries and stuff. quarterback wasn't playing real good. And then they rally, they got healthy. Quarterback started playing better, got on a worse peak, got back in the hot, was actually blotted in the fifth seat. All that there was one the last game and and they slipped up and Cincinnati really the bangles. Yeah, I know. It's one of the things that you always got to be careful of your division rival. Yeah, because it's always like a playoff game to them. It doesn't matter. They are over 16. It's still that one game that got in them. That's right. Yeah, I got to ask this question. If it's the anything you would like to leave with anybody out there that's listening or is watching this live. What is it something that J. Johnson wanted to take away? Well, I mean, I think the the main thing and being in the financial show, if there's any young guys out there listening, you know, never never forget who you are.   I was living in Queens and you know, it doesn't matter you know, we're 100 bucks or a hundred million dollars. You know, we're all here. Everybody else is saying and just enjoy life. OK, well, you know, I'm going to tell you what I learned from you was to keep it simple, right, stick into what you know, maintain humble and the biggest thing that you said in the beginning, he started a budget and he kept it simple, started a budget, keeping it simple, that's into what he knew, you know, you didn't get into nothing that's super quick. Hey, I'm going to get you rich. I'm about to get rich in the next six months. If you're going to jump on the train with me, just what we knew it felt comfortable with real estate. And he found an advisor that helped him out as well. So that's glad to hear. Now, I say one of the best it's one of the best words of advice a coach told me my rookie year is when we were going home for the off season. He said, I don't care what anybody presents to you. No real estate deal. No marketing plan. Nothing that anybody can present you will make you more money than you can make out there on that green grass on that football field.  Go home, work out, stay in shape, take care of your body and focus on football because that is the greatest investment you'll ever make if you have the opportunity to play in the NFL because everybody wants to go out and make money elsewhere. Don't work out.  You know, keep it simple. Do what you do best. Don't even go out there trying to start a chain of restaurants or whatever else. You know, you stick with what you know. That's true because not too many places can beat the NFL play chat. So. But definitely, Josh, thank you for stopping by. I really appreciate it. Really, if anybody out there wants to talk to you and get in contact with you, what's the way you tell them to reach out to you? If they want to reach out to you, if you want to be reached out to. Yeah, I don't really want to be reached out.  Maybe he might want to be there. Yeah. Yeah. But OK. Yeah, that's pretty much. I mean, I don't really do I do Instagram. I get to check on Instagram, but other than that, I want Twitter. So. Well, Josh, thank you for stopping by. Thank you for dropping the gems. As always, guys, this is the principle of investing. My name is Prince Dyke. Thank you, guys, for tuning in until the next video book podcast, whatever you seem to do crazy around the globe. Peace. Be safe. I'm out and thank you.


Hey guys, welcome back to my channel. My name is Sinali if you guys don't already know me and today I'm gonna be doing a holiday morning routine. I honestly don't even remember the last time I did a morning routine. I'm so excited to share this video with you guys. I think it turned out really awesome and thank you to Ryan for helping me film You Are the Best Bay. It's crazy how fast Christmas came around. I personally don't usually participate in Christmas even though I am Catholic. My parents kind of stopped doing the present thing when we were like in elementary school or middle school or something but this year me and my sister decided to get in the festive spirit and actually do Christmas with presents, cookies, everything like that. Christmas is tomorrow. I'm actually filming this on Christmas Eve. So Merry Christmas and happy holidays to everyone. I hope you guys are enjoying the break off of school slash work as much as I am. So let's get on to the video. Good morning. So on holiday breaks I like to take advantage of sleeping so I sleep pretty late in the day. If I can I'll sleep till 12 but most of the time I wake up at 10 or 11 but when I do need to go somewhere I'll set my alarm and this is pretty much what I look like when I hear that alarm. I never want to get up. So like everyone else the first thing I do is check all my social medias but before that I like to get comfy.  The first thing I check is Twitter and if you guys want to follow me on Twitter it is so underscore gnarly n-a-r-l-y. Then I go on to Instagram and it is the same username. Funny story I really want to handle Sonali and I searched who has it and they only posted one picture in 2010.  Then I make my way over to Snapchat and see what everyone did while I was sleeping and my username for this is Sonali underscore prebu. And the last thing I do is check my emails. I have like a weird obsession of like refreshing my emails every single minute of my life I feel like it's weird. Then it's finally time to put my phone down and get into some cozy slippers. These slippers are from Aripostal and the cheeks light up on these slippers. They're literally so cute. I can't get over them. Then I finally get out of bed and make my way over to my desk. I bring my laptop and my swell bottle and I start editing my vlogmas vlogs. If you guys have not seen my vlogmas vlogs yet there's a whole playlist on my channel so I will link it down below. I was so proud of my vlogmas intro I hope you guys really enjoyed it because I thought it was so creative. Sophie slowly wakes up and she goes to the stair and she says mommy feed me. Okay not exactly like that but that's what I sound like when I'm hangry. So she makes her way down the stairs as fast as her little paws can and I follow right behind her with my snowman slippers. And then I go into my pantry and reach for Sophie's food. I personally am not really a big breakfast girl so I don't eat right away but I do later in the day. Sophie's like what are you doing giving my food? So then I go back upstairs and start getting ready for the day so come on in. The very first thing I do is braid my hair if it's not already braided. I usually like to do a french braid because it's tight and it keeps my hair out of my face. Then I go straight for my toothbrush because my morning breath is something else. Mesapillo los dientes. I took Spanish this semester and it finally came in handy. Next I move on to skincare and it's pretty simple. All I use is my Clarisonic and this deep pore cleanser that came with like my Clarisonic set. I rinsed it off and I didn't show this but I use First Aid Beauty's Ultra Repair Cream. Then I go through my closet and find the comfiest clothes I can. Sometimes I do go to the gym but today I didn't. I just decided to take my dog for a walk. This is what I ended up picking up just like a cute capitol to tank top and some mesh leggings from Forever 21. This sports bra, my Nike Roche Runs, and of course my knockoff swell water bottle. Oh my god I know I'm so cheesy for doing this but I had to. I forgot to put on chapstick so I'm gonna use my mint rosebud salve. Now it's time to take my daughter out for a walk. Oh wait did I say daughter? I meant dog. Then once I get back it is finally time for breakfast. As I said before I'm not a big breakfast girl so this is basically my lunch. My brunch? Yeah. What's a morning routine without making some avocado toast? Am I right ladies? Just kidding. I actually eat avocado toast pretty regularly because it's something easy to make and it tastes really good especially if you put garlic salt on top which I always do. Then I like to sit down and watch TV while I eat my breakfast and today I wanted to watch TV on the deck. My dad has the projector synced up to this really cool app so basically I never have to search for a remote again. I can just use my phone and that's so convenient. I usually put on E-network and watch the Kardashians but unfortunately the Kardashians were not on at this time so I just had to watch the wedding planner. Then after I eat I'll put on makeup if I have plans but if I don't I just skip it for the day. One of my favorite everyday lips is Ashton by Anastasia Beverly Hills. I love this color but I don't really care for the formula as much as I do over cosmetics liquid lipsticks. I'm finally done getting ready so I changed into this Forever 21 Turtle Neck Sweater. The color is one of my favorites for this season and this past fall. Then I usually run errands so I get in my car. The first thing I do is put on my new high key Desi Birkin sunglasses from Key Australia. I am obsessed with these. I got them in the gold color and the black and silver color. Merry Christmas to me and that completes my morning routine. I hope you guys really enjoyed this video. I'm so glad to be back home for a break and in my beautiful room that I can film in and not have to worry about lighting even though daylight savings is really killing my vibe because I literally have no time to film. At least it feels like it but again I hope you guys have an awesome break and if you're traveling safe travels and I will see you guys in my next video. Bye guys!


Honourable Chief Guest, Deputy Minister for Ministry of Environment and Forest, Mr. Abdullal, Islam Jaffa, distinguished guests on the panel, participants at the CBA 10 conference, ladies and gentlemen, I'm reminded of a speaker who was speaking after a long line of other speakers who said, everything I wanted to say has been said, but not by me. So I'm going to repeat it. Don't worry, I'm not going to repeat it. But I will take this opportunity to say a few words on the general issue of adaptation and knowledge sharing on adaptation, which has already been alluded to, and direct some remarks particularly to our Honourable Chief Guest, Minister and Senior Colleague from the Ministry of Environment. And this is the following. In the context of knowledge exchange and learning and technology transfer, particularly in the climate change arena, there's a very big difference and distinction between technology transfer when it comes to mitigation, which is reducing greenhouse gas emissions, which tends to be very largely hardware oriented. It's about solar panels and wind energy. It tends to be north to south, developed countries develop the technology and they transfer it to the south in packages, hard things, they put them in and you learn how to use them. When it comes to adaptation, that paradigm of developed countries knowing more and having to teach developing countries does not hold. As Umar mentioned, the poor are often much more resilient than the rich. And adaptation is about resilience and building on resilience. And so the rich can learn much from the poor on how to be resilient. The other thing about adaptation technology is again, it is not best exported by taking experts to another country, showing them PowerPoint presentations or even videos. One doesn't really learn from that. The best way to learn about something is to go to where it is being done and spend time with the people who are doing it and learn from them. And so there was a big conference on adaptation technologies in Germany at the UNFCC Secretaryate some months ago where a number of developed country and multilateral agencies were telling about their adaptation technology transfer programs, one after the other, the UK, the US, Germany, France, UNDP, and they all have these programs of technology transfer, which are essentially consultancy contracts to consultants to fly into a country and hold a workshop on something. That really isn't building much capacity. And I stood up afterwards and I said, I have a capacity building program that doesn't involve any money at all. It involves you, whoever's interested in learning, buying a ticket and coming to Bangladesh. And when you land at the airport, I will receive you and I will look after you for the next seven days. And you tell me where you want to go and I'll take you to people who are actually doing something on the ground. They're farmers, they're fishers, they're people on the ground. They're never going to go and write a paper that you can read or fly to another country and be a consultant. But they are the ones who know how to do things because they're doing it. They're on the ground and spend a week with them with an interpreter, ask them questions, find out how they did this, how they do that. You need to interact with the people to understand what they've done and how they've done it. And so when it comes to adaptation knowledge exchange and export of knowledge, you don't send the knowledge out. You bring the people who want the knowledge to where it's being developed and it's being developed on the ground in practice. And in Bangladesh right now, there's a huge amount of adaptation practice going on, a huge amount of learning going on in different sectors on flood tolerance, on saline tolerance, on drought tolerance, which we can share with other countries. And this is my proposal to the government of Bangladesh. Already in the scientific community, we have a program called Babashuna. In the NGO community, we have a program called R-CAPS, stands for Action Research on Community Adaptation in Bangladesh, who are already accumulating this knowledge and information and finding out where it's available and offering to host people to come and learn about it. We've documented almost 100 adaptation technologies already taking place in Bangladesh. We are already in discussion with the government of Bangladesh, the Department of Environment, represented here by Shaukat Mirsa, who is the focal point for adaptation in the CTCN, the UNFCC's technology transfer mechanism. And we are offering to the government, and I'm making this offer to both the minister and the senior additional secretary of the ministry, to help the government together in a public private partnership promote Bangladesh's adaptation technology by inviting other people from other countries, whether it's south-south or even north-to-south, who want to learn about different technologies. Let them come here. We will host them. We will arrange for them to go and spend time with people who know what they're doing, and thereby they will learn from Bangladesh, and we will learn from them. From my center side, we are planning to do a trip from a group of people from Myanmar in the next month or so, sponsored by UNEP, by the United Nations Environment Program, where they're bringing us a group of people from Myanmar who have already expressed an interest in learning from Bangladesh. We'll arrange a one week long tour for them to go and see the different aspects of adaptation that are taking place here. So this idea of knowledge exchange, which Barney also mentioned that the global adaptation network is promoting, is something that I think we can think about, discuss during the part of the conference, the rest of the conference, and maybe at the closing session come out with some sort of move forward, hopefully between the government and the non-government sectors here, as something that we can take forward as a concrete program of action coming out of this conference four days from now. With that, let me wish everybody who's here for the conference a good time. I'll tell you my number one criteria for a good conference is, did you have fun? If you didn't have fun, it was a bad conference. So tell me afterwards whether you had fun or not. Thank you all very much.


I'm an investigator and an assistant professor at Cornell University, interested in genomic technology development and its application to understanding evolution. You got a speaker talking. Thank you to the gentleman up there. And I'm very excited to be here to moderate this session with my co-chair, who will introduce himself. Yeah, so I am Claudio Mello. I am at the Oregon Health and Sciences University. I study, actually, many parallels with Eric Jarvis. I also study birds, including finches, parrots, hummingbirds, a lot of comparative work, interested in basic mechanisms of vocal learning, vocal communication. So it's a pleasure to introduce our first speaker, Emma Farley, from University of California, San Diego. So I first became familiar with Emma's work when she was a postdoc with Mike Levine and published a beautiful paper pointing out that a lot of transcription factor binding sites in actual genomes were sub-functionalized and were really hard to define using sort of off-the-shelf position weight matrices. And she's continued her interest in genotype-to-phenotype relationship. She uses a wide variety of models. So Siona, she was telling me she's added zebrafish and mouse to the fold now as well. So I won't take up any more of her time. So let's thank her for being here today. Thank you very much for the introduction and for inviting me to give my perspective on genomics and comparative evolution. Can everybody hear me? OK, excellent. So I'm really interested in how the precise patterns of gene expression required for successful development are encoded in our genomes. So how do we have this beautiful neural expression pattern seen here? And we've heard that it's enhancers that control when and where genes are expressed. And we've also heard earlier today about using epigenomic approaches to annotate regions of the genomes to find enhancers. But that doesn't tell us whether or not the sequence is actually functional, let alone what sequence within that region actually drives expression. And this is really important because small changes in enhancer sequence can have really dramatic effect. And so here you can see the developing limb bud. And so sonic hedgehog is expressed in this purple domain. And this ensures that we get five digits on our hands and our feet. And a single base pair change, an A to C out of 850 base pairs, leads to an expansion of this pattern and polydactyly. And sequence changes within enhancers can also be really beneficial. And it would help us to understand them all, all of the ones hidden in our genomes. So for example, here is a red blood cell and there's an enhancer that turns on a membrane protein in our red blood cells. And this membrane protein is how the malarial pathogen gets into our system. And so we are malarial susceptible. And a base pair change within this enhancer makes the enhancer no longer functional. You don't express the membrane protein. And people with this variant are resistant to malaria. And so we know that 90% of variation associated with disease and phenotypic variation is in the non-coding genome, mainly within enhancers. But we have no way of knowing which variants are simply a net variation between individuals and which ones actually have a functional consequence. And we have all these genome sequenced, which is really exciting. But I feel like there's a frustration because we can't get all of the information out of that to help us understand evolutionary adaptation and disease. And so I wanted to take a different approach, a synthetic biology approach, to understand how sequence encodes function and see if we could get to some rules that could help us understand this in a general way. And so here you can see we've zoomed in on an enhancer and we know enhancers contain binding sites. So in blue, there's a binding site and then a different type of site in orange. And this enhancer binds ETS transcription factor to the blue sites. And garter, which is expressed in the ectoderm, the skin and the nervous system, binds to the orange sites. And this leads to the turning on of gene expression in the overlapping pattern shown in green. And this turns on the gene OTX, which is important for neural development. Here's a later embryo just because it's easier to see the head and the tail. But clusters of ETS and garter binding sites are found throughout the genome. Some of them don't turn on at all. Some of them activate expression in the heart. Some of them during blood development. Some of them in the gut. So why is it that this sequence is turning on specifically in the nervous system? What changes are gonna lead to a functional consequence, a change in gene expression and a phenotype? And so to look at this, what I wanted to do was keep the core of the binding sites constant, so GGAA for X and GATA for garter, and randomize the rest of the sequence. Now we hit a problem here. This is a very small enhancer. It's 69 base pairs. If we were to make every possible sequence variant, it would be 10 to the 30 variants. And so when I saw this number, it made me think we need to test millions, if not billions of variants for function. And once you find the functional features of the enhancer, perhaps there are only five binding sites that's all you require. How many ways can you arrange these binding sites and get the same expression? So if we change the spacing, the order, the orientation. And again, this is a combinatorial problem and it quickly goes exponential and we're talking about billions of variants. Obviously, so what I wanted to do was make as many variants as possible and test them for function. And because enhancers drive tissue-specific gene expression, it's not enough to test these in a single cell line. We need to test them in every single cell of a developing embryo. And so for this, we need a special model organism. And I think that SIONA is ideally placed to do this. So although the adult doesn't look anything like us, here's an adult SIONA. It's a member of the Eurocordates, the sister group to the vertebrates. And it has a notochord, cell-shown in red, a dorsal nerve cord, and even a heart, the cell-shown in green. And the transcriptional program specifying these tissues and the transcription factor specificity is conserved between the Eurocordates and the vertebrates. But beyond this, they're an ideal model organism for this particular question because of the power of electroporation. So we can electroporate a reporter construct with the enhancer, a promoter, and GFP into hundreds of thousands of synchronously developing embryos, and then we can read out expression. So in an hour-long experiment, we can electroporate millions of embryos. This is less than 1% of an electroporation. And so my approach has been to make enhancer variants to look at sequence constraints and enhancer variants to look at grammatical constraints to see how changes in these affect gene expression in whole developing embryos. And so I'm going to talk you through the first experiment I did on this because it really led me to a focus on enhancer grammar. So Charles alluded to this. So in the first experiment, I was able to make 2.5 million different enhancer variants with randomized sequence outside the core. Each enhancer is attached to a promoter, GFP, and a barcode. So if enhancer A is active, we will see barcode A as mRNA. So we can electroporate these into fertilized eggs, wait till the normal time the enhancer is active, and then extract all of the mRNA and specifically sequence the barcodes. And because we know which enhancer goes with which barcode, we can identify the functional enhancers. And so in the first screen, we found 20,000 enhancers that were active at or above the levels of the endogenous enhancer. I should say now we are making tens and hundreds of millions of variants. But we wanted to know what was it that it was important for the expression of those 20,000? And when we did analysis, we came up with this really simple answer which for me was kind of confusing. So anybody who maybe studies transcription factor binding might recognize these motifs. So I told you I kept the core of the binding site constant, this G-G-A-A and G-A-T-A. And it seems that particular dinucleotides flanking the core are important for expression. But if you look at these, these are PWMs for ets and garter. And so the most represented base at each position gives you the sequence that binds the transcription factor with highest affinity. But if all you need is high affinity binding sites to mediate expression, we should be able to just put our favorite high affinity binding sites together and design tissue-specific enhancers. And that doesn't work, as I'm sure many of you know. And so I wanted to look at the biology. So we went back to the wild type enhancer and we scored the affinity of the binding sites within this enhancer. So highest affinity being one. And we see that we have two relatively high affinity binding sites, but then we have these low affinity binding sites. So we wanted to test the hypothesis that all you need is the flanking to make high affinity to mediate expression. So we took inert enhancer variants from our library that drove no expression. And we asked, could we make this into a functional enhancer simply by manipulating the motif, the flanking? And so if we make these high affinity binding sites by making just a few nucleotide changes, we do turn in inert piece of DNA into something that drives transcription, but we've lost tissue specificity. Yes, we have neural expression, but we also have posterior brain, which we shouldn't have notochord and endoderm. And so we wondered, maybe you need these low affinity, suboptimal affinity binding sites in order to mediate restricted expression. And so to test this, we took the inert enhancer and simply by changing nucleotides to mirror the wild type affinity. We saw that this recapitulated the endogenous levels and location of expression. And we did this on many inert backgrounds which were chosen at random. And I should say that many people have seen this in the past, but as a genomics community, we seem to get into a habit of matching things to PWMs and away from the original studies of the SV40 enhancer and even the lack operon. But having shown in this high throughput way, the sequence is required for expression. We were able to look further and see how the organization of the binding sites impacts function. And so here you can see the wild type affinity binding sites and the spacing, so 10, 15, and 13. And we wanted to do changing, is the spacing between the binding sites important for expression? And so if we insert three base pairs here, regardless of the three base pairs, this leads to a three-fold increase in the levels of expression, suggesting that spacing affects levels of expression. And if we delete three base pairs here so that we have 10 and 10, we see a dramatic reduction in the levels of expression. And so this is interesting because the wild type enhancer, along with having these suboptimal affinity, low affinity binding sites, also has a spacing which does not give the highest levels of transcription. So it's suboptimal for transcriptional output. So enhancers integrate information about the binding affinity and organizations. What happens if we completely optimize the features of this enhancer? So we have the high affinity binding sites and we make this spacing 13. And we were surprised to see that we've completely lost tissue specificity. We have this really strong expression in the notochord, the posterior brain and the endoderm. And so these are regions of FGF and X signaling and we've lost combinatorial control. And so when I saw this, well, first I was really scared because I would love one day to be able to look at a genome and find all the enhancers involved, say, in notochord development and try and pinpoint, like all of us, mutations that would lead to phenotypic variation.  There's only one way to be organized in the way that gives strongest expression. But there are many, many, many ways to be a low affinity binding site and you're combining this across many binding sites so it makes the enhancer code very degenerate. And so I think that this idea of suboptimization has really made it hard to find the features within enhancers that drive expression. And it's for this reason that I became very interested in enhancer grammar because I wanted to see if this is such a complex problem, is there a way for us to make it less complex? Are there any interdependencies that we could use to make the problem less complicated? And there was one thing I noticed that maybe some of you might have noticed. So the higher affinity binding sites had the worst spacing and the poor affinity binding sites had the spacing that gave higher levels of expression. So good spacing, poor affinity, poor spacing, good affinity. So I wondered if there was a balance or an interplay between affinity and organization and if we could get that dependency, we would be constraining or reducing the degrees of freedom on this problem. And so I went about investigating this. I randomly selected one of the enhancers from the synthetic library that I showed you. And this one drove very strong notochord expression. And I demonstrated that this notochord expression was driven by this six site shown in red and a low affinity ets and a high affinity ets. And so having found how this sequence encoded notochord expression, I wanted to see how changes in the spacing affect expression. And again, we see that spacing affects levels of expression. But if there's an interplay between affinity and organization, here we have poor affinity and what seems to be a good spacing. And here we've now got poor spacing, poor affinity. If there's an interplay between affinity and organization, we should be able to recover this expression by improving the affinity of this site. Such that now we have poor spacing but good affinity where here we had good spacing and poor affinity. And indeed, this does recover the levels of notochord expression. And so it seems that there is this interplay and I wanted to see if other aspects of binding site organization impact function. And so here is the wild type OTXA enhancer on which we've added the ZIC and the extra ets. So we have the endogenous neural and then we have this notochord expression. These two sites are pointing towards each other. Is that important? We don't know. We change the direction and we lose expression suggesting that orientation of sites is important. And so a defined enhancer grammar, specifically as the interplay between affinity and the syntax meaning order orientation and spacing. And I wanted to know, could we use these rules to find notochord specific enhancers in the genome without looking at anything other than sequence? So I haven't shown you all of the high throughput studies we did but we found that we needed two ets and a ZIC. We found a range of affinities. We knew that 11 base per spacing was really optimal and that directionality was important. And so we wanted to search the genome and use these parameters for find enhancers. And we were particularly interested in ones you couldn't find in the genome from previous approaches. So how far could organization compensate for affinity? If we had really good organization, how low affinity is a functional site? And I'm just gonna show you the most extreme example. So we found this region upstream of the Brackery promoter. Brackery is a key gene in notochord development. And this has the 11 base per spacing. They're both pointing towards each other but the affinity is 14% and 25% relative to the consensus. So really low affinity binding sites. I never in my wildest dreams thought that this would work and I was shocked to see that this drives really strong notochord expression. And indeed we've found 130 regions that conform to this grammar within the Siona genome. And I also mentioned that ZIC and ets are expressed in vertebrate notochords including mouse and human. And we've used the grammar to search in there and have found the hundreds that conform to this as well. So we're now testing these to see how good our rules are and how we can improve them. But beyond that this demonstrates that we can use regulatory principles as an orthologous method to comparative genomics to identify enhancers in the genome from sequence alone. And that potentially there's an entire class of enhancers that have poor affinity but good organization in our genomes that we haven't really studied. And so in my lab we're studying enhancer grammar and I'm wondering how many types of enhancer grammar are there and what classes exist. Are there ones for different types of biological processes? Is it transcription factor dependent? And I want to tell you about some unpublished work on this enhancer shown here. So here we have two U-sites and R and an X. These bind suppressor of hairless, HES and we don't know what binds to this one. And this is a really surprising enhancer. So here is the sequence conservation of this enhancer. It's about an 800 to 1,000 base pair piece of DNA. And you can see that the only things that are conserved are the binding sites. And the sequence between the binding sites is not conserved at all. And you may be thinking, great, but how many organisms are you looking across? And so this sequence conservation is all of these organisms. So it goes across the bilaterians from the rough periwinkle and the invasive snail in the gastropods to human and zebrafish in the vertebrates. And so we were really shocked to find this and we wouldn't have found this by looking at sequence alignment, more we found it by looking at rules. And so we wanted to know, is this, I should say as well, the binding site affinity for these is really highly conserved between the organisms. So it's around 0.9 and this is 0.8 to 0.9 and this one is slightly lower. And the spacings are really highly conserved. So this is always 16. This is a range here and this is between 30 and 50. So it's a really unusual and I think a novel type of conserved enhancer. It's not a whole block. And so we wanted to know, are these actually functional enhancers? So we took the Siona enhancer and we tested it in Siona. And you see the neural expression.  And then we took the most extreme which is the invasive apple snail. So this is a proteostome, a gastropod. And we tested this enhancer in Siona. And we were shocked to see that this also drives expression in the posterior brain, the anterior brain, the dorsal nerve cord and the muscle. Are these sites what are important though? Maybe it's something else about the sequence. So when we delete these binding sites, we see a dramatic reduction in the expression and we see the same with the apple snail. And I haven't got time to show you. So I showed you Siona and the invasive snail. But actually we've tested the enhancers from all of these species in Siona and they all drive expression in the nervous system which is where we expect expression because it drives a neural gene. And we're currently now testing these enhancers in sea urchin and zebrafish and doing genome editing experiments in mouse and Siona to really understand this in more detail. But I think this opens a question of why does this enhancer need such a rigid grammar while other enhancers are encoded in a much more flexible manner? And what I'm trying to get across to you in this presentation is really this idea that you can use regulatory principles, synthetic biology in model organisms to gain a lot of insight into gene regulation, hopefully. And so what I mean by regulatory principles was this idea of suboptimization within developmental enhancers, especially those regulated by pleotrophic factors. But this means that enhancers are incredibly degenerate, hard to understand. However, all is not lost because we were able to find grammatical constraints and this interplay between affinity and organization to predict tissue-specific enhancers from sequence alone and that this was really a very flexible grammar. And now what we're looking at is this very rigid grammar that we are shocked to see as conserved across bilateria, well, it's conserved in both proteostomes and deuterostomes and we're investigating the biological basis and need for such strong selective pressure. And so I think that these principles can help us identify variants associated with disease and phenotypes. So here's the limb enhancer and much like the other enhancers I showed you, the binding affinities for the transcription factor X here are very low and these are the validated important functional sites. And I told you an A to C mutation led to polydactyly and an expansion here but we didn't know why. And I think if enhancers use low affinity binding sites then mutations or variants that increase the affinity could be gain of function dominant mutations and that these could be underlying a lot of regulatory changes in phenotype. And indeed this change, this A to C leads to a tripling of the affinity of this binding site and we're currently studying this in mouse to see if it's the affinity change rather than the sequence change per se that's driving the phenotype. We should find out next month, so that's exciting. And so my vision for like the next 10 years, I guess I don't know how many of you know Strunk and White. I found it very helpful. If you don't know, I would recommend it. It's a book about the English grammar and how to write well. And I would love for us to have an atlas of grammatical rules that help us understand how the genome and how enhancers encode tissue-specific gene expression. And I think this could help us identify tissue-specific enhancers in the genome like the notochord, but I also think mistakes or errors in the grammar that we find within the genome could help us get away from what we have now which is these pool of variants associated with a phenotype or disease and try and pinpoint the causal variant that's driving a phenotype. And so in order to get there, I think we need functional approaches. And when I say functional, how sequence impacts expression and phenotype using massively parallel reporter assays, genome editing assays. And I really think that we should take advantage of synthetic biology and the massive diversity it can give us to combine with comparative genomics and that this requires improvement in oligosynthesis so that we can synthesize 1KB regions and test potentially all the attack-seek regions predicted to be enhancers and see which ones are and which aren't. And then phenotyping at scale, obviously we have single cell technologies which help us look at RNA changes. But I think we need spatial omics on a really grand scale with integrating sequencing, automated microscopy, proteomics, and then a wealth of computational tools to take advantage of this. And so with that, I would like to thank, I was a postdoc in Mike Levine's lab, so I'd like to thank him and all the people involved in the first part of the talks project. And this is my lab and I'd like to thank NHGRI and the director's office for funding and thank you very much for your attention.


Live from Las Vegas, it's theCUBE, covering Knowledge 16, brought to you by ServiceNow. Here are your hosts, Dave Vellante and Jeff Frick. Welcome back to Knowledge 16 everybody. This is theCUBE, we go wall to wall coverage, we go out to the events, we extract the signal from the noise, this is day one for us, we'll be going three days of knowledge extraction from Knowledge 16. Ray Wong is here, he's the founder and principal analyst and chairman of Constellation Research, up and coming, smoking hot research company, Ray, always a pleasure to see you, thanks for coming on. Hey, excited to be here, man, it's been a world-win week of events, so. I'll say, so you were down at Sapphire, right? You were over at Tampa at Amplify, and. I'm off the N suite after this, I mean, this is crazy. Normal week for you, right? It's a normal week for all of us, I mean. So you were telling us off camera that you were at one of the earlier knowledge events down in San Diego, so you got a lot of experience with this company. You know, it was in a tent, it was outside, they had decked it out, I think it was like a park, I'm not even sure what it was, I just, but I remember there was once it was 150 people, next it was like 500 people, three years later, it was pretty wild. So they've come out of the blue, and really escalated a lot of momentum, the latest billion dollar software company with a plan to get to four billion, so stepping back a second, just looking at the software landscape, one has to be impressed with the progress that ServiceNow has made, what's your take on the industry and ServiceNow in particular? Well, I think what people don't understand is ServiceNow is a platform, right? There's a business model platform, or the way that we used to look at PEGA, or the way we used to look at a lot of those companies that were actually sitting in the middle of that orchestration. What's changed is because everything's in the cloud, what we now have the ability to do is abstract, orchestrate and do it in a way that we've never seen before, right? So you can take specific business problems, take the heart of what's actually happening on the idol piece, use it to not just manage the process, but also do the analytics and the monitoring. So when we get to things like IoT, IoT is really about having a set of smart services and being able to put that in a construct is a lot of the opportunity that we see going forward. So I said three years ago in theCUBE that after I saw the platform capabilities, I said, wow, this is a collision course with Salesforce. Investors Business Daily wrote an article today, a collision course with Salesforce, so I'm glad they caught up. They did the research, they did the research. But, I mean, you can kind of see it coming together. Now, Frank lays out this vision this morning of you got the ERP estate, the CRM estate, and IoT or service management rather, kind of bridging those two. How do you see it? No, we definitely see this as a platform play. Now, here's what's interesting is that lots of the developments, and you see this all the time, it's been happening in the app dev side of the house. Package apps have kind of been at a standstill for innovation compared to what's going on on the custom side. And so every so often we see that flip on platforms. This is the beginning of that flip. Yeah, more than one person said IoT is going to be the end of the app era, right? Because we're going to put all the intelligence into the interaction, you won't have to go to the specific app. No, and the fact is what becomes important is the ability to orchestration, the intelligence, the recommendation. And what you want to be able to get to is the part where I'm making the right set of recommendations to augment the next set of processes. That's what gets really powerful. And these platforms that are emerging on what's in the next set of clouds, that's going to be where we're going to see a lot of this advancement. So the API essentially becomes the product? Is that kind of? It's the orchestration of the APIs, the way the context is delivered against those APIs. And more importantly, how we actually pull together those journeys. Like a couple of things that we talk about all the time, mass personalization and scale, you need lots of context, right? So roles, relationship, identity, weather, location, time, all important, then choose your own adventure journeys, the ability to actually abstract different processes from different places and bring them together. And then more importantly, what we call intention-driven design, which is I'm going to give you three or four choices, learn over time, take that machine learning and then apply that to next set of recommendations and then start building against that. And that power sits in the network, that power sits in these new platforms. So you're here speaking to the service now, customers about customer experience, right? It's something we hear a lot about, you're an expert in that space. What did you say? What was the reaction? What was the feedback? Well, I think the important thing is we're seeing new business models. I mean, you've heard me say this before. It's we're in a post-sale, on-demand attention economy. And what that means is everything after the sale is what's happening right now. That's the service, that's the experience piece. The on-demand pieces, we're accessing smaller and smaller slices maybe not even a product, a service, maybe not even a service, an insight, maybe not even an insight, an experience. And then more importantly, it's an attention economy. If you're not capturing my time and attention, which is mind share, or if you're not saving me time and money, I don't care. And that's what we're in. We're in these business models that are built around this. Is it interesting, came out of the Oracle Marketing Cloud shows, well, same thing, just smaller and smaller slices of attention based on the way you interact with all the other applications you have. You don't have time to give somebody the big story. You've got to get them when you can. They could be standing in line, they look at their phone, they're in the middle of their kids switching in into the baseball game and you've got to get in that little tiny window. That in-between time is so important because if you don't close there, you lose them, right? And it's not for something really big, it's to move them along the needle down the journey. Correct. What do you make of this, Dave Wright was just talking about the new state of work. IBM has been talking about a new way to work in he is kind of running the collaboration group now. You talk about millennials and how they work. What are you seeing in state of work? Well, a lot of the research we're looking on the future of work is by one of my colleagues, Alan Lepofsky. And what he's been really looking at is this shift in terms of conversations as a service. He's been looking at the shift in terms of intelligent collaboration, right? And all this stuff is actually leading to the point where we're actually using technology to augment our ability to do decisions, handle a lot more automation than we had in before, but then cognitive assistance pop up, right? And they help make us smarter and they learn from our different interactions and all that's starting to come into the workplace which is exciting and a little bit creepy and scary at the same time. So what's new with Constellation?  Give us the update on Constellation. You know, I think the big thing is this digital transformation story we've been talking about for the last five to six years is huge. The next set is really not about transformation. It's about finding growth in times where there is no growth. That's where we're going to talk about the next five years at our conference, really talking about what are those factors, right? We've got to jumpstart growth. Global GDP is growing two to 3% at best. Every company has a target of like five to 10. Someone's going to lose and it's going to be very interesting. So you think that growth is going to come through productivity improvements or investments in technology that actually drive sort of new productivity levels? Or taking it away from someone else? I think we're taking it away from someone else. That's what I'm really scared about that. There's smart growth that's sustainable and it helps people with the jobs and the job transitions. And there's what we've been doing which is a lot of destructive growth which is actually limiting a lot of the jobs and actually making it harder to grow in the long run. Well, so yeah, we've talked about this in theCUBE a lot and machines replacing humans which they've always replaced humans but it seems to be now happening at the cognitive level. And that's scary. I know you guys do valleywags. VCs are a little nervous right now. You guys, are you more sanguine than the VCs? Well, we have these three big areas where we see a lot of investment. Deep learning happens to be one of them, right? We see a lot of medicine going on. Some of the smartest people I know are all focused in on deep learning. Very interesting thing. If you look at that University of California Irvine, there's a whole department around this artificial intelligence that just lifted itself up and became a private corporation, right? So there's very interesting things there. There's nanotech, which is also some very interesting things on the material science piece that's also playing a big role. And then of course there's stem cells on the biotech piece. Those three things are converging and it's more than just building out the Star Trek roadmap that Apple's been doing. It's a lot bigger than that. There's some big societal shifts that are happening. What's next for you? You say you're heading to NetSuite. Where can we find Ray Wong? I'm off to Sweet World next. There's a monotate next week. There's a whole bunch of other events picking up in June as well as you're going to be at them. But I think we do our retreat every year. At the end of the year, May, June, we're going to be at Stanford, the faculty club, all the constellation folks get together. And then we go back out into the field and it's a crazy summer as well. I mean, I don't even know when this stops. It doesn't, it's professional. You can always find them on Twitter though, that's for sure. But I look for you guys. Where you're at is where the events are. Well, hopefully our paths will continue to cross. We love having you on theCUBE. Always a great guest. Really appreciate your time. Thanks for coming on. Yeah, thanks for having me. Have a great conference. Safe travels. Keep right there, everybody. We'll be back after this short break. This is theCUBE, we're live from Knowledge 16. Right back.