Welcome to a reading vlog. Isn't that right, Kaz? Kaz with speed. She's on the mend. She's almost done with her comb, but got a little bit more comb life left, so that'll be lots of fun. I haven't done a vlog in a while. Hey, stop that. I haven't done a vlog in a while because I mean I've been very busy and also like vlogging for my patrons kind of like gets all of like my vlogging energy out, so I just like don't feel like doing any additional other vlogs, but I do like doing regular channel vlogs as well. So now that I'm done with my ridiculous October TBR, I have a little bit more time in November, although not a ton, because like that is what's still on my TBR this month. That and three books next to me that I'm about to go over and then like I finished those already. Still a lot. It's just come October. It's like oh no. Any hoosies. Yeah, so today and tomorrow, Saturday Sunday, this is a weekend vlog. So can you tell I haven't done this in a while? I don't know what to say anymore, but yeah, I'm gonna be vlogging. So currently, I just started this morning while I was like tidying up because the house is a mess because Kaz got spayed, and so there's just like a lot around from her being on the struggle bus, and like she keeps getting like litter stuck in her cone, and then spilling that litter all over the house. And yeah, it's just been a lot. So like I kind of like left things because I'm like she's just gonna ruin it all again in two seconds. So like why bother? But it was getting ridiculous. I was tidying this morning, which is getting to the afternoon because I went to bed at 3 a.m. last night. Do not recommend. So I woke up a little later and then did some tidying, and I still haven't had coffee or breakfast yet, and we're getting to the time of it. It's almost 11 o'clock, so I guess brunch is a thing, yes, on weekends. But while I was tidying, I started listening to Half the World by Joe Abercrombie, which is the second book in the Shattered Sea. I already finished my reread of Half a King, which is the patron buddy read for October. That's that stack over there. Yeah, the second time through. I do, I will say, even though I'm listening to Half the World, and it's the same narrator, I feel like the narrator doesn't do these books justice. He's not bad. It's just like the Shattered Sea as compared to First Law feels so dry and boring and dull and flat, which sounds very harsh. But I mean, it's as compared, like it's not bad. It's just as compared to First Law, you're like, where's the pizazz? So that said, some of it's to do with the narrator, because like if you really listen to what he's saying, a lot of it is like quippy and sarcastic and witty, but he's reading it really like dead and dry and like not sarcastic, that makes sense. So like while you're going through it, you're like, this feels very serious and dry, but you're like, no, he's just all these things that are actually like sarcasm and bits of wit. He's just not reading them like that. So I kind of recommend not doing audio. It's not terrible. It's just very dry and on. I mean, he's no Stephen Paisley. That said, a lot of people said that the other books in the series are a lot better than Half a King. And I was like, well, maybe it's just the narrator, but I'm still listening to this on audio because I have it from the library and, you know, it's efficient while I'm cleaning until something to listen to. So I thought I might, you know, flip back and forth and read some of this instead of just listening to it. But even though the narrator is still the same and he still has the same kind of problems, he, this book is already a lot more interesting to me. And I barely started it this morning. I'm not referring to it. It follows the main character from Half a King is still in it, but he's not the main character. It's a different main character. There's more than one main character. We have multiple perspectives now, which Half a King didn't have. And I'm already liking it more. So yay for that. I always had hopes when people said the rest of the series is better. I was like, what for hope so? Anyway, so Half the World just started it today. Then I am rereading The Name of the Wind this month. I just barely started. As you can see. And yeah, this is my third time reading The Name of the Wind. November seems always like a good time to be reading The Name of the Wind. Because it's not an October rebook. It's like, it's not like a spooky book and it's not a Christmas book, but it is very much a fall book. So November's a good time for that. So I'll probably chug along through a bit of Name of the Wind. And I need to film some regular channel videos today. And one of those videos I need to, I mean I'm not going to try to reread Name of the Wind before I film it. And I don't need to. But Name of the Wind is going to be relevant to that video. So I kind of want to like read a bit and like get my brain heading to the halls of my mind palace where the Name of the Wind stuff is stored. So Name of the Wind. And then it's time. I think just start the wheel of time. The show comes out November 19th I think. So I want to start reading this now. And I was thinking maybe of just vlogging separately this and then my reaction to the show. But I've obviously decided to get to that because I'm considering starting it here. That said, I might vlog again later this month when I'm watching the show. And then then you'll get my thought there. So anyway I'm hoping to start the Eye of the World this weekend as well. So I have kind of a lot going on and I've got a late start. But yeah so I need to be reading those books and get as far as I can get in them. And film some regular channel videos. Vlog for y'all. And you know do some you know eating sleeping this sort of thing. Yeah I mean I feel very tired from going to bed so late. So I kind of just want to sit on the couch drink coffee. I watched Great British Bake Off for like five hours. But no we are reading. And that's part of the reason I'm vlogging. Because you know I'm vlogging and I can't just be a couch potato. I have to actually read. So I can do it. I can and I will and you shall see it. Anyway I probably should make some breakfast or something. Coffee at the very least. So let's us do that. So I'm still very much in the beginning. In this beginning bit of Eye of the World. And it's just this little girl like flapping around her town so that she can info down about us about her town and who inhabits the town and what they're like and what the town's feast days are. And what a water carrier is. And it's just like okay not exactly like an exciting start to this book. Well whatever. Older fantasy books. Older books in general. Weren't too worried about like wowing you on the first page. Like I get that. But um when people say that Robert Jordan Strongster does not characters I already think I feel like I know why. Because right this is like you know a close third person. So like it's in third person but we're clearly seeing things from the perspective of this little girl who is worried about people thinking of her as a little girl and like wants to be seen as one of the big kids but she doesn't get why like the older kids would like look romantically at each other like you know. So she's like very much a little girl. So she thinks about things kind of in a silly way which is kind of annoying but also like that's that's actually fine. That's what makes this like unbelievably the perspective of a little girl. But since we're also info dumping about the town this little girl thinks a lot of things to herself and I'm like well little kid things like that. So like for example um she's looking at this kid that she knows is a little bit older than her and she's watching him um she's observing like how he's swinging his water bucket around and um that it's probably empty the way he's swinging it. You uh and it said that she this little girl she frowned. The furtive was the only word to describe it as she was like trying to figure out what he's up to. What little girl thinks that someone is furtive? No no little girl that's who. And then similarly she's observing this other boy's mother. She says Jocelyn Abara was a pretty woman and when she smiled it seemed the sun might hide its head in defeat. I'm sorry a little girl's perspective is saying the sun might hide its head in defeat about some adult woman's smile. Like this doesn't feel like it's genuinely this kid's perspective.  So this stuff doesn't so like either make this a close third person narrative from this kid's perspective or don't. But this halfway between the two is just it's weird info dumping and inconsistent character voice so far that I am. This is my introduction to this so we're off to a good start. So I'm basically editing this book in my head as I go. It's just never a good sign. But like okay so I don't like the writing style which no one is surprised. There's so many times when like yes it's overly descriptive and people plenty of people warned me about that so I went in and expecting just copious amounts of description from which there are. But the thing about even copious amounts of description like the efficient use of words is appreciated and not just because I mean like description is arguably extraneous in any amount but when you belabor the point then it's it draws the attention even more to it.  Like I don't want to make it sound like description is always a waste of time but it is like you know like I think I'm making sense. Anyway so I've just been generally an authoritarian style but I just felt like the perfect example of like why did no one catch this on an edit or maybe they did and he was like I like it like that which you know you know how men be. But um okay so this feller is walking around we're getting tons of description of his clothes and his quiver arrows and his bow which is in his hand and he knows how to use it because of this and such person teaching him and you're like okay that's a lot of information or whatever. So we get to hear about all the different weeds and things that he's walking on. So only trees that kept a leaf or needle through the winter had any green about them. Snarls of last year's brown bulls spread brown webs over stone outcrops under the trees. Nettles numbered most among the few weeds. The rest were the sorts with sharp burrs or thorns or stinkweed which left a rank smell on the unwary boot that crushed it. Stinkweed is a really uninspired name but I mean naming it that at least you know you don't have to explain what it is because it's a dumb name but it's clear to any reader what the stinkweed is. But no we named it something obvious and dumb and explained it. Stinkweed which left a rank smell on the unwary boot that crushed it. Do you see what I mean? Like stinkweed is already descriptive enough so just leave it at that. Or if you want to give it an actual kind of proper sounding name like an actual name for the plant make up a random jumble of syllables that sounds like the name of a plant and then explain that it's stinky. But to say stinkweed which left a rank smell on the unwary boot that crushed it I'm just like yeah no duh why are you wasting my time with this. So I don't know that it's necessary to tell me about all the weeds at all. And then you named it stinkweed which is like okay well it's very obvious what that is so. And then you explained what stinkweed is which you know what stinkweed is it's exactly what you thought it was. It's a stinky weed. So like do you see like that's why I'm like this this needs an editor because it's constantly stuff like that where I'm like I mean already the POV doesn't really match the voice because of what is being called attention to by the person where I'm like this kid wouldn't be thinking about that this kid wouldn't think those words this kid wouldn't have that perspective. And then these over descriptions were again like multi-fold.  Okay okay so I don't think I'm gonna like this book but we're gonna crack on. I have spent the morning catching up on where I hoped to get to yesterday in Eye of the World because last night I ended up just finishing Luther like or calling it Luther, Lucifer. So I did I finished like the whole like what was left of this series like it's done as over so I won't just the desire to binge watch it won't allow her to distract me just got it over and done with. So yeah I'm a little over 100 pages into Eye of the World and oh my god it's so bad it's so bad that I could feel you know meh about it like I thought it extremely unlikely that I would love it and I was like maybe I'll just feel like it's it's fine like not my cup of but like it's whatever it's honestly so painful to read. It is a pointless and bad and aggravating simile and the whole time like nearly every it's exhausting to read because nearly every sentence my brain is wanting to edit it wanting to rewrite it wanting to cut it out entirely like I'm not wanting to proof it I just my brain can't stop from editing it as I go it's just I can't turn it off um and I keep thinking too about like you know Abercrombie's thing I've always asking about whatever he writes is that true and like again with all the similes like no it's not true this is why is this here this is not helping to illustrate like visually what's going on it is not helping to flesh out the characters it is just the author thought that this made it sound cool but really it just like wasted even more time and didn't help to flesh anything out and oh my god okay so one that like really operated me okay and so like they've been attacked um I guess my own spoilers but I'm hardly into it and it's like it seems very clear that that's going to happen that too like these first hundred pages almost nothing happens and I'm not just talking about like you know plot-wise nothing happens because also plot-wise almost nothing happens but I don't mind if plot-wise nothing happens if we are still really getting like a deep dive into the characters really getting to know them or getting I don't know a lot of lore or something like that but this is just so service-level and painfully so and I don't care that it's derivative I really don't care if things are derivative I don't even have to be original you just have to do it well you have to be writing a story that feels real and compelling and immersive and again like you can have a village and you can have a dark evil force that people are afraid of that's become the stuff of like I mean yeah like 10 billion books do that but if you do it well it doesn't matter this is not doing it well oh my god okay anyway so yeah they get attacked and uh okay all of the similes that are in what's his name ran's mind about what's going on I'm like who in the middle of panicking about being attacked by a creature that he thought was out of myth and lore would be coming up with similes in his head about how he's sneaking around like a mouse in a hawk's nest and I'm like uh and just like all of this thinking to himself things that just feels like a narrator trying to flesh things out in a way that takes all the tension out and doesn't make him seem like a character or if it is like a really dumb character and um and then so like his father and him like sort of like reconvening uh in the woods and uh you know the like the things that attack them are still nearby so they're like you know trying to like speak in hushed tones except having like a full-on expository dialogue where I'm like and at one point like he even draws attention to it he like tells him to hush and keep his voice down and then as soon as he said hush keep your voice down then has like a paragraph of like talking about what they need to do next and I'm like cool like crouching in the woods afraid that these crazy animal beasty demon things trollocks so they're all just they're just called trollocks anyway would come they came and attacked you and you barely escaped and think they're still around and you're crouching and hiding and you're like panicking about it we're also like trying to like figure out what to do who speaks in paragraphs at each other like this like is ridiculous it doesn't feel real it doesn't feel tense like like they're they're doing like info dumps about like what they believe about trollocks and why you know they thought they were from myth but obviously they're not and what to do next and I'm like this is not the time for this like this what why are they having this conversation right here right now can you imagine crouching and hiding from beasties and having a full-on conversation about them and about what to do no no you wouldn't you would do that later when you well and truly made your escape like having like a brief moment of just like oh my god I can't believe they're real like that would be enough that would be enough to convey to the reader that like this is something out of stories and you can't believe you're encountering them not full sentences about how like you thought they were from myth and legend but like oh wow I guess they are real like you wouldn't say all of that you just wouldn't um also you know dad got injured he got you know I guess stabbed or hurt in some way he's bleeding but also so this happened like a minute ago right you know they've just made it to the forest and they're still crouching and hiding the things that did them and his son notes that you know he's like really hot like he has a fever and I'm like who would have a fever I'm not an expert on wounds or wound care or like body's reactions to wounds but I'm pretty sure you don't develop a fever a minute after getting stabbed I'm pretty sure if you have a fever that is caused by a wound it is because that wound has has become infected so this whole he's feverish like one second after getting like if he's feverish because the blade that struck him is magical in some way well then now's the time to be thinking paragraph long thoughts Rand about how people don't get a fever when they get stabbed immediately so there must be something more to this blade maybe the blade is poisoned maybe it's a magic blade that is hurting him in some way but no he seems like it's you know upsetting that dad's been injured but it seems in no way out of the ordinary that he'd have a fever immediately immediately and I mean feverish dad who got stabbed was also able to have this paragraph long dialogue with his son about what's going on and what to do next like I just I just cannot with this I just cannot oh my god so these first 100 and what are we doing 114 pages could have been 20 pages and they could have been paced so much more economically like there I cannot even tell you how many times the village the towns people said the same thing over and over to each other in different versions of it just so you could like get a bunch of names of towns people and then get the vibe that they all think and feel this way like I mean you do not need to do that for 100 pages you don't a few a few sentences could convey this very effectively and it wouldn't like if you're worried about telling instead of showing it's doing tons of telling so if you're going to be telling anyway because the whole point of like going through it down like this and hearing what everybody has to say would be I guess in theory to show rather than tell instead of saying everybody's talking about this you know you want to show everybody time of this there's tons of telling and people just constantly speaking in expository ways that no one ever would and just the similes the constant similes that are stupid like oh my and this isn't even a simile but it annoyed me for the same reasons that the similes do but uh Rand is you know crawling around on the ground trying to like hide and get away right and uh he crawled on across the farm yard keeping as low as he could but trying to watch every direction too he had never thought he would envy an earthworm who would okay that's stupid but who would think that who would think that while they're trying to crawl away and hide from these things that attacked you wouldn't be crawling around trying to hide and be like oh never thought i'd envy an earthworm like do you see what i mean that's not like it's not helping to flesh out the character because no what character would think this way none none uh it's that line you could just cut it it doesn't serve any purpose the fact that he's crawling around got it he's crawling around makes sense what purpose does the earthworm sentence serve other than to annoy me and it well if that was the purpose it succeeded now i just mean the amount of times that people say things that are meant to make it sound old-timey or like make it sound like fantasy even though the pros and the dialogue is quite modern and basic but then they'll say things like you know oh but that is just for myth and legend or those are stories of the olden days and i've heard it told like that kind of thing where i'm just like uh-huh uh-huh great um also the number the sheer number of nouns that have been capitalized of like just regular nouns that have been capitalized to make them like a thing like people make fun of uh white dystopians for doing that white dystopians ain't got nothing on the eye of the world i should have counted how many not just how many times those words appeared because then that would be like in the hundreds but how many different just regular nouns got capitalized to mean a thing that's like special in this world oh my god i don't think i could do this like i'm really considering just dnfing this because i know it's not gonna get better i know that in fact i also know that if i was to continue in the series which i absolutely will not happen um there are books that are considered bad by the people who love this series the slog this is supposed to be one of the not sloggy ones but good ones so i would say the first hundred pages of this was a slog a slog a bs exposition content telling over showing just like absolute nonsense just oh my god oh my god has robert robert jord never meet human beings does he think people talk like this because they do not oh my god i cannot with this i'm so angry i just i just i mean i'm gonna read a little further before i decided to nf this also that yeah so like since i stayed up and watched lucifer lucifer not lucifer instead um i don't think i'm gonna film any regular channel videos today because i would like actually like to get some reading done all the reading that i didn't get done yesterday because i watched lucifer and lucifer why do i keep calling it lucifer i know lucifer's also a show a show that i like but um yeah so i think my new method is going to be because i these are all if you are wondering why i have tabs when i clearly have not gone that far in the book yet um these are just like goal chunks for like when i sit down to read so i'm not like oh my god i have to finish this whole book i can never uh with longer books i often put like reading checkpoints in so like my goal is and to finish it my goal is to get to the next sticky i guess roughly like a little over a hundred pages for each sticky but anyway yeah so i think my new method is going to be to uh treat myself to a chapter of name the wind after each sticky uh it's like a reward for getting through it however that might be a terrible idea because i already think that this is badly written and then to juxtapose it so immediately with the prose of patrick roffus might be unduly cruel to the eye of the world which never had a chance in hell of measuring up to patrick roffus even at its best so maybe i won't do that but i need something some kind of carrot to get me through anyway so that's how i'm doing with this i hate it i hate it so much i hate it so oh wow very rude child so i originally planned to make it to my second checkpoint not quite gonna make it i don't think um i'm at page 174 i finished chapter 10 i might read a bit more today but honestly i hate it so much um so yeah like i don't care that it's derivative i really don't i i almost never care that things are derivative like that's never gonna be the thing that i complain about it might be a thing that i point out um i'm more likely to apologize for it in something that i like than to complain about it in something that i dislike um but so well hello cans yes precious when i say hi to everybody they're really here to see you not me everyone thinks you're way cuter especially what you're called are you the cutest little baby kitty black my face that's who you're here to see i know what's going on baby yeah you're okay anyway um yeah back to the eye of the world um there's just so many things okay so i've already already complained about the sim i think i complained about the similes there's so many similes and they're not good similes and they're they're both not good in terms of like describing or helping to describe the thing they're also not good in terms of developing characters they're just like extra what's the matter baby you want to reunite the world and then there's just like a ton of little things that like make the world not actually feel like it's well built or well thought out um it's just like been oh what's like an old-timey vibe without actually like making any kind of sense like there's like white linen napkins at the inn in this backwater town and they have a a down comforter using the word comforter and i'm like do they have comforters in like koala medieval villages i don't think so and i think like it's really really like they have like a goose feather pillows and whatever and i'm like i don't know this seems a bit fancy for this tiny town but whatever and then there's this whole thing of uh so they're leaving the town now right because like because this is the fellowship of the ring so they've been attacked by trolleycks you know now they're leaving to go on the grand adventure the grand quest and they need a horse and so rand his dad's like doing better now he's on the mend but he was interviewed leaving his dad no on his own because he's going off on this quest and the horse that like fled when the trolleycks attacked it actually went to the town so the horse is there and that's the only horse that i am as far as i can tell that rand and his father have and so now this like girl from the town wants to go with them on this quest and she's basically doing a marion tip in where she's like i'm coming to where are we going and they're like we're being attacked by trolleycks and she's like that's ridiculous you just want to go see the world i'm coming to no one disabuses her of this like i don't i guess it's being played for last but i mean like she doesn't believe her peers when they say this is happening but the ace to die moraine is standing right there and she doesn't go like no mean they're serious like they are really being pursued by trolleycks so just you know if you do still want to come with us that's important to know no she doesn't she just let this girl think that this is just a for fun adventure which is just irresponsible and stupid and just really stupid but anyway so they need another horse now for this girl that wasn't supposed to go on their quest so rand volunteers their horse fella and as far as i know that's the only horse that he and his dad have he's leaving his dad now with like a farm that has no more sheep in it because the trolleycks killed them all and there's like other mastic cleanup and his dad is still recovering from this like life threatening injury that he had and now he's gonna not have a horse because rand was just like i'm offering our horse not asking dad about it just we're digging the horse too and he uh mentions or like he's thinking to himself that he usually when he does ride bella which isn't often because i guess they use her to like pull the cart um he usually rides her bareback she's not used to having a saddle so when he grabs a saddle to put on her she's like weirded out by it and i'm just like who's saddle are you using like if you don't regularly use a saddle for this horse presumably you don't own a saddle for this horse so who's saddle are you taking because in a small village like this where you're complaining about the fact that your crops are failing as the sheep are being killed and you're like a very small town out in the middle of nowhere like the just end of the world you don't just have like extra saddles lying around like that's an expensive thing to have so like did you you wouldn't just like casually have one lying around like oh no one's using this let me just take this saddle like that belongs to someone and this isn't addressed and it's like stuff like that where i'm like i wouldn't have questioned it if they had just said well to use our horse and like i got her saddle on her and we're going to go like i'd still question him taking the horse away from the dad probably needs it but i wouldn't question the saddle thing but you've gone out of your way to tell me that you don't use a saddle with this horse but you're just grabbing a saddle and playing it on his horse and i'm like who's saddle so like felt like that just completely rips me out of the story all the time because like the characters are thinking things that they wouldn't doing things that like i'm like have more questions than answers about that like we get tons of info dumps about how they shear their sheep and whatever hey stop that cuz um but then there's like a whole saddle situation and i feel like i'm making a big deal about the saddle but it's still like that where i'm like it's the little things that like if you're gonna constantly throw bullshit detail at me that i know what asked for about like the names of the weeds in the forest that you're trampling on well then you can't not think about the details when it comes to something like a saddle because like honestly that is immersion breaking because if you want me to feel like this is a real lived in world then the having or not having a saddle would be important to this person's life it would be more logical it would be more reasonable for ranch to be thinking about where he's going to get a saddle from when his horse doesn't have one then for him to be comparing or saying that he never thought he'd envy an earthworm when he was trying to run away from the Trollix what baby what i have a similar problem with like the mayor or you just like tossed out the fact that you have a mayor and i'm like is the mayor elected is the is this is a hereditary position are you guys paying taxes to any kind of like central government or are you out on your own here and there is no central government because that is not been addressed we get a lots of info dumping about other things but i'm like i don't actually know how this world and economy works so like again if you didn't say that he was a mayor if he was just like a town elder then i'd be like sure a town elder but a mayor that's a very specific position so i'm now asking how do you have a mayor who chooses the mayor who made him the mayor does the mayor answer to a governor like how does any of this work so you're going off on this quest to this wider world and i'm like i don't even understand how this like little microcosm works because you've told me a lot of bullshit detail about stuff that i didn't need to know about but then neglected to consider the details when it comes to other things so like you kind of have to do all or nothing if you're going to bother with that amount of detail so i hate it basically i hate it the pros is bad characterization is bad frankly the real building is at least poorly described um and of course then it is extremely derivative and like it being derivative is not it's major crime that's just like doesn't help like because at the very least if everything else that i just said was true but there were some really original world building ideas i'd be like all of that is still true so like if you need to fix it but at least you've got some fresh ideas so like at least we can say that for it but we can't say that either because it's completely derivative so i cannot think of a single positive thing to say about this book like literally like i can't do a compliment sandwich because i cannot think of a single compliment to pay it i hate it i hate it i hate it i hate it so much so excited to crack on with it oh it killed me now anyway um i gotta feed this little hellion who's whimpering and winding at me is that what you want you want food you can hear that but anyway um thanks for watching if you're still here um and let me know all the things in the comments down below i post videos on saturdays other random times as well definitely saturdays so like and subscribe join my patreon if you want to see more vlogs and i'll see you when i see you


That's a great search brought to you by DigiKey and Adafruit. Thank you DigiKey for making this happen every single week. Lady, to use the power of engineering help you. Yes, you find the things that you need on digikey.com. Searching for parts is an art. It's a skill. It's a thing. Lady, what are you looking for this week? Okay, so one thing I did this week is I've been trying to get some of these boards that have like very discontinued, unavailable part shortage things on there. And the feather sensor is one of the ones that was really challenging because they had so many sensors on it and all the more from different companies and they were all unavailable. But a lot of them came back into availability recently. I wanted to get this design back into the shop. And so the part that was, you know, on the great search, we actually covered like getting the list 3MDL, getting a replacement, and so other components and crystals and new pixels. The part that I want to try to replace today is this one. So this was the LSM 6DS33, which is a IMU. It's a triple oxytocelarometer gyroscope. And this is obsolete and no longer manufactured. And they recommend, digikey recommends a alternative, but you know, it's always good to like search on your own just in case if there's something you want that's a little bit different. So sorry, I was zoomed in so much. Absolutely totally unavailable. So the only thing with the gyroxylorometer is like I know just because if you go to LSM 6DS33, I used to stock it. So let's look at the discontinued ones. All right, discontinued. So this was a 16G, 2 to 16G and 125 to 2000 DPS, I scored to your SPI. I only really used I scored to be honest. And then like, you know, double tap, tap detection free fall. But it's very basic to be honest. It's a very basic IMU because the feather sands and the clue wasn't meant to be like a commercial drone or, you know, VR helmet type thing. It was like, I just kind of wanted to do some basic sensing of location. So one of the very inexpensive sensor. So like I said, we searched for nine DoF IMU replacements and nine Tomter replacements. The suggestion here is the LSM 6DSO, but let's see. There might be other options. So what we want is, well, let's just go to IMU and we'll just search because maybe we don't want ST. So let's go to stacking. Okay, so we're going to look for active. Important. I'm going to do that again. And then I want surface mounts. I'm just going to skip over chassis mount. Normally stocking, which already cuts out because again, so many chips were discontinued. And then what do I want? Biometric pressure sensor? No, but that's kind of nuts that they have that built in accelerometer and gyroscope. I don't want with a magnetometer. That's a nine DoF. I want a six DoF accelerometer gyroscope. Whether that temperature, I don't want a magnetometer. I wanted to have I squared C and SPI. Some have I three C as well. Good for them. Looks like we've got 31 options. Okay. So Bosch STTDK worth. Like totally what we expected. So there is a bunch of that, you know, that one that they suggested the LSM 6DSO TSR. And so I was like, well, let's just swap by price. And there's a couple of options. What's nice is that the prices are like reasonable again. Having seen for like a while there, it was like $100 for like a six DoF sensors kind of nuts. They're back down to two bucks. So the question is, which do I want? So I'm, you know, I'll say honestly, in this particular case, because I'm replacing the existing component and the component is the LSM 6DS family, I'm going to go with that same family. If I was starting over with a new design, I might be like, hey, you know what, let's change and go with the Bosch sensor. But I'm a little bit like I'm already doing enough work. I want to replace it with something that's the same family. So I picked ST to pick only the ST components. So now the only thing is I'm a little like actually was like, wait, there's the 6DSM TR, TR means tape and rail. So you can actually come back and ignore the TR part. There's the LSM 6DSM DSL DSO DSR DSO 32 DSV for very nice micrometer. I don't know. And then I was kind of like, there's way too many of these. I need help to know. And then the DSR X. So I, you know, I stored these by price. So in general, it's probably going to be lower quality or higher quality. But and what is nice is I'll say, you know, I'm going to get it just, I've already done this research, they're all pin compatible. They all use the exact same pin out. Thankfully ST picked, they picked this like two by three, like rectangular shape. And they put the pins always in the same locations. They did that after the DS33. So all of these are going to be pin compatible. So, you know, I could swap between them, but I really, I want to pick one if I can. So, you know, I was kind of Googling to try to figure out what the, what the deal is. I'll be honest, a little, little unclear. Some of them are a little, you know, they, they explain like, okay, this one is designed for camera stabilization. Not that it matters. So let's go to, I'll show you how I kind of like figured out what's up. So you go to the inertial module, which is just the entire family. And this is on the ST.com website.  And then product selector, I'm going to shrink this down. Okay. Product selector. And then what I did is I was like, well, I know that the angular rate I wanted to have was, you know, to 2000. Because remember that was the, at the bottom here, I only need up to 2000. You're going to pay for more and more. So I don't want it to be more than 2000. And the accelerometer, I don't want it to be more than 16. And so I think this filtered it. So now I only have 12 options. And you do see like DSM, DSO, DSL. So then I kind of look into the table. I was like, well, what's, I don't think toast. There is some power mode changes. But the real thing that you're going to spend, and I'll tell you another thing, you can't, you can't sort by price here. What you can do is sort by noise density. And that's actually going to be the same as the price. Because the thing that is what makes these accelerometer drives expensive. First off, accelerometers cost like nothing. Accelerometers are very inexpensive for the most part. This has been figured out, you know, MEMS accelerometers. Not that they're, there's some that are a little bit better. They might have better filtering, but the technology is kind of well established. And the quality is kind of well established. Derascopes, what you're going to deal with is, is noisiness and drift. Because that's the thing that's going to introduce the most error into your calculations when you're doing like nine doff, you know, attitude calculations or absolute orientation calculations. And so the higher the noise density, like the more you're going to see like wiggle and drift as things like start kind of moving when they should be moving even when they're still. And you can tell, and I know, I know, for example, for a fact that the DS3TR is the least expensive of all these, not surprising, it's going to have the highest noise density. And then the lower, you know, the ISM series, we stock this one. It's a very, very nice accelerometer gyro. It's going to be lower. It's like, you know, significantly lower. It's like 30% less than the DS3TR. And then from then on, it's like the DSL is next and the M is next. So, you know, although they're very similar, they only go down by like five each one, the DSO and the DSOX, which we stock, they're kind of nice down at 70. But you start paying much, much more like the price increase, even though it goes down only by five micro G for square root hertz. It is going to be, it's going to be significantly more expensive. And so I want to get the 3TR, the DSL or the SM.  The SM is actually a little bit less expensive. And that's actually kind of nice because it also is a little bit higher quality. If you see here, it's 75 instead of 80. But otherwise, it's the same power and the same current consumption. So I think the end, which they have 40,000 stock, is the winner or is it the nice one? About two bucks in quantity. The board doesn't need to be redesigned to handle this new 2x3 pinout. But here's the good news. On the off chance that the M is suddenly unavailable, I can swap to the L. It's a firmware change only. And then, you know, maybe you don't promise more than the L model performance. And then they get the M, then it's higher quality and a little less expensive. So this is my pick for the great search. That's a great search.


The question I keep asking myself, was that worth it? This is Bashar. Ten years ago, he found himself at the heart of a revolution. Together with thousands of people, Bashar was part of the occupation of Cairo's main roundabout, also known as Medan al-Tahrir or Liberation Square. Internationally, the so-called Arabs bring promise to bring down dictators and replace them with democratic systems made for and by the people. And in Egypt, protesters demanded the stepping down of President Hosni Mubarak after nearly 30 years in power. We look for freedom and we will get it. A decade on from the Egyptian Revolution, I wanted to know how Bashar looks back on his time on Tahrir Square. It's something that I actively avoid thinking about. It brings out a lot of not just memories, but also emotions of complete devastation. There was a moment where we had it all and then it was just lost. I first interviewed Bashar in 2016, five years after the events in Tahrir Square. We met through friends of friends and he agreed to talk to me anonymously. It was very like it was something that we never lived before.   Mubarak's regime ended on the 11th of February, 2011. But the changes that followed did not spell democracy, human rights or an end to police brutality. Presidential elections took place in the summer of 2012 with the highly contested results giving the Muslim Brotherhood a narrow victory. But on the 3rd of July, 2013, following months of civil unrest, the military staged a coup d'etat. General Abdel Fattah, LCC, has been the president ever since, consolidating his grip on power by winning elections effectively and opposed. But what happened to the eve of the revolution? People took one of three directions, especially young people, youth, my age, you know, 20s. It's either being totally, it's being totally, it's being totally, it's being totally, it's being totally, it's being totally, it's being totally, it's being totally, it's being totally, it's either being totally pro-regime because they probably hated the days of the Muslim Brotherhood. Some people who are the supporters of the Muslim Brotherhood, they are totally anti-regime and whatever good or bad the regime does, you totally slam it.  Today, Bashoy is living in Europe. But did leaving Egypt make it easier for him to re-engage with politics? Before I come here, I was like, okay, this would be a good opportunity to start thinking, how can we unify some opposition? But once I came here, I was like, actually, no. I just want to have a normal life, have a family, settle somewhere. That would not be possible in Egypt. One of the demands of the Egyptian Revolution was a fair economic system and wealth redistribution. But that didn't happen. Instead, Egypt has gone further into debt, receiving two loans from the IMF in 2016 and 2020, totaling $20 billion. Thanks to the government's severe austerity policies and the devaluation of the Egyptian pound, even the average family now struggles to survive. And it's increasingly dangerous to speak out against the LCC administration. The crackdown is worse than ever, worse than Mubarak now. There is literally no media, no NGOs, like all the little things that we were mad about even during Mubarak, now we don't have. Five years ago, I asked Bishoy whether he had any hopes for the generation that brought down Mubarak. His answer was simply no, but he noticed something changing in those younger than him. We used to have this big game when kids play on the streets. It's called the Askeru Haramaya, the police and thieves. Right after the revolution, I found the kids at my street playing at police and Thawragaya and revolutionaries. And the police were the people actually running from the revolutionaries. Maybe these people are the hope one day. Do you feel like there is possibilities within the younger generation for a shake-up? The fact that they grew up in all of this mess in 2011 and they saw on daily basis that things can just change from one day to the other and that you can actually say no to authority. This does make them quite different. So, yeah. I don't know how can this materialize, but that's the beauty of revolutions. You can never see it coming.


news update. Good morning, everyone. Basil Chappany on this Thursday, the 16th of November. We're looking at the Dow down 84. That's 34,905. There's probably going to be a peak beat today in the Chapman methodology. There should be because the technical is all strong. There's a buy mode in place by signal upgraded to buy mode. There should be higher highs to a peak C and then a peak D. Then we have to reassess everything. S&P is exactly the same thing. No new high today. Good chance that we're making a peak B here so far as a little doji candle from yesterday. A little warning that we could have a reversal as a tiny little down move so far down 7 at 44.95. Key support will be about 44.82. That's initial support. Let's put it that way. QQQ is the same thing. QQQ is the index 100 trading at 384.33 down a dollar 29. Also 387.75. What's the high yesterday? There's a peak B. It should go to a C&D. Look at this beautiful cup formation with a left-side high. Almost tested by fraction yesterday. We're looking at the IWM which is the rest of 2000. Quite weak today. It is down. We're going to go down 3 in a little bit at 175. It's actually quite a sharp move down from yesterday's turnaround. We're looking at gold. Gold had a very nice rally earlier on. It's still holding very well. It's up 22. Getting to the chaff wave. Inside track repellence zone. Silver was much stronger. Silver actually broke out to the upside. It's up at 24, up 0.46. This is going to be interesting because Crudeau is down 3. This is really negative action. This should be positive for the market. What about Jets? Let's have a look at Jets. Jets is the U.S. airline index. U.S. global Jets ETF. Yeah, a nice move up. Not great. Just a nice move up. It's down today. But it's off the 1450 low. It's at 1655. Let's look at the TLT. TLT is in fact a rallying sum. So yields are pulling back a little bit. It's up a dollar 28 at 89.81. Have I forgotten anything? I think I did everything. I did that. Yes. So a couple of things. If the Dow is down minus 60 or more after 115 this afternoon in eastern time, there's a good chance we're going to have a lower close. And that'll make it a peak B in those daily charts that I was talking about. If it manages to get to a plus 40 at any point after 150, that is really impressive action because buyers have been swarming in and you've got some of the leading stocks still acting very well. So with that said, stay tuned. We've got Steve Rhodes coming in and check out my opening call my dating newsletter. See you tomorrow.


But today, on this time where it is one year since this illegal invasion, we again say to President Putin, stop this war now. We draw your forces now. This is an unprovoked attack. No one is threatening Russia. No one is threatening Russia's sovereignty. There is no need for you to continue this war, which is causing damage not just to the people of Ukraine but to those Russian soldiers who are being sent to the front line. And it's right to peace, freedom and democratic rule. Today we're announcing additional support for uncrewed aerial systems, some call them drones, to provide support for the people of Ukraine. Today also, 200 Ukrainian soldiers will graduate from the Australian-based training that's occurring in the United Kingdom under Operation Kudu.


All right, so we're doing a multi-random here. This is from spectra basketball case number 16 I think it took place earlier this week. It is a rookie dual auto rookie dual patch autograph redemption Cade Cunningham Evan Mobley, so random here between the pistons and Cavaliers Good luck to both teams Thank you for joining the break This is a three and a five that's eight times on our random. That's a three Randomize eight times whoever's up top gets the card one two three four five six seven and eight Card goes to the pistons pistons up top and that'll do it. Thanks again. We'll get the car right out to your pistons


You must pay close attention to this message as it concerns your safety and security. This emergency alert is from the SCP Foundation, an international group concerned with your safety and security. The SCP Foundation is delivering this message with the authority of your national government, and you must pay close attention. A dangerous psychological anomaly is in your area. This anomaly, named SCP-3199, is a humanoid with human and chicken features. SCP-3199 can be terminated fairly easily, however they regurgitate large eggs, similar in size to ostrich eggs, and scream while they do so. These eggs are extremely resilient to harm, and will produce another instance of SCP-3199 quickly. SCP-3199 are capable of producing an infinite number of these eggs, to fill any indoor space they occupy. There are therefore an exponentially growing number of SCP-3199 instances in your area. If you hear an SCP-3199 instance screaming, evacuate the area, or you may be overrun by multiple newly hatched instances. Otherwise, try to stay inside, and defend yourself with firearms, if possible, as they are effective at terminating SCP-3199. Do not stay anywhere warm, as warm comfortable areas can attract SCP-3199, and cause their eggs to hatch faster. Thank you for your attention, and cooperation. The SCP Foundation will arrive in force soon to re-contain SCP-3199. Secure. Contain. Protect.


Hi everyone. I'm Sam Cahane. This is theCUBE on the ground at the Talon Beer and Big Data event at the Harpoon Brewery in South Boston, Massachusetts. Not a bad spot for an event. I'm here with Dan Allen, the senior ETL developer at Cashstar. Dan, first time in theCUBE. Thanks for coming. Yeah, thanks for having me. So you're in from Portland, and you're just talking. Dan just went to my favorite restaurant, Duck Fat. What do you suggest for anyone who goes to Portland? What should they get at Duck Fat? Well, I mean, the fries are amazing, because they fry them in Duck Fat.  They're amazing. So everyone, make sure to go to Portland, go to Duck Fat. So Dan, you work for Cashstar. Can you tell us about the company? Yeah, we're an electronic gifting company. We work with some of the biggest retailers in the country, Home Depot, Target, places like that. And we just provide their e-gifting experience. Fantastic. And you are a Talon user, is that correct? Yes, yep. So can you tell us what was the problem you were having, and then why did you decide to use Talon? Yeah, so we're a small-ish company. We're only a few years old. And we have a lot of clients who need reports. And they were originally doing all that reporting directly out of our transactional systems. And as we grew, we realized we had a need for a data warehouse. And as our systems expanded, it became apparent we needed data integration software, because we weren't just reading everything out of one database or one system. So that's when we started looking into Talon. Okay, so at the event, what are you hoping to learn? Why did you come down from Portland? Well, we're hoping to learn more about some of Talon's new offerings with big data and unstructured data and hopefully figuring out how we can utilize some of that stuff to learn some more about our clients and our users and how they're experiencing our pages and things like that. Okay, and I want to back up a little bit. Sure. So before you started using Talon, was there an evaluation process? What other vendors were you looking at? Well, we explored a few other vendors. We looked at Informatica, which was way out of our price range. We looked at Pentaho, and that really didn't seem to serve the needs that we had. Before that, we were just doing straight up Java. Straight up Java. Just pure Java. Yeah, exactly. And what type of results have you seen? Extraordinary. So we were using the Talon Open Studio, and then we transitioned to the enterprise platform. And by using some of the dynamic schema components, we've been able to streamline a ton of the data integration that we do. Great. So any words for the viewers about CacheStar or Talon that you want to leave them with? Sure. You can look over in the eye if you want. All right. Talon is a great tool and for the price and for what you get for that price. I don't think that there's anybody that can beat it. And that's coming from somebody who previously worked at an Informatica shop. So I think it's a pretty extraordinary tool, and everything comes straight out of the box. And I think that that's great. Dan, that's a strong testimonial. Thank you. Congratulations on all your success. Awesome. Thank you. I'm Sam Cahane. Thank you.


So, good morning everybody. Thanks for coming. I feel very honored to introduce Dr. Enrique Rodrigues-Poulin today. We are very lucky to have him here today. He is very busy and traveling a lot. He is an outstanding scientist who is famous for his work in cell biology and in RPE and in epithelial biology and let me briefly tell you a little bit about his academic career. So, he received these from Argentina and he received his MD, can you hear me all? Or shall I talk through the microphone? It's okay. Okay. So, Dr. Rodrigues-Poulin is from Argentina. He received his MD from the University of Buenos Aires and then after three years of training in biophysics he transferred to the United States to NYU in New York and trained there as a cell biologist. And during that time as a postdoc and subsequently as when he moved into assistant professor position he co-developed the MDCK model and used it to study how epithelial polarity is established and maintained. And for example one of his really key papers is that his laboratory discovered in 1978 that enveloped viruses can be butted from MDCK cells in a polarized manner. So, this was one of the first papers that showed that molecules can be expressed and located, localized in a polarized manner. He then became associate professor at Weill Cornell Medical University Medical College and this was in the department of cell biology. He also became Joseph Hinze professor for cell biology and then subsequently he was appointed as a Jules and Doris Stein professor in the cell biology department of cell biology and of thermology, excuse me. And then he was appointed as a scientific director in the Margaret Dyson Vision Research Institute. And since then he has been appointed as a Margaret Dyson professor of atomic research in this vision research institute. He's also professor of cell and developmental biology and professor of neurosciences now. And he also was director of the vision training grant in the department. He has received many awards and honors and for example the Irma Herschel Award, the Bensley Outstanding Young Cell Biologist Award and the Established Investing Award of the American Heart Association. And we originally had this visit scheduled in November but he couldn't come unfortunately for us but fortunately for him because he received the highest award that you can receive as a scientist in Argentina, the RISE Prize. I hope I pronounced that correctly. He has been funded by NIH for over 30 years. He has published 194 publications so far and I just want to emphasize that his research is really, he has discovered many key processes in apical basal sorting and trafficking and epithelial cells and he has made many very exciting and interesting discoveries in RPE cell biology. So this is very important especially for macular degeneration. And I stop now and let you talk. Okay Sabina, thank you very much for the very nice introduction. You have a pointer. Yes. Okay, so this project started a few years ago in the lab and it's part of our, my intention to do something that is a bit more translational. Most of my work has been at a very basic level, basic cell biology level, the cell biology of epithelial cells, epithelial polarity. And in the lecture I'm going to give later today, I'm going to deal a little bit with that. But this one is more focused for this audience on the problem that we have been interested for a while, which is the problem of lipofusing. How lipofusing damages the RPE, how lipofusing causes blindness and if this is possible or not to get some kind of therapy for these type of diseases. So this by the way is where I work. This is Wild Cornel Medical College. This is Rockefeller University. This is the East River. Sloan Kettering Central Park. And this is where I live. Okay, so. So this is a monogenic disease usually caused by mutations in the APCR4 transporter. And there are large amounts of lipofusing deposited in the RPE and causes macular dystrophy and blindness by about the fourth decade of life. And this is a clear example of this disease that lipofusing is bad for the eye. So what is lipofusing? We're going to go into that. In terms of macular degeneration, lipofusing accumulates age in all of us. With age, we have an increasing amount of lipofusing. And by the age 70 and above, we may have up to 20% of the cytoplasm occupied by lipofusing. But whether this is a factor or not in the etiology of AMD is not clear. The work by George Hyman and others have clearly shown that AMD is linked to a variety of genes that can predispose to AMD. But lipofusing in particular in APCR4 is not particularly linked in that sense. However, there's the possibility that lipofusing could somehow contribute, be one of the contributing factors to develop the disease later on in life. So what is lipofusing? Lipofusing is a fluorescent material that accumulates with age in the RPE. You see this in the section of the retina. This is the RPE. And when you look at the cell loaded with lipofusing, an RPE cell, you see all of these dotted elements in the cytoplasm. And those dots are lysosomes. So the lipofusing some material accumulates in lysosomes in the RPE. And it also accumulates in many organs, most organs in the body with age. But the lipofusing that accumulates in the brain, for example, or in the liver is completely different from the lipofusing that accumulates in the eye. The celloid lipofusing that accumulates in the brain, for example, is mostly based on protein. The lipofusing in the eye is mostly based on lipid. So we know very well that from the work of young that photoreceptors are continuously regenerating. And it takes about 10 days to move material synthesizing the inner segment to the tip of the outer segment, where it's then phagocytosed by the RPE cell. And in our lab, Sylvia Fineman discovered one of the two major receptors in RPE phagocytosis, the alpha-V-beta-5 integrin. And with Marti K, these two receptors mediate this daily phagocytosis of outer segments into phagosomes, which are then converted into phagolisosomes and degraded. The material, the outer segments degraded there. Now the lipofusing is a consequence of this activity, the activity of phagocytosis, and the activity also of the visual cycle, which is a cooperation between the photoreceptor and the RPE that leads to the production of this retinoids. This is shown in this slide in a little more detail. So we get from the blood 11c retinal, which is converted into 11c retinal and shipped to the photoreceptor, and it's a prosthetic group of rhodopsin. So when light hits rhodopsin, 11c retinal is released and converted into old trans retinal on the inner side of the sac, in the photoreceptor of the membrane sac. And then ABCR is a free-pace that transports old trans retinal to the cytosol. Here we have, the old trans retinal is relatively toxic, so there's a mechanism to reduce it throughout dehydrogenation to old trans retinal. The alcohol is less toxic and it's moved to the RPE where it is, through a series of steps, isomerized back to 11c retinal and shipped back to the photoreceptor, and so that's the visual cycle. Now, a branch of the pathway is the following. Part of the old trans retinal doesn't follow this route, but follows an alternative pathway and becomes dimerized and linked to phosphatylethanol, informing these retinos, which have these shapes. And the process is completed in the lysosomes of RPE cells, and these components are relatively very stable, so they can stay for years. They are quite resistant to all known hydrolysis, so they are very difficult to deal with. It's sort of like a lipid diamond, if you wish. Now, under, in Stargardt disease, ABCA4 is mutated, and so this pathway, this alternative pathway is enhanced enormously, and therefore we have an enormous production of these viscretinoids. And the accumulation of these viscretinoids is actually quite toxic. For example, if you can incorporate them in vitro, you can synthesize them, and in this experiment what we did was to synthesize an A2E or the old trans retinal dimer to different viscretinoids and incorporate them into the cells by exposing them to this viscretinoid. So, at concentrations that we know result in intracellular levels similar to those of an aging eye. In those concentrations, we can see that there's a clear effect on viability of both these RPE cell lines and the human fetal RPE cells. So, the objectives of this project in our lab are to develop a drug that would remove lipofusing from RPE. Then, if we obtain it, we would like to see whether this drug can stop stargon disease in humans. And of course, if we would come to that point, it would be interesting to see whether it has any effect on patients with AMD. So, this is A2E, and the way that we started looking for a drug that would bind into it was to use a property of these viscretinoids. These viscretinoids are fluorescent, and the fluorescence, this is the fluorescence in water of A2E, for example. The fluorescence of these viscretinoids enhances when you place them in a medium, in a nonpolar medium. For example, this is the fluorescence in methanol, this is the fluorescence in DMSO and in exane. So, the most, when the polarity is decreased, the fluorescence is increased. So, then we screened drugs that would cause an increase in the fluorescence of the viscretinoids. And one drug that came to mind right away were cyclodextrins, for several reasons. Cyclodextrins are native compounds. They are formed by several units of glucose linked so that the core, the inner core is hydrophobic, whereas the external surface is hydrophilic. So, we have the alpha cyclodextrin has six molecules of glucose, the beta has seven, the gamma has eight. And this is the core that I showed you before, the fluorescence of A2E in water up to exane here. And this is what happens when you expose, when you put A2E in the presence of different cyclodextrins. What you see here is that in the presence of alpha cyclodextrin, this practically no increase is the green curve here. With gamma cyclodextrin, the increases are bigger. And with beta cyclodextrin, you have the highest increase in fluorescence. So, this suggests that the hydrophobic arms of A2E, which are fluorescent arms of A2E, are being encapsulated within the hydrophobic core of the cyclodextrin. And you can use, you can see what is the fluorescence that you get in the reaction as a function of the concentration. This is micromolars of the different cyclodextrin. So, you see that clearly the one that has the highest increase in fluorescence is the beta cyclodextrin, which is relatively not very soluble than the methyl beta, which is more soluble, so you can use it at higher concentrations. The gamma, you get fluorescence at the higher concentrations of cyclodextrin and the alpha, of course, you don't get any fluorescence. So, in a paper that we published last year, we studied different properties of the interaction of bifuridinols with cyclodextrin. So, this is a demonstration that when you incubate, you know, when you expose bisretinoids to light or to an oxidative environment, the typical absorbance spectrum of this bisretinoids. This is not fluorescence, but this is absorbance. It has two shoulders corresponding to the two arms of A2E. If you expose it into photoxidation, you lose that spectrum. You lose the two shoulders. If you incubate the A2E in the presence of alpha cyclodextrin, you don't protect against the loss, against the effect of oxidation, but beta protects very well. Gamma has an intermediate protection. And the same is true for auto-oxidation. Oxidation just by leaving the A2E in a tube for a week. For example, you lose the shoulders and alpha doesn't protect, beta protects very well and gamma, intermediate protection. What we did was then to model the interaction between cyclodextrin and A2E. And this was work done in collaboration with Harrell Weinstein, who is an informatics. He's the chairman of the physiology department and an expert in this modeling technique. So, he helped us with it. And this is how A2E looks. It has these two arms and the short arm, the long arm. And it has a size, a diameter at this level of about, the maximum diameter of about 6.5 Armstrong's. And here you have the inner diameters of alpha cyclodextrin, beta cyclodextrin and gamma cyclodextrin. So, alpha has an inner diameter of 5.6, so it's clearly too small to allow penetration of the arm of A2E. Whereas beta cyclodextrin has an inner diameter of 6.8 Armstrong's, smaller one. These are toroidal molecules, so they have two, on one side the diameter is 5.6, on the other side is 8.8. For beta it's 6.8 and 10.8. So, this clearly has the right size to accommodate A2E. Whereas gamma cyclodextrin is a little large, so the arm enters into the ring, but sort of it's not very tight. So, and this modeling work told us that we can get even one or two molecules of cyclodextrin, one per arm. And all of these configurations are possible from the modeling point of view. And one prediction is that beta dimers would bind A2E with higher affinity. And actually this work done by Ronald Breslow, who is a very prestigious chemist at Columbia University, he's a member of the National Academy of Sciences, who several years ago published a very interesting paper in which he studied the interaction of cyclodextrin with different types of substrates, either monomeric substrates or dimetic substrates, some of them V-shaped like the cyclodextrin. And this work clearly showed that, and this was experimental work of very, very high quality. They produced and tested a whole variety of different cyclodextrin. And demonstrated that some cyclodextrin, sorry for it, I keep having problems, some cyclodextrin, when you make cyclodextrin like this, a dimer with a fixed angle and so on, you can get affinities which are up to, you know, tend to the affinity of an antibody for an antigen. So we have eventually the potential of developing very powerful cyclodextrin in the future, and we have been talking to him about going this route. Now, we don't know if affinity is an important, it's important to have such a high affinity. That would be helpful for the drug effect or not, at this point. I want to emphasize this point. So what an experiment that Marcelo Nociari, who led this project, did with Guillermo Lehmann, was, as I told you, we can load RPE cells with A2E. And then when you do microscopy on these cells, you can see this type of pattern, which is typical of lysosomes. So you have these yellowish fluorescence of A2E. And when you incubate these cells, in the presence of a cyclodextrin, you can remove a good amount of it in over a period of 24 to 48 hours, about 50% removal on average. And you can measure that by quantitative microscopy, or you can measure also this by HPLC, which we did in collaboration with Roxana Radu at UCLA. Also, the other experiment that we went, one step ahead, was to do the removal experiment in excised eyes from a mouse, which is a mouse model of a Stargard disease. So it's a mouse that we got from Chris Polchevsky. This actually is more than Stargard, because it has a double mutation. It has a mutation in the ABCA4, and it has also a mutation in the dehydrogenase. So it's a double knockout mouse. And these mice accumulate very large amounts of lipofusing in the RPE. And so what we did was to take the eyes of these mice, enucleate them, so cut them in half, then take the back half of the eye, peel the neural retina, and expose the eye cap, the remaining eye cap to the cyclodextrin, and then we shipped within measurement, quantitative microscopy and HPLC. And we saw that in both cases, about 40-50% removal over a period of 72-hours treatment measured by a little higher with HPLC. And the removal was... These are the different peaks that you find, different these retinoids, A2E and old transredinal dimers are the most abundant ones, but they are smaller ones. And it was pretty effective for all of them, the same efficiency for all of them, the removal rate. And we were trying to show an effect in vivo. Here the issue was what is the best delivery that we can use, the delivery route we can use for the drug. So after talking to several people, we decided to go to use the intravitrient injection of the cyclodextrin, simply because it had been tried for other drugs, and so testing other routes was not so easy to think at this point. Anyway, so this is not so easy to explain. That was a work of Guillermo Lehmann in the lab who is very good with his type of procedures. And he injected in one of the eyes in the mouse, the cyclodextrin, and in the other eye, buffer. And we shipped the eyes to Roxana Radu, who can measure the cyclodextrin, just one mouse eye. So the HPLC sensitivity is good enough to measure all of this in one eye. And so this is comparison of pairs of eyes. In every case, we saw about 25% or 30% removal after these type of protocols, several injections in a week. And it was efficient for several different B-thread denoids. Now, based on these initial observations, we were invited to submit a proposal to this newly created institute, Transitutial Therapeutic Discovery Institute, in which Michael Foley is the director. And this is a new initiative in Cornell, in which people who have, researchers who have a project in the so-called Death Valley status, meaning you have a drug, but you have an interesting effect, but you are very far from having a drug that you can use in humans. You need to go through many different steps in between, and Greg can tell you about this very well. So the question is, this is a situation in which, we consulted several different companies and they said, well, it's a nice band. You need to have more. You are not yet, in terms of convincing us that this would be useful in clinical work. So this was a good opportunity because this institute selected our proposal together with a proposal by Fred Maxfield in our institution, who has been using cyclodexins to treat, or to develop a treatment for nemenpic disease. Nemenpic disease is a disease in which kids accumulate cholesterol in lysosomes. They cannot get rid of cholesterol because they lack a particular cholesterol transport. Nemenpic C protein. So, and that causes death very early in life. And there have been some pretty good successes in working, for example, with cats that develop this disease. Doing intrathecal administration of beta-cyclodexins prevent them from getting the disease. So now they are using this, people are using cyclodexins to treat some kids who develop the disease and there's a foundation, a precision foundation that supports this because I mean the kids are actually precision. They are in the family and they're desperate to get some kind of treatment. So this has been, and some of the cyclodexins are actually FDA approved. Cyclodexins are used as delivery vehicles for drugs. So in a way, that's already a step that has been crossed. And then finally, the collaboration in this case involves putting a group of Japanese chemists from Takita Pharmaceutical in a space in Cornell and then helping us develop different derivatives of cyclodexins. So what is, how can we make cyclodexins more powerful? Well, A2E or lipofusine accumulates in the lysosomes, but so the cyclodexins has somehow to get from the outside to the lysosome. And the conditions that we are using them now, they are getting to the lysosome through pinocytosis or cell drinking. That means it's a very inefficient process. Now the cells, all cells in the body have this type of conveyor belt to transport lysosomal hydrolysis secreted into the medium that have minus 6-phosphate, they bind to minus 6-phosphate receptor and by a process of endocytosis, they reach the lysosome. In principle, one can get a speed of about 100-fold or 1,000-fold bigger using this than the regular pinocytosis. This is Fred Maxfield, who is interested in getting better cyclodexins for the treatment of pneumatic disease. So because we were going to get several different tubes every month to test, we developed a more high throughput type of assay to measure removal of lipofusine. And this is shown here, so we use CHO cells, which are very easily loaded with lipofusine. So we load them, the lysosomes are loaded with lipofusine. Then we expose them to cyclodextrin for 16 to 20 hours and we stain them with lysotracker for the lysosome. And then we can do quantitative microscopy of the fixation, making the ratio between lysotracker, which marks lysosomes and A2E fluorescence. And so I'm going to show you some of the drugs that we tested using this assay. So this is alpha-cyclodexin. As you know, this is too small and doesn't have any efficient removal. It doesn't remove A2E from the cell. This is the one, the cyclodexin that we have been using so far, beta-methyl-cyclodextrin. It has a removal effect, a concentration of about 500 micromolar. This is the Amono-Amino cyclodexin that is used by the chemists for the first step in the production of the other cyclodextrin. This one doesn't have a very efficient removal capacity. This is one cyclodexin in which a Manosyx phosphate was added as a ligand to the drug. And here you have a removal capacity at least 10 to 50 times higher than the original cyclodexin. So now it's in the order of the micromolar range. This is another variation of Manosyx phosphate cyclodextrin, also pretty efficient removal. A different variation of Manosyx phosphate, also pretty efficient removal. When two Manosyx phosphate tags were added, the removal was sort of not very good, so this is not helping the process. And so by using now the fluorescence of the A2E phosphate, we were able to measure the affinity of the cyclodexin for the particular A2E. And so this is what I showed you before. The fluorescence of A2E in the presence of alpha, beta, gamma, or the difference Hp, beta, or m beta cyclodextrin, different cyclodextrin. And these are the affinity. Methyl-beta cyclodextrin, for example, is the one that we have been using. It's in the order of 10 to 7 times 10 to the minus 4. So it's in the order of micromolar and high micromolar range, low micromolar range. Addition of Manosyx phosphate actually decreases the affinity. The Kd goes higher. So even when the affinity is decreased, we have a much higher removal capacity. And this is probably because we have the ability to get the drug faster into the lysosomes. And so one interesting observation here is that this acido, some product that came up from this screen is an acido cyclodextrin. This one has a pretty high affinity compared to the other ones. But it doesn't have Manosyx phosphate that however can remove very efficiently, almost as efficient as the Manosyx phosphate. So we're interested in this product as well. So as I mentioned before, it may be possible to get cyclodextrin that have an affinity of 10 to the minus 11, a Kd of 10 to the minus 11. Again, we don't know if that would be good or not. That's something that we have to test. And that's because we don't know what is the mechanism of cyclodextrin is using to remove the lipofusing from the cell. So in conclusions so far, a single Manosyx phosphate tax improved considerably the potency of CDs to remove A2E. Introduction of Manosyx phosphate tax reduces 10-fold the affinity of CDs for A2E, and nonetheless they are still much more efficient. And in some cases we see that higher affinity of CD for A2E correlates positively with removal potency, in the absence of Manosyx phosphate tax. So clearly what we would like to do in the future is to understand more about the mechanism for function of cyclodextrin. How do they penetrate the lysosomal compartment of A2E? Do they promote lysosomal exocytosis? Lysosomes are not immobile organelles. They are very dynamic organelles. And now in the last few years, the work by Andrea Balavio in Naples has shown that lysosomes have a tremendous flexibility in terms of response to different situations that the cell has to respond to. So we see that the cyclodextrin, we don't really know how they work. I mean one possibility is that the lysosomes may be now fusing in higher amounts with the cell surface and removing this to the exterior. Or another possibility is that somehow the cyclodextrin are promoting transfer from the lysosomal compartment to a different compartment in the cell where the lipofusing can be degraded. And actually in that sense, there's an interesting experiment that was reported. We were at some point interested in studying how I mean thinking, could we get some kind of hydrolysis that can be degraded to be lipofusing. I told you that it's very difficult. And one idea that we had was maybe we can go to an expert, a microbiologist who has a lot, a collection of different bacteria. And since there are some bacteria that can be degraded, oil, it may be possible to find some bacteria that would degrade lipofusing. And actually we had already made a contact and a paper came out and someone else had the same idea. And actually Janet Sparrow collaborated with that work. And interestingly they found that some peroxides can degrade lipofusing. And this is interesting because peroxides are concentrated in the peroxisomal compartment in the cell. So one possibility is that somehow in terms of mechanism of action is that the cyclodexins are promoting transfer out of the lysosome to peroxisomes where they may be degraded faster. So that's a clear possibility for the future. Anyway, so what we need to do next is to find a way to study removal, not only removal of lipofusing from the eye in animals, but also to restoration of vision. So that would be the next step. Can we restore vision? Can we prevent loss of vision by this treatment? And there are many issues, administration route, then with developing of optimized cyclodextrin, et cetera. And we have to consider in this is that the Manus X-phosphate receptor in most cells is expressed on the basolateral surface of epithelial cells. So in the case of RPE, the separating cyclodextrin from the vitreous would have to get first to the apical surface of RPE through the neural retina. And we don't have a receptor there. So that would be a good route of administration in that sense. It would be better to come from the scleral side in that sense. And this localization of Manus X-phosphate in RPE is clearly basolateral in the lysosomal component. And this is a co-distribution of Manus X-phosphate with a basolateral marker in RPE. So, again, another view of the basolateral localization in lysosome. So in terms of in vivo experiments, we started a collaboration with Glenn Bruski who's a vision physiologist working in a difference in the center for visual restoration in Burke Institute, which part of Cornell University in Westchester, a little bit upstate. And so he developed this technique to measure vision in mice, auto-kinetic tracking, as you may know, we have heard about. So in this technique, the mouse is placed in a platform in the center of a virtual cylinder that moves around the mouse with stripes and the stripes can vary in intensity, contrast, speed, and so on. So you can measure two parameters called spatial frequency and contrast sensitivity. So these are the DKO mice at 200 days old, 600 days old. We can see that there's a continuous increase in lipofusing in the eye. And at 700 days old, that's when we see that the first evidence of damage to the RPE cell. This is almost two years old mouse. Up to this point, there was no damage noticeable to RPE cells, but at this time we see that the RPE cells become larger indicating that many of the cells have died and the other cells are occupying the space. Interestingly, when we do the visual function tests, what we see is that you know, using spatial frequency as a parameter, the vision of these mice is normal up to about 600 days. And the case, very drastically, between 600 and 700 days, these would be the control mice. They have a much more gradual degrees of vision at this point. In terms of contrast sensitivity, these mice, these are bad parts of this. We had accumulated all of these mice over three years and so we were able to send them mice of different ages so they could do these measurements, but obviously this is not an easy model to work with. If you have to wait 200 days to 700 days to do the experiment. So there are ways to improve the model. We think that if we would expose the mice to more light and probably they would develop regular levels of light, because the levels of light that you have in the mouse room are pretty low. You would have a faster development of this. Anyway, so also we saw that there are some loss of contrast sensitivity with age. These are mice of about 300 days old and 380 goes here. So this shoulder disappears after 300 days. So this is a little better. It's one year instead of two years, but still pretty long in terms of looking for a model. Our first experiments in trying to inject intravitrally the drug into mice didn't show it was just one injection and looking seven days later just to do some trials. We didn't see so much effect in the special frequency, but we saw a small prevention for three mice in the decrease of the contrast sensitivity from here. Instead of one here, one here for three mice. It's a very small effect and it's also one initial trial. So in conclusion, using a screening acid for small molecules that interact with A2E, we identified beta-cycloidextrin, which has small oligosaccharide rings with a toroidal hydrophobic cavity. Beta-cycloidextrin, but not alpha or gamma, prevent quenching of A2E fluorescence by water and prevent their photo-oxidation. The protective function of these beta-cycloidextrin originates in the ability to encapsulate the hydrophobic arms of A2E into their hydrophobic cavity. Beta-cycloidextrin can remove A2E from our p-cells, but the mechanisms are still unclear. Syncl-6-4 post-weight tags improve considerably the potency of CDs to remove A2E in vitro. In the future, we would like to test beta-cycloidextrin and improve derivatives for recovery or prevention of vision function in the KOMIs. Eventually, if this works, we would like to test them in start-up patients. A form of beta-cycloidextrin is already FDA approved and is being used to treat nemenpic disease. If beta-cycloidextrin is effective in start-up, obviously it would be interesting to test them in patients with atrophic AMD. Marcelo Nociari and Guillermo Lehmann did a lot of the work reported here. Chris Barnes, a graduate student, also participated in the last group of experiments with nanosexphosphate. Collaborators, I mentioned, Fred Maxfield had Weinstein. Cilar Kiss, who advises a clinical assistant professor who advises with star-grade disease. David Warren and Matthews helped with the PNAS paper as the chemistry-cycloidextrin. We have a patent filed and published in August 2014. We received funding from all of these places. And this is the Trinstitutional Discovery Institute with Michael Foley and the group of Takeda chemists who have been helping us. Thank you very much and I'm glad to answer any questions. Can we have light? Yeah, you mean kinetic model to study binding? Yeah, for the binding, we study the property of fluorescence of the cycloidextrin and the fluorescence increases when they are sort of better protected from the water by the hydrophobic cycloidextrin. We didn't go beyond studying the KDE but what we are interested in doing is really trying to see whether to understand more about the biology of the system because we don't really have anything about the removal process. Clearly, they are not there anymore so they disappear. So they cannot be detected by HPLC in the eye after you apply the cycloidextrin. So where are they going? Where did they go? They go out, so we are trying to figure out if they are removed out of the cell intact or were they degraded? So, and I mentioned the possibility that they could be shipped to a different organelle. And actually, in the case of Neman picthesis it's known that when you add cycloidextrin to the, that's the theory that Fred Maxli has. When you add cycloidextrin to the lysosome, somehow they fulfill the role of the missing Neman pic protein which was actually to move cholesterol from the lumen of the lysosome to the membrane of the lysosome so that it can be shipped out of the lysosome. So something like this may be happening also for A2E. Maybe they are sort of clustered in some kind of a crystal in the lumen of the, because these are hydrophobic compounds in the lumen of the lysosome and when you add the cycloidextrin you are helping it dissolve and maybe reach a different compartment in the cell, we don't know. So and also we've seen for example that we're interested in seeing where is the mechanism of cell death because that could give us an additional tool to use in the future. If we understand how the cells are being killed are they being killed by ER stress or by what is the process that is going on. We have additional ways to work downstream from cycloidextrin. Yes. Well I mean our friends, we became pretty good friends with Japanese chemists, they are producing our fluorescence cycloidextrin so we can really follow them as part of the project right now to see whether we can follow the distribution in the eye. Yeah, sure. Great. You mean stargars versus not in the eye or in the eye. How similar is the stargars labofucine versus the eye agents labofucine. Yeah, I don't know that there's a complete study on that but I think that many aspects of the stargars labofucine are similar in the sense they have A2E all trans the dimer all trans-radial dimer but there are other things also there's so-called melanolipofucine there are other components and I'm not sure really on how different they are and I'm not sure it's very well explained in the literature so yeah. Okay, thank you very much.