Hey guys, what is up? Welcome to my channel for today's video. One of my most highly requested literally for the last year. I'm going to be ranking all of my Pat McGrath palettes from my least to my most favorite. So if you want to see what comes out on top, then just keep watching. Hi guys, if you're new here, my name is Morgan. I am a product knowledge enthusiast. I just love knowing anything and everything about all of the new makeup on the market and sharing my thoughts with you guys. One of my most asked questions is always about Pat McGrath palettes. So a couple of years ago, I came out with a ranking of my Pat McGrath palettes. A lot of palettes have come out since then, obviously. So I am doing my updated rankings. I don't know if the Pat McGrath sale is going to still currently be going. I'm filming this on Friday, Black Friday. So hopefully it's still here the day that I upload it. If not, I'm very, very sorry. I hope that this is still a helpful resource for you. I did change up my location. I'm in the middle of creating a glam room. My moved rooms in the house and I have a room dedicated to my makeup. And I'll have a video for that soon, probably in the next couple of weeks as I do the finishing touches. Anywho, I decided to only talk about my palettes that are still available to purchase for you guys. You guys always tell me you use this video as a resource to help you pick out which palette you should purchase. So I wanted to make sure I was only sharing with you palettes that you can get your hands on. I currently have a total of 16 of Pat McGrath palettes that are on sale right now. Let's get into it. We'll start off with number 16. And unfortunately, this is from one of the newest holiday collections. This is the Celestial Divinity Luxe Squad in Fluor Fantasy. Now, if you're new to my channel, Pat McGrath is my favorite brand when it comes to eyeshadow palettes. So really none of her palettes I'm going to share with you today are bad. This is the only one I would say that I really am kind of disappointed in. For me, it's just not a color story that I find myself wanting to gravitate towards. I find it to be just very light, kind of lacking depth. I think this will be really gorgeous in the springtime. But for it coming out over the holiday season, this is not a palette I want to grab for at all. It's really, really light on the eyes. I don't think it's going to work very well on deeper complexions. And even on me, I just wanted more from it. When I think of Pat McGrath, I don't want to do a natural look. And I feel like you get a really soft finish to the eye with this. And it's just not what I want when I reach for Pat McGrath. Do I think it's a bad palette? No. I think it is a very nice palette still. It's just not what I'm looking for when it comes to a Pat McGrath palette. So that's why it is currently my least favorite. Moving on to number 15. This came out in the holiday collection last year. It is still available on the website. This is the Blitz Astral Quad in Iconic Illumination. And this is so stunning. From this point on, I really, really enjoy the palettes that I'm sharing with you guys. Really gorgeous neutral tones. I love the Blitz Astral quads that came out last year more than the quads that came out this year because I just like this formula a lot better. I just don't find myself reaching for this a ton because, again, those neutral tones. When I want a color look, I'm going for the colorful palettes. When it comes to Pat McGrath, I love the quality in here. This is an amazing deep chocolate brown. They have an amazing special formula here. All around a really great quad. And if you're into neutral tones in a great Pat McGrath formula, I do highly recommend this one. Moving on to number 14. We have a quad again from the holiday collection this year. This is the Risqué Rose. I love the packaging. And I actually really, really did like this one. I found that it just wasn't one that I wanted to reach for. The only color that I'm really amazed by is lavendering right here. I think it's one of Pat's best. I just love it. It's so unique. But the other colors in here, I feel like aren't quite so unique. I feel like I have these colors in a billion other palettes. So I don't feel the need to reach for this quad a lot, except for lavendering. I would reach for this quad for lavendering alone. But everything else about this quad, quality is great. But I'm just not necessarily impressed by the color story. Moving on to number 13. We have a mothership palette. I guess she hasn't really come out with too many mothership palettes. This is the only one I believe that she currently even has on her website because she's come out with a lot of these. But this is the Rose Decadence. It's really a gorgeous palette. I don't think the quality in here is the greatest. These shadows felt a lot more dry to me compared to the others. I love the color story here. I think it's stunning. But Pat, you'll see as this video goes on, she has a lot of different rose palettes and I prefer those. So that's why this is kind of on the lower end. You know, if this was the only Pat McGrath palette that had come out, she didn't have all the other stuff. I would say this is a really gorgeous palette. But just compared to what she's come out with, it's not that great. Honestly, I'm very surprised. I still think it's wonderful quality. I love the color story. It's just not unique in her line. And I just feel like you should grab for other palettes. But it is a great way to get rose colors in this formula in a smaller palette. So I still do like this one. Moving on to number 12. We have the Decadence palette. This is an order palette from her for a while. This was nearly impossible to get a hold of. This has a very interesting story. This was on sale when it first launched for a very long time. I honestly believe it couldn't sell it. And then as soon as it sold out, people were like, well, I want to buy that now. It was in stock, out of stock, restocked for the longest time. And as far as I can tell, it is currently still available, which is awesome. This isn't my favorite mothership palette because it doesn't have her special glittery shades. All of her big 10 pan mothership palettes has a glitter formula except for this one. So I think the formulas in here are extremely creamy. These aren't necessarily colors that I reach for a lot. I just think it's a bit too deep and grungy, smoky for what I typically wear or the looks that I typically go for. The quality is really great. It's a very interesting mix of colors. I do find it to be very, very unique. She's not my favorite. She's got other good ones in my opinion, but it's still stunning if you love the color story. Moving on to number 11. I think this one is probably going to shock you guys. It's just not one that I reach for a lot, but it is one of the ones that I recommend to you guys the most. So that's why it might shock you. This is just the original Divine Rose. Now I got mine in special limited edition packaging. That is why mine is in this gorgeous pink packaging. But I really love this. If you are into neutrals, you're going to love this palette. So if you don't wear a lot of colors, you don't really like to step out of your comfort zone or maybe, you know, you're just looking for a good work palette. But you want to take Pat McGrath into your collection. This is the one that I recommend you going for. It has very mobby neutral rose tones in here. Very, very wearable. Probably one of her most wearable palettes in the line, which is why I highly recommend it. I think the formulas in here are very nice. Just again, for me, like I said, I like going a little bit crazy when I'm going for Pat McGrath. So for me, this one isn't my favorite, but you know, the quality is really great. And I think the color story is very versatile for a lot of people. So I highly recommend that if you love neutrals. Moving on to number 10. This is from her very, very first launch when she launched her original re-mothership palette. So this is called the Sublime palette. And I just don't find myself reaching for this palette a lot. So you'll see as we get into these big motherships, we have four glitters here. That's just what the decadence didn't have. And I really like this one. I think the color story is beautiful. But when I looked at all the other color stories I had from her, I just liked them better. Nothing against this palette. I think it's really great. When you cover these four shades, you'll see how wearable this palette is. I don't know. I just think she has a prettier color stories. Moving on to number nine. We have a Blitz Astral Quad. Again, another one of those great launches from last year where you get four beautiful formulas from Pat McGrath to Ritualistic Rose. Oh my gosh. This is so stunning. I do love pinky tones. It has a gorgeous gold tone, two different tones of pinks. This one is really gorgeous, very, very glittery. And then you have a brown. I love this. I used this for a while every day last year. And it is so stunning. I highly recommend you pick this up before they no longer sell it. Just because I think it's a great everyday palette, but you get that Pat McGrath look on your eyes. You're super glittery, very easy to apply. Just a look. I feel like you cannot replicate with another formula. Moving on to number eight. This is one from this year's Holiday Collection. This is my favorite of the quads. This is Interstellar Icon. I just find myself wanting to reach for this. It's a little bit more deep and grungy than what I'm used to reaching for, but genuinely, it's so good and it's so pretty on the eyes. I feel like every time I wear this palette, I am feeling myself. Of course, I'm definitely going for a more crazy look when I dig for this palette, but I am telling you all, it is so stunning. 10 out of 10 recommend. Moving on to number seven. This is going to be my last quads and I know a lot of the mother ships, 10 pans, I haven't spoken of that because they're so amazing. They're at the top, but this is the... What's this one called exactly? This is the Nocturnal Nirvana that came out last year. This one is so, so special. I mean, it's a very interesting mix of colors, but I just love popping one of these lid shades on all over my lids after I've done my crease colors. You can actually create a really cool look if you just use these four shades. I honestly remember creating one of my favorite looks I've ever done using just all four shades in this palette. I think it's such an interesting mix of colors. They're not alike, but they blend in so well together. If you think of color theory, yellow to green to blue to purple, it really does have a cohesive flow to it. While still being four very, very different colors. Love the formula here. I just think, again, before this sells out, this is such a fun one to own from Pat. All right, let's move on to number six. We have the Midnight Sun Palette. It comes in this gorgeous purple packaging. And let's take a look on the inside. So I have two shades in here that are going to fall out. These two right here, but this is an interesting color story. This is actually the palette that I chose to wear today because I don't reach for this one a lot and I don't know why I just don't. So I did a pretty neutral look as far as Pat McGrath goes. And this guy is the star of the show. This is really what is giving me that stunning bronze copper glow to the eyelid. This palette I think is wonderful for deeper complexions. You have a lot of really great warm neutrals here on this side. You have a great olive tone here, a great shimmer, glitter color, a light gold. And you have a fun pop of purple as well. I don't think this purple is the greatest quality. When it comes to Pat, I feel like she has such smooth pigmented formula. This one feels a little bit dry and it doesn't quite give me the oomph that I want. But I think it's just a really great easy palette to go for. If you're into those deeper, warm, smoky eyes, I really think you're going to love this. This is a really fabulous palette for the fall and winter time because of the tones in here. So I think it's really great. It's just not the one that I reach for the most. Moving on to number five, the palette that I was completely shocked by. And I've talked about it so many times recently on my channel. This is the Celestial Divinity Palette. A palette like Pat has never done before as far as the format goes. You get 18 shades in here. Not her special glittery shades, but I feel like the value of this was really great. It was under $100 for 18 shades. And if you compare that to some of the other values that she has to offer, this one truly is the best. And I really feel like she didn't skimp on quality here with the exception of not having her glitter shades. She had every other formula in here extremely creamy. I've loved every single look I've created with this palette. This palette really does inspire me as far as the color stories go. I don't know. It's like currently a palette that I have to put away in my makeup collection. So I stopped grabbing for it. So that's when I know it truly is a favorite of mine. Let's move on to number four. And I'm very, very surprised at how high this ended up ranking. But again, it was a palette that I found myself constantly reaching for. And this is the Divine Rose II. Now, since I wasn't in love with the first Divine Rose, I wasn't very excited for this palette just because I was just like another rose palette. But I love this guy. Again, I have limited edition packaging, but this color story to me is insane. I think the quality is impeccable. I really was surprised at how often I reached for it. I love actually using the shade as a blush and the shade as a highlighter. They look stunning on the cheeks and the rest of the shades, ugh, they're scrumptious. If you like pinky rose colors, you're really going to enjoy this one a lot. Like I said, I was not excited about it. And it's one of my favorites. Now, if you're more of a neutral wearer, no, no, no, no. You will not like this. Make sure you go for the original Divine Rose palette. But if you like a little bit of color, we have a multi-chrome in this palette. This one is awesome. One of my favorites. Let's go on to number three. And this palette I think is very underloved. It does not get the attention that it deserves from people. So this palette is one of my favorites. It is the Subliminal palette. This is from her original launch and it looks so boring, but I promise you on the eyes, it is incredible. Now, I think the reason why I love it so much and I've always loved it is because it clearly is a very cool tone palette. I love this before I knew I've loved cool tones and the reason I kept reaching for this palette was because it was those cool tones that I love. I feel like you pop any of these shades in the crease and then you pop any of these shades on the lid and you're going to be in love with the look that you create. It's a great work palette if you're into more neutral tones and then you also have these really fun nighttime pops. So Office is top six and then at the end of the night just pop one of these and you're good to go truly incredible. They layer beautifully over these shades, particularly the black. I find these three shades look stunning over this black shade. So if you're looking for a really unique smoky eye, this palette is amazing. Over to number two. This was my favorite palette last year. This was my number one. So I know I know you guys can't believe it's been demoted. So this is the bronze seduction palette and this is the number one palette that I recommend to anybody wanting a top of graph palette. That was what I said in my last video two years ago and I still stand by that. I love this palette. I love the color serene here. It is absolutely incredible gray warm tone neutrals here for every day and then you also have a really cool glittery pink and just everything about this palette. I feel like it has every single tone that I love and the glitters in here I think are very, very special. They look so unique on the eyelid. I love that there's a plum in here. You get some browns as well. I just feel very comfortable with this palette. If there's a look that I'm not sure what I want to create but I want it to be a pat palette. Normally this is the guy that I dig into. So as far as an everyday palette for me, this is the one that I would go to for Pat McGrath. It's not a wearable palette. It can certainly be made wearable but if you love makeup, you love experimenting with makeup but maybe you're not into a rainbow eye. I think this one is great for everybody. Definitely my number one recommendation if you are looking to dive into Pat McGrath for the first time as well. And let's move on to number one and I know you guys are probably shocked but yeah, this did not rank at number one. Two years ago when I also still have this palette but for some reason in the last year I have felt continually inspired by this palette. There's so many looks that I still want to create with this palette and I think the more that I've gotten into this YouTube world and experimenting with makeup and seeing what I can create for you guys the more this palette has come in handy for me. So it's not my number one recommendation for everybody but to me this is such a unique palette and it inspires me to create different looks and that's what I tend to look for the most in a lot of palettes. This is the Mothership 3 subversive palette. I just love the color story of this. I think it is a daring color story while still not being too intimidating. You have greens, purples, golds. You have a sheer highlight color. You have a glittery black, a shimmery plum. Then you have some great basic neutrals as well. I just think you can't go wrong with this palette when it comes to a different unique kind of smoky eye.   Well, I don't think this is for everybody. It is a color story that I find to be extremely unique. It's one of those palettes where every single look I create with this palette, I am obsessed with. This definitely in the last year has been promoted to number one because every time I've used it I've fallen more and more in love with it to the point where I'm like, you know what, this is just my favorite. I love it. All right, you guys. So that is all I have for this year's rankings of my current Pat McGrath palettes. I hope you guys enjoyed it and I really, really do hope you guys found it helpful. If you aren't subscribed to my channel already, I would absolutely love it if you would consider taking the time to do so. Yes, Natasha Denona is next and I will see you guys in the next one. Bye guys. Have a good one.


Today, we will learn numericals to calculate molecular weight of a given polymer from a topic polymers. This is the learning outcome for today's session. At the end of this session, students will be able to define polymer, degree of polymerization and by applying the knowledge of degree of polymerization, how to calculate molecular weight of a given polymer by making use of two methods such as degree of polymerization and molecular weight by number average molecular weight method. This is the content we are going to learn in this particular session. First we will learn the definition of polymer, degree of polymerization and then we will see how to calculate degree of polymerization and how to calculate molecular weight of polymer. So the first question is that what are polymers? Polymer is a material which consists of several time repetition of the same molecule. Polymers are organic, high molecular weight materials. Polymers are mainly used to prepare different types of plastic. Polymers are of both types that is natural and synthetic. Therefore, the material used to obtain polymer is known as monomer. Some of the examples of the polymeric material are polystyrene, polyvinyl chloride, bacrylate resin, nylon, etc. So what are polymers? Polymers are the high molecular weight material which shows several time repetition of the same molecule. So the monomer is a single molecule which on repetition forms polymer and these are known as polymers which are used to prepare plastic. Now what do you mean by degree of polymerization? If we want to calculate the molecular weight of a non-polymeric molecule it is very easy to calculate. But it is very difficult to calculate molecular weight of a polymer and therefore the degree of polymerization concept we have to learn before going to calculate molecular weight of a polymer. So it is degree of polymerization that is DP. Degree of polymerization indicates the average number of monomer that is repeatedly present in a molecule of polymer. So it is average number which is repeatedly present in a molecule of the polymer. Degree of polymerization can be controlled during the reaction itself by adjusting concentration of monomer, catalyst, temperature etc. Generally polymer with low degree of polymerization exists in the form of liquid state and with moderate degree of polymerization the polymer exists in viscous state whereas the polymer with more degree of polymerization exists in solid state. Therefore degree of polymerization should be more for better durability and quality which is denoted by the small n. So degree of polymerization indicates what is the average number of monomer that is repeatedly present in a molecule of the polymer and which can be controlled during the preparation itself whereas it is expected that in a good polymer the degree of polymerization should be higher for the better durability and quality. Now what is molecular weight of polymer? Generally molecular weight of a molecule is calculated by doing the sum of atomic weights of all the atoms present in that molecule. So it is known as a routine method to calculate molecular weight of any molecule. So what we are doing in case of calculating the molecular weight of any molecule just we are doing the sum of atomic weights of the atoms present in that molecule. It is a routine method but that routine method is not applicable for polymer to calculate molecular weight. So molecular weight of a polymer cannot be calculated by this routine method because in a given polymer the repetition of a monomer is not defined because it depends upon various external conditions that is the concentration of monomer, temperature, catalyst, duration of the reaction etc. Therefore in the same example of a preparation we may get the different polymers with a different molecular weight. Therefore molecular weight of a polymer can be calculated by applying the concept of degree of polymerization and number average molecular weight method. Now we will apply the knowledge of degree of polymerization and number average molecular weight here. So this is the first numerical, ethylene on polymerization forms polyethylene with degree of polymerization 450 calculate its molecular weight. So what is the example given ethylene it is a monomer on polymerization forms polyethylene and particularly for this example the degree of polymerization is given that is 450 it means that in this particular example the average number of monomer that is repeatedly present is 450 calculate its molecular weight. So what is the formula for this one? So we know that degree of polymerization is indicated by small n. So n is equal to m upon m0 where n is degree of polymerization, m molecular weight of polymer, m0 that is molecular weight of monomer. So we can easily calculate the molecular weight of monomer by routine method and for given example it is 28 it is given here. But we have been asked to calculate molecular weight so the modified equation becomes m is equal to degree of polymerization multiplied by the molecular weight of monomer. So for this given example the value of the degree of polymerization is 450 so it is multiplied by the 28 that is a molecular weight of the monomer that is ethylene and the answer is 12600. So this is the molecular weight of ethylene to polyethylene. Now here I would like to ask you one question. Styrene that is one of the monomer on polymerization forms polystyrene with a molecular weight of 18000, its degree of polymerization is dash dash dash. Option A 173.07, option B 273.07, option C 373.07 and option D all of these. Think for a moment and the correct option is that option A 173.07. So how the answer we got this 173.07 because we know the standard formula that is n is equal to m upon m o. So we have been asked to calculate n, m is given what is the m value they have given that is 18000 and what is the value of m 0 that is 104. So 18000 divided by 104 the answer is 173.07. So the correct option is option A 173.07. Now this is one more numerical, this is one more numerical that is vinyl chloride on polymerization forms polyvinyl chloride with a molecular weight of 17500 gram. Calculate its degree of polymerization. So we know the formula n is equal to m upon m o where n is degree of polymerization, m is molecular weight of polymer and m o is molecular weight of monomer. So for a given example the weight of the monomer that is vinyl chloride is 65. So by putting the value we are getting the answer for degree of polymerization for this particular example that is 269.23. So these two numericals we have made a practice on how to calculate degree of polymerization if a molecular weight of a polymer is given or how to calculate molecular weight of a polymer if the degree of polymerization is given. Now this is the second type of the numerical. So what is the numerical? A polymer is obtained which consists of 100 molecules with molecular weight of 1000, 200 molecules with molecular weight of 2000, 300 molecules with molecular weight of 3000. Calculate molecular weight of polymer by number average method. So this is an example where after polymerization we got 3 varieties of molecules of the polymer that is 100 molecules with 1000 weight, 200 molecules with 2000 as a molecular weight and 300 molecules with 3000 as a molecular weight. So the formula is that m bar n is equal to summation of ni mi upon summation of ni. So it is ni n1 plus n2 plus n3 plus that is number of molecules mi is m1 plus m2 plus m3 plus again continued and that is nothing but the molecular weight of the first type of the molecule, molecular weight of the second type of the molecule and so on. So by putting the value what answer we got here that is m bar n is equal to 2333.33. So it is one of the method how to calculate molecular weight of a polymer if the different varieties of molecules we have with their corresponding molecular weight that is m bar n. So one more numerical we will do here as a practice. A polymer is obtained which consists of 150 molecules with molecular weight of 1500, 250 molecules with molecular weight of 2500, 350 molecules with molecular weight of 3500 calculate molecular weight of polymer by number average method. So we know the formula m bar n is equal to summation of ni mi upon summation of ni. So by putting the value what answer we get here that is 2766.66 because we have three types of the molecule 150 with the molecular weight 1500, 250 with the molecular weight 2500, 350 molecules with the molecular weight of 3500. So by putting the value we get the answer 2766.66. So all this I have prepared by referring a textbook of engineering chemistry written by Jain and Jain. Thank you.


Let us look at more specifics on analytical expressions of things, analytical expression just like we did it for exponential growth. Let us take a quick look at what we have here. The underlying equation is dS by dt, this is S star minus S divided by the adjustment time, this is what we already have. Let us follow the same scheme that we did dS by S star minus S is equal to dT by 80, integrating both sides 0 to T dS by S star minus S by 50, dT by 80 is a single variable, this is minus logarithm of S star minus S of, let us make it out 50T is equal to T by 80. Here I have a logarithm of S star minus S of time 0, it will be S star and T S star minus S of time 0 minus T by 80, which will be equal to S star minus S of time T divided by S star minus S of time 0 e power minus T by 80, which means my S of time T is equal to S star plus S naught minus S star e power minus T by 80. Again these are linear systems, there is no non-linearity hence we can nicely solve it like this. Stalker time T is desired goal of this system S star plus initial stock minus the goal d power minus T by 80. So, e power minus X should be the expression because you can look at the curve that is happening. So, it is e power minus X e power minus T by 80. So, given the desired, given the goal as well as the initial stock we can compute what happens at time T for whatever values we need to know 80, we need to know S star and we need to know S naught.  So, one of the thing we saw was when adjustment time 80 units passes then what happens? Some time of 80 passes S at T equal to 80 would be S star plus S naught minus S star e power minus 80 by 80.  So, S at time T equal to 80 will be S naught plus 0.632 times your S star minus S naught. As time unit of 80 passes we adjust 63 percent of the discrepancy using a simulation since time step was 1 the resolution was not great. So, we took it about 60 to 65 percent, but if we reduce the time step you can see that the 63 percent of discrepancy is about 63 percent of discrepancy is adjusted for every time period 80. So, 60 percent discrepancy is adjusted for every time period 80. Right. So, what we mean is you have a graph like this, this is your stock, this is your time, so if we call it 80, 280, 380 and you get it like that. Stock is changing from across time 0, 80, 2, 80, 3, 80 times etcetera. So, up to this will be 63 percent of S star here initial value of stock is 0. So, wherever it is reaching that is your S star is reaching at infinite time. So, that initial value is 0. So, 60 percent discrepancy is fulfilled when 80 time period passes. So, at this point at time 280, 63 percent of S star minus S star time 80 is satisfied. So, every time unit 63 percent of remaining discrepancy gets satisfied increment and so on until at 380 again it is 60, again some discrepancy gets satisfied etcetera, decreases your goal asymptotically. Not very well, but it answers the purpose. The idea is 60 percent discrepancy adjusted for every time period 80 for the remaining discrepancy. Now, we will ask as we saw an extra rate level plot, we had the level on the x axis and rate on the y axis and we saw that it has any positive slope G, then you will have exponential growth. So, this is a goal seeking system. So, you have a negative slope. So, when you ask any negative slope system as example that shows here, here the equilibrium point is at 100 because 100 was the goal of the system, the goal defines the equilibrium point. So, any push on either direction will bring the system back to that same equilibrium point. That is how system is going to go and any again depends on the slope it will affect the time attitude takes to reach the equilibrium and that is F nothing, but 1 over 80. Yeah, time constant adjustment time is 1 over F, time required to reduce 63 percent of discrepancy, smaller 80 corrects discrepancy faster, larger F corrects discrepancy faster. We will stop here and next class we will look at system compensation and there is other how do you control when there is uncontrolled variables in the system also.


What's the word y'all? Hey, this is the earliest recap video I have ever filmed because the Warriors are down by 47 with a whole quarter and a half to go and they close our game with no Jammerant. They're down by 47. This is why this game is so great to me because it's as unpredictable as possible. I mean, I thought that the life was sucked out of Memphis after the last game where they were up or at least in it without Jammerant. Jerry gets his shot blocked and Steph Curry turns up in the fourth quarter. I just assumed that even if the Memphis Grizzlies were to win this game, I just assumed that the Warriors would come and fight. It is 108 to 60 right now. Are we serious? Shout out to Jerry. Shout out to the Memphis Grizzlies defense because they are turning these boys over like it's nobody business. Steph Curry's done for the night. There's 15 minutes of gameplay left. Which is smart. I mean, why even playing when you're down by 50 almost, right? But wow, the earliest, earliest I've ever done it. It is now 110 to 61. It is 110 to 61. Clay Thompson is done for the night with a minus 45 and 25 minutes.  As of right now, listen, these numbers are just gonna increase. Actually, no, I would assume that Taylor Jenkins is gonna pull his starter soon. Not that he see that the Warriors threw the red flag in. But Jaren Jackson, Jr., 21 points, eight rebounds, three assists, four threes. Dez & Bane, four threes. Tyus Jones is the most premier non-turnover point guard in the history of basketball. Today, 21 points, nine assists and literally zero turnovers. They have three as a team right now while the Warriors were sitting at 18. 18 of them things. And that is as disappointing as it gets if you're a Warriors fan.  But the way to ease Memphis Grizzly's team, this team has been playing over the last two games. You can tell that they are not afraid. Last game was a stinker on both sides, but you can tell that these boys are not afraid at the moment. They play pretty solid without Jamerant being in the lineup during the regular season. But then, I think before tonight, they had lost their last five games without Ja.  Make it a game, man. What you did tonight is replicable in the sense that you can force this team to turn the ball over. It's insane because their offense is so fluid and so great. And I guess that's the reason why they turned the ball over so much. But in the regular season, they were 29th in turnovers per game, only in front of the Houston Rockets who played 18-year-olds. You know what I'm saying? Shout out to Stephen Adams. You're going against a team that basically doesn't have a center or doesn't play a center. He came in and got six offensive rebounds, five offensive rebounds for Brandon Clark, and then three for Jarron. They came out with a game plan and they succeeded. I made a joke about coach Mike Brown because he is the interim coach because I guess Steve Kerr is in health and safety protocol and they have not looked good under Mike Brown in these two games. So I made a little jokie joke about it and King's fans are not happy because jokes are typically at their expense.   The way this Boston Celtics team blew a game. It was very reminiscent of earlier in the season. You remember early in the season before the Boston Celtics went on the legendary run, they were blowing 20-point leads. They were just collapsing under pressure. Today was the first half. They've done that in some time and it couldn't have been at the worst time in the 2-2 series and game five. It is the most important game of the series, I think. I'd like, actually, let me go get those numbers because I remember reading those numbers in its back from NBA.com. Teams that went game five with the 2-2's best of seven series, going to win the series 82.8% of the time. So game five is about as pivotal as any other one. You know what I'm saying? It's as pivotal as any other one because now the Boston Celtics were just at home and they lose and now they gotta go to try to win two more games, one in Milwaukee and one back at home. It's gonna be hard, man. This boy, Giannis is ridiculous and I just saw a statistic that in closeout games in the Bucks' favor and the coach's butt error, they are eight and oh. When they have an opportunity to step on your neck, they do that and they do it successfully. So this was a game that you needed, especially considering the circumstances. You were up by, I don't know how many, actually, let me go look and see how much you were up by. With eight minutes to go in this game, the Celtics were up by 11 points and it felt like they had it. You know, that's still a lot of time for sure but it felt like they had a lot of the momentum going into that. And then a lot of things started to change and here go my list of notes of things that change in that eight minute span. The first thing on my list says, Mark is smart, check out my hair, we gonna get to that. Bobby Portas' rebounding came up extremely, extremely clutch. Let me see this box score. How many did he finish with? Seven offensive rebounds from Bobby Portas and none of them was bigger than the one off the Miss Giannis Frito very late in the game. And that was make enough for a play where he had a wide open layup and he like completely, basically air balled it. Huge rebound from Bobby Portas.  Bobby running the fast break. He gets it on the wing and he had an open three but decided to one more. And I think he won more than to Pat Connaughton and Pat Connaughton hit a huge three or it might have been Drew Holiday. It's all rubbing together today because Drew Holiday hit some big ones. Pat Connaughton hit some big ones. Pat Connaughton got one of the quickest releases. It don't matter where he catches the ball, he's shooting from it. If he catches it above his head, he's releasing it right there. If he catches it to his left, he's releasing it right there.  Coach Budd decided, hey, George Hill can't play 30 minutes. So he only played 12 and he, I mean, he was a minus 15 in those 12 minutes but he decided that actually this lineup with George Hill in it is not it. We gonna ride with our dudes. And I mean, I gotta mention Yannis because another 40 point performance, 40, 11, three assists, some clutch free throws down the stretch again. He missed that one, but it was like calculated. You feel me? He knew that Bobby was gonna get that rebound but Yannis continues to be just like the greatest in the world. Simple as that. Let me go back to my notes. Oh, there's a tweet. There was a tweet that I saw on the timeline that kind of sums up this fourth quarter for the Boston Celtics and it is from, it's from Keith Smith. I knew his last name was Smith but I could not think of his first name. So Keith Smith rewatching the fourth quarter the Celtics gave up at least four, three pointers because someone usually Tatum, Brown or Grant were barking at the refs and didn't get back on defense. And that had been a big problem for the Boston Celtics this game where the other team goes on a huge run on a fast break because somebody doesn't get back. Tatum had to play in this game or ended in a Wesley Matthews three because he was talking to the refs because he didn't get a call that he thought he deserved. You cannot do that in a game five when this team is having momentum and having this comeback. Whether or not you think you got fouled or not, you got to go play defense. You wait to the next day of ball if you really got something to say to the refs. But let's be honest with you, how much of the complaining to the refs do you think actually changes the way the refs do their thing? I think there's an argument that it matters to some extent, right? Like I've definitely seen clips of Steve Kerr telling to the refs, watch the way he doing that on Steph. And then three possessions later, the defender does exactly what Steve Kerr told the ref to watch and then it was a foul. I know it can help, it can open up the eyes to the referees, but like if it's happening to this extent, to the extent that Keith Smith said, what do you say, four, three pointers were given up because somebody wanted to complain to the refs and not get back on defense. Insanity, bro, insanity. Easily avoidable outcomes. And then this is a conversation deeper than this initial game or any game at all. And we actually had this conversation on our podcast about flopping. Flopping is a big thing in the NBA. It always has been, you know, from as long as I've been an NBA fan, flopping has been a thing. From Manu Ginobili, Andre Karolinko, though like I know we remember these players fondly, but they were floppers too, you know what I'm saying? It goes from the best players in the league to the worst players in the league. It's a part of basketball at this point. It's ingrained in our culture as fans or in the NBA world and it needs to change. It needs to change, you know? I'm not specifically pointing the finger at Marcus Smart, but he's the perfect example right here, right now. And the play where Drew Holiday ripped him on the very last possession.  And there was a play earlier where he flopped and got an offensive foul. And I guess this gamesmanship, Kenny, flopping in general has become a part of our game and it makes it hard, not just for the NBA fans to enjoy the game because of it, but it makes the game harder for the referees. We always talk about, oh, ref was trashed, it was terrible, bout a boom, bout a bam. And then you have to realize that these refs are being manipulated by the players because Marcus Smart or Giannis or Pat Connitum, Garrison Matthews, Grayson now, I did that in my main channel video. I called Garrison Matthews, Grayson Allen, and I know the comments about go crazy, that video's coming out tomorrow. But because they're flailing their arms and they've become so very good at selling a call, that it's hard for the referees to know, was he really hit? The thing happening game four versus the Warriors in the Memphis Grizzlies, right? Steph Curry got pushed in the back late in the game and it was a foul on, I think it was Desmond Bain, then they showed a replay from a different angle, he wasn't even touched. But because Steph Curry just so good at flailing his body around, it was a foul. And I don't mean the guys are trying to have this conversation, how do you fix this? Because it is such a big part of our game. The NBA said years ago, we gonna start finding these players, how many times have you legitimately seen the player get fine? Maybe a handful, seven in the last five years since they talked about this thing, it doesn't happen often. So I'm trying to figure out what do we do next? And the idea that came up to mind, and it's literally, we did it on the podcast, right? And I didn't even prep for it, this was the idea that I had in mind and you tell me, cause I guess the audience is bigger here than with the podcast, what you think of this idea when it comes to flopping? Now I will not tell anybody that once a flop happens, then we need to go look at the monitors and go see was it a flop or not because the game is already as long as it is when you look at these monitors. I'm not trying to add to that because it's slow, it slows down the pace, it slows down momentum. But what I will say is there could be some type of retroactive punishment if you wanna call it that, similar to them waiting to after the game to find somebody. But we start using these extreme flops and I don't mean like just like some flops are more impactful or bigger than others, right? And when we get to these extreme flops, these flops that manipulate the refs in a big moment, we gotta start figuring out a way. And the thing that I said was we start to turn them into technical fouls retroactively. Now I don't mean that one flop means one tech because I think that just gives such a small window for these players, right? Because in my mind, when you get a certain amount of technical fouls, you get suspended for a game. And I think you can use that type of method when we're talking about flopping to just discourage players from doing it. Marcus Smart won't flop as many times. This player won't flop as many times if he knows that if I flop 20 times, I'm gonna get suspended for a game. And my team needs me. And you know these things carry over to the playoffs. My team needs me. I don't know what it is, but that was the first thing that came to mind. And I don't say I love the idea, but that was just the first idea that I had. Anyway, let's talk about Drew Holiday because Drew Holiday has had a ton of ups and downs in this series alone. Because in some of these games, you can tell that he is trying to make up for the loss that is Chris Middleton. And it makes sense. I mean, Yanis can do everything by itself and they don't have a ton of shot creators. They got shot makers. We talk of Pat Conniton. We talk of Brooke Lopez. They got shot makers, but they don't have a lot of shot creators. So Drew Holiday over the series has tried to put that backpack on and take over some of those possess for Chris Middleton. And in some of these games, you could tell he's trying obviously, but he had been struggling for the entirety of the series right now. He's shooting 34% from the field, 35% from three. And obviously that's not going to cut it, but he's averaging 22 points per game. But in this game, it shows why Kevin Durant, it shows why some of the greatest players in the league say that Drew Holiday is the best perimeter defender in the league because when he is locked in, he is locked in. And I think, you know, I watched a lot of Bucks games this season, not all of the Bucks games. I thought that in the regular season that he didn't show this type of intensity as often as we're used to, which is okay, they just got off a championship. Why do I need to give my all defensively for 82 games in a season when I know I could turn it up into playoffs? And that's what he has been doing, man.  The snatch block save and to get the ball back is ridiculous, Drew Holiday's defense. And then the very last play, no time out for the boss of Celtics. Something happened where Marcus Smart was the only player that was looking to come to the ball. That's one thing I can say about Marcus Smart, even though he had some bonehead plays where Bobby Porter gets the offensive rebound. Some of that is because Marcus Smart didn't box out completely or the Drew Holiday block. Marcus Smart is never afraid of the moment and sometimes it's to his own detriment, as you see today. But if you look at their post-game interviews, he says in it, these plays were built for Jason Tatum, but something fell apart. There's some miscommunications and now nobody knows what to do. Everybody was standing around. This is literally what Marcus Smart said after this game. This was built for Jason Tatum. It didn't go through, so everybody's standing around, so somebody had to do something. So he decided it was going to be him. And he said, obviously, if he knew that Drew Holiday was there, he wouldn't go and open that shot, but Drew Holiday happened to be there. It was like, damn, I was trying to think of an anime reference. I know there's a ton. There's a ton I can make, but I'm struggling. Also, it's eight minutes left in this game and the Grizzlies are still left by 50. They have 126 points and they have the bench warmers in. And the Warriors probably won't crack 90. I'll bet the under if you said it's at 90 for the Warriors right now. Damian Lee for three, he hit it. Uh-oh, I would have just lost the money. They got scored 11 points in eight minutes. They probably gonna do that. Either way, Drew Holiday just continues to be the guy defensively that you need. Just coming up huge in these moments, man. And if this Bucks team go on to win this series and they go on to, because a lot of people believe, and I'm trying to figure out if I believe this as well, that this is the finals. I don't know. I don't know. Nobody has been super convincingly amazing so far in this playoffs. And that's what's making the playoffs amazing to me. Like the heat have been really good, but I can't say that they're the favorite to win. The 76 have had their moments. I can't say they're the favorite. Same thing with this matchup. Well, the Warriors down by 50 to a team without Jamarran. And then Luca sometimes single-handedly taking on the entire Suns team. And then sometimes then the entire Suns team is taking on Luca. And then Jaws out for the playoffs. So there's no team that's had and shoulders over the other ones. So some people look at this as the championship series that whoever wins this is gonna win the conference and go on to the championship and win. I don't know if I believe that just yet, but Drew Holliday, absolutely incredible in the last six, seven minutes of this game, man. And switching it on to Marcus Smart. Yeah, man.  But this is a whole team thing. This was not a Marcus Smart thing. Again, he's gonna be the guy to get a lot of the hate, if you wanna call that a lot of the criticism because of the block shot, because of the mis-rebound or because of the turnover that Drew Holliday forced with zero seconds left, whatever it was. But I think it was way bigger than that. Like I said, these are moments where the team in general has to be better. Might be the smallest you'll ever see me on a video screen, but I wanted to let you see Tatum on his play. If we look at the play that the Marcus Smart block, I mean, he sees an opening. And I think 99% of Hoopers see this opening and they're going at the rim. But he didn't have the peripherals to see Drew Holliday, who's normally will probably be attached to Jaylen Brown here, but he just makes the executive decision to come over. Oh my God, I didn't realize that Pat Connaughton recovered so well. Like even right here, if Drew Holliday doesn't even contest, this is a hard basket to finish either way. But you can see, like Marcus Smart said in a sports game interview, this play was drawn up for Jason Tatum to come off this Al Horford thing, but something happened where it was miscommunication. I don't think Al Horford saw that the ball was inbound because he's supposed to go set that screen for Tatum and Derrick White has the ball. You see, he's looking like, is anybody gonna do anything? And now Marcus Smart, like nobody's moving. So I guess I'll do it, you know? So I can't, I mean, I guess I fought Marcus Smart for taking the shot because there's still a lot of time to maybe reset and just go with plan number two. But I don't know, man, I just don't think these guys were super aware of their situation. Okay, I forgot about this turnover with 50 seconds left. I forgot that this one even happened. Wesley Matthews, oh my God. I don't know how I've gone as far as I'll mention the name Wesley Matthews. He played a credible defense down a stretch on Tatum. Forced Tatum to take some really tough shots. I had people on the timeline questioning Jason Tatum's shot, quality, if that's the word I'm looking for. And Wesley Matthews did a great job on him. But this one right here hurts more than all of them combined because find Jason Tatum on your screen, all right? There's the pass here. They say the inbound players, the, oh my God. I didn't realize there was a player down, oh my God. Wesley Matthews ends up falling here. They always say the inbounder is the most dangerous player because he's got this full head of steam now and the opening, right? He's got a scene. He gets it back.  He kicks his head up. That's a shot for Jay, or at least a temp. They didn't get the shot up. So that's the temp. I'm sure that Yann sort of came over to cover this ground. Oh, but maybe not. Now he's got to make the decision. No, he's going out to contest Jason Tatum and letting Derrick White take the game time shot. I'm living with Derrick White taking the shot. I'm contesting Jason Tatum. But you know, there it is. There's the Drew Holiday swipe and the Drew Holiday seal of approval, man. And hey, it's going to be extremely, and I mean extremely, extremely hard for the Boston Celtics to take this series. I'm not saying it's impossible because nothing really is, but I'm not betting against Yannis in a closeout scenario. I just saw him drop 40 tonight. I've seen him drop 15 closeouts. I know that he wants to end the series and he's going to try his best to do that thing. So let me know what you think about these games. Update to the score, 126 to, oh my God, 82. Kaminga with a huge dunk. They can't even celebrate over there on the bench because we're down by 40. I appreciate y'all.


How to continue a conversation in English from espressoenglish.net Here's an example of how not to have an English conversation. Did you have a good weekend? Yes, I did. And you? Yeah Unfortunately the conversation stops here because there's no natural way to continue it. You have to think of a new question This is okay if you only want to have a quick conversation For example, if you are quickly passing a co-worker in the hallway, but how can you have a longer conversation in English? Today I'm going to teach you three keys to continuing a conversation The first one is to ask questions that start with question words like who what when where why and how Try to avoid yes or no questions Because yes or no questions can be answered with a very short answer. Yes or no But questions that start with question words will bring out more information from the other person For example, if you ask the other person, how did you spend your weekend? Then they will start talking about the activities they did The second key to continuing a conversation is this in each of your answers give one or two Details that will help continue the conversation. You don't need to talk for a long time So it takes the pressure off The third key is to talk about these topics family interests and hobbies sports TV movies music popular culture current events Travel and interesting places and your experiences or the other person's experiences Unless the other person is a very good friend of yours Avoid topics like politics religion sex life health problems and personal finances These are considered topics to be discussed only among very close friends or family members Here are two example conversations Notice how each person adds one or two details and then there was a follow-up question about the details Conversation one Hey, how was your weekend? Pretty good. I went to a baseball game with my brother Really who was playing? The Yankees and the Red Sox were huge Yankees fans Yeah, how is the game? Very exciting. It was tied until the last inning when we won two to one That's great. I can't say I'm a baseball fan myself. I prefer basketball basketball, huh playing or watching Both I've played basketball since I was a kid No kidding. You must be really good. Well, I just play for fun. It's a great workout I bet I could use more exercise myself, but I don't think I'm cut out for basketball I was thinking of joining a martial arts class That sounds interesting. Which one? So you can see how the conversation goes from the weekend to baseball to basketball and then Exercise and martial arts each person just gives one or two details and then the follow-up question kind of comes naturally Here's another one conversation number two. This conversation takes place in a park What a beautiful day. It feels like summer Sure does. I can't wait for the summer. We're taking a big family vacation in June. Oh Where are you going? We're going to Colorado for a month of hiking and camping. Have you ever been there? Yes, I've actually been to Denver twice on business trips, but they didn't involve any hiking How about you any special plans for the summer? No, not really. I'm saving up my vacation time for December when I'm going to Costa Rica. Wow. Why Costa Rica? Well, my best friend from college lives there now She owns a hotel and she invited me to spend a couple of weeks there to escape the cold winter weather How wonderful do you speak any Spanish? Barely any only what I remember from classes in high school Again, it's easy to keep the conversation going when you ask about the other person's plans and experiences. I Think it's great to learn spoken English from conversations and in my everyday English speaking course you have that opportunity You'll read and listen to a dialogue and then I'll explain the phrases and expressions Click on the link in the video to take a free sample


State Nordic ski meet today at Giants Ridge and it was a good day for the Grand Rapids Boys Team Junior Garrett Beckridge, the individual state champ, won the freestyle in the morning, 7th in the classic first overall total time of 28 minutes, 45.7 seconds as teammate senior Alex Kelling also a top 10 overall finish. He's 8th with the total time of 29. 38.9 but here's Beck rich on being the state champ. I could hear go onters and go Luke and I was like, oh boy here here they come and and then I got a couple more hills up and I look back and I didn't see him. And then I knew I pretty much had it on the downhill. Congrats to Garrett. Here's some of the other top local finishes for boys. Little falls with a pair in the top 40. Hunter is up going Colton York. Rainers Evan Storback in 52nd and Bemidji Soren diving is 79th on the girls side. Here's some top local athletes Grand Rapids with three in the top 34 led by Emma Sturz and 6 for Bemidji senior Sadie Hammond. She gets 76 overall little falls. Has Alice foot in 86 place if you enjoyed this segment of Lakeland news. Please consider making a tax deductible contribution to Lakeland PBS.


Welcome to Toffy TV, it is the Everton News Daily. Fabian Delthes pulled out of the England squad with a hamstring injury. Hopefully it is just a precaution and he'll be back for the next fixture against West Ham United. He hasn't been in the squad for some while so obviously I'm sure it took a lot for him to part the squad but hopefully he is fit in the next game then it will have been worthwhile and we've obviously seen plenty of players do this in the past so hopefully he will be available. Jibril Sadebi as well has been called up for the France squad for their games over the next couple of weeks. The player you'll have to play in Everton's next game obviously due to Seamus Coleman's suspension. Obviously played half an hour of the game on Saturday as well so he's been in obviously France squads before, he's a France well-cut winner as well and is back in the squad so that's him and Lleucadine. Everton have got France's left back and right back which is just mad considering the way we defend so that's good news for him. Michael Silver's agent has spoken about Michael Silver. Carlos Gón Calvez has said that they signed a three-year deal at Everton and he said because of the money that's been put in people want instant success. He said but success is built gradually. He said though but results will determine obviously how long Michael Silver is at Everton Football Club and obviously a lot of people believe that and the results should mean that Michael Silver is not at Everton but Michael Silver is still Everton's manager with some sources suggesting that he won't get sacked and you know West Ham will be that big game for him. I mean I think that's absolutely ridiculous if you're going to put someone's someone's whole career based on one game it should be on a section a game or a complete record and putting it down to one game just seems absolutely mental to me but yeah we'll have to we'll have to wait and see what happens over the next couple of weeks. So I'm at the Everton managerial situation. Richard Keyes the much-loved Richard Keyes has spoken about Rafa Benita's and said that Rafa Benita's wanted to leave Newcastle on two occasions to come to Everton before before Sam Allardyce was given the job and before Michael Silver was given the job and he said he would walk back from China to get the opportunity for a move to Everton Football Club. He said he doesn't care about emotions it comes down to the job being right for him and he said he feels that the job is right for him at Everton Football Club for Rafa Benita's and obviously Rafa Benita's name has come up and a lot of people have questioned whether he would come to Everton obviously with his links to Liverpool but it's well known that his family still lives on Merseyside and you know obviously him being in China I'm sure he's away from his family as his girls grow up and is over on the will and his wife's there as well so I'm sure Rafa Benita's would come back from China to come to Everton but whether he's ever offered the job is another thing. I mean for me personally I think Rafa Benita's would be a great Everton manager and that is not something an opinion that I've formed over a long time. For a long time I thought Rafa Benita's would split the fan base but for me now I think that if Everton neither the manager I think Rafa Benita's would be perfect and I think that we have to just be a little bit more grown up about the situation you know I'm sure there are managers out there that are have been more successful but would they fit the criteria would the marino come to Everton with a leg re-come to Everton maybe not but would Rafa Benita's come to Everton I think he would and he is a manager who's won trophies he went to Chelsea and won a Europa League when a lot of people said didn't want him at Chelsea but he just got on with the job but Malcolm Silver is still the Everton manager I have to respect that but if he wasn't the Everton manager I would certainly be calling for Rafa Benita's so Richard Key's there and Richard Key's I don't think's got a great relationship with Rafa Benita's either so this is obviously his professional view rather than just a personal sort of connection with the with Rafa Benita's so yeah so interesting anyway I'm sure people out there will have their feelings on the whole situation but we'll have to wait and see what happens over the next couple of weeks and see where we go with the whole thing anyway let me know your thoughts in the comments on any of the stories we've talked about today especially that Rafa Benita's won because I think that's a dead interest among that whether you know whatever you feel on the managerial situation I'm sure Rafa Benita's would would I'm not saying split the fan base but I'm sure it would lead to some strong opinions I just wonder how strong they would be um let me know your thoughts in the comments thanks for watching the Everton News Daily we'll see you tomorrow


Great session. So we will have a keynote. If anyone has questions for our speakers, we will probably reduce the discussion time. So we do have time for a break. And we'll have the rapid fire and make sure that Dr. Lang has time for his talk and questions. So you can email the speakers with your questions. Thank you. So again, we thank the Knights Templar Eye Foundation for support of our keynote lecture series. And I'm very honored to introduce to you Dr. Richard Lang. Dr. Lang received his PhD from the University of Melbourne and the Ludwig Institute for Cancer Research. He had postdoctoral training with Dr. Michael Bishop at the University of California, San Francisco, and has had a strong academic career working in New York and now at the Cincinnati Children's Hospital Medical Center, where he also holds the Emma and Irving Goldman Scholar Endowed Chair. His scientific interests include early eye development, the role of myeloid cells in development, and effects on the vasculature of the developing R.I. And he's won numerous awards. He's earned them, including research to prevent blindness, Neum Wasserman, Merritt Award, and the Secular Lecture. So I want to have you join me. I'm so excited to hear Dr. Lang's talk. And it will be on Opsons 4 and 5 and Vascular Development in the Eye and the Implications of Therapy. Thank you. Well, first of all, thank you very much, Emmy and everybody else, for the invitation to come and speak. It's been especially interesting for me to hear the clinical perspective on the problems that I'm interested in. I don't often get a chance to come and listen to these kinds of presentations. And so you'll find that what I'm going to present is a little bit different. But we'll see whether it raises some interesting discussion points for the clinical operations. So this is just a reminder about where we live. We live on a ball of rocks suspended in space. There's a star close by. And what that means is that we are washed with electromagnetic radiation with this rhythmic pattern. Now, the availability of photons has been much to interesting a phenomenon for evolution to ignore. And so of course, we have evolved the visual system in response. We've evolved a circadian system that generates a rhythmic physiology. Our circadian clocks are photoentrained. We've also developed what's a much less well-characterized seasonal clock. But what the Lang Lab has been interested in the last few years is the question of whether there are other light decoding mechanisms that affect developmental processes. And that's what I'm going to tell you about today. So from this very zoomed out view to this very zoomed in view, this is, of course, a structure that we all care about and one that's evolved in response to the availability of photons. The Lang Lab for many years has been interested in the mechanisms by which these fetal vascular structures, the pupae membrane, the tunic vascular alentus, and the vassal hyaluridae appropriate or hyalurid vessels, undergo a scheduled regression. It's a very interesting developmental timing problem for us. And of course, we view this as an adaptive process because these structures are light scattering. If the regression did not take place, that would have a negative impact on high acuity vision. And over the years, we've learned quite a lot about the nuts and bolts of the regression process. We know the myeloid cells are essential. We know the wind pathways involved. We know the angiopoietin and wind pathways are integrated in a way that's rather unique. Most of the studies we performed actually on the high load vessel system, as I'll show you. But a little while ago, we became interested. You don't know that this is my best side, right? So a little while ago, we became very interested in the possibility that a light response pathway might be involved in triggering the regression process. I would often get asked the question, how does this process begin? And I had no answers. But we thought about this very carefully and considered the possibility that a light response pathway might be involved. After all, it's an eye. It's a structure that's designed to respond to light. And what we imagined was that when the mouse was born, that was our primary model, the light level would go up. That would initiate a signaling response. And that would be a great way to time regression of these structures. And that turned out to be a very good thought. But it's a lot more complicated than we first imagined. And so this is what we published a few years back now that explains an initial study on how light response pathways regulate vascular development in the eye. And this pathway basically involves this opsin, melanopsin, opium-4 that we know has a number of different functions in the eye. It includes it's involved in circadian entrainment of the suprachiasmatic circadian clock, the suprachiasmatic nucleus circadian clock. It's involved in the pupary light response. This is just another thing that it does. And so through a process we really don't understand very much yet, stimulation of melanopsin at a certain stage of development actually controls retinal neuron fate. And it actually controls the number of retinal neurons that arise. So what I'm going to tell you is basically that an ROP baby has too many retinal neurons. That's what you observe in the mouse model. If this opsin, melanopsin, is a loss of function or you dark rear an animal from late gestation to about a week after birth, you end up with a retina that has too many neurons in it. Cellularity is high. That elevates oxygen demand. You then get elevated levels of VEGFA. Some of that VEGFA remains within the retina. And you get this kind of promiscuous angiogenesis pattern. This is a dark reared animal. And this is P8. Some of the VEGFA makes its way into the vitreous and suppresses regression of the high load vessels. So this was consistent with this whole idea that a light response pathway was important for regulating vascular development in the eye. The real surprise from this project came from data suggesting that the crucial light response with window was not after birth as we'd originally imagined, but it was actually before birth. So the data suggested that the crucial light response window was E16 to E17. In other words, photons are traveling through the body wall of the mother, stimulating melanopsin in the fetal eye, and eliciting all of these developmental responses. Now, some of my colleagues have an issue with the idea that photons can travel through tissue. And so I'm going to start with some complicated chemogenetic rescue experiments that address this question that are a bit complicated, but bear with me. So the first thing you need to know is that opcins are of course G-coupled receptors. And melanopsin actually couples through a molecule called GQ. So if you can do a gain of function GQ, you can mimic light signaling via melanopsin. So one of the first experiments we did was ask whether if you delete, if you do a loss of function of GQ in melanopsin-expressing cells, do you get the same phenotype as a melanopsin loss of function? And the answer is that you do. And so these are just counts of high-load vessels in various genotypes of animal. And if you do a, this is a flux conditional deletion of GNAQ using opsin-faucre, in other words, restricted to the melanopsin-expressing cells. If you do that, you get the persistent high-load vessel network that's characteristic of dark rearing or melanopsin loss of function. So it's just a way of saying that these cells couple through GQ. It's consistent with that pathway. So having established that, we then had the opportunity to take advantage of these fantastic tools that were developed by Brian Roth, the dreads, or the designer receptors exclusively activated by designer drugs. And these are basically engineered GPCRs that allow you to use this unnatural ligand called CNO to activate a particular pathway. And so there's a molecule called HM3DQ that is engineered to activate GQ that is available as one of these stop-flux alleles. So in other words, you can transcriptionally activate this in a cell of choice. And so we decided to do an experiment where we would activate this HM3DQ stop-flux alleles using melanopsin CRE. And so of course, that restricts the transcription activation to the melanopsin retinal ganglion cells. And then we could deliver CNO as a means of activating that pathway in the absence of either melanopsin or the absence of light. And so it's a rescue experiment. We're asking whether we can replace the activity of melanopsin or the activity of light with this gain of function molecule. And I'll show you that you can do that. But the key point about the experimental design is that you deliver CNO before birth. So you're asking whether activation of this pathway before birth is sufficient to elicit all of these developmental responses like discussed. And so you also arrange the genetics so only the fetal mice can respond and only a proportion of the fetal mice can respond so the experiment can be well controlled. And so this is just an experiment where we've done all of that. Here is a persistent high load vessel network in a control animal, but in an animal that has opium-4-CRE activation of HM3DQ has CNO delivered before birth. And it's also opium-4 loss of function. You actually see that you can restore the high load vessel number to normal. So this is an indication that you can replace melanopsin activity with this gain of function HM3DQ but only if you activate before birth. The crucial experiment in my view is this one where you can actually simply withdraw the environmental photons. Normally what you get is this persistent high load vessel network, but if you do this gain of function GQ with CNO injected before birth, you can completely restore the high load vessel number to the normal level. And so this is a nice chemogenetic rescue proof that activation of this melanopsin response pathway before birth is sufficient to give you all of these developmental processes. Now that's a very long-winded complicated experiment. So fortunately, I'm working with this genuine David Copenhagen, who's at UCSF, and he's an electrophysiologist. So he can do experiments like I'll show you on the next few slides where he simply takes a fetal mouse retina and asks whether he can elicit a light dependent response from melanopsin positive cells. And this is one example of that kind of experiment. So this is what we've done here is put a calcium reporter, G-CAMP3, into melanopsin RGCs with opium-4-CRE. This is another stop-fox allele. And then we've stimulated those cells with the appropriate wavelength of light and asked whether we can get a calcium response. And you can, as long as melanopsin is intact. If you do this in a melanopsin loss of function animal, nothing happens. And so this is an E16.5 mouse retina that is showing a melanopsin dependent response. And this is a more recent experiment from David where he's actually done patch clamping for melanopsin RGCs but used different photon flux to try and elicit a response. And so what you can see here is that the latency of the spiking response is longer at lower photon flux. But what's exciting about this is that if you measure the photon flux within the visceral cavity of a pregnant female mouse, you get about this many photons, about 3 by 10 to the 12 photons per centimeter squared per second. And so what David's shown very nicely here is that you can elicit a melanopsin response out of physiological photon flux. And so if you put that complicated chemogenetic proof together with this, you can pretty much be certain now that the retina of fetal mice is light responsive in utero. So obviously one of the big questions, so we're just to summarize there, obviously what we've shown is that light response could be a normal developmental cue and that a developing mammal can respond to light signals in utero. But one of the big questions we face is whether this pathway exists in humans. And obviously that's a bit more complicated to address, but one of the first questions we had to try and answer was what was the equivalent stage of human fetal development to an E16 mouse? One of the ways to do that is just to take advantage of the Carnegie staging that compares surface anatomy of different species. And if you use this scale to make the comparison, what you come up with is that an E16 mouse that has a light responsive retina is about equivalent to a day 58 human fetus. Okay, so that's the middle of a first trimester. So what we're claiming here is the first trimester human fetus retina is going to be directly light responsive. And of course, you've heard all about retinopathy of prematurity. This was the obvious disease in which to address this question because many of the vascular changes you see in retinopathy of prematurity are similar to those you see in a menalopsin null or a dark-reared animal. And so the way we went about doing this, or perhaps more to the point, my colleague Michael Young from CCHMC went about doing this was a multiple logistic regression analysis in which we simply asked the question of whether there was any association between average day length over particular periods of gestation and the risk of severe retinopathy of prematurity in his particular pool of patients. He gathered five years of patient data in which he was able to do this kind of analysis. So obviously what we're doing here is using average day length as a surrogate for light exposure, okay? And this is just a reminder that we have seasons and the day length varies at different times of the year. And so this was a natural experiment. We had kids who were gestated at different times of the year and we could ask whether there was any association between the average day length and their risk of ROP. And so what we're really asking is whether there's a season of gestation dependent risk of the disease, okay? And so this is one concluding table from that study and there are various risk factors that we identified, but here is an interesting outcome that average day length over the first 105 days of gestation after conception, in other words, approximately the first trimester, you get a significant association between that and the risk of severe retinopathy of prematurity. This is one of my favorite data comparisons and this is the chart I showed you originally which is the chart that allows you to approximate the stage of human development that is equivalent to an E16 mouse based on the Carnegie staging. On the right hand side here, I'm showing you a chart that actually has, is very dense with data, but it's one that Michael produced where he's actually assessed the value of his disease risk model for different windows of time from conception, okay? So he's looking, for example, from one to 30 days, 31 to 61 days, 61 to 90 and so on. And the reason he's done this, of course, is that this represents different trimesters and it represents different phases of this developmental process. And so the area under the receiver operator curve tells you about the value of the model and so the higher it is, the better the model of predicting disease risk.  And what you can see here is that for these intermediate intervals, you have a very significant p-value, but as soon as you flip to the second trimester, which is this 121 to 150 time interval, you lose significance. And so this is a good day because it's the anatomy and the math telling us exactly the same thing. And this is just another way to look at these data. What Michael's done here is document in three month intervals the presentation of a series of patients that need to be assessed for ROP, but then he's represented in the same three month intervals those patients that actually go on to receive treatment. And what you can see is that they're distributed differentially throughout the year. In other words, there is a season of gestation dependent risk of the disease. And so what we can conclude from that is probably that this pathway does exist in humans. And so what we're saying here is that if you have a kid whose first trimester gestation was in the short months of the year, their melanopsin pathway was insufficiently stimulated. They then grow a retina that has too many neurons in it and they are much more susceptible to hypoxia as a consequence. Okay. Okay, so you think that would be complicated enough, but it turns out that there's another option involved in this process. So what I'll tell you about for the second part of the talk here is how this molecule, Opsin V neuropsin, is involved in regulating vascular development of the eye. And this is all about the hyoid vessels. This has very little impact on the retinal vascular as far as we can tell. Direct impact on the retinal vascular. So neuropsin, this is a 380 nanometer violet light sensitive Opsin. It is actually expressed within retinal ganglion cells of the eye, as I'll show you a bit, it's expressed in a whole lot of other places as well. And it raises this really interesting question, which turns out to be true, about whether tissues outside the eye are light responsive due to the expression of this Opsin. I won't talk about that today, obviously. But it has all the features of a classical Opsin. It's been shown to mediate light responses in a couple of settings. And what I'll mention is that Ethan Buren, Russ Van Gelder, have shown that Opsin V actually runs the circadian clock within the retina. The retina has its own independent photorentrainable circadian clock. Opsin V is the crucial detector for that activity. And so obviously, given our interest, we were curious about the possibility that the Opsin V null mouse might have a vascular defect, and it does. This is a retinal ganglion cell expressing Opsin V according to Opium V pre-brainbow activation. These cells are a distinct subpopulation of retinal ganglion cells from the melanopsin-expressing RGCs. And this is the first account of the vascular phenotype in these animals. These are highlight vessel preparations that we generate as flat mounts, and we simply count vessels as a means of understanding what its status is. And you can see that at P1, control the Opsin V null mouse have normal numbers of highlight vessels. But at P8, and this is a stage we typically assess to understand whether there's a persistence or some other phenotype, you actually see that the Opsin V null mouse has fewer vessels than normal. In other words, it has a precocious highlight vessel regression. And this is a unique phenotype. All the other animals that have a highlight vessel phenotype have a persistence response. And so this rather suggested that the mechanism of involvement of Opsin V is going to be different from that of Opsin IV. This is just a nice way to represent the distinction between the Opsin IV and the Opsin V phenotype. Here's the persistence over a time course of the Opsin IV null phenotype, and here's the precocious regression of the Opsin V null. We of course wanted to assess whether this was a light response pathway. And so what we do these days to create light in our mouse rooms is use an array of light emitting diodes, red, green, blue, and violet that target the different Opsins. And they have the same photo and flux as the standard mouse room lights. If you create a lighting conditions that excludes the violet light that open five responds to, you can actually reproduce the precocious highlight vessel regression that is characteristic of the open five null. And so this is an experiment where we actually withdrew the violet light postnatally. And so this makes a pretty strong case that Opsin V modulation of highlight vessel regression is actually a postnatal activity. And so of course this suggests that Opsin IV and Opsin V regulation of this process occurs with distinct timing. And I'll come back to that question at the end. Mintan Nui, the postdoc who was doing the work on this mouse had noted that the open five null mouse had this unusual expression distribution of tyrosine hydroxylase, an enzyme that's involved in the biosynthesis of dopamine. This pathway, we know dopamine has many important functions in the eye, but this pathway is under feedback regulation. And so this disturbance suggested there might be a modulation of dopamine levels within the eye. And that turned out to be the case. And so for example, if you take, if you just do a short time course postnatally and compare dopamine levels within the vitreous of the mouse eye under normal lighting conditions, LD or dark rearing, you get elevated dopamine levels suggesting that light is normally suppressing dopamine levels within the vitreous. And we could also show that in an Opsin V null mouse, you have low levels of dopamine within the neurons of the retina. So this is a lysis to do the dopamine level assessment. But within the vitreous fluid, the Opsin V null mouse has an elevated level. And so that's consistent with this dark rearing experiment. Now the reason this matters for vascular development is the following. And this is a publication from Sinhard, our while back that showed that dopamine can have a direct effect on vascular endothenial cells through dopamine receptor two. And what dopamine receptor two does is activate a phosphatase called SHP2. And SHP2 can defosfolate virge receptor two as a means of inactivating its signaling. And so when we saw these dopamine level data, we wondered whether it was acting as an intermediate and could be an explanation for the precocious regression of the high-level vessels. And so we tested that possibility, or one of the requirements of that hypothesis was that there was a dopamine receptor expressed in the high-level vessels. And here is dopamine receptor two GFP reporter showing your expression in the vascular endothenial cells of the high-level vessels. And this is antibody detection of dopamine receptor two. And indeed, if you do a conditional deletion of a dopamine receptor two, phloxed allele, using PDGFBI-CRE-ERT2, which is a vascular endothenial cell-specific creativity, you eliminate the immunoreactivity with the antibody. So indeed, there's a very clear signature of dopamine receptor two, expression in high-level vascular endothenial cells. This animal with the conditional DRD2 deletion has a persistent high-level vessel network. This is just the count of vessel numbers. And so this is a very clear indication that dopamine has a direct effect on the high-level vessels and its normal function is to promote high-level vessel regression. And so we could also do this kind of experiment where we asked whether on the background of the open five nile mouse, which is this high-level vessel persistence, would the deletion of dopamine receptor two in vascular endothenial cells reverse the consequences? And so you can see that when you do that deletion, that conditional deletion, you end up with a persistent high-level vessel network again. And so this is a clear indication these two have opposing functions within this vascular development pathway. And so one of the predictions of this hypothesis was that the activity of VEGF receptor two within the high-level vessels would be elevated if you didn't have dopamine receptor two present. And so we tested this simply by doing some immunoblots looking at this activating phosphorylation of VEGF receptor two in high-level vessel vascular endothenial cells. And so this is just a short serial dilution of the lysate you can get from both a control high-level vessel and that in which DRD2 has been conditionally deleted. And what you can see is that the level of phosphorylated VEGF receptor two is elevated in the absence of dopamine receptor two and you can quite nicely quantify that here. And so this establishes this proposed mechanism for a direct effect of dopamine in promoting high-level vessel regression. So this is the model that we've come up with that is designed to help us understand how the melanopsin pathway and the neuropson opium-5 pathway integrate to regulate vascular developments in the eye. So this left side here is what I told you at the very beginning where melanopsin light stimulation actually regulates the number of retina neurons that arise and that gives you hypoxia susceptibility, gives you elevated VEGF A if there's either a dark rearing or a loss of function of melanopsin. And on the right hand side here, what we're suggesting is that opium-5 regulates dopamine release to the vitreous and we know quite a lot about the precise mechanisms and I won't go into all of that but it involves this molecule called DAT or dopamine transporter. That's actually regulated by neuropson activity. And so that's that explanation. So then we're suggesting that dopamine that makes its way to the vitreous is actually involved in suppressing the signaling activation of VEGF receptor too and so dopamine has its effect of promoting high-level vessel regression. Now this occurs at a time in development of the mouse eye when dopamine levels are generally rising. So what you get in the absence of opium-5 is a precocious elevation in the level of dopamine. And so we have this opium-4 and opium-5 regulating these opposing influences on high-level vessel regression. And if you work through all those arrows, what you get is that the net effect of opium-5 is actually to sustain the high-level vessels. This is quite interesting. We think this might be an adaptation to get the timing of high-level vessel regression right. Obviously, if it regresses too soon, you're going to create hypoxia in the retina. And so we suspect this is an adaptation to ensure that you don't get high-level vessel regression until the superficial vasculature of the retina is complete. And so that's a way to balance oxygen supply to the retina. And it's actually interesting that there's an interesting clinical correlate. Dopamine is sometimes used to treat hypotension in premature infants. And this has been shown to elevate the risk of ROP. And probably the explanation is that when you give dopamine, you're prematurely promoting regression of a high-level vessel and making the retina more susceptible to hypoxia. So of course, all of this raises this very interesting possibility that you might be able to use these light-response pathways as a way to treat ROP. The first component of this, the Melanopsin pathway, I've told you that we think this is active as early as the first trimester in humans. And so that's going to make it very difficult to take advantage of that in a kid that's born prematurely. Obviously, there's a suggestion that you might take preventative measures. There's a big question now primarily emerging from the circadian biology field that is asking the question of whether living inside under artificial lights is actually detrimental. We obviously evolved outside in sunlight. And so we are under-stimulated arguably. And so there's this interesting idea that maybe our physiology is underserved by light stimulation because of the way we choose to live. And so this is relevant to this question as well. Ensuring that every first trimester pregnant woman gets sufficient light stimulation, that's a massive public health problem. I'm not sure I can solve that one. But it's a very interesting question to address. But this second pathway that we've identified, Opium 5, is a much more interesting prospect because as far as we can tell, it's probably going to be functional in mid to late gestation. And so this interesting suggestion that after a premature birth, maybe violet light wavelengths could be used to suppress dopamine and sustain the high load vessels. Now as far as we know, dopamine doesn't have any impact on the retinal vessels. And so this is a way that you would target sustaining of the high load vessels as a way of suppressing hypoxia in the retina. So that's a really interesting prospect and worthy of further consideration. And so as I mentioned, the effect of dopamine on vascular, we think is restricted to the high load vessels. And it would probably be wise if we chose to do these kinds of studies to deliver light with a circadian rhythmicity because we know there are other issues if you don't do that. And so the sort of experiment where the sort of study we're thinking about now can probably be executed in the next few years because it turns out we're building a new critical care building at Children's Hospital. And I managed to persuade the architects and the people in charge of that project that we should put spectrally tuned lighting in the NICU rooms. And so this is just an architectural rendering of one of the NICU rooms, but the light fittings are going to be research grade, spectrally tuned lighting systems. So in other words, there's a possibility that we could perform this kind of manipulation and ask in a clinical study whether there are any beneficial consequences. So with that, let me finish and identify the people who work with me on this project. This is my fantastic crew. There are a couple of ringers in here. Some of you will notice that this is Russ van Gelder and this is Ethan Buer and Ethan's postdoc, Nico Diaz. They were visiting on this particular day, but I work extensively with Russ and Ethan on all of this work. As many of you will know, they worked on the non-canonical ops since quite extensively. But these are my lab members who've made a contribution and I've had lots of wonderful collaborators on all of this work, including David Copenhagen, Michael Young, Michael Vaughan, Rashmi Hedde and I mentioned Ethan and Nico and Russ and funding from the NIH and the NEI and Urban Goldman Chair. So with that, I will stop and I will be happy to take any questions. Thank you for your attention. And the retina in the, I think the melanopsin knockout, right? So did that, did you also look at how much the vessels extended peripherally and was that increased as well? You do get a slightly accelerated extension of the vessels to the peripheral retina, yes. So that would be useful for ROPs and... Quite possibly, yeah, yeah. It's a wonderful work really and I'm very surprised about the dopamine on the effects of the fetal vasculature. So do you think it has effects on the PFE formation or can be used during the treatment or... It's a very interesting possibility. I mean, persistent fetal vasculature is a slightly different animal from the changes that I'm showing because there are many other cells associated with those complexes. And so it would be simple enough to check and see if the dopamine receptor was present and if it was, then it will become a real prospect, I think, yeah. Great study. Have you done any work in like Scandinavia countries that have such disturbed circadian, they're short days and I mean, that would, you would think it might extend, augment the effects you're seeing and like some place closer to the equator. Yeah, so absolutely. Is there a latitude dependent component of disease risk? And it's actually a question that we are currently addressing with Lois and her collaborators because the data set that they have extends to all parts of the planet. And so we expect to be able to understand whether there's any latitude dependence to the disease risk, but it's a great question. I have a basic question about the vascular biology of the hyeloid plexus versus the intrarational ones. So I want to understand in terms of the oxygen, the impact of vascular perfusion on intrarational arterial oxygen tension of that particular vascular bed. And I ask in particular, I don't know if you remember, but in 2000, you showed that the hyeloid retracts by apoptosis, whereas we then studied the retina and we couldn't find the apoptosis. We found that the vascular endothelial cells actually, when they regress, they migrate into the neighboring vascular segments. So I guess from a vascular biologist point of view, I just want to understand a little bit more about the differences between the biology of the hyeloid plexus versus the intrarational plexus. Right, so I mean, there are clear distinctions in the way the retinal plexi are remodeled versus the hyeloid, that's absolutely clear. The idea that you get a remodeling process that involves cell migration within the retina, absolutely, I think that's pretty solid now. Within the hyeloid vessels, apoptosis is certainly one component of the regression process. Is there a migration component? We haven't addressed that directly. And I think about those two processes as rather distinct. One is a complete regression of the structure. The other one is a remodeling. And to be honest, those sort of nuts and bolts details have not been our primary interest. We've been interested in how you regulate the overall process. So there's still this interesting possibility open, I think. That was so terrific. Thank you very much. We would like to prevent you with a gift. Thank you. From a little bit from Utah. Thank you. Thank you very much. All right, you know, we're gonna do the rapid fire, okay? So yeah, do you wanna, is that okay? So we are gonna have our rapid fire presenters for this session. And what we're gonna ask people to do is come up to either side, present their research for two minutes, and we'll have two-minute discussion questions, okay? So, Markle, are you first?