On a Midsomer Day in 1772, a drably dressed 51-year-old man climbed the low rise of hills that fringed the western edge of Northamptonshire to look down on the town of Bambry in the valley below. He had already travelled far that month, but he had barely made a fifth of the distance that he would walk from June until September of that year. John Mormon was a Quaker from Mount Holly near Philadelphia in the province of New Jersey. He was not yet an American, that country did not exist yet. He departed from the colonies by ship from the port of Chester on the Delaware River at the beginning of May to attend Quaker yearly meeting in London. Having failed to make sufficient impact there, he decided to tour local Quaker meetings across England to spread the message he had travelled all his way to promote, that slavery must be ended. This was not abnormal. Quakers often travelled far and wide to carry news, to visit friends and to preach. John Mormon had arrived in London on the 8th of June, or as early Quakers said to avoid the use of pagan names, the 8th day, the 6th month. He left London a few days later, perhaps via Bunhill Fields, where he may have visited the grave of the founder of Quakerism, George Fox. For much of his life, Mormon wrote a journal, from where we learn many of the details of his life in the colonies and his journey through England in 1772. Though far more detail about Mormon's travels in England were gathered by Henry Cadbury in his 1966 study, John Mormon in England, based on the written accounts of many of the Quakers who had met John Mormon along the way. By the 15th of June, Mormon had attended the meeting in Hartford, then via Baldock he reached Northampton around the 25th or 26th of June. The road to the northwest of England continues from there via Rugby Coventry in Birmingham, so why did he take a left turn and go south? There are two possible reasons. Firstly, it's an easy route to follow. In 18th century England, this road was the equivalent of a modern trunk road. Bambry Lane, the road between Bambry and Northampton, is an ancient, quite probably prehistoric, trackway. It's sometimes called the Cotswold Ridgeway. Like its more famous counterpart on the south side of Oxfordshire, this route begins in the coastal fringes of Lincolnshire and the Wash, follows the valley of the River Neen to Northampton, then takes a line through Bambry along the northern edge of the Cotswolds to the Iron Age site at Crickley Hill. The second likely reason for woman's diversion was that Bambry was a notable centre for Quakerism. The town had a large Quaker presence since the beginnings of the Society of Friends in the 1650s. Crossing the medieval stone bridge on Bambry Lane, of which just two of the seven archers survived today, he arrived in Bambry knowing that he would be welcomed. It was barely a century since the centre of the town had been rebuilt after its destruction during the Civil War. In the high street he would have seen the house of Edward Viva's, one of the founders of the local Quaker meeting in 1655, much as it is seen today. What he would not have seen though were Bambry's crosses, which had been destroyed by the Puritans a century and a half before. Coming to Bambry Quaker Meeting House, he would have seen it much as it looks from the outside today. The wall, along the leaves enclosing it, and behind, the stone front of the then almost new 1751 meeting room facing horse fair. And as you stand in the old meeting room, these are the same walls which witnessed his ministry to the meeting in Bambry that day. We have no detailed account of what John Warman said in Bambry. What was noted in the minutes was that it was a precious meeting, though from what he had said before we can hazard a guess. Even by Quaker standards, John Warman can be considered truly radical, and in the colonists he had travelled around meetings and markets to oppose the evil's slavery just as the plantation system was beginning to dominate the economy there, as he wrote in his pamphlet of 1753. Man is born to labour, and the experience abundantly shows that it is for our good, but where the powerful lay the burden on the inferior without affording a Christian education and suitable opportunity of improving the mind and a treatment which we, in their case, should approve, this seems to contradict the designs of providence, and I doubt not, as sometimes the effect of a perverted mind, for while the life of one is made grievous by the rigor of another, it entails misery on both. John Warman's influence upon Quakers in the colonies, and his walk around England in 1772, no doubt played a role in stirring the debate over slavery, just as it was beginning to be taken seriously. Only a few days before John Warman arrived in Bambry, echoing Warman's message, the British courts had declared, The state of slavery is of such a nature that is incapable of being introduced on any reasons moral or political, but only by positive law. It is so odious that nothing can be suffered to support it, but positive law. The term positive law means that there must be a specific law which makes the enslavement of certain people, and not others, legal, and since no such law existed, slavery could not be permitted on the British mainland. It would still be another 62 years before slavery was formally ended in the British Empire, and only then after slave owners were paid £20 million in compensation, the equivalent of £17 billion today, a British government debt which was not paid off until 2017, meaning that most British adults today have each paid compensation to slave owners rather taxes. In an era of expanding trade in the pursuit of wealth, echoing many aspects of the ecological debate today, John Warman advocated a simple life. His clothes, which many remarked were plain or drab, were an outward sign of his rejection of what we would today call consumerism, as he wrote in 1763. Wealth desired for its own sake obstructs the increase of virtue, and large possessions in the hands of selfish men have a bad tendency for by their means too small a number of people are employed in useful things, and some of them are necessitated to labour too hard, which, having no real usefulness, serve only to please the vain mind. In a time when such practices were not even questioned, Warman was a vegetarian because he objected to the treatment of farmed livestock. Many of his other ideas on what constituted a truthful life would still be considered radical today, prefiguring what is now called voluntary simplicity. As John Warman said, my mind, through the power of truth, was in a good degree weaned from the desire of outward greatness, and I was learning to be content with real conveniences, that were not costly, so that a way of life free from much entanglement appeared best for me, though the income might be small. At a time when European states were beginning to battle over the spoils of empires, John Warman felt the need to act beyond the traditional bounds of the Quaker peace testimony, advocating both conscientious objection, and a refusal to pay taxes which might fund conflict, both positions which, again, will not become a major focus of action by the peace movement for well over a century. As he wrote in 1755, I believe that there were some upright-hearted men who paid such taxes, yet could not see that their example was sufficient for me to do so, while I believe that the spirit of truth required of me, as an individual, to suffer patiently the distress of goods rather than pay actively, to refuse the active payment of the tax which our society generally paid was exceedingly disagreeable, but to do such a thing contrary to my conscience appeared yet more dreadful. Even though he travelled far, towards the end of his life he began to refuse the use of a horse or take carriage, he objectured to the harsh treatment of animals in the pursuit of an ever-faster world, as he wrote in 1772 on his journey through England. Stagecoachers frequently go upwards of 100 miles in 24 hours, and I've heard friends say in several places that it is common for horses to be killed with hard driving, so great is the hurry in the spirit of this world, that in aiming to do business quickly and to gain wealth, the creation at this day doth loudly groan. John Warman left Bambi on the 29th or 30th of June, following what was then Ogilby's Road, which bears little relation to the modern B Road today. On the 1st of July he attended the meeting house in Shipsall on Stour, the building that today houses the town's library. From there, Warman turned north once again, through Warwick and Coventry, arriving in Birmingham on the 17th of July. Following the Trent Valley, he arrived in Nottingham on the 26th, and then took a circuitous route via smaller Quaker meetings until he arrived in Sheffield on the 2nd of August. From Sheffield he would travel through the heart of what was still not the fully developed industrial Yorkshire, which William Wordsworth would rail against when he came this way only 30 or so years later. Following the Ribble and Loone valleys, he made his way to Quaker meetings at Settle on the 16th of August, then via Lancaster to Preston-Patrick on the 23rd of August. At this point he starts to become ill, and his pace slows. Via Grey rig, he crossed the Pennines into Wensleydale, to the lovely meeting house at Counterset, and then on to Leyburn by the 13th of September. Then crossing the valley of York to Firske, he arrived in York for the meeting there on the 22nd of September. A day or so later, Warman was taken ill. He had contracted smallpox, quite lightly from meetings some days before. He died on the 7th of October 1772, and was laid to rest in the Bishop Hill Quaker burial ground two days later. Some have called John Warman the quintessential Quaker. His words are still challenging for many today, and certainly that he chose to actively live those ideals in his daily life was unsettling to many then too. But that is probably John Warman's most important challenge to us today, to distinguish the language of the pure spirit which inwardly moves upon the heart. 250 years after John Warman travelled to give his ministry here, everyone is still welcome to attend Quaker meetings in Bambry at 10.30 on Sunday mornings.


Welcome back to the Dominic Doll Show presented by Buffalo Wild Wings. I'm Sam Murray, joined now with Stevenson Men's ice hockey head coach Dominic Dolls and coach Rough weekend last weekend fallen overtime to Brockport and then fall to eighth ranked Genesee One of the top scoring offenses in the country I guess one of the positive things you can take away is last week three games You did score 11 goals. How do you keep the offensive momentum going while also cleaning things up on the defensive end? I mean, I think we talked about a little bit late last week of just we're starting to get to spaces more And I think that is what's helping us create a little bit more of opportunity and that's when we we weren't scoring goals or struggling to score goals That's we just we weren't getting to the net. We weren't strong on our sticks and we're doing a little bit better job at that So I think that's where the offensive production comes from this weekend However, that it was the defense that kind of got the best of us I mean, we've been pretty good all year long in terms of being a defensive team and taking pride in that and I think it just got away from us a little bit Defensively through the first one and a half years in the program never allowed 50 shots against After the New Year this year twice you've allowed 50 goals against. How do you You know limit the pucks the amount of pucks at Capri season the game Well, I mean that Brockport game was like a track meet That was a I think a unique game in terms of just the way both teams were playing It was very very back and forth a lot of Shots off the attack the teams didn't really possess the puck on either side a lot So I think that's where a lot of the shots come because then you look at the next night I mean Genesis a much better team than Brockport. I think and You know that was more of them possessing the puck controlling the puck and I so I think that's where a lot of the shots An opportunity came from You know for us in terms of limiting them I mean it's we've done up. I think a pretty decent job. We've outshot most of our opponents all year It's just gonna be a matter of you know on a given night what type of shots or special teams I think all adds into the equation. Yeah, we flip the page to this week back in conference play two road games You face Lebanon Valley and Chatham two teams you saw earlier on the air You know one seven to one in both those games, but it's later in the season It's gonna be a different matchup this this time around. Yeah, I mean we talked about yesterday in the locker room In Lebanon Valleys, they beat Utica. They beat Elmira. I mean they've beat almost everybody they've played So they're having a pretty pretty good year and a pretty good second half here so far So we're gonna have to make sure that we're ready prepared. It's it's gonna be a good hockey game And we need to be ready for that.  So Compete for what our what our goals are and turn the page here from a from a rough weekend But we're gonna have to we're gonna have to compete if and that's gonna be you know That's kind of been our backbone here when we've done well and if we're not competing we're gonna we're gonna struggle Oh coach, we wish you the best of luck this weekend. We'll see you back here next week. Thank you for coach Dominic dolls I'm Sam Murray and this has been the Dominic Doll Show


In Ethiopia, the military carries out an airstrike on Mekele, the capital of the Tigray area. The government said it targeted a weapons factory. In Syria, two bombs explode near a bus carrying troops in Damascus, killing 14. In Hong Kong, the mother of a pregnant Hong Kong woman killed in Taiwan in 2018, demands government officials work with Taiwanese officials to bring the suspect to trial. And in Japan, Mount Asso explodes sending rock and dust hundreds of meters into the air.


Hi guys, what is up? Welcome to my channel. So for today's video I am going to be doing a shop or drop. It's been a long time since I've done this. I say this at the beginning of every shop or drop video, but like I definitely don't do these videos as frequently as I should. But basically I go through Trend Mood's Instagram page and then I tell you whether or not I will be shopping for the product or dropping it from my list. Obviously this video was inspired by the original Will I Buy It series from Samantha March. So definitely check hers out. I just like to call it shop or drop for something fun. We have some space here. I'm gonna be putting the products here so let's get into it. So I'm going to be starting from January 22nd and moving up and then maybe I'll throw in a few extra products. But the first thing we have here is the Too Faced Highlighting Trio. I do believe these are available now, but these are the Too Faced Highlighting Trio Compact or Illuminating Pressed Powder. They are part of the newborn this way, the new Naturals Collection, and I cannot lie. These are really beautiful. I'm definitely getting hourglass vibes from this product. This is not a product that I am going to rush to pick up, but I can see myself picking one up during a Sephora VIB sale just to try it out, get to know the formula, stay educated for you guys. But other than that I am in no rush to pick up this product, but I have to say it does look quite gorgeous, so I am interested. It's on my wish list. I don't know, Too Faced also leaves a bit of a sour taste in my mouth sometimes, but I really feel like this product's really pretty. Now the eyeshadow palette that this collection comes out with, I'm not so into, but this whole pressed glowy powder compact, I'm really digging it. So let's talk about some of the new Fenty releases that have come out. These are currently available. I saw them at Sephora yesterday. So she's coming out with three new lip glosses, a clear one, sweet mouth, and a chocolate one, sweet mouth, and the chocolate one I already own. I got them in a mini holiday set, so I will not be picking those up, but they are very pretty. Definitely had my eye on the clear one, which I believe is called Glass Slipper, just because she does have a wonderful formula. However, I am going to pass just because, I mean, the lip glosses aren't cheap. They are $19. And even though I like the formula, $19 is a lot for a clear gloss. I already own a clear gloss from ColourPop that kind of fits my needs for that. So I am going to pass, but I'm super attracted to it because it also just looks really cute, just a clear gloss and that's super nice packaging. The What It Do makeup refreshing spray, I have heard really nice things about that. I heard the mist is wonderful. I am tempted to get it. I am going to pass because I have a whole drawer full of sprays, but I am going to challenge myself. The next spray that I finish, I'm going to pick up this Fenty spray. I have a very good feeling about it. It's a hydrating mist. I love hydrating mist. Not right now, but treating myself once I finish one of my facial mist, which it's coming close. And then also she has this lipstick trio for Valentine's. I'm going to pass on that. I just don't need that, but yeah, those are the new Fenty products. All right, so Norvina released a new eyeshadow palette for ABH. And I feel like didn't she tweet that she was hardly going to release any palettes and she's already released two this year? I don't know. Just food for thought. But anyways, this is another one of those mini pro pigment palettes from ABH. I'm passing on this. I already got all three of the big ones. I don't need any of the little ones, so definitely dropping that from my list. Don't want it, not interested in it. The color scheme doesn't really speak to me at all. I saw it in stores, wasn't into it, so just nothing about it tempts me at all. So we're going to be moving on from that. Next, we have the Dominique Cosmetics Latte 2 palette. I love Dominique. I think she's a very sweet person. From what I can tell, I don't know her. I don't watch her videos too much. She's not my favorite person to watch, but from the videos that I have watched from her, which are quite a lot. I just really like her, so I like supporting her brand. I love her latte palette. That's honestly one of my favorite eyeshadow palettes, one of my go-to eyeshadow palettes. I haven't loved every palette that's come out from her, but for the most part, I like her stuff. And I'm attracted to this. I will definitely be shopping it. I wasn't in a rush to pick it up as soon as it released, but I definitely want it. It's in my Sephora cart right now. I think it looks super pretty. It is not anything that I need, but I like her formula. I like her brand. I like what she stands for, so I will be picking this up. I think it is gorgeous. So hopefully it's as good as the original latte palette. That's what my fingers are crossed, because they look super pretty. Hourglass. Okay, so it looks like they are releasing new ambient lighting palettes. There are four diffuser edit, dim edit, ethereal, and luminous edit. It does not look like they are currently available, but I am definitely interested in picking this up. So I'm going to put it on my shop list. Obviously not all four, because that's a bit redundant, I feel. I definitely want to pick up one. I do love Hourglass products. I put them on my makeup kit. I wear them for every day. They really just are such a special formula. I'm very interested in this. It's definitely something though that I would have to see in person to pick out my favorite one, but I'm very into it. Don't expect like a whole review on all four, just because that sounds very expensive. I'm trying not to be as crazy of a spender as I once was, but no, I am definitely into the way that these are looking. So definitely going to shop those once I get more information on those. And then moving on, we have a new ColourPop collection. This is their Valentine's Day collection. I was on the ColourPop website this morning looking at these items. I decided to drop them from my list. Originally I just wanted the eyeshadow palette because I wanted to do a video on new eyeshadow palette releases, but that one didn't even really fit into the scheme or the color scheme of the other palettes that came out. So I decided to pass on it. I don't need it. I won't use it that much. And quite frankly, I don't really care for the color scheme as much. So I did decide to pass on this collection, but you guys know I love ColourPop collections, but this one personally just didn't speak to me. So I did decide to drop that from my list. We'll not be picking that up. And honestly, I just don't think it's that cute of a collection. They've just come out with cuter collections. And in my opinion, this is not cute. Makeup Revolution has released a new concealer. These are called the Conceal and Define Infinite XL Concealer. So it's supposed to be full coverage, long wear. This sounds like it's going to make my under eyes crease. I personally like a more moisturizing luminous concealer. That looks like it's gonna show all of my lines. However, I have to admit I do like Makeup Revolution's concealer formula quite a lot in their foundation. I'm actually wearing the foundation right now. So I like their base products, believe it or not. And I think once this is in Ulta, I will pick it up just to try it out, to support the brand because I do like their base products. I hate their eyeshadow products, but they have good base products. So not rushing to pick this up, but I definitely can see myself picking it up from Ulta on a whim in the future. Not super interested in it right now, just because it's not my jam. It doesn't sound like something I would really like. I will pick it up to test it out for sure. MAC has also released this beautiful collection. Oh my goodness, it is the loud and clear collection. I think that this packaging is impeccable. Like this should be their new packaging for their brand. I think it's just such a cool vibe, very clean and just different. It's way better than the black, just a nice change for the brand to kind of revamp themselves. But of course this is just a collection. I saw this collection in stores. There were a couple lipsticks that are beautiful. There's Yash, and then the lightest one, I don't know what it's called. Eyeshadows aren't very interesting to me. Don't need any more lip glosses as much as I would love to purchase them, and don't need any more lipsticks. I did actually already purchase the lighter highlighter. This is the highlighter in Postmodernist Peach. Let me tell you guys, it is so stunning. From the packaging to the color, it's just a really smooth formula, a very natural highlight. If you like something super beaming, this isn't super duper beaming, but it is so pretty. I had to pick it up along with that. I don't know if these are in the collection, but these are the glow play blushes that a lot of people have been talking about. They were on separate displays. Like the blushes were not a part of this collection, but they have the same packaging. Anyways, I did pick two up. I picked up Grand right here, and then these were quite sheer when I was watching them, so I got the brightest one. No shame, but I think you can build it up. But anyways, yeah, these I heard such good things about. I did already pick up a couple of these in case you were curious, and I'm very excited to play with these. These look stunning, and if I love them, I want to get more colors because I'd need them in this packaging. They're everything. Colourpop also came out with an Ulta exclusive collection, particularly the eyeshadow palette is what caught my eye. This is called the Yura Cutie eyeshadow palette. I actually went to Ulta and picked it up today. This was the only item that they had from the collection. They had the display with everything else, but they didn't have the actual product, but they had this, which I was excited about, because this is actually in line with the palette video that I'm going to do of all the new releases, because this is very similar to some other palettes that have recently been released. So I'm very excited to play with this. I think it is stunning. So obviously I shopped this palette. This is my kind of color scheme, perfect for the time of year, for Valentine's Day, and I'm really into it. I have not yet swatched it, touched it, done anything with it quite yet. So I can't tell you what I think, but I did pick that up because it is even more gorgeous in person than it looks online. Also, something that has been haunting me because I originally posted these on my community page to let you guys know that they were released, but these are the new Pat McGrath glosses. They're called the Opulust glosses. They have a lot of multi-dimensional sparkles. I said no because I do not need another lip gloss, especially a lip gloss that is $30. I was like, nope, dropping that for my list. Dang, they're doing such a good job with their marketing and all of the ads I'm seeing and all of the pictures she's posting of how glittery and luscious the lips look. I'm saying drop now. I've already said drop, but these are definitely something that I see myself falling weak and purchasing when I see them as Sephora and swatching them. So I might end up picking up a couple, but for now, pass. I'm going to be weak. I know I am. I know me. Ooh, yes. This is interesting. Melt Cosmetics is coming out with a new collection. It's a Valentine's Day collection. This is the Millennial Pink's collection. It is available right now on Melt's website. I will be picking it up from Sephora. Just the palette. There are some other interesting things like those. What are those? Are those eyeshadows? I think those are eyeshadows. And then you have the eyeliners. I'm just picking up the palette. I think the palette is really pretty. It doesn't speak to me, but I am into it, so I do want to pick it up. So I'm going to shop for that. Everything else is a pass for me. I do like the Melt palettes, and the last couple haven't really caught my eye. I've been passing on those, but this palette is one that I feel like I'll actually use. So I will be picking that one up. So many MAC collections. I'm just, I don't even want to talk about them. Oh, this. Okay, we got to talk about this. I mean, you guys already know my answer, but I do want to give you my thoughts on the new Pat McGrath complexion products, which are going to be concealers, and it looks like a new under-eye powder and some brushes. Yeah. Okay, anyways, definitely will 100% be purchasing. Absolutely. They come out February 21st. The concealers are $32 each. Powder is $30 each. We'll not be picking up the brushes, but we'll be picking up the actual products. Super excited for that. I'm going to be wearing my foundation in preparation just to see how that reacts with concealers and to see how it reacts with this new concealer. Super pumped for this expect a full review on that. Anything else interesting? Oh, Selena's coming out with a brand, Selena Gomez, called Rare Beauty. Listen, I love Selena, but I'm really tired of celebrities that really aren't known for makeup and hardly probably ever do their makeup come out with makeup brands.  I don't think Selena is really in love with makeup. I do follow her makeup artist on Instagram and he does beautiful work, but even Lady Gaga, Victoria Beckham, I'm sorry, but if her line is really good and I'm super interested, I'm not going to say I'm not going to buy it. I will, especially for what I do and to answer your guys's questions. But I just don't, you know what I mean. Okay. Let me move on. We're coming towards the end here, people. Okay, the Marc Jacobs. It looks like they revealed some items in their new coconut collection, which comes out in the summer. They do like a coconut collection every year. First of all, I love his coconut bronzers. I use them in my makeup kit. Actually, when this collection comes out, I might order a fresh one. I don't know if it's going to be like a new one or an old one, but I'm going to pick one up, probably that lighter one in the photo, just because I literally have hit pan on mine. And then there's also like this bronzer balm will probably be picking that up. I love a good bronzer stick. So we'll be picking one of those up and picking up the actual bronzer. So from what is released from this collection, thus far, it's not very much, but I really like cream bronzer and I really like that coconut bronzer. So nothing exciting, but definitely going to be shopping at those items. Oh, this skincare item, good molecules. I really like good molecules. You can purchase them on Beautylish. They have very affordable products. They are coming out with these caffeine energizing hydrogel eye patches. I've never gotten into eye patches, but these are really good. Like next time I order from Beautylish, I'm going to add these on. They're $18. You get 60 patches, which are 30 pairs, which that's a lot for $18, I feel like. So I don't know. These are intriguing to me. I like this. So I think definitely going to be shopping those. That was a fun item. And it's very rare that skincare excites me, but that excites me. We're going to finish with something that I know a lot of you are going to feel very, very strong about. I already posted about it on my Instagram. Let's talk about the new Morphe and Jacqueline Hill palette that's going to be releasing. Now, I'm going to tell you now, I am going to be shopping it. It's not really something that I'm super excited about. To be quite honest, the color story, like yawn? I don't know. There's just something about it that's not super exciting to me. I just, for the collector in me, I will be picking it up. I don't even use her original palette that much, to be honest. It's a Morphe palette. I have this weird thing where I do enjoy collecting Morphe palettes. Her first palette was pretty. We're going to see if this is actually the same formula, or if she's coming up with a lie. I will be picking it up. I don't see myself using it a ton as a palette. And the color story isn't exactly that pretty to me. There are some purples in there, and there are some shimmery neutrals that do look really pretty. But it's just not that pretty of a palette, you know? There's so many colors in this palette, and it's still not speaking. She's saying it in the same tones. I know it's a much brighter palette than her original, but she could have gone really fun. I would have loved to see some jewel tones, or pastels, or something different. But this just seems like the same with some brighter colors. I don't know. And then of course, you know, the whole drama aspect of her products and stuff. I mean, I try and stay out of that for the most part.   I really liked her original brush collection. I didn't purchase it, but I did pick up a couple of brushes.  There was a concealer brush, and then I picked up like one eyeshadow brush, and all of which I really like. They feel very sturdy. They feel like better brushes than the actual regular Morphe line. Not something I'm going to go and pick up every single brush, but you know, once they come into the store, and I see them, if it looks like a brush that I want, I'm not going to say no, because they're affordable. And from what I've tried from the Jaclyn Hill brush collection, they're pretty nice. So I mean, if you're looking for affordable brushes that are good, the Jaclyn Hill ones are really good. They're not the dirt cheap ones, but you know, you pay for what you get. So I would pay a little bit more to get a little bit of better quality. I'm not opposed to purchasing any of these, just won't be jumping on them. But anyways, that is all I have for today's video. I hope you guys enjoyed it. Let me know your thoughts on the new products coming out. I know a lot of you are going to have a lot to say about Jaclyn Hill, so I definitely want to hear your thoughts on that. Yeah, so I feel like there wasn't anything too, too exciting in this video, but definitely stuff worth talking about. So thank you guys so much for watching this video. I hope you guys enjoyed it. If you are not yet subscribed to my channel, I sure do hope you take the time to do so. And I will see you guys in the next video. Bye, guys. Have a good one.


So today we're going to take all that ridiculous amount of pathways and try to step back a little bit and look at the overall flow of metabolites. And so a lot of what we're doing is review today, but there is one topic that's new, which is the biochemistry of cellular signaling pathways. And that feeds into our previous discussion of regulation with insulin and glucagon because those end up, those regulations end up being through signaling pathways. So we're going to look at the role of different organs in metabolism. So a little bit more of a medical slant today's lecture. We're going to look at regulation. We've already pointed out throughout the class instances of reciprocal regulations. So you don't want to be making glucose and taking it apart at the same time, for example, but we're going to sort of look holistically at everything. And so the last part has a little bit of a tie-in to insulin and glucagon. But we're also going to be talking about epinephrine, which we really didn't say much about yet. And then more generally about the diversity of biochemistry and signaling pathways. And so we've already seen the central role of ATP. This is the currency of energy. This is not really a long-term storage place for energy. We use molecules like glucagon and triacylglycerols for that. But it can be rapidly utilized to do biochemical work, a variety of enzymes use ATP. It's used in the biosynthesis of sugars, carbohydrates, fatty acids and amino acids. We've also looked at the role of carrying electrons, so these NAD and NADP. And so we've seen that in general the big role for NADH is in the mitochondria delivering electrons to electron transport chain. And we've also seen many examples of NADPH being used in anabolic pathways. And so there's this general theme of catabolic pathways converge, anabolic pathways diverge. And so we've looked at, for example, in our amino acid lecture, we've looked at, in the anabolism of amino acids, we've looked at a variety of molecules either in glycolysis or TCA cycle that can be siphoned off to synthesize ATP. And we've also seen this general regulatory system where you have alternate pathways around regulated steps. So, you know, glucose, gluconeogenesis, PFK1, for example. And, yeah, so these are the central themes that we've been looking at. So here's the whole second part of the class in a slide with a few of the details omitted. So we spent a whole lecture, remember, talking about photosynthesis. This is the way we make carbohydrates for carbon dioxide. And we're also producing oxygen. And then the parasites take those oxygen molecules and deposit the electrons, the terminal electron storage location at the end of oxidative respiration. And so in our cells, we have catabolic processes generating ATP and NADPH and a variety of molecules. We've seen examples of many of these molecules being taken off to make more complex molecules. And so these exist in the glycolysis and aerobic respiration and TCA cycle. And then we haven't really talked that much yet about synthesis of large biopolymers. That's actually in the third part of the class. And so this is the general flow in us of metabolic pathways. So proteins can be degraded to amino acids. Amino acids can be fed into pyruvate, but we've seen examples of amino acids being fed into lots of locations. For example, anaphylurotic reactions. So pyruvate can be used anaphylurotically, right? If you carboxylate it, you can feed it into the Krebs cycle. But you can also directly feed the degradation products of these alpha keto acids into the TCA cycle. But if we make acetyl-CoA, that acetyl-CoA is ultimately destined for synthesis of energy, ATP molecules, either after being transported to another organ, being reconverted to acetyl-CoA, and then being fed into the TCA cycle. Now acetyl-CoA can be also assembled into fat. So these are the catabolic pathways here. We know that the beta-oxidation of fatty acids results in acetyl-CoA. And so we've talked about the central role of pyruvate and acetyl-CoA, and that this pyruvate dehydrogenase step is completely irreversible. And so we're not able to make glucose molecules from acetyl-CoA invertebrates, because there's just no way to get there. In plants, we have the glyoxylate cycle. So acetyl-CoA can be used to feed into the synthesis of HMG-CoA. We're starting reagent for the synthesis of cholesterol and ketone bodies. Acetyl-CoA can also be synthesized to fatty acids. Remember, we make that malonyl-CoA first, and that's the thing that you successively add on with the synthase enzyme. We've talked about the transport, the lactate dehydrogenase enzyme, that in the muscles you can convert pyruvate to lactate, which is a way to transport that lactate out. And today we're going to look at the corey cycle, which is how we take that lactate and reconvert it into glucose in the liver and shoot it back to the brain or the muscle. And so alanine, we saw that that was a way for, in the degradation of amino acids in tissues other than the liver, we can transport ammonia on a pyruvate molecule. Pyruvate is the alpha-keto acid of alanine. So when we degrade amino acids and cells other than the liver, of course we use that alpha-keto part to feed into either anaphyrotic reactions or energy generation in that peripheral tissue, but the ammonia has nothing to do with that because we can't make urea in the peripheral tissues. That's only done in the liver. So this is the big picture so far. And we've talked about this, the irreversibility of key regulatory steps. They tend to have large negative delta G's. And we've also talked about this idea of tagging metabolites to make separate pools to, for example, the synthesis of malonyl-CoA. So this is, once you've synthesized malonyl-CoA, that's only used for fatty acid synthesis. And we've seen all kinds of different ways to regulate enzymatic activity. You can regulate the levels of enzymes. Remember, HMG-CoA reductase, that was an enzyme that actually is degraded. So if we have enough cholesterol, that activates the cycling or the removal of the whole enzyme. But we've also seen many examples of allosteric regulation, either non-covalent or covalent, for example, with phosphorylation or adding ADP or AMP to a molecule substrate. So we've talked about the role of mitochondria and cytosol. And so that's very important to think about. And today we're going to be stepping back even a little further, reinforcing some of the concepts we've talked about in organ, the role of different organs in your body in metabolism. Some questions so far, so we're just sort of surveying. And during today's lecture, you might want to, you know, think about the more intricate details. And we're not going to go through all the details again. We don't have the time, obviously. But for some of the key details, I'll bring some of those back and repeat those slides. And so there's a variety of ways in which the enzyme, the enzymatic activity can be regulated. We can do this at the level of the synthesis or degradation of proteins. And so we have, for example, we'll see in today's lecture an example of a signaling pathway that culminates in the activation of a transcription factor which causes the transcription of a gene. And so after translation you now have a new enzyme and that enzyme can be tagged for degradation. We're going to cover that in the third part of the class, the biochemistry of protein degradation. And so you can, we've seen many examples where we have a regulatory polypeptide that binds to a catalytic polypeptide and that binding event affects the activity. We've seen phosphorylation as a way. So kinases add phosphatases take the phosphate off. And just because something's phosphorylated doesn't mean that it's, that's active. It can be either active or inactive. The change of whether a protein is phosphorylated or not can be a switch either on or off. But it's sort of like rooms that have two switches. It can have one over here and that affects the other one. And so phosphorylation doesn't always turn things on. And we've seen examples of that. And we can have, we've seen allosteric effectors, these homotropic allosteric regulators. So ligand itself can also, for a multimeric enzyme, affect the catalytic activity at other active sites. So lots of different ways to do this. And also localization. We haven't really talked about localization, but today actually the transporter for glucose is kept away from the plasma membrane. It's actually not a ligand-gated ion channel. It's a regulation of when you want to take glucose up into the cell is a signaling pathway that culminates in movement of the glucose transporter from the endoplasmic reticulum up to the plasma membrane. Okay, so let's think about all the different organs that have some use in biochemistry. And so the pancreas is where we're making insulin and glucagon. The liver is the distribution hub for all of biochemistry. So gluconeogenesis for export of glucose occurs primarily in the liver. And, you know, we can take in a variety of metabolites from our diet. The brain in general today is extremely selfish and just does one thing. Doesn't do any gluconeogenesis, doesn't make any fats, doesn't store any glycogen, doesn't store any fats. It just burns fuels. And it's a purely aerobic respiration because anaerobic respiration in the brain is insufficient for all of the ion channel activities. So you can imagine a lot of the energy in the brain is taken up by, you know, the transport of ions. So we use this electrogenic transport. So we have to use a lot of energy to set the voltage potential on a membrane and to cause molecules to be transported across. Now the heart muscle that, you know, just keeps going and going. Do not want that to stop consuming energy. And adipose tissue is where we're storing fatty acids. So that's important. So you have trisoglycerols are stored there. And we'll think today about skeletal muscle in two states, the resting state and the not resting state or the active state. Okay. So this is an overview of what's going on the liver. This is a central UPS hub of all metabolism. So in the metabolism of sugars, so you can take liver, but there's a lot of glycogen and trisoglycerols that are stored in liver. And so that glycogen can be made in certain instances, but you can also take the glycogen and degrade it down through glycolysis into pyruvate. Pyruvate goes into the matrix of the mitochondria or actually, yeah, put you in the matrix of mitochondria and gets converted to acetyl-qua. Acetyl-qua can be used in the Krebs cycle, but also in fatty acid synthesis. Okay. And the pentose phosphate path, remember that's the pathway that takes one of the glycolytic intermediates and converts it to ribose 5-phosphates, which is important in navalism of nucleotides. Okay. So one of the main roles of the liver is to provide glucose. Add all costs to the rest of the organs in the body. So glucose is central. And so amino acids can also be processed in the liver. So liver can receive proteins from the diet or also we can receive alanine, remember from, which is ammonia coming in, hitching a ride on pyruvate from the degradation of amino acids in the periphery. And so, and alanine can converge pyruvate as we've already said. And so these amino acids can be ketogenic or glucogenic, if they're ketogenic, then you can't use those to fill up the TCA cycle. So they form acetyl-qua, for example. And so those are used in the synthesis of ketone bodies. Okay. So this is boring because we've seen it all, but it's sort of nice to say, oh, okay, yeah, yeah. And to bring it all together. So when you're studying for, this is going to be the last lecture, thank goodness, for the second exam. So actually the lecture, the welcome back from spring break lecture is not on the exam because we think that you should be relaxing in spring break and you can study when you get back. So this is important. We didn't always do this and the students expressed their opinions on our welcome back from spring break midterm, which we used to have. Okay, so, but use these slides. As you're looking at the details in all the other lectures, this is the big picture of everything. Yes, you can relax. Hopefully many of you are going to Florida in nice sunny places. I'm working on research grants myself. Not in Florida, unfortunately. Okay, so lipids are also metabolized in the liver. So remember, acetyl-CoA is central in that. So fatty acids can be synthesized. Acetyl converted to malonyl-CoA, assembled into fatty acids. Those can be transported out of the liver. It can hitch a ride on these plasma, lipoproteins, these particles we've talked about. And so fatty acid beta-oxidation does not lead to pyruvate. It leads exclusively to the synthesis of acetyl-CoA, which can go in many directions. It can go into the Krebs cycle. It can be transported to another tissue as a ketone body, regenerating the acetyl-CoA and the mitochondria of the not-liver tissue. Or it can be used to synthesize cholesterol. And so cholesterol is one of the seed molecules for a large family of steroid molecules. So you can see, liver is the most unselfish organ out there. So it's providing, it's receiving some of the fuel from the diet and then it's distributing this fuel around the body in a variety of forms, ketone bodies, glucose and fatty acids. And so adipocytes are also not that selfish. So they're a place where we can store our fat in form of these triacylglycerols. And so these can be stored in there. And then when we need them, we can extract them out. And so there's two different types of adipose tissue, so-called white adipocytes and brown adipocytes. So the brown color comes from the high density of mitochondria, literally makes those types of fat cells look brown. So while this is used for storage, the primary role here is not necessarily storage. Can you imagine with so much mitochondria, what might be the reason to have brown adipocytes or brown fats? Yeah, so heat production. So this is actually babies.  And so they have this brown fat, a large amount of brown fat, and that just uncouples oxidative respiration to generate heat.  And then over time, they build up some of the white adipocytes, or a larger amount, and they don't need this sort of built-in heater. So this is a time-sensitive type of cell. Now, we do have some brown adipocytes, but mostly these white adipocytes, which are just storage places for fatty acids. Okay, so the brain, this is sort of a parasite.  So right now, like in all your heads, you're trying to understand what in the world I'm trying to say, 15% of your lunch is going to what's going on up in your brain. Your brain's not doing anything besides thinking about things. There's voltages. There's electricity up here. So there's a lot of energy is used in the brain. And so brain would very much prefer glucose. But, you know, if it gets really bad, it'll take ketone bodies, because those can be still respired aerobically, right? So ketone bodies, when they come to the brain, they get regenerated as acetyl-CoA, and that feeds in the Krebs cycle. And so in the brain, we don't really have this problem of decreasing the Krebs cycle intermediates, because we're not doing gluconeogenesis in the brain. We're not making glucose there. So all we've got to do is just keep delivering acetyl-CoA equivalents to the brain. And one of the most common, remember we learned there's three different ketone bodies? One of the most common ketone bodies that's used as the preferred ketone body in the brain is beta-hydroxybutyrate.  Thinking back to that lecture, I ask questions that slow us down periodically. Hi.   Like, is the harder you think, right? Oh, wow. Like, if I got really confusing or acted irrational, would you, would that generate more energy? I don't know. You might want to ask a neuroscientist that, whether, I don't know that we know enough details yet, but you could probably track metabolic usage using some kind of imaging so it could stick you in MRI, and I'll say something crazy and see, like, how the energy is affected by this. It's a fascinating question that I don't have an answer for. Probably not, yeah. Sounds like there's some neuroscientists in here. So back to our ketone body, beta-hydroxybutyrate. Can you think about what that, why is that preferred? And hence, there's one, one of those ketone bodies was not quite like the others. Do you remember why? The courageous guesser in the audience? Is that good? That's right, that's okay. So an important observation is that it has an alcohol group instead of a ketone. One of the ketones has been converted to an alcohol group. So why does that make it happier molecule for the brain? Unlike the others, one of the ketone group has been converted to an alcohol. What kind of chemistry is that? Oxidation reduction. And so this is that one special ketone body that's able to transport an NADH equivalent. So every beta-hydroxybutyrate that comes into the brain, that's 2.5 ATP equivalents arriving in the brain because that NADH that was deposited and the reduction of the ketone to the alcohol in this molecule can then be re-harvested when you re-oxidize in the brain that alcohol back to the ketone. So you can go back to the slides, but that generates NADH. So it's a way to transfer that's helping metabolism. We just want to generate as many ATPs as quickly as possible and that helps us with this goal. But for acetyl-CoA equivalents coming in that aren't in this reduced state, you're able to get less energy out of those molecules. And so the brain is just taking that ATP and converting it to ADP, driving a lot of it as electrical. So transport of molecules across membranes is very important in your brain. So the battery charger, remember, is that sodium-potassium-ATPA sets up the gradient that allows you to do electrogenic transport. Many of the molecules transported in the brain are charged molecules, so the voltage across the bilayer is important in that process. Okay? This is enough brain? So, yeah, if you're bored, does it use more ATP or less? That's another question that might be relevant to today's lecture. So here is the usage. So here, what happens if you starve? Look at the time scale here. This is not zero to 40 hours. This is zero to 40 days. So say you just, day zero, you just stop eating. You know, you have to have a little water, but so you have no food at all. What's going to happen if you look at metabolites? So you have glucose, and there's no longer glucose coming in for your diet. So there's initial time where glucose levels drop slightly. But then the liver says, okay, let's go, let's go, let's go. And so it turns on gluconeogenesis at the highest rate as possible. And so, and you immediately begin to, you actually have fatty acids being consumed. So they're being produced at a similar rate as they're being utilized. So these are free fatty acids. And the adipose tissue, they're not free, and they're being released from there, but being taken up, converted into acetyl-correct.  So if you look at people that are starving, they begin to not think straight. And so to try and do something to counteract this, we begin to transfer acetyl-CoA equivalents from the liver up into the brain. Okay, and so this is an interesting way to look at things. So let's think about the muscle. Yes, question? Sure. So acetone is also a ketone body. Yeah, so I don't know why they stopped collecting data. I don't know who collected this data, or whether it's an artistic rendition. But yeah, no, so acetone is used up. It doesn't vanish for sure. There would not be, you know, one day all of a sudden a switch comes on and the acetone D, or acetone-eating enzymes, like, go into ultra-high gear. So yeah, I think that's just a, they stopped collecting data. Maybe the student was not well-fed, and he stopped collecting data. Do you do? Do you think bodies are used on the extent of period because they start damaging like neurons in the brain? Yeah, I mean, so if there's an insufficient amount of energy, you could eventually cause brain damage. And a lot of it has to do with the exact amount of glucose. The brain-damaging area is pretty far out. But yeah, the brain, if you started for too long, you could do damage there. But the goal here is, and the lucky thing is that with the combination of synthesis of ketone bodies and gluconeogenesis, we're able to sustain ourselves for a pretty long time and then recover once we find some food. Okay, any other questions? Yes? Is there any specific ketone bodies that contribute to cell death? No, no. It's just, if you have just, if glucose levels go too low, I mean, glucose is still better than ketone bodies. You get another NADH out of there. Well, I guess it depends what ketone body and you actually get an ATP. No, it's not like there's some kind of direct, that's an interesting question. Are solvents bad for cells? Like acetone, you put acetone on plastic. Let me say that's a ketone body that seems like it would melt membranes or something. But yeah, I'm not aware of how it's possible. Acetone's pretty nasty stuff. But yeah, I think it's mostly just from not having enough fuel. Okay, that's a guess. I'm speculating. Okay, any other questions? Okay, so we have ketone bodies. No, let's go into the muscle. So in the muscle, there's two different states. There's the running around state and the resting state. Okay, and so what you're able to do is when you have a large amount of activity, the muscle has some amount of storage, direct storage of glycogen. And it makes sense that there's a little bit of fuel stored in your muscles because sometimes you need to move quickly.  You can't just wait for your liver to provide some fuel. You need to have some glycogen. There's actually two different types of energy. So this is, I would consider, a fuel, glycogen, because you can actually burn it. You can cause it to become oxidized, generating an ADH. This other molecule, phosphocritin, is also stored in your muscles. Maybe some people that are athletic might know about creatine. So this is a molecule that is the conversion of creatine to phosphocritin, converting ATP to ADP, stores ATP equivalents in a cell. So the levels of ATP are actually reasonably low. It's still, I think, a millimole or something, but there's a lot more phosphocreatine or creatine that's available. So if we just had ATP, an ultra-fast, quick fix for energy, that wouldn't be good. So we store some extra ATP equivalents in this phosphocritin molecule. Remember, this is this idea of substrate-level phosphorylation. This molecule, its hydrolysis, is going to be more exergonic than ATP hydrolysis. And so we use ATP when the muscles are doing work and convert it to ATP. And so when we're resting, we need to replenish these stores. We need to replenish the phosphocritin and the glycogen, and that can be done in a variety of ways. You can have fatty acids being fed in, ketone bodies if you're in that metabolic state, or glucose. So glucose is always coming into the muscle, and it can be used, obviously, both when you're resting and when you're active. And so muscles are important consumers of energy. They're not really providing energy for other types of cells. Okay, so here's this molecule, creatine. This is short-term storage of a molecule. I would not classify as a fuel, because we're just storing ATP equivalents. There's no readout. When you think fuel, you think burning gas or something. So this is just storage of ATP equivalents. Okay, and so the way it's made is by combination of amino acids. So we have arginine and glycine coming together. The guanidinium group from the arginine is transferred to glycine, the amino group of glycine. We then add a methyl group to this nitrogen here. So methyl group is provided by a SAM, this adomet cofactor. Remember, SAM is made when you add an amine to a methionine, and that causes, remember, the positively charged sulfur. And then you have the methyl, and so when you remove that methyl, it's a great methyl donor. But we need methionine, and that's providing the methyl group. It gets loaded on the prosthetic group here and then transferred from this molecule to make creatine. Now, phosphocreatine is simply the phosphorylated version. And so enzymes that add phosphorylation are called kinases. So creatine kinase adds a phosphate to this guanidinium group, and that makes phosphocreatine. And you might remember we had that table that had lots of different sort of phosphorylated molecules, and we had ATP. And we're thinking about, you know, what's more exorbitant hydrolysis of these molecules or ATP? And remember, we talked about it. A lot of times it has to do with resonance. So here, you know, two products of this hydrolysis have resonance. This creatine molecule is where as an inorganic phosphate, whereas when you hydrolyze phosphate off of ATP to make ATP, there's just the inorganic phosphate. So this is the transfer of a phosphate to creatine is an exogonic process, right? Yeah. And you can release it when you... Yeah. And so you can take that phosphate and transport it back to... Actually, this is actually the opposite. So when you take phosphate, recover it from phosphocreatine, put it on to ADP, that is a negative... It's an exogonic process, a negative standard change in free energy. Okay, so this is a temporary storage place for phosphocreatine, or for ATP equivalents. Okay, so phosphocreatine is a new thing to us. Chloracyl, not really new. It has the scary word cycle. But really, this is very, very similar to a similar cycle that we saw with alanine. So the only difference here is the thing being transported is lactate. Okay, and so the purpose of the Chloracyl is to transfer metabolic burden from the muscle to the liver. So the liver is where we have tons of glycogen. We have lots of fats stored. Okay, and so this process is illogical when you think about it thermodynamically because we're just burning ATPs, right? So every time you go through this cycle, you have glycogen going through glycolysis to make lactate. Remember, that's important. We regenerate our NADH. Lactate is removed, but then we need to use... So we make two ATPs here in the net, and we use six ATP equivalents regenerating glucose. And so that's wasted at four. ATPs are wasted with this cycle. But the benefit is that we can store all our energy here, and muscles can focus on being muscles. They don't have to provide lots of room for storage of energy. So that's all stored in the liver and transported in the form of glucose. Okay, so gluconeogenesis is... the majority of gluconeogenesis for export of glucose is occurring in the liver. Okay, does this make sense? So it's very, very similar to this alanine moving of ammonia out of tissues, yes. Is the muscle is storing lactate which has been removed? No, the muscle is quickly as possible. Unless you're really working on health, when you feel burning, that's when the lactate is not completely being removed, because it literally is a carboxylic acid in your tissues. But generally, if I'm just doing this and I don't feel any burning, then the majority of the lactate is being exported out and being going to my liver. My big liver. Okay, any other questions? Okay, so that's the so-called corey cycle. Yeah, and it's not 100% efficient if you think about the whole organism, but it allows muscles to be more efficient, right, because you don't have to waste ATPs here. You're doing nothing but harvesting ATPs in the muscle. This is a very important chart, and it's important that you know this chart for exams. This is summarized. I always ask questions at some point in the class on this chart. So this is a summary of all the different important tissues in metabolism. The fuels that are stored. Now, I'm defining fuels as something that you burn, right? So the way that these tissues store fuel, if they do store fuel, they're preferred fuel, and what, if anything, they export. Okay, so we've talked about the liver, and so liver is, there's a large amount of glycogen and trisoglycerals in the liver. And liver is very ambidextrous. It's like, yeah, whatever, amino acids, glucose, ketone bodies. It doesn't really care. Now, this one, I don't really, doesn't seem to make much sense. So I guess if other tissues are making ketone bodies, you could use it as fuel, because it wouldn't make sense to make ketone bodies in the liver and use them in the same place. That would be a feudal cycle. So, but yeah, so the liver is using basically anything it can get that it can use as a fuel, and it's exporting fatty acids. You know, so you can have beta-oxidation in the liver. It's exporting glucose through gluconeogenesis, or by rerouting, glucose coming in from the diet goes through the liver and then gets rerouted out of the liver. So adipose tissue, this is the fat tissue.   And then they're able to export the cleavage products of trisoglycerals. So when stored, so the fuel comes to the fat cells as fatty acids, but then it gets a symbol to trisoglycerals in this fat globule.  But then if you want to harvest that fuel, you have to cleave up the fatty acids from the glycerol molecule in the trisoglycerals, and that's what's exported. The brain doesn't export anything, doesn't store anything. Its purpose is just to understand confusing lectures. And so the brain prefers glucose because that's the most, you know, the energy pack. Well, I guess you could, it could technically use fatty acids, but probably something about the speed of harvesting energy has to do with its preference for glucose. And so glucose is the preferred fuel, but if there's not enough glucose, you have either death or you have ketone bodies. And so you're doing, it's trying to be as resourceful as possible, but you just can't turn off all the circuitry that's going on there. If you do that, then you are not alive anymore. So we use ketone bodies as an emergency. Now we have two states of the muscle. We have the working state. We're not going to be storing fuel if I'm working out my muscles. It's time to consume fuel. We're not going to be exporting fuel, but we are going to be exporting lactate so we can do the quarry cycle. So it's sort of a fuel because a lactate has some ability to be oxidized, right? So you could consider it a fuel, but that's converted through gluconeogenesis back to glucose and fed back up. And so glycogen is the preferred fuel here. But you know, I'm using the strict definition of a fuel, so I do not include phosphocreatine. Although there is some storage of phosphocreatine, it's not oxidized. The energy is harvested just by the substrate level phosphorylation and in synthesis of ATP. Now, skeletal muscle when you're resting, you're building up your stores, right? So you're beginning to store whatever glucose is coming in through the blood primarily being rotted through the blood from the liver. You're storing that glucose as glycogen, and you can use glucose, fatty acids, ketone bodies when you're resting. And it's not a tissue that's important in export. This is a utilization of energy tissue. Hard muscles, obviously, you don't want to be storing fuel. It's just constantly, it's a constantly working muscle, right? And so it has a preference for fatty acids. Because fatty acids, remember that chart? That's the most consistent fuel available. So if you start starving, the levels of glucose start changing. You don't want that heart to be any different rate. You want a rock solid fuel. And so fatty acids provide that security for the heart. Okay? So that's something that you definitely want to put on your list of things to study. Make sure you know that table. Okay, so as you're metabolizing fuel and you stop eating, that can affect your glucose levels. Now, gluconeogenesis will try to keep those glucose levels as high as possible.  But then if you start starving, gluconeogenesis will try and keep up to feed the brain as much glucose as possible. But you begin to have some impacts, physiological impacts. You have trembling and convulsions and lethargy. And, you know, when you get down to about 5 megs per 100 milliliter of glucose, it's not good. You have to have at least a little glucose for the brain to survive. Okay, ketone bodies alone is insufficient. Okay? That's me. All right, so this is our central UPS logistic center here, the liver. And so let's think about these different metabolic states. So if you're fed, your pancreas is going to release insulin. Okay, so on insulin the signal is I've just, you know, had some lunch and there's glucose, the pancreas senses there's glucose in the blood and releases insulin. And that's a signal to the tissues in the body to start using, to switch their metabolic pathways. So insulin, remember, is important in the import of glucose into cells. So patasites, when insulin is present, we begin to have glucose transporters on the surface of those cells. Glucose gets imported. In the fed state, we want to just keep feeding the brain glucose. That's a great fuel for the brain. But we can also begin to make fats, right? And we can metabolize glucose, make energy as well. And these fats can be transported to the adipose tissue. So we're converting glucose coming in to fats and glucose coming out of this tissue. Okay? So that is the fed state. Now we get to the fasting state. When glucose levels drop, the pancreas detects that, stops releasing insulin, begins to release glucagon. And so remember, if you can go back through all these lectures, we had little insulin and like a little happy green triangle or red X or something. So these are produced by the pancreas, this glucagon or the insulin. So when you stop eating, you're fasting, glucose levels go down, glucagon is released. And then the whole metabolic landscape, completely rearranges in the liver. And so you begin to do gluconeogenesis. You want to have glucose levels be as constant as possible to feed the parasitic brain. But then also, from fatty acids, you can begin, you deposited those fatty acids, you know, those went from the liver to the adipose tissue. Now when glucagon comes on, the flow goes in the opposite direction. The fatty acids are released from the adipose tissue, get imported to the liver, where they can be converted to ketone bodies to provide fuel.  So that's fasting. But what if things get really, really bad? So the problem, if things get really bad, the liver will keep trying to make glucose. And it just won't stop as soon as these Krebs cycle intermediates begin to decrease. So we can start processing amino acids. Amino acids could be used both for filling up this reaction, but at a certain point, there's just not amino acids left to metabolize. And at that point, the anaphylactic reactions cannot keep up with the gluconeogenic pathway. But as soon as you use this up, that causes problems. You have accumulation of acetyl-CoA, because there's just not enough Krebs cycle intermediates to metabolize the acetyl-CoA. So we get into desperation mode. We provide much, much less glucose to the brain, sort of a lighter blue arrow, and we provide more and more ketone bodies. So the fatty acids, remember that level of fatty acids, even through 40 days of starvation, is pretty constant. So that's a constant stream, and that's our last resort. Keep feeding ketone bodies up here. But if this drops too low, then gluconeogenesis will completely turn off, and your glucose will dip below that 5 meg per 100 ml level, and that's it. So you always have a little bit of dribble of gluconeogenesis. As you find, perhaps, new stores of amino acids, something to feed into here. So this is desperate state. And so you have increased lipolysis, in other words, released of fatty acids, here from the adipose tissue, increased beta-oxidation. You've got a great fuel, fatty acids going to acetyl-CoA. You make ketone bodies, ketogenesis, and you also try to make ketone bodies from proteins and amino acids as well. But then eventually you have decreased oxalacetate in all the crab cycle intermediates, TCA cycle shuts down, and we have less NADH being produced because the crab cycle is off. Right? Okay. So we're going to switch gears a bit if there isn't any questions. So up to this point, it was sort of magical. You have the pancreas releasing these things, and you all of a sudden had green triangles and red Xs next to your enzymes. What's in between? Is it a direct? Does insulin come into the cells? Find those enzymes, bind to them allosterically? Or is there another route? So there's a variety of different hormones that can be released in your endocrine system. And so from the pancreas, you get insulin and glucagon. Those are released from your pancreas and go into the bloodstream. And then instead of going into cells and binding to those enzymes, they instead bind to receptors of target cells. So we have something called a glucagon and an insulin receptor. But there's another way to do this. So there's other cases where you want to generate a lot of glucose, where you want to simulate a starve state. And that's if something scary is happening. So you guys might have heard of epinephrine or adrenaline.  Those signals from the neurons are converted into release of epinephrine. So this epinephrine then goes into the blood and has also receptors on cells. And those receptors are functionally redundant to glucagon receptors. So the same type of response that you get from glucagon is what you're going to get from epinephrine. And we'll look at why that's the case as we look at the pathways going from the receptors to the enzymes that are the ultimate targets. So this is the whole endocrine system. But in terms of metabolism, these are the critical parts. So you have blood glucose level being directly sensed by the pancreas and insulin and glucagon being released. But then you have these adrenal cells where you have a nervous signal. You see something and it's scary. And the body says, get ready to move. Make glucose. Get going. And so that epinephrine can directly affect target cells. But it can also affect cells in the pancreas. So if you want, you can add an arrow here from epinephrine up into the pancreas. So there's epinephrine receptors on the pancreas and the reception of that signal also turns on the synthesis of glucagon. So both the epinephrine and it's sort of like a reinforcing thing. We want to turn things on in the target cells but we also want to have extra amount of signal to turn things on more quickly by triggering the release of glucagon from the pancreas. So it really should be an arrow there. So these are hormones. There's a lot of different hormones. Many of them have nothing to do with metabolism. We've looked at some of these structures. We know that some of them are derivatives of a cholesterol and you can see a similar structure there. This is epinephrine. So it's a small molecule received by an epinephrine receptor and this unlabeled molecule that you might want to label to is insulin. So insulin is two polypeptides attached to each other by disulfide linkages. And so this polypeptide, small polypeptides released from the pancreas into your bloodstream floats around and lands on a pertinaceous receptor. Glucagon is also a polypeptide molecule that's released by the pancreas. It's just a single polypeptide. There's not two chains there. Okay, so let's think about what glucagon is doing. And so glucagon is responding to low blood glucose and we've seen in the pathways we've looked at that glucagon turns up, gluconeogenesis turns up the breakdown of glycogen, turns down glycolysis, turns down glycogen synthesis. Okay? Now, insulin is an indicator of high blood glucose. This is just a summary of things collected in one slide from previous lectures. And so high glucose increases glucose uptake by movement of the glucose transporters to the cell membrane, plasma membrane. And so if you take more glucose up, there's less glucose in the blood and it's consumed, in other words. Insulin also stimulates the breakdown of glycogen and reduces glucose generation. Yeah, so glycogen breakdown is decreased and glycogen synthesis is increased. You have too much glucose, might as well store some up, make some fatty acids, make some triacylglycerols. Okay? That was an abstract side without the details. Here's a little bit more of the details. Some of those critical enzymes that are affected by these hormones. And so the ones marked with stars are the places of reciprocal regulation. Okay, so for example, glycogen synthase, when you have a... Let's see. So where do we have here? Glucogon. Okay, so glycogen synthase increases when you have insulin. Yep, so insulin. And so when you have insulin, you have increased glycogen synthase activity, decreased phosphorylase. Remember that was the enzyme that degrades glycogen and increased glycolysis. So these are the pathways affected and the critical regulated steps. Whereas with glucogon, you have increased phosphorylase activity, so glycogen breakdown is increased. You have decreased glycogen synthesis, so you have less synthesis, and PFK1 is decreased, so you've decreased glycolysis. Okay? And so this is important to realize that this is referring over here to the liver.  The brain cells consume and consume and consume. You could have as much glucagon or insulin floating around. They're not going to change what they're doing. It's all about aerobic respiration. You know, with that oxygen, within four minutes, that's it. Try holding your breath for four minutes and see what happens.  That's how important aerobic respiration is. Okay? And so the starred molecules or enzymes are the reciprocal regulation steps. And so here's these adrenal glands that are literally hooked in to the nervous system. You have nerves coming down your spinal cord, emanating at the adrenal medulla. And you get nerve impulses, and this gland just starts releasing epinephrine. Okay? And this epinephrine is a small molecule, and it's released when you're scared, when you need to respond quickly. It's an evolutionary adaptation.  You've got to go. And so epinephrine increases glucagon secretion and decreases insulin secretion. So there's this direct feed from epinephrine into the pancreas. Okay. Okay, so let's think of some, there's some metabolic diseases where these hormones are misregulated. And so many of you have probably heard of diabetes. Probably most of you have friends or you yourself suffers from this horrible disease. So diabetes is, the fundamental problem here is insulin is not produced or the insulin signal is not received. Okay? And this affects billions of people. This is a horrible disease. Now in type 1 diabetes, there's actually problems in your pancreas. The insulin never gets produced. You can have glucose, but no insulin is going to come out. So people with type 1 diabetes, you'll see them actually injecting insulin because their body literally doesn't have the cells to make it. In type 2 diabetes, the signal does not get received. So your pancreas makes insulin no problem. But the target cells for whatever reason become resistant to receiving it. So the insulin binds to the insulin receptors if it's even there. But then the signal is going from those insulin receptors to the metabolic enzymes. There's some problems there. There's blockages. And there could potentially be lots of reasons for this resistance. Okay? And so the metabolic consequence of not perceiving or making insulin correctly is to have elevated levels of glucose. So one of the big roles of insulin is to cause the import of glucose from the blood. So if you're not importing glucose from the blood, then you're going to have elevated levels of glucose. And this is the monosaccharide form. This is bad news. Remember, this is a hemiacetal. This is not an acetal safe storage form. This is a hemiacetal. In fact, it's floating around the album hides, right? So this is not good news. And so, yeah, we have blocked the uptake. Gluconeogenesis is stimulated in the liver inappropriately. You've got glucose. Blivers like, dude, I never got the insulin signal. I'm going to make it. I think something's wrong here. And so you even add to the problem. Not only do you have the glucose coming in from your diet, your liver is kicking out glucose. It's like, I didn't see any signals. And so then you also have overproduction of ketone bodies. So many severe diabetics, you can actually smell the acetone on their breath because their body literally is thinking that it's starving to death and is responding in urgent ways, making ketone bodies. And that's obviously not a good thing. Okay. And so this is how it works. You release the glucose on your insulin to the bloodstream from the pancreatic cells, and they emerge out of the bloodstream and are received by cells, target cells. But what exactly is going on here? What is the biochemistry of the cellular signaling pathways when you receive these signals? Okay. Well, it's all fundamentally about receptors. So by definition, a receptor molecule is a molecule that binds a ligand. A ligand could be either a small molecule, like epinephrine, or it could be a small polypeptide, like insulin or glucagon. And this binding, there's two different general large kingdoms of receptors, ones that sit on the plasma membranes and others that don't. Okay. And so steroid hormones, for example, do not need a receptor on the cell membrane because steroid hormones are hydrophobic. Many steroid hormones are derived from cholesterol. Cholesterol is made in this lipid bilayer. So these steroid hormones just come right across the bilayer. They don't need a transporter. But then they bind to a receptor either in the cytosol or the nucleus. If they bind to a receptor in the cytosol, that changes the shape of the receptor and causes it to go into the nucleus. Or the first encounter of the steroid hormone and the steroid receptor could be in the nucleus. And there, a conformational change, in either case, leads to a binding affinity for responsive elements on your DNA. And this leads to transcription. So these are very simple signaling pathways. They go right to transcription. But other pathways, such as the ones that involve insulin and glucagon, involve a lot of different steps in between here. So you have a glucagon or insulin being bound to a receptor that induces an activity which can activate proteins. So it can turn on a cascade of enzymatic activities, amplifying signals, and also you can get the production of so-called second messengers. So the first messenger is the hormone. The second messenger is some other small molecule, right? So technically this hormone doesn't have to be a small molecule, but these small metabolite signaling molecules are called second messengers. And so we're going to see today how insulin receptor or actually glucagon receptor and epinephrine receptor culminate in synthesis of the second messenger cyclic AMP. And so the whole idea here is to cause some kind of change. And so we've seen the outputs. We've seen in metabolism the enzymes with the insulin, you know, green triangle or red X next to them. So that's the output. And those are generally, we've seen some examples of changes of phosphorylation. But what are the exact steps in this process? I've left out the details up to now. And so there's a lot of, if you think about signaling generically, there's receptors, and the binding of a ligand to the receptor in general induces a conformational change. Very much like how the binding of an allosteric regulator to a protein or an enzyme can change its activity. But then you know this receptor can change its shape and that can either turn on an intrinsic enzymatic activity in the receptor or option B is it can cause the new association of new proteins or disassociation of proteins from the receptor. Okay, we're back in business. So with these signaling pathways, if you have enzyme activating enzyme, activating enzyme, at every step more than one substrate is turned over. So we don't need to make, you know, the number of insulin molecules does not need to be the same as the number of end target enzymes that are turned on. We can just make a very small amount of the insulin molecules. And because these insulin molecules activate a cascade of enzymatic activities, we can amplify that signal millions of fold in cases. Okay? We can have elegant regulation affecting the sensitivity of the signal by having so-called feedback regulation. This can be positive and negative. We're not going to really go too much into this, although it does occur in the insulin receptor signaling pathway, but we're going to leave a lot of that out. You can integrate signals. We'll see an example today of a so-called scaffold protein. They can receive multiple signals from multiple sources, combine those signals and have an altered input or a more intense output, altered output or a more intense output. Okay? So there's lots of different general signaling. So we're going to be talking about signaling from a wide-scale overview, as well as its role in metabolism. There's all kinds of different signaling pathways. Many of you have probably thought about these, seen these. Maybe even some of you have done research on these signaling pathways before. So we have G-protein coupled receptors. Those can cause the synthesis or the binding of the ligand to those receptors, induces release of a so-called subunit of a G-protein. That G-protein can then drift off and bind to an enzyme turning the enzyme on. And so we'll see an example of that. Whereas receptor kinases, so the binding of the ligand induces aggregation of the receptor, change of conformation, which turns on a kinase activity in those enzymes. You can skip all those G-protein mess and get right to the business of making a cyclic second messenger so you can have some receptors, you bind a ligand, and you directly make a second messenger. You don't have to have proteins moving around. We've thought in our lecture, in lecture six about how we can regulate an ion channel, so the binding of a ligand to the ion channel can open or close it. The glucose transporters are not such ligand-gated channels. They're regulated by the localization. And then some of these things can lead into many outputs, change of phosphorylation of metabolic enzymes or change in transcription or activation of protein turnover. These are general classes. Let's dive into each step. The epinephrine receptor or the glucagon receptor are the same basic thing. They're different receptors, but the output, cyclic AMP, is identical. They both work the same way. Let's look, for example, at this receptor. The binding of the epinephrine ligand to this receptor causes this heterotrimeric G-protein to exchange an associated GDP molecule for a GTP molecule. So when this ligand binds, changes the conformation of this protein, kicks out GDP, and there's actually no discrimination of what comes in, but cellular levels of GTP are about 10-fold higher than GDP. So if GDP comes back in, nothing's going to happen. But if GTP comes in, this thing changes conformation and is released from this complex. So there's this alpha-beta-gamma subunit, and the alpha-subunit is released when GTP binds. And then the GTP bound form of the alpha-subunit of this G-protein binds and changes the conformation and activity of an adenolil cyclase. And this takes ATP molecules and converts it into a cyclic. The first phosphate wraps around in binds, makes a new covalent bond to the ribose. We'll see that in a second. But the output, so we've made a cyclic AMP, that protein or that small molecule can activate a kinase. And that kinase is called one of the most important protein kinase A. So it's like number one, PKA. It's a very important kinase. And that kinase then phosphorylates the metabolic enzymes. And so let's think about this G-protein in a little bit more detail. Not only do we have this change of conformation when we go to the GTP bound state, but we also have intrinsic turnovers. We would have a state of cancer if we turn the signaling pathway on and if we had no way to turn it off. So it's efficacious for us. We only want this pathway on when we're in a starvation or a scared state. As soon as that goes away, we want this to turn off. So even if you remove the glucagon, this thing is still here, bound here. So this alpha subunit, as soon as you bind GTP, you start a clock. And within a certain amount of time, there's an intrinsic phosphatase activity and that GTP is cleaved to GDP. And so you have just a certain amount of time. If you don't find an admiral site-place to bind to, you're not going to activate anything. So after the clock has expired, you go back to the GDP form, which cannot bind admiral site-place, and that eventually finds its way back to reconstitute the trimeric G-protein. So there's a recycling here. And so Calera does something bad to this and makes a toxin. And this toxin adds a modification, a covalent modification to the alpha subunit. And so this inactivates the GTPase activity. So this is bad news, right? So as soon as you get that one protein receives its GTP, you're never going to hydrate it off and it'll just keep making cyclic AMP until the protein is degraded. And so this is bad. You're going to have inappropriate... When you have a meal, it'll just keep going. It'll keep sending this signal that you're starving when you have a meal. So this organism can actually affect that phosphatase activity. So it's really important. You're in a bad shape if you can't regulate the turnover of this activity. So not only do you have a problem with the turnover of this activated G-protein, you've also made a small molecule second messenger that also is in a sense an activating molecule. So you're going to need a way to degrade that as well. If you just make cyclic AMP and it stays forever, every time it finds it, every pKa in the cell will become activated. And so we need to be able to turn the signal off here as well. And so there's a cyclic nucleotide phosphodiesterase, which is just sort of roaming around the cell and it finds its victim, the cyclic AMP, and converts it back to AMP. So it reconstitutes the original form here and turns off the activation. And again, this is a clock. So you have a clock here in this phosphatase activity, in the alpha-sylvenin and the G-protein, and you have a clock for how long cyclic AMP lasts. There's things that just go around and take them apart. But you might still be starving, right?  So you continually need to reactivate the signal. So this is a beautiful structure of cyclic AMP. So you have ATP, this adenolial cyclase, converts to AMP, so you have this first phosphate making a new phosphoester bond to this 3-prime position. And this is an alternate form of this metabolite, or this small molecule, which can act as an alasteroid regulator of PKA. Okay? So this makes sense so far. We're regulating. We turn it on, but it's actually always going on-off, on-off, on-off. As soon as the signal goes away, there's no more on. But when it's on, it's on-off, on-off, on-off. And it's just a matter of seconds before a signal that's turned on is then turned off. So we have a question from the audience. So why is there a constant supply of fatty acids that are not fasting-composed? Because there's a lot of fat cells. So it just has to do with, depends on the person, right? So as you're fasting, there's a lot of room to pack these fatty acids. Okay. I know there's a lot here. So we have, here's this concept of activation. Let's think of it in the context of epinephrine. So say we have one epinephrine receptor, single small molecule of epinephrine that binds and activates the alpha subunit of the G-protein. And this could potentially bind. So this could come off. Another inactive G-protein could come in and you could still activate here. Depends how quickly you remove this epinephrine from the receptor. So you might activate about 10 molecules of the alpha subunit. That turns on an enzyme and will cyclase. So for every single and will cyclase turn on, you're going to make maybe 20 molecules. So you've amplified your signal to 200 molecules. Now, cyclic AMP, as soon as it's made, it's either degraded or it finds a pKa. So not every pKa would necessarily be activated here. So you might lose a little signal in the activation of pKa by cyclic AMP. But then you're activating a kinase, which activates a phosphorylase and enzyme. This phosphorylase can affect the production of glycogen. So when you go through all these steps, these are all amplification steps. So you get from one molecule coming in, you get 100,000 molecules of glucose being released from glycogen. It's a very efficient. You don't want to flood your bloodstream with insulin. It would be metabolically wasteful. It takes a lot of energy to make a polypeptide. This is this phosphorylase kinase we saw on an earlier slide in an earlier lecture. And that's here. And that's actually getting phosphorylated by pKa. Okay? Tyrosine kinase. So an insulin receptor is a tyrosine kinase. The binding of an insulin receptor causes the aggregation of the receptor, causing intrans phosphorylation. So one kinase molecule phosphorylates the other. This phosphorylation takes a substrate blocking appendage of the kinase and gets it out of the way. And so when this kinase becomes activated, phosphorylates this loop, which is sitting in the substrate binding site, the kinase substrate binding site. It becomes phosphorylated, that gets it out of the way. Now you can have the binding of targets of this kinase. Okay? So this is an insulin receptor. We know kinases add phosphate, phosphatases take the phosphate off. Here we're talking about tyrosine kinases, in the case of insulin receptor. Okay? So this is an important slide. We need to get through for the clicker. And then we'll skip to the clicker. So the insulin receptor gets activated. That leads to phosphorylation of IRS-1, a scaffolding protein with no enzymatic activity. That phosphorylation leads to recruitment of GRB-2, an adapter protein with no enzymatic activity. GRB-2, bound to the IRS-1 phosphorylation site, changes conformation. The change in conformation leads to binding to SOS, son of 7-less, very scary sounding protein. That protein is a guinean exchange factor. RAS is active in the GTP bound form. So RAS, again, binds GTP when son of 7-less binds to RAS. And that binding of son of 7-less to RAS causes GDP to be released, GTP to be bound. RAS changes conformation, binds to RAS. RAS kinase. RAS kinase activates MEK. MEK kinase. MEK kinase activates ERK. ERK kinase. The phosphorylation version of ERK moves into the nucleus, where it then phosphorylates a transcription factor, making a metabolic output. The other output, so that's a transcriptional output. So IRS-1 can become phosphorylated, and that leads to recruitment of a kinase. You know what's happening? No, this is a lipid kinase. This PI3 kinase is a phosphotide nostril 3 kinase. And so that phosphorylates in a nostril containing lipid from a bisphosphorylated form to a triphosphorylated form. This new lipid then binds to a kinase. That kinase becomes activated. In that one, that kinase phosphorylates another kinase. In that, instead of turning on that other kinase, it turns it off. That kinase, if it's on, inactivates glycogen synthase through phosphorylation. So this is, insulin comes in, turns off the inactivation of glycogen synthase. And so glycogen synthase is then turned on. Just think, ain't no thing. So it's a double negative. So this negative counteracts this negative turning it on. Because there's nothing there to turn it off anymore. Okay? You got it? No? Maybe we'll see how you guys do on the clicker. I'll know whether you've got it. And if you don't, we'll discuss it more and maybe give you some more time. I'll give you some hints. Yeah. I can't hear you? Yes. Yes, PKB and AKT are the same things. PDK1 phosphorylates PKB. Not the best.