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[Assistant] So that bacteria and viruses can't reproduce as well. So we're going to increase body temperature.


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[Assistant] To make it less of a good environment for bacteria to replicate.


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[Assistant] Hasn't made it to the textbooks yet, but we actually also are realizing that immune cells travel better when it's hot too. Uhm, they travel around the body better.


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[Assistant] So uhm, we're going to see these kind of changes in body temperature.


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[Assistant] What's another word for an increase in body temperature? What do you usually call that? Yeah? Fever! Uhm, so these inflammatory cytokines are leading to fever.


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[Assistant] This is showing some of those effects of the inflammatory cytokines on the liver to make that acute phase response, on the bone marrow to release more cells, on the brain, uhm, where they can do things like, uhm,


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[Assistant] Impact body temperature. Sometimes they can make you feel a little sleepy. Uhm.


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[Assistant] Lethargic, muscle pain, no appetite, nausea, kind of feel blah, malaise is an official term for that. Uhm, so notice.


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[Assistant] That many of these are the things that you think of as being sick.


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[Assistant] Yeah, they're not anything a microbe did to you. They're things that your immune system did to you. They are actually signs that you're


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[Assistant] And part of that is actually to make some of those metabolic changes for fever.


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[Assistant] So what I'd like people to realize is, you know, know that these symptoms are actually signs that your immune system is doing something. Uhm, I...


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[Assistant] Often, I am planning to get, uhm, some vaccines later this week.


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[Assistant] And I assume I will have a little bit of fever and a little bit of aches and things like that.


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[Assistant] Whenever my friends get vaccines and they complain on social media about like, oh, I feel crappy because I got my vaccine.


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[Assistant] Yeah, you're supposed to. That means your immune system is doing its job.


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[Assistant] And I always write a comment like, I'm so glad to hear that your immune system is working as it should. And no one has punched me yet. Uhm, they would definitely have thought, I'm pretty sure they definitely thought about it.


[User] Please transcribe this text

[Assistant] So uhm, realize that uhm, you know, these, these physiologic signs, these physiologic things that you are feeling,


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[Assistant] Are in fact signs that your immune response is happening as it should.


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[Assistant] Uhm, I also just have a list here. We've been talking about cytokines, and specifically we've been talking about inflammatory cytokines.


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[Assistant] Every so often I have some students who look at this and are like, oh.


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[Assistant] All cytokines are inflammatory cytokines. No, that's just one kind of them. There's other kinds of cytokines.


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[Assistant] There actually are anti-inflammatory ones. There are survival cytokines. There are all sorts of kinds. So we're talking about a specific kind, the inflammatory kind.


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[Assistant] Don't think that all cytokines necessarily are inflammatory.


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[Assistant] Our macrophage that was living in the tissue.


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[Assistant] Detecting bacteria that has entered.


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[Assistant] Making inflammatory cytokines as a result of PRR signaling.


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[Assistant] Uhm, and we have those cytokines making changes in the local vessel as well as hemokines calling in other cells.


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[Assistant] Now we can have additional cells coming into this area.


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[Assistant] And those invading cells are going to be able to kill bacteria.


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[Assistant] Uhm, and in particular these invading cells are neutrophils now, uhm, as opposed to macrophages. Yep.


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[Assistant] If you look in most immunology textbooks, you would not think so. However,


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[Assistant] Uhm, more and more we realize the answer is yes. In fact, many important proteins in the blood clotting cascade are either made downstream of the acute phase response or are actually made by the macrophage because of PRR signaling.


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[Assistant] Uhm, and those are, and to be honest with you, I didn't even totally understand that until the COVID-19 pandemic. Uhm, when we started seeing patients having weird things going on with blood clotting. So the answer is yes, uhm, it's perhaps not well understood, and sometimes I'm like, hey, immunologists, uh,


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[Assistant] You know that fixing the wound probably should be something our system does too. We should probably think about that. Uhm, so wound healing is kind of this newer area.


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[Assistant] And blood clotting falls in with air too.


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[Assistant] Neutrophils who are going to come to the site of infection and try to get rid of the microbe.


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[Assistant] And the neutrophils will do that process by phagocytosis. So you can see that the neutrophil will.


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[Assistant] Uhm, actually extend its membrane out and make a little compartment around, uhm, the microbe.


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[Assistant] Uhm, the process, this process is called phagocytosis. And so when the cell gets a new compartment,


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[Assistant] Because it wraps a membrane around the microbe.


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[Assistant] We call that new compartment the fagazole.


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[Assistant] Cause it was an organelle made by phagocytosis.


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[Assistant] That phagocytosis, that phagosome will then, um, fuse with other granules in the cell, um, and go through some other changes to become very acidic and


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[Assistant] The bacteria will be completely destroyed. You can see that same process in a figure from your textbook here.


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[Assistant] So here you can see the neutrophil, uhm, starting to engulf the microbe.


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[Assistant] Makes a phagosome, that new organelle that was created by phagocytosis. And some of the different granules in our granulocyte, in our neutrophil, will fuse with the phagosome.


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[Assistant] So that we can destroy everything that is in that, uhm, that five zone.


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[Assistant] Some of this happens because of different chemical compounds.


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[Assistant] These chemical compounds are made through a process known as respiratory burst.


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[Assistant] And they include things like superoxide, hydroxyls, hydrogen peroxide, hypochloric acid, as well as, these are all reactive oxygen species, as well as some reactive nitrogen species.


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[Assistant] Peach goes, uh, down, more acidic. Yeah.


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[Assistant] Uhm, there are also a number of different enzymes.


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[Assistant] In those granules that will, uhm, help to break down those microbes.


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[Assistant] And then one final thing will happen. And this is the final thing that I'll leave you with today. After the neutrophil goes through this process of doing phagocytosis and killing microbes, the neutrophil dies.


[User] Please transcribe this text

[Assistant] Those neutrophils will probably get phagocytosed by a macrophage in order to recycle nutrients.


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[Assistant] Uhm, but the neutrophils don't live that long and you actually already knew that the neutrophils die?


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[Assistant] Uhm, because you may have seen a collection of dead neutrophils on a wound before, which is pus. So that white icky stuff.


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[Assistant] That you see when you have a wound that's healing, that's pos- that's all the dead neutrophils.


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[Assistant] If you are ever going to make a lecture about this, do not do a Google image search for pus to try to put an image on your slide because you will get things you didn't want to see.


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[Assistant] Uhm, so I will see you guys here tomorrow for lab. The lab handout is already posted. Uhm, you're gonna wanna make sure that you have it and are ready to go tomorrow. You definitely need lab coats tomorrow. Uhm, so I'll see you tomorrow.


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[Assistant] Have you looked for other ways of innovation in foreign politics than technology?


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[Assistant] The Greenwood Boys are a group of pop singers.


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[Assistant] We were going to Darwin and we come to the crossroads. Either come back here or go to Darwin.


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[Assistant] I said to Jane, do you really want to go to Darwin? She said, no I don't. I said, good. And we came back here. And done some more fishing.


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[Assistant] By now we know a lot about cells. We have a decent idea of how the first prokaryotic cells formed. We know how they merged with one another to form more complicated eukaryotic cells. And we know about a variety of unicellular life.


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[Assistant] But humans and all the other animals that have ever existed are multicellular. We are made of trillions of eukaryotic cells. So how did multicellular life come about, and how did it eventually transform into the wide variety of species we see today?


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[Assistant] Also, how is it that so many species seem so well suited for their environment, able to swim and jump and camouflage themselves?


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[Assistant] Why do so many different species have such similar features?


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[Assistant] Later we will talk about evolution on the grandest scale, but first, let's ask a simple question. At some point in biological history, a single cell divided into two identical cells, but instead of staying separate, they stuck together.


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[Assistant] How did they do this, and how do different cells in the same organism become different from one another?


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[Assistant] We can learn a lot about this by looking at an animal's zygote.


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[Assistant] Animals reproduce sexually with meiosis in the reproductive organs yielding haploid gametes, those being a sperm and an egg. When the sperm fertilizes the egg,


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[Assistant] This yields a zygote, a single cell with all of the genetic information from both parents.


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[Assistant] This will undergo cleavage due to mitosis, which we have learned about, to yield two cells, then four cells, then eight cells. This eventually results in a blastula, which is a hollow ball of cells surrounding a cavity called a blastoseal. This is where things start to get specialized.


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[Assistant] Gastrulation is the process by which these cells will fold into layers of embryonic tissue that will eventually line the animal's digestive tract, and all the other tissues and organs will later form in a similar manner.


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[Assistant] So what happened over half a billion years ago when animals first evolved?


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[Assistant] Researchers look to unicellular protists, like choanoflagellates, and see that they are incredibly similar to collar cells on certain sponges.


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[Assistant] This and other data leads us to believe that ancestors of animals looked like this.


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[Assistant] In order for these to become multicellular, they had to evolve new ways for cells to stick together and communicate with one another.


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[Assistant] We don't yet know with certainty precisely how this happened, but with what we know about gene expression, it's not much of a stretch to see how novel proteins could come about in coanoflagellates that would serve these functions.


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[Assistant] So just the way endosymbiotic theory showed us how unicellular organisms came together to form more complex cells by way of a symbiotic relationship


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[Assistant] We can imagine how individual cells produced during mitosis could also become an individual organism through the advent of cell specialization and the mutual benefits that are then enjoyed by all the cells in the organism.


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[Assistant] In order for cell specialization to occur, all that has to happen is for different cells to receive different signals that each guide gene expression in that particular cell, because gene expression dictates all of the activities of the cell.


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[Assistant] We know a bit about the regulation of gene expression, so we can imagine that certain cells are receiving signals that result in the expression of particular genes that produce a particular shape and set of functions for that cell.


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[Assistant] In this way, cell specialization accounts for all of the different types of cells in an animal, from muscle tissue to a neuron to any other type of cell.


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[Assistant] Then this mass of different specialized cells must assume a specific three-dimensional shape, and this process is called morphogenesis.


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[Assistant] So one might ask, how is it that the different chemical signals reach the correct cells for all of this to work out just right?


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[Assistant] Much of this comes from cytoplasmic determinants that are already present in the cytoplasm of the mother's egg cell.


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[Assistant] This cytoplasm is not homogeneous, and there are various RNA molecules, organelles, and proteins distributed unevenly.


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[Assistant] This means that after a couple rounds of cell division, each resulting cell will have a different quantity of these determinants, and this plays a large part in determining the fate of each cell, as these play a part in cell differentiation.


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[Assistant] Then once the number of embryonic cells grows to a certain extent, the environment surrounding a particular cell will also play a huge role.


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[Assistant] Some cells will secrete signals to neighboring cells, so this has the effect of coordinating the activity of all the cells in a particular area, through a process called induction.


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[Assistant] Once a cell is determined to be a particular type of cell, it will become that type of cell, even if removed and placed in another part of the fetus.


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[Assistant] This is because events have been set into motion whereby certain genes are expressed and others are not, which results in the production of proteins that are specific to a particular type of tissue.


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[Assistant] So it really is the presence or absence of various signaling molecules early on that results in widespread and directed cell differentiation within an organism.


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[Assistant] But an organism must also establish a body plan, and superimpose this on the developing cells. This begins early on in the embryo when the general axes of the organism are established.


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[Assistant] This means that left and right, top and bottom, and back and front are decided.


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[Assistant] This is all controlled by positional information, again provided by cytoplasmic determinants and inductive signals.


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[Assistant] There are also genes that code for substances called morphogens that help develop these and other features of an organism, like where a head or tail will go.


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[Assistant] Now that we know how cell differentiation happens for embryos, it's just a small leap to understand how chance mutations in the genome of unicellular organisms could have resulted in the first basic multicellular life.


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[Assistant] Which blossomed into a huge variety of species during the Cambrian explosion around half a billion years ago.


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[Assistant] From there, life evolved in countless ways to eventually produce human beings that can think and feel and wonder about how they got here.


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[Assistant] Evolution is something of a hot button issue in certain circles, and to those who don't study biology, it seems like a gigantic leap of faith.


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[Assistant] But the field of evolutionary biology comprises a mountain of evidence for our current model of the descent of man. So let's get through some of this information next.


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[Assistant] Just arrived on the Coburg Peninsula. It's about 300 kilometres northeast of Darwin and about as far north as you can get in Australia's top end.


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[Assistant] And for as long as I can remember, I really wanted to come here because about 25 kilometres to the east of here, a chapter in Australia's history unfolded that I think is one of the most extraordinary in the whole history of the continent.


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[Assistant] In the early 19th century, this was the frontier for European settlement in Australia's north. A tantalising prospect for any explorer.


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[Assistant] Even today access is limited to boat or plane in the wet season or one long dirt road in the dry.


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[Assistant] The people who cut this block of ironstone 180 years ago.


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[Assistant] Thought they were laying the foundations for one of the world's great trade cities.


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[Assistant] They were fantastic optimists, and they named the place after their young queen, Victoria.


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[Assistant] I'm keen to find out why the Victoria settlement, which became known as Port Essington, was conceived with such enthusiasm and confidence, yet within a few short years had been abandoned as a bitter failure.


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[Assistant] This was the site of British attempts to, in effect, ring-fence the nascent colony.


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[Assistant] Paranoid about a French foothold, Victoria was first about defence, and then trade.


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[Assistant] Just look at that chimney on the married men's quarters here on the outskirts of the settlement. That must have taken a huge amount of effort to build. It's absolutely solid. You look at it here.


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[Assistant] There's probably a few weeks work going into building this, cutting a stone, shaping the fireplace.


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[Assistant] And all the energy you put into doing this in a climate where all you need is an open fire, 364 days a year, is energy you don't have for other things.


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[Assistant] History professor Alan Powell has written extensively about the maritime record of northern Australia. Ah, Alan Powell, is it? Yes, indeed. Hello.


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[Assistant] It's difficult to comprehend the conditions that the settlers endured here. Dressed in their thick woolen uniforms, in their stone buildings, on a day that was so hot that you'd be bathed in sweat just standing still. And when you add to that the malaria,


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[Assistant] The other illnesses, the snakes and a hospital full of colleagues in various stages of death and dying. You know it's a wonder they endured as long as they did.


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[Assistant] You know, almost everyone who arrived here came by sea. But there was one man who walked into Port Essington.


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[Assistant] His name was Ludwig Leichhardt and he was one of Australia's greatest explorers.


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[Assistant] It took him 15 months to cover the 4,800 kilometres between South East Queensland and here.


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[Assistant] And on the way, he discovered some of the best pastoral property in the whole of Australia.


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[Assistant] One of the things that makes Leichhardt so interesting is that he wasn't just a geographical explorer. He was a culinary explorer as well.


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[Assistant] One of the greatest scourges for people travelling through the country or even at sea was scurvy.


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[Assistant] Explorers in Australia came home with their skin so black their wives didn't recognise them, with their gums so swollen they couldn't swallow, all as a result of the disease. But Leichhardt was the exception. He never got scurvy, neither did his crew. And part of the reason lies in this humble looking little bush here, a thing called billy goat plum. Leichhardt tried the fruit as he went along and he discovered


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[Assistant] In those small berries up there, one of the richest sources of vitamin C on earth. And that's what you need if you want to keep scurvy at bay.


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[Assistant] The same couldn't be said for those doomed pioneers of Port Essington, who were sick, despondent and isolated. And this was the last stop.


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[Assistant] For many of them. The cemetery. So Alan, what happened here at the end?


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[Assistant] Well one day in 1849, the last survivors of the poor Dessington settlement walked down that jetty, you can see the remains of it behind me, and bade farewell to this place, presumably without regret.


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[Assistant] Their story was really one of heroic endurance, but for me it's a deeply disturbing story because they didn't seem to learn through the experience of living in this land. They weren't like Laicat, they weren't like the Aborigines.


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[Assistant] And really, you know, at the end of the day, it was this country that defeated the greatest empire the world's ever seen, the British Empire. And to this day, it's as it was.


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[Assistant] But the harsh country wasn't done claiming its pioneering victims.


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[Assistant] Just three years later, Leichhardt himself disappeared while on another continent crossing journey.


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[Assistant] His warmth towards Port Essington contrasts with another famous visitor's bile. Biologist Thomas Huxley visited by ship in the settlement's last days and recorded his disgust in vivid terms.


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[Assistant] But perhaps fortunate for the Coburg Peninsula and its unspoiled environment.


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[Assistant] When European settlement took hold far away in Port Darwin.


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[Assistant] These black rocks, they're not just rocks. They're some of the oldest living things on our planet.


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[Assistant] This is known as a landfall light. So what this is saying is like, hello, hello, this is Cape Otway, I'm here, you've arrived. This is coast! Australia!


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[Assistant] This is known as a landfall light. So what this is saying is like, hello, hello, this is Cape Otway, I'm here, you've arrived, you've made it to Australia, well done.


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[Assistant] Yeah, this way, this way, come through here, and it was known as the Beacon of Hope. Immigrants come into Australia, they've been sailing for two, three, maybe even up to four months without seeing any land. And when they see that beacon, that Cape Whatway light station, oh thank goodness we've arrived, we've made safe passage, we've got the entrance, the guiding light into Australia.


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[Assistant] That was the huge time of population explosion in Victoria, and you would have looked out on this ocean and you would have seen big clipper ships, 60, 70, up to 80 ships a day passing through Bass Strait. Wow, really? So it was an amazingly busy highway. It was built just in time. Yeah, exactly, yeah.


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[Assistant] It's the first of June and in winter, which is the southern hemisphere, you can't see anything until about 7 or 8 o'clock in the morning. And this is at 4 or 5 o'clock in the morning.


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[Assistant] Look, he's only a young guy, five foot four and a half inches tall, and the strength and fortitude that he had is damned amazing.


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[Assistant] In 2002, the Victorian government wanted to choose a new marine emblem for the state, so it organised a public vote.


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[Assistant] These beautiful creatures are rare, and in my years of diving, I've never seen one.


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[Assistant] It really would be a thrill to examine the Weedy Sea Dragon close up. They fascinate me.


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[Assistant] So I've tracked down marine researcher Richard Wiley, who took that award-winning photo.


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[Assistant] With the light filtering down under the pier, there's an almost ethereal quality to the water here. It's actually rather beautiful. The dragons are masters of disguise, almost impossible to find.


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[Assistant] Today, however, the conditions mean there'll be no award winners snapped in my presence.


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[Assistant] But I reckon just seeing the Weedy Sea Dragon was reward enough.


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[Assistant] And these little creatures have had a fan club for over a century.


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[Assistant] Well before Richard snapped them on this state of the art technology.


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[Assistant] Back on dry land, marine educator Harry Briedle is about to show me the proof that the elusive sea dragon was first documented by an extraordinary artist with an extraordinary story 130 years ago.


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[Assistant] German-born Ludwig Becker was a genuinely fascinating chap who'd arrived in Australia in 1851. A skilled artist, he was also a keen astronomer and geologist.


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[Assistant] That in 1860, Becker joined the Burke and Wills Expedition, which aimed to travel from Melbourne to the Gulf of Carpentaria.


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[Assistant] Becker struggled on, but sadly seven months later he succumbed to scurvy and dysentery.


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[Assistant] It was a heartbreaking end for a truly talented man. But his work is still being exhibited.


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[Assistant] Proof of his ability to capture the essence of the regions wildlife.


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[Assistant] Wildlife which continues to inspire Becker's modern-day contemporaries.


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[Assistant] Hi, my name is Bill Carosella, I'm a master's student in the School of Education. Uhm, early on you talked about uhm, struggling in your days financially, or not struggling, but just worried about finances in your PhD study days, and then you also talked about public service.


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[Assistant] What advice do you give to students that are weighing those kinds of decisions?


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[Assistant] I know them well. We used to do quite a bit of contract work with them in the past.


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[Assistant] But unfortunately, they're still in the past, clinging to antiquated technology. From what I understood, they're still planning on new tech development. Not easy to do without any money. I doubt they've got anyone looking to fund them.


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[Assistant] I assigned you this project because of your widespread reputation as a shrewd negotiator. Have you taken pity on them? No. Well, technology investments always a gamble.


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[Assistant] There's no way to know until it's too late if it's the right choice.


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[Assistant] You have to be ready to take responsibility if it were to fail.


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[Assistant] It's quite risky. Wouldn't it be smarter to just go ahead and buy out their land?


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[Assistant] The president of the plant. He's an old acquaintance of mine.


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[Assistant] Honestly, I never gave a damn about that stupid hole.


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[Assistant] Let's pull up our loading menu and let's take a look at a Nucleosome. So last time,


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[Assistant] We looked at DNA, and now we want to understand a little bit better how DNA is packaged in the cell. So, in the biochemistry series, we did talk about nucleosomes quite a bit, the way that DNA


[User] Please transcribe this text

[Assistant] Wrapped around histones as we can see here. And it's just great to be able to visualize this a little bit more accurately. So we can clearly see the DNA with the backbone in green.


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[Assistant] And then the proteins, we see all those alpha helices. So, uh, I and J here are going to be our two complimentary DNA strands.


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[Assistant] So there's one and then there's the other. And we can even highlight individual, uh, individual nucleotides here.


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[Assistant] Uh, we can see those being highlighted. And as we scroll through, it's important to see that there are 146.


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[Assistant] So here's the second one. And uh, so there are four different proteins, but there are two copies of each. So that makes this octameric disk. And we can go ahead and look at these one at a time.


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[Assistant] All of these proteins do have three alpha helices. So those are the red ribbons that we're seeing.


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[Assistant] And, uh, so all of the histone proteins do have very similar structure. There, there are slight differences, like this one has this, uh, this section projecting outwards. Uh, but on the whole, they're very similar and they form this octameric disc. We can take a look at each one, uh, continuing here.


[User] Please transcribe this text

[Assistant] Uh, and that is essentially the structure of the octomeric disk of histone proteins. So once again, a nucleosome is just these histone proteins and then the DNA that wraps around them. And so that is, uh, the essential structure of the nucleosome.


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[Assistant] And, uh, so there's a lot of other things that we can do here. Uh, if we want to get a little bit of a, a better sense of the way this looks, we can zoom in a little bit.


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[Assistant] And, uh, one thing we can also do, why don't we, why don't we get a sense of the, the size of this thing here, right? So we know that we can, uh, measure distances with this tool.


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[Assistant] And so let's just, let's go all the way across here. Let's see what this, uh, what the dimensions are from one end to another. So we, let's zoom in a little bit so we can see what we just did. And it looks like from one edge to the other, we've got about 118 angstroms or 11.8 nanometers. So it looks huge, but of course, compared to macroscopic objects, it's still completely invisible. Um, so let's get rid of that.


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[Assistant] And, uh, so that gives you an idea of the scope of the Nucleosome. And of course, there are many, many, many of these in a row, which then super coil.


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[Assistant] But I find it's nice to get a sense of this thing if we just make it real big and kind of fly through it. That's another way to look at it. Sometimes we like to make it very small and look at the whole thing, but it's, uh, it's very interesting to sort of fly through this whole structure and feel what it would feel like to be the size of an atom. So here we go.


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[Assistant] And we're about through to the other side. So that is what it would feel like to be inside a nucleosome.


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[Assistant] So a couple more things about this, uh, we did say that there are 146 base pairs, uh, associated with this nucleosome. And, uh, in terms of the number of turns, uh, there's going to be about 1.6 to 1.7 turns. So starting here at the free end.


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[Assistant] We can start going around and around and around.


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[Assistant] And then we will cross up over into this second section here.


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[Assistant] And all in all, once we get to the end, the 146 bass pairs are going to span about a 1.6, uh, about 1.6 turns around, after which it will then connect to the next, uh, Nucleusome. And, uh, just we'll get a bunch of these in a row, which once again, supercoiling.


[User] Please transcribe this text

[Assistant] Further supercooling will give us our chromatin, which is how it looks in the cell. So we can look at this a few other ways. I just turned ribbons off. So uhm,


[User] Please transcribe this text

[Assistant] You know, once again, those ribbons on the DNA backbone and on the alpha helices, those are just formalisms. Uh, sometimes it's useful to just take a look at this without those ribbons and just see all the atoms and bonds and that's what that would look like.


[User] Please transcribe this text

[Assistant] And, uh, so that's one interesting way to look at this. We can also turn off the atoms and bonds and just leave the ribbons.


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[Assistant] Because that gives us sort of a different sense. Remember all of these are representations, even the ball and stick. It's just, it's one way of imagining or visualizing it, just like these ribbons. So none of them are completely accurate, but if we, if we use a bunch of different


[User] Please transcribe this text

[Assistant] Ways of visualizing this at different times, we can, you know, get a better sense of the reality of the situation. So, there's that and we can even, uhm,


[User] Please transcribe this text

[Assistant] We can even turn the surface on. So this gives you sort of a space-filling model and the influence that this has on its surroundings in terms of electron clouds. So that's a little bit about Nucleosomes, a few different ways of visualizing it, and then a few different facts about them. So stay tuned for next time.


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[Assistant] Thanks for watching, guys. Subscribe to my channel for more tutorials, support me on Patreon so I can keep making content, and as always, feel free to email me.


[User] Please transcribe this text

[Assistant] Understands implicitly if not explicitly this tour of duty notion.


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[Assistant] So I don't think that, that the vast majority of, of modern, uh, good companies to work at.


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[Assistant] Uh, have this notion of you go and really do some great things for a couple years there.


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[Assistant] That they then, you know, kind of beat on their chest and say, what? You're leaving the startup company now? How could you possibly do that? Given of course,


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[Assistant] Here, us being here, we all do that to some degree. That's what happens.


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[Assistant] Is because the relationships that you form are really important. Uhm, the ability to actually see how the team works and if you're yourself gonna start a company and say, how does this group dynamic work in terms of everyone? So, I generally speaking don't think that consulting is a


[User] Please transcribe this text

[Assistant] A good employee where you have a tour of duty, e.g. you're there for a while, you do some stuff.


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[Assistant] Assuming the passengers lived through the initial contact, well, the aircraft itself is only stocked with two days worth of food and 1,200 liters of water. If they're able to ration it out to the most meager of portions, they won't last for more than two weeks.


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[Assistant] The first round of talks between humanity and Yahakui Zashonina was held in a public venue with access given to media outlets from around the world.


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[Assistant] Zashunina explained that he was a visitor from what he called an anisotropic realm, a territory that exists outside of our universe, and promised to release all of the passengers held within Kado.


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[Assistant] When asked to explain his reason for visiting Earth, Zashunina claimed to bring advancement to humanity in the form of an isotropic device called WOM.


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[Assistant] Light years beyond human technology. These alien tools offer the promise of an infinite source of energy for all mankind.


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[Assistant] He offered up 167 WOM, which are now in our possession.


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[Assistant] It's a broad spectrum to say the least, but if I have to sum it all up, I'd say confusion is reigning supreme.


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[Assistant] Should we try to remove Kado from Haneda by means of military force? There are some extreme opinions floating around.


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[Assistant] I don't know seems to be the dominant reaction amongst the populace.


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[Assistant] The Security Council finds Japan's possession of the WOM to be highly problematic.


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[Assistant] Our information indicates that they're even going so far as to consider sanctions.


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[Assistant] To be honest, I think that we're better off without it.


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[Assistant] Today's video is sponsored by Keeps. Find the link in the description below. When I was a little kid, I used to have this fear that my bladder would explode if I held my pee in for too long. And I remember that my big sisters one day decided to exploit this and lock me out of the house when I desperately needed to pee.


[User] Please transcribe this text

[Assistant] So there I was, pounding on the door, super viciously, screaming at them to be let in, but of course, they didn't, because they're big sisters, but luckily for me.


[User] Please transcribe this text

[Assistant] My bladder did not explode. Instead, I just aggressively peed my pants on the front porch. But it begs the question.


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[Assistant] Was I just being an irrational seven year old or is it actually possible for your bladder to rupture? In today's video, we're going to use the cadavers to take a look at the urinary system to answer that very question. So if you haven't used the restroom lately, now might be a good time to do so. Let's do this.


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[Assistant] Let's start off by taking a look at the urinary system and discussing some of the basic functions of the organs and structures inside of it. So here, we have a kidney that's been cut in the frontal or coronal plane, meaning that it's just been divided into front and back portions. Now the kidney's job is to filter your blood as well as adjust hydration levels.


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[Assistant] So this outer rim of the kidney that I'm tracing with the probe here is called the renal cortex. And this is going to be filled to the brim with tiny little filtration units that will filter the blood and drop waste into these darkened portions here called renal pyramids.


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[Assistant] These renal pyramids will then transport the waste with water


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[Assistant] Which we now call urine into the actual urinary tract which is going to begin in this area here. And then,


[User] Please transcribe this text

[Assistant] It's going to transport that urine down this really long tube.


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[Assistant] of a female pelvis, we can see the pubic bone, you can see the vaginal canal right there, you can see the uterus, but this structure here is going to be the urinary bladder that has been cut in the mid-sagittal


[User] Please transcribe this text

[Assistant] Normally, most people, around four to five hundred milliliters, which is around two or so cups of urine, at that level, that's when you're like, you know, maybe I should probably go ahead and urinate. But do remember that one liter maximum capacity because that'll be important later. But it's also important to understand that the urinary bladder is a convenience organ.


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[Assistant] Meaning, you don't actually need to have a urinary bladder, and some more many creatures on this planet don't. They simply produce urine, and then the urine leaves their body.


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[Assistant] But the reason why most people think we have a urinary bladder is to help mark our territory. So we can pee on things and say, hey, this is mine, or this is my space, or I've been here, or this is a warning, you're entering my territory. So you'll save up all this urine and then you can...


[User] Please transcribe this text

[Assistant] Expel it as you choose, but you can also do it at the right time, and that's going to be important also coming up later.


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[Assistant] But the bladder will then have another extension coming off of it called the urethra. Now we can't see that in this cross section here, but you can kind of picture that there would be this short muscular tube coming off of the bladder. Now, how short depends on whether you're a male or a female. Females are obviously going to have shorter urethra than a male would.


[User] Please transcribe this text

[Assistant] I was in denial about my hair loss for years. I can't tell you how many times I would defend myself when my friends would make jokes about my receding hairline by saying that, no, I just have a really high forehead.


[User] Please transcribe this text

[Assistant] But eventually you see enough pictures of yourself that you can't really do that anymore and you just have to start accepting the fact that you are losing your hair. But here's the thing.


[User] Please transcribe this text

[Assistant] It doesn't have to be that way all of the time for everyone. And that's why I'm excited about the sponsor of today's video, Keeps. Keeps is a subscription service devoted to helping men keep their hair.


[User] Please transcribe this text

[Assistant] These treatment plans are affordable and they're delivered straight to your door. The fact is, two out of three men will experience hair loss by the time they're 35 years old. Which is why, if you're starting to see those early signs of hair loss, now is the best time to jump on this and take advantage of these doctor-recommended treatment plans without ever having to visit a doctor's office or a pharmacy.


[User] Please transcribe this text

[Assistant] Plus, you'll even get refill reminders, so you'll never run out of the products you need to take care of your hair. Hair loss stops with Keeps. To get 50% off your first order, visit keeps.com slash anatomy, or you just click the link in the description below. That's K-E-E-P-S dot com slash anatomy.


[User] Please transcribe this text

[Assistant] Let's get back to it. Let's start by discussing what's called the micturition reflex. Now that's a big word, but micturition just means the desire to urinate.


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[Assistant] So, we go back to this mid-sagittal section of the pelvis. Again, this right here is that urinary bladder. The inside lining of the bladder itself, as well as other aspects of the urinary tract,


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[Assistant] There's a specialized type of epithelium called transitional epithelium. And the reason it's called transitional is because depending on how much urine is inside of the bladder and urinary tract, it will stretch and transition to different thicknesses. So less urine, it's thicker. More urine, it's more flat and stretched out. Thus, transitional epithelium.


[User] Please transcribe this text

[Assistant] This is called detrusor muscle. That's its name, but it's really just a type of smooth muscle. Now, smooth muscle is involuntary, meaning you are not in charge of when this muscle here contracts. Instead, that is going to be reflexive.


[User] Please transcribe this text

[Assistant] Now we can't see the urethra coming off of here, but the urethra is going to have two sphincters, which are just really thick and tight, uh, muscular rings.


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[Assistant] The first sphincter is called the internal urethral sphincter. And again, this is involuntary. You're not in charge of contracting or relaxing this sphincter. We'll see why that's important in a moment.


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[Assistant] But you are in charge of the more distal sphincter called the external urethral sphincter. This one's made of skeletal muscle, which means you can decide when it contracts and when it relaxes. But what you need to understand


[User] Please transcribe this text

[Assistant] And what they're doing is they are monitoring how much urine is filling inside of the bladder.


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[Assistant] And what they're gonna do is send that signal, so they're gonna send their signal up the spinal cord.


[User] Please transcribe this text

[Assistant] And that spinal cord will then send a motor neuron back, or a signal back, to the detrusor muscle, telling it to contract. That's right. So once you reach about around like, I think it's 200 milliliters or so of urine, what's gonna happen is, those stretch receptors will send a neuron, and they'll get another neuron and signal back saying, contract.


[User] Please transcribe this text

[Assistant] And that's also going to tell that internal urethral sphincter to relax. So this is that initial urge to pee.


[User] Please transcribe this text

[Assistant] Alright, when you're like, oh I gotta pee here, what's happening is the bladder is actually contracting and the first sphincter is opening, letting urine down.


[User] Please transcribe this text

[Assistant] But, you are in charge of that external urethral sphincter. And that's because at the exact same time, signals are going up the spinal cord, they're going


[User] Please transcribe this text

[Assistant] Inside of the ponds, there is something called the Pontine Micturician Center.


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[Assistant] And what's gonna happen is you are able to decide, hey,


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[Assistant] This is not a good time to urinate. I mean, think about it. Imagine you're in like a, you're at a social gathering, right? You're among friends. If you didn't have control of that external urethral sphincter, well, your body would just start urinating on your own and you'd just be peeing your pants.


[User] Please transcribe this text

[Assistant] So that, the decision to keep it contracted comes from the cerebral cortex up here, right? You can actually make the decision. What you have to understand though,


[User] Please transcribe this text

[Assistant] Is the PMC and the cerebral cortex are working together to kind of not only figure out how or when we should be peeing,


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[Assistant] But, how to actually do it? Because when you decide to P, then the signal's gonna go back down that same pathway, and it's gonna be reflexive again. It's gonna cause this detrusor muscle to contract.


[User] Please transcribe this text

[Assistant] It's very unlikely to happen simply from you holding your urine unless you had something else already wrong with the bladder.


[User] Please transcribe this text

[Assistant] So let's look at this. If the bladder ruptures, there are two different types of bladder ruptures. If it ruptures into this space here, into the pelvic cavity, this is called the peritoneal space. If it ruptures, say on the top of the bladder here,


[User] Please transcribe this text

[Assistant] And goes in here, we call that an intraperitoneal rupture.


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[Assistant] In this event, the urine will be reabsorbed by the body, which will then kind of cause havoc and chaos with your bloodstream, because the urine is literally being reabsorbed into it, but it's also going to require surgery to close off that rupture.


[User] Please transcribe this text

[Assistant] But if it ruptures at another point, let's say deeper down in this tissue here, we call that an extraperitoneal rupture. And this is actually easier to manage because you can just administer a catheter and drain out the urine from that space. But you may be asking,


[User] Please transcribe this text

[Assistant] How does this happen though, right? If, if, if, if I'm saying that there needed to be something else wrong with the bladder, well, most cases of bladder ruptures happen due to this bone here. This is the pubic bone.


[User] Please transcribe this text

[Assistant] And if this breaks due to some kind of trauma, that can cause ruptures to the bladder. And the most common cause of those ruptures are going to be automobile accidents. Picture the steering wheel hitting your pelvis, hitting the pubic bone, and then it ruptures some aspect of the bladder.


[User] Please transcribe this text

[Assistant] But other things that can happen are like bladder cancer, right? If you have bladder cancer, that can weaken the wall of the bladder, and then it makes it more likely for bladder rupture to occur. Uh, vaginal birth.


[User] Please transcribe this text

[Assistant] Simply putting the child through there, there have been instances where that has actually caused a bladder rupture to occur. Maybe someone is administering a catheter to you, right? They're gonna drain the bladder and they don't do it correctly and they cause an injury.


[User] Please transcribe this text

[Assistant] Those are all pre-existing conditions or some kind of trauma event that is weakening the bladder, which is causing that to occur, the bladder rupture to occur. Simply you holding your urine,


[User] Please transcribe this text

[Assistant] It's really not all that likely. I mean, I looked in preparation for this video, I was looking in the published literature, looking for case studies of spontaneous bladder ruptures, and finding them without some kind of pre-existing condition, I couldn't find any that were really reliable.


[User] Please transcribe this text

[Assistant] It was more just mysterious. As in, we saw this happen, we saw this individual, this happened to them, but when you trace back their history, it does seem like they had some kind of inciting event. Something else happened to their bladder at some other point.


[User] Please transcribe this text

[Assistant] The reason why this is so unlikely is because as that bladder is reaching that maximum capacity of one liter, it makes far more sense for the urine to go up the ureters to go head towards the kidney. And that can and does happen. That can create


[User] Please transcribe this text

[Assistant] Urinary tract infections, kidney infections, you can send you into kidney failure, you can actually die from urine going back up the kidneys. But a far more likely result, instead of your bladder just rupturing, is exactly what happened to seven-year-old Justin when your external urethral sphincter just opens and you aggressively pee your pants.


[User] Please transcribe this text

[Assistant] See, that makes more sense from a body's perspective, right? Like, would you rather have the bladder rupture


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[Assistant] And urine go into this body cavity or into the tissues.


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[Assistant] Or would you just rather pee your pants and suffer a little bit of humiliation? Again, both are not ideal.


[User] Please transcribe this text

[Assistant] I'm pretty sure I know which one I would choose. Thanks again to the sponsor of today's video, Keeps. Be sure to click the link in the description below or just visit keeps.com slash anatomy and get 50% off your first order today.


[User] Please transcribe this text

[Assistant] As always, be sure to like, comment, subscribe if you feel so inclined. We really do appreciate those subscriptions. They really do help our channel perform better so we can get in front of more people so we can teach them about their bodies. So it is very much appreciated if you feel so inclined. But thanks again for watching and I will see you in the next video.


[User] Please transcribe this text

[Assistant] The first rule uhm, that I discussed uhm, was to look for disruptive change. And the reason uhm, that I said look for disruptive change is because


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[Assistant] It's what are the opportunities that come out that are really new opportunities that are something, and because the opportunity generally speaking has to be large. It can't be something that's like, well, boy, you know.


[User] Please transcribe this text

[Assistant] It's been sitting there for 10 or 20 years and no one's ever really thought about it.


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[Assistant] You could, you could make something, uh, significant out of. It's not really high impact. And the kind of pioneer parallel to this is


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[Assistant] That if you're gonna actually kinda pack up your wagons and go somewhere, make sure that where you're going is potentially really good.


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[Assistant] And the difference is, is, is that, you know, you might as well shoot for something large because you can still end up with something smaller.


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[Assistant] But aiming for something large is really important. And part of the reason why this is kind of a rule of entrepreneurship, and maybe this is the kind of thing that this room is like, yeaah, we already know this, we're living it. Uhm, I hope. Uh, is because the, if you, if you don't


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[Assistant] are basically have to think globally in nature these days, uhm, because of the way that the


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[Assistant] You know, part of that in terms of a pioneer parallel is again, how do I go somewhere that is, that is, that is substantial and unique.


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[Assistant] Because as much as we tend to glorify the entrepreneur as


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[Assistant] It's actually, it's actually brought about by lots of different people. There's everything from your co-founders, there's the early employees, there's investors, there's customers, uh, some businesses have distribution channels.


[User] Please transcribe this text

[Assistant] That was usually a recipe for, uhm, failure.


[User] Please transcribe this text

[Assistant] Uh, really one of the things that's really important to, to make these things more like, more likely to succeed is to assemble a network around them that where that network


[User] Please transcribe this text

[Assistant] What kind of network are you assembling around your company? So for example, the practical advice is when you're looking at financing, it's what additional


[User] Please transcribe this text

[Assistant] When I'm doing the financing because it's a very good opportunity to get people to have their interest aligned with yours. The fourth, and this is actually


[User] Please transcribe this text

[Assistant] Uhm, a tricky one to explain is the plan for both good and bad luck.


[User] Please transcribe this text

[Assistant] It works out and then things keep going. Well, good luck actually comes in...


[User] Please transcribe this text

[Assistant] Uh, opportunities that you don't, uh, you don't normally, uhm, you don't normally see. So for example, uh, PayPal.


[User] Please transcribe this text

[Assistant] Uh, started as a encryption on mobile phones company.


[User] Please transcribe this text

[Assistant] Uhm, because it was too close friends of mine, I joined the board when they founded it. Even though I thought encryption technology and mobile phones


[User] Please transcribe this text

[Assistant] Uh, back in December 98 was a, uh, was a not a good idea, which I told them.


[User] Please transcribe this text

[Assistant] And that's an instance of what I think of as planning for good luck, which is...


[User] Please transcribe this text

[Assistant] You basically, you go, okay, sometimes what happens when you start the journey of going down a company is you're looking for an opportunity that


[User] Please transcribe this text

[Assistant] You come around the corner and all of a sudden there's new opportunities available to you and that you head very strongly to that. And so good luck is not just, oh look, my plan worked. It's, you will encounter


[User] Please transcribe this text

[Assistant] The plan A is, okay, this is what we're thinking of doing. Plan B is


[User] Please transcribe this text

[Assistant] Well, if that's not working, what are my parameters of flexibility? I'm still trying to get to that, the same, you know, build the same product, the same product market fit. I'm still trying to get there, but maybe if I try this rather than that. So for example, when I


[User] Please transcribe this text

[Assistant] Well, as it turned out, we launched the network and, you know, and a couple weeks later we're growing at 2,000 people a week. And I was like, well, that's not fast enough.


[User] Please transcribe this text

[Assistant] So, uh, what were the other ideas we had in mind? The kind of plan B. And the plan B was, well, uh,


[User] Please transcribe this text

[Assistant] And that caused our growth rate to go from like 2000 a week to like


[User] Please transcribe this text

[Assistant] I think it was about, like, uh, 20,000 a week. Right? So, uh, and that's, you know, without that I don't know if we would have succeeded. Maybe other Plan Bs would have worked. And then Plan Z is what happens when it's just not working at all. Right? It's kind of a lifeboat plan. And that's part of the how you, uhm, you plan for both good and bad luck.


[User] Please transcribe this text

[Assistant] The last, uh, well no, there's two more rules I'm gonna go through. Uh, one of them is,


[User] Please transcribe this text

[Assistant] Pioneering parallel to this, but it's so important for entrepreneurs to understand this, which is, uh, maintain flexible persistence.


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[Assistant] And entrepreneurs are given two pieces of advice with equal vigor. When you look at them, they're in contra- they're in contradiction. One is have a vision. You know, plow through the wall. Keep your vision.


[User] Please transcribe this text

[Assistant] You know, don't allow yourself to be defocused from that, keep going. The other one is listen to your customers, listen to market feedback, listen to your network.


[User] Please transcribe this text

[Assistant] It's a very difficult thing to teach other than by doing, right? Other than by the...


[User] Please transcribe this text

[Assistant] The activity of going out and being an entrepreneur.


[User] Please transcribe this text

[Assistant] Uh, and, and making those decisions. And so the reason that the rule is maintain flexible persistence is because it's both keep a vision


[User] Please transcribe this text

[Assistant] So for example, if you think about the kind of the ABZ planning framework, it's like, look, I've got a plan I want to try to get there. This is my main plan.


[User] Please transcribe this text

[Assistant] And if that doesn't work, how do I shift to a different destination, a different location? That's part of the Plan Z. So the last rule that I'll go through for


[User] Please transcribe this text

[Assistant] for today, uh, before we get back to kind of entrepreneurs as pioneers in education, is, uh, that these are, these rules are not


[User] Please transcribe this text

[Assistant] Uh, rules of physics, they're not natural gravity, you know, gravity not just the idea of the law. They are...


[User] Please transcribe this text

[Assistant] Uh, they are, they are kind of rules of thumb by which you navigate. And that's part of what makes entrepreneurship so interesting because


[User] Please transcribe this text

[Assistant] Usually almost every company has something of a unique pattern, uh, to how it operates. Now, sometimes a unique pattern is where it's operating in the world, uh, sometimes


[User] Please transcribe this text

[Assistant] Uhm, but one of the things I love about the consumer internet, which is what I focus on with, uh, the vast majority of my time, is that


[User] Please transcribe this text

[Assistant] Uh, each thing to elevation kind of defines its own unique space and that, and that what you're really looking for is a, a unique pattern of getting there and so the,


[User] Please transcribe this text

[Assistant] The, the problems that are in front of a company, even though there's family resemblance to them, like, well okay, how do I scale a sales force? Or, what do I do in terms of financing? Or,


[User] Please transcribe this text

[Assistant] You know, how do I work with, uh, potential, you know, uh, financiers and all the rest of this? How do I make all that happen? And there is a skill set there. The combination and how you


[User] Please transcribe this text

[Assistant] How you pull it together and which is your strategy that pulls it off. That's how new strategies are created.


[User] Please transcribe this text

[Assistant] Uh, usually when I'm telling someone that I think something isn't gonna work, I never say, well that'll never work. Well, actually, sometimes I say that.


[User] Please transcribe this text

[Assistant] But usually it's like, well that's gonna be really hard and you're really betting the farm on that one idea which doesn't strike me as, as it's potentially gonna work. And so,


[User] Please transcribe this text

[Assistant] You know, these are the kinds of rules that are the kind of things you have to learn in the journey that you take when you


[User] Please transcribe this text

[Assistant] And the reason I use this metaphor is because it's kind of, it gets you really focused because the ground's coming. Right? Financing isn't success, it's a thermal draft.


[User] Please transcribe this text

[Assistant] My name is Yahakui Zashinina.


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[Assistant] Thank you. I have gained the minimum of your world's information from this device. And thus, I now possess the fundamentals of your communication. Are my words effectively reaching you, Koji Roshindo?


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[Assistant] Kojiro Shindo, I, Yahakui Sashinina, formally appeal to you for your cooperation.


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[Assistant] One, one, one, one, zero, zero.


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[Assistant] Two million four hundred eighty three thousand one hundred thirty six seconds. Six hundred eighty nine point seventy six hours.


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[Assistant] I know you didn't.


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[Assistant] I will share with the people outside what I have already shared with you. And let them know my purpose for coming here.


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[Assistant] Sure, but I can't. I'm still stuck in here for now, right?


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[Assistant] Kado is currently implementing the processing required to safely transfer the passengers to the world outside.


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[Assistant] The speed of the operation depends on the subject's mass and thus requires 29 days to process all of them.


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[Assistant] But for Koji Roshino alone, it only requires 2.74 hours.


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[Assistant] A fracture in our communication, I apologize. Koji Roshindou.


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[Assistant] I wish to advance this world for the better.


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[Assistant] I require a means of communicating with all of humanity.


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[Assistant] The factor known as Koji Roshindo will greatly accelerate that process. This is my second request. Please help. I require your assistance.


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[Assistant] Interaction will occur in 10 hours, 2 minutes and 5 seconds. Koji Roshindo.


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[Assistant] You see, I know of something that suits humanity.


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[Assistant] I chose the one I deemed the most efficacious and acted upon it. Their arms should be given to humanity, and they must be shared throughout your world as soon as possible.


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[Assistant] This must be done because it is the right answer.


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[Assistant] That's correct. There is a shielded room within the JSDF tech lab.


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[Assistant] Shindo and Dr. Kanata Shinowa are there. They are working diligently.


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[Assistant] I suppose your science might offer a fuller picture.


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[Assistant] In other words, what is required now is speed.


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[Assistant] You must be the one to make that decision. You're the only one who can. The right answer is before you and I hope that you will find it, Prime Minister. In order to help bring you closer to it, I must speak with you.


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[Assistant] So uhm, they are a source of power sufficient for humanity's needs. More than sufficient, in fact. This struggle for them, it is a wanton frivolity. At the core of this dilemma is the concept of difference.


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[Assistant] Humanity is divided, split up into nations by borders, with each nation bearing its own unique interests. This invokes societal fractures. As a result, the equilibrium is in stagnation.


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[Assistant] I'm sorry, Spynodal.


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[Assistant] Country A willfully prevents bread from going to Country B. Therefore Country B plots to steal bread from Country A.


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[Assistant] This process spreads between geographical areas, ethnic groups and down through every other layer.


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[Assistant] They are an infinite spring of accumulation, and they will rain down upon all.


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[Assistant] Who should be the one to determine it? Should it be you?


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[Assistant] I spoke with an individual who believes that the WOM has sunk humanity into a state of chaos and initiated conflict. They told me that I should have never given the WOM to you. I completely disagree.


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[Assistant] Uh, so today we are going to finish talking a little bit about antibody structure and function.


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[Assistant] Uhm, and, uh, then move into, uhm, this issue of generation of antibody diversity.


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[Assistant] And the things that are unique about different isotypes. We had specifically talked about IgM.


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[Assistant] Smooshing together a bunch of different subclasses of IDD.


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[Assistant] When I think about IgG, there are kind of two big functions that I tend to think about. This is one that I've already alluded to today. Uhm, which is that IgG, uhm, tends to be made


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[Assistant] When we talked about IGA last time, I told you that IGA was great at neutralizing.


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[Assistant] What the baby was seeing compared to her. Uhm, so there is sort of this evolutionary piece to this.


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[Assistant] So like, this, this is really far off, and this was a huge problem. Immunologists, uhm, were


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[Assistant] In coming up with, uhm, this, they had some other observations that they made that influenced some of their ideas about how antibodies are made.


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[Assistant] So I want to tell you a little bit about these observations. I'm just gonna sort of lay them out as kind of bullet points.


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[Assistant] I'm not necessarily gonna give you the mechanics behind all of them until, say, Wednesday, or later. Uhm, but,


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[Assistant] But one of the, so we knew that there was something going on with a B cell.


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[Assistant] We know that the B-cell receptor has this ability to make a couple different forms of this protein as either the receptor or as, uhm, a secreted protein.


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[Assistant] Or the fact that one cell makes one type of receptor.


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[Assistant] I've already told you about one aspect of combinatorial diversity.


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[Assistant] Uh, him to understand that this mini gene hypothesis of combining small gene segments


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[Assistant] Was the way that we were able to solve this problem of different types of diversity.


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[Assistant] Uhm, so this is kind of showing you this in sort of more detail.


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[Assistant] When we are thinking about heavy chains of antibodies, heavy chains are made up of three different uh,


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[Assistant] Uhm, in the light chain, the V segments.


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[Assistant] And then there's a constant region. So again, here we're talking about just this variable region that's being made up by the V and the J. The constant region makes up the rest of the antibody.


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[Assistant] Uhm, and, uh, kind of wha- how it's important and why it's important, uh, next time. But we are going to spend, uhm, a fair amount of time going into specific enzymes and their functions. There will be a point where I am drawing sequence on the board, uhm, so,


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[Assistant] Long time no see. Wake up, Hanamori. Hey! Hanamori!


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[Assistant] When we looked at Mendelian genetics, we learned all about genotypes and phenotypes, alleles and Punnett squares, but even then we already began to see that the basic model of dominant and recessive alleles does not explain certain phenomena.


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[Assistant] We looked at incomplete dominance, such as when true breeding red and true breeding white snapdragons are hybridized to yield an entirely pink F1 generation.


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[Assistant] Thus, a third intermediate phenotype is involved, totally unlike complete dominance, where only the dominant phenotype is expressed.


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[Assistant] We also looked at codominance, where two phenotypes can be expressed simultaneously, as was the case with the cows with both white and brown coloring.


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[Assistant] Building on what we already know, let's continue to extend this understanding into still more interesting and complex patterns of inheritance.


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[Assistant] First, it is important to understand that in cases of dominant and recessive alleles, one allele is dominant simply because it is visible in the phenotype, and not because it somehow subdues expression of the recessive allele.


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[Assistant] With heterozygous individuals, both the dominant and recessive alleles are expressed. It is simply that the product of the expression of the dominant allele produces the relevant phenotype.


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[Assistant] For example, when Mendel examined seed shape, he noticed that seeds could be round or wrinkled, with round being dominant.


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[Assistant] We now know that this is because the dominant allele codes for an enzyme that helps convert unbranched starch into a branched form.


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[Assistant] While the recessive allele codes for a defective form of that enzyme, thereby allowing unbranched starch to accumulate, which causes water to enter the seed by osmosis, and when the seed dries, it wrinkles.


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[Assistant] So if at least one dominant allele is present, in the form of the heterozygous or homozygous dominant genotypes, the correct enzyme will be produced, and the seed will be round.


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[Assistant] With the heterozygous organism, both the effective enzyme and the defective enzyme are produced, but there is enough of the effective version to get the job done.


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[Assistant] Only if homozygous recessive will there be no effective enzyme present at all, in which case the seed will wrinkle.


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[Assistant] Now, with the understanding that all alleles will be expressed, we can better understand situations involving multiple alleles, meaning more than simply one dominant and one recessive.


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[Assistant] With this, there are three alleles that are possible for a single gene. These are IA, IB, and I in lowercase, where the I stands for immunoglobulin.


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[Assistant] The letters A and B refer to carbohydrates that can be found on the surface of red blood cells, whereby the expression of IA yields the A carbohydrate, expression of IB yields the B carbohydrate, and expression of lowercase I does not result in any carbohydrates.


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[Assistant] We discussed the compatibility of blood types for transfusion in the anatomy and physiology series, so head over there for more information in that context.


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[Assistant] Now let's step things up a notch. Until now, even in situations with multiple alleles, we have only seen cases where a particular gene influences only one phenotypic character. Oftentimes, however, a single gene can have multiple phenotypic effects.


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[Assistant] This is a situation called pleiotropy. In humans, pleiotropic alleles produce multiple symptoms associated with hereditary diseases like cystic fibrosis and sickle cell disease. Whereas with pea plants, a single gene determines both flower color as well as the color of the outer surface of the seed.


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[Assistant] In contrast, there are other situations where multiple genes are involved in the expression of a single phenotype.


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[Assistant] When this happens because of the interaction of the products of gene expression, it is called epistasis.


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[Assistant] For example, in Labrador Retrievers, the dominant coloring is black, while recessive is brown, represented by a capital B and lowercase b respectively. This allele determines the pigment that produces the coloring of the dog.


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[Assistant] However, there is another gene that determines whether or not the pigment will be deposited onto the fur, with a dominant allele resulting in the pigment being deposited.


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[Assistant] So if the dog is homozygous recessive for this trait, then the dog will end up yellow no matter which alleles are present for the pigment, as the pigment will not be deposited onto the fur.


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[Assistant] Only if the dog is heterozygous or homozygous dominant will the phenotype for color be expressed.


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[Assistant] So the gene for pigment deposition is said to be epistatic to the gene that codes for black or brown pigment.


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[Assistant] Mating two dogs that are heterozygous for both traits to get a dihybrid cross clearly shows the law of independent assortment in action when examining the distribution of dogs with different coloring.


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[Assistant] An even more complex situation regarding multiple genes contributing to a single phenotype is called polygenic inheritance.


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[Assistant] In these cases, traits are not as simple as existing as one out of two or three discrete options. Instead, they exist as gradations along a continuum. An example of this is skin color in humans.


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[Assistant] Most people have skin of one particular tone, and this is determined by a variety of genes, but this tone can be very dark,


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[Assistant] Very light or any of a number of intermediate shades.


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[Assistant] This is because all the genes working in tandem can have dominant or recessive alleles in any combination and thus produce darkness in an additive manner, and through a variety of genotypes, given the incredible number of combinations possible when three or more genes have alleles assorted independently.


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[Assistant] And finally, there are even phenotypes that are subject to environmental factors, such as flowers that can display different colors depending on the acidity of the soil, or other such stimuli.


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[Assistant] Such characteristics are referred to as multifactorial, which means that many factors, both genetic and environmental, contribute to the presence of a particular phenotype.


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[Assistant] So beyond our previous introduction to Mendelian genetics, as well as the degrees of dominance we had already examined, we have now broadened our understanding of methods of inheritance to include phenomena like pleiotropy, epistasis,


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[Assistant] Polygenic inheritance and environmental influence.


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[Assistant] With all of these additional complications, it is incredible that Mendel was able to do the work that he did.


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[Assistant] But more importantly, we are now able to elevate our comprehension of inheritance such that we may examine a variety of genetic disorders and come up with strategies for treatment, thanks to our modern understanding of molecular biology.


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[Assistant] Thanks for watching, subscribe to my channel for more tutorials, support me on patreon so I can keep making content, and as always, feel free to email me at


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[Assistant] The function of a boundary object like Kado is to straddle the divide between the universe and the anisotropic. This point is equidistant to both of them.


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[Assistant] Did the arms reach out to you? Yeah


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[Assistant] You see, the Nanomus Heim, it has a broader practicability than the Womb or the Sansa. This is one application.


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[Assistant] The Nanomus Hine is what makes that level of control possible within the universe.


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[Assistant] I can, for starters.


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[Assistant] You create more than you need. And that's not gonna happen? No, it won't. Humanity's production will never exceed its consumption. Not now, nor ever, for the rest of eternity. Is that a fact? How can you be certain?


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[Assistant] Alright then, how does it work? This might be difficult for you.


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[Assistant] I corrected you for the sake of conveyance, but it is true in the larger context. Dimensionally, the number depicts the quantity of information. One dimension, two dimensions, and three dimensions.


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[Assistant] To provide an analogy, imagine each cube as a bit of information, and the entire cluster as a CPU. Do you comprehend this?


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[Assistant] The anisotropic would add 37 more to the universe.


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[Assistant] We face a painful paradox as the endless needs of our world are too easily fulfilled.


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[Assistant] Cascading downward and washing over us, more than we could ever process.


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[Assistant] We and isotropic beings chose to create the information cocoon.


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[Assistant] Silk worms are raised to extract silk from their cocoons. As opposed to threads of silk, we harvest information.


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[Assistant] And waited for the cocoons to yield high density information. Waited for what you would call an eternity. When at long last, the ultimate information thread was born.


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[Assistant] That miraculous thread was the first unknown body of information the anisotropic beings encountered.


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[Assistant] A singularity.


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[Assistant] So what exactly was that thread?


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[Assistant] Each information cocoon is a universe. And the ultimate thread borne forth is humanity. The anisotropics create it all, including your world. We open the space and determine the initial values. We even set some of its natural parameters.


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[Assistant] The alteration of temporal values, it is not the exchange of momentum you surmised. You see the Ninomus Hine, it alters the settings of the universe and allows one to bypass them.


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[Assistant] I apologize, Shindo. I only intended to briefly alter our relative times. What felt like the passing of 10 seconds to me, it was closer to the passing of 70 hours for you.


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[Assistant] This is a facsimile of you from several hours ago, before our conversation. I will start over with this one.


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[Assistant] That's enough, Sascha Nina! I won't let your plans go one step further!


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[Assistant] Because I love this universe! Exactly the way that it is!


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[Assistant] So you've seen the equations for how to implement BatchNorm for maybe a single hidden layer. Let's see how it fits into the training of a deep network.


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[Assistant] So let's say you have a neural network like this. You've seen me say before that you can view each hidden unit as computing two things. First, it computes z, and then it applies the activation function to compute a.


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[Assistant] And so you can think of each of these circles as representing a two-step computation. And similarly for the next layer, that's Z21 and A21 and so on.


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[Assistant] So if you were not applying BatchNorm, you would have an input x feed into the first hidden layer and then first compute z1.


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[Assistant] And this is governed by the parameters w1 and b1.


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[Assistant] And then ordinarily you would feed z1 into the activation function to compute a1.


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[Assistant] But what we'll do in BatchNorm is take this value z1 and apply BatchNorm


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[Assistant] Sometimes abbreviated bn to it, and that's going to be governed by parameters beta 1 and gamma 1. And this will give you this new normalized


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[Assistant] Value z1, and then you feed that to the activation function to get a1, which is, uh, g1 applied to z tilde 1.


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[Assistant] Now, you've done the computation for the first layer, where this batch norm step really occurs, you know, in between the computation from Z and A.


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[Assistant] Next you take this value a1 and use it to compute z2. And so this is now governed by w2 b2.


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[Assistant] And similar to what you did for the first layer, you would take Z2,


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[Assistant] And apply it through BatchNorm, abbreviate that BN now. This is governed by


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[Assistant] Batch norm parameter specific to the next layer, so beta 2, gamma 2, and now this gives you z tilde 2, and you use that to compute A2 by applying the activation function, and so on.


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[Assistant] So once again, the batch norm step, you know, kind of happens between computing Z and computing A.


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[Assistant] And the intuition is that instead of using the unnormalized value z, you're going to use the normalized value z tilde. Uh, that's in the first layer. In the second layer as well, instead of using the unnormalized value z2, you're going to use the mean and variance normalized values z tilde 2. So the parameters of your network are going to be w1, b1,


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[Assistant] It turns out we'll get rid of the b parameters, but we'll see why in the next slide. But for now, um, imagine the parameters are the usual, uh, w1, b1, through wl, bl.


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[Assistant] And we've added to this neural network additional parameters, beta 1, gamma 1, beta 2, gamma 2, and so on. You know, for each layer in which you are applying batch norms.


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[Assistant] For clarity, note that these betas here, these have nothing to do with the hyperparameter beta that we had for momentum or for the computing the various exponentially weighted averages. You know, the authors of the Adam paper had used beta in their paper.


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[Assistant] Beta 1, beta 2, and so on that DashNorm tries to learn is


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[Assistant] Different beta than the hyperparameter beta used in momentum and in the Adam and RMS prop algorithms.


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[Assistant] But so, now that these are the new parameters of your algorithm, you would then use whatever optimization you want, such as gradient descent, in order to implement it.


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[Assistant] So for example, you might compute D beta L for a given layer, and then update the parameters, beta gets updated as beta minus the learning rate times D beta L.


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[Assistant] And you can also use Adam or Armourous Prop or Momentum in order to update the parameters Beta and Gamma, uhm, not just Gradient Descent.


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[Assistant] And even though in the previous video, uh, I'd explain what the batch norm operation does, computes mean and variances and subtracts and divides by them. If you're using a deep learning programming framework,


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[Assistant] Usually you won't have to implement the batch norm step or the batch norm layer yourself. Uhm, in some of the programming frameworks it can be sort of one line of code. So for example, in the TensorFlow framework you can implement batch normalization with, you know, this function.


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[Assistant] We'll talk more about programming frameworks later, but in practice, you might not end up needing to implement all these details yourself, but it's still worth knowing how it works, so that you can get a better understanding of what your code is doing.


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[Assistant] But implementing Batch Norm is often, you know, something like one line of code in the deep learning frameworks.


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[Assistant] Now so far we've talked about batch norm as if you were training on your entire training set at the time, as if you were using batch gradient descent. In practice, batch norm is usually applied with mini batches of your training set. So the way you actually apply batch norm is you take your first mini batch and


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[Assistant] Compute z1, same as we did on the previous slide, using the parameters w1, b1.


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[Assistant] And then you take this, just this mini-batch and compute the mean and variance of the z ones on just this mini-batch. And then BatchNom would, uhm,


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[Assistant] Subtract by the mean and divide by the standard deviation, and then rescale by beta 1, gamma 1, to give you z1, and all this is on the first mini-batch, then you apply the activation function, you know, to get a1, and then you compute z2 using w2, b2, and so on. So you do all this in order to perform


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[Assistant] One step of say, gradient descent on the first mini-badge, and then you go to the second mini-badge, X2.


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[Assistant] And you do something similar, where you now compute Z1 on the second mini-batch, and then use Batch Norm to compute Z1 till there. And so, here in this Batch Norm step, you'd be normalizing


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[Assistant] Z tilde using just the data in your second mini-batch. So this batch norm step here is looking at the examples in your second mini-batch, computing the mean and variances of the Z1s.


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[Assistant] On just that mini-bash and then re-scaling by beta and gamma to get z tilde and so on. And you do this with the third mini-bash and keep training.


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[Assistant] Now, there's one detail to the parameterization that I want to clean up, which is previously I said that the parameters was WL


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[Assistant] But what BatchNorm does is it's going to look at a mini-batch and normalize ZL to first have mean zero and standard variance and then a rescale by Beta and Gamma.


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[Assistant] But what that means is that whatever is the value of BL is actually gonna just get subtracted out. Because during that batch normalization step, you're going to compute the means of the ZLs and then subtract out the mean. And so adding any constant,


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[Assistant] To all of the examples in a meanie bash, it doesn't change anything because any constant you add will get cancelled out by the mean subtraction step.


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[Assistant] So if you're using batch norm, you can actually eliminate that parameter. Or if you want, think of it as setting it permanently to zero. So then the parameterization becomes ZL is just WL times AL minus one. Uhm, and then you compute ZL


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[Assistant] You end up using this parameter beta l in order to decide what's the mean of z tilde l, which is what gets past the next layer.


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[Assistant] So just to recap, because BatchNorm zeroes out the mean of these ZL values in the layer, there's no point having this parameter BL and so you might as well get rid of it.


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[Assistant] Which is a parameter that controls, that ends up affecting the shift or the bias terms. Finally, remember that, uhm, the dimension of ZL, because if you're doing this on one example, it's going to be NL by 1, and so BL had dimension


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[Assistant] Beta L and Gamma L are used to scale the mean and variance of each of the hidden units to whatever the network wants to set them to.


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[Assistant] So let's put it all together and describe how you can implement gradient descent using bash norm. Assuming you're using minibash,


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[Assistant] Gradient descent, you iterate for t equals one to the number of mini batches. You would, uh, implement forward prop.


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[Assistant] On mini-batch xt, and doing forward-prop in each hidden layer, uhm, use batch-norm to replace zl with z tilde l. And so this ensures that within that mini-batch, the value z


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[Assistant] Although technically, since we've gotten rid of b, this actually now goes away. And then finally, you update the parameters. So, you know, w gets updated as, uh,


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[Assistant] W minus the learning rate times this as usual, beta is updated as beta minus the learning rate times dB and similarly for gamma.


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[Assistant] And uhm, if you've computed the gradients as follows, you can use gradient descent.


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[Assistant] That's what I've written down here, but this also works with gradient descent with momentum, or RMSProp, or Adam.


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[Assistant] Where instead of taking this gradient descent update, you could use the updates given by these other algorithms as we discussed in the previous week's videos. So these other optimization algorithms as well can be used to update the parameters beta and gamma that batch norm added to your algorithm.


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[Assistant] So I hope that gives you a sense of how you could implement Batch Norm from scratch if you wanted to. If you're using one of the deep learning programming frameworks, which we'll talk more about later, hopefully you can just call someone else's implementation in the programming framework, which will make using Batch Norm much easier.


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[Assistant] Now in case BatchNorm still seems a little bit mysterious, uhm, if, you know, still not quite sure why it speeds up training so dramatically, let's go to the next video and talk more about why BatchNorm really works and what it's really doing.


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[Assistant] So today, whenever the projector heats up, uhm,


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[Assistant] I'm going to continue talking about, uhm,


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[Assistant] The problem of antibody diversity that we started talking about last time.


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[Assistant] So I want to give you, uhm,


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[Assistant] Some, that's a scary projector noise. I'm going to give you some general info about this process and then we're going to get into some of the details. Also,


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[Assistant] Thank you for turning in your second inquisitive assignments. Uhm, the ones that were due on Monday. Uhm, all of the grades are updated on Moodle.


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[Assistant] I told you that there are two solutions to this problem. One...


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[Assistant] The, uh, issue of combinatorial diversity, the other, junctional diversity.


[User] Please transcribe this text

[Assistant] And we were talking about combinatorial diversity last time.


[User] Please transcribe this text

[Assistant] We noted how uhm, we've got pairing of different heavy chains and light chains.


[User] Please transcribe this text

[Assistant] Helping us to address this problem, uhm, as well as the use of different mini genes, the VD and J mini genes.


[User] Please transcribe this text

[Assistant] Uhm, to help us address this problem. There's also, uh, junctional diversity that we will see, uh, a little bit more of today.


[User] Please transcribe this text

[Assistant] Uhm, an overview of that VDJ process that we talked about where


[User] Please transcribe this text

[Assistant] Uhm, in the germline, so in the general genome of all cells.