You're watching FJTN, the Federal Judicial Television Network. The Federal Judicial Center presents Science in the Court Room, a series of programs for judges on science and scientific evidence with an introduction by Stephen Breyer, Associate Justice of the Supreme Court of the United States. Welcome to the Federal Judicial Center's series of science programs for judges. This series is a response to two significant developments. One is that as time goes on, an increasing number of cases on your dockets are turning upon the application of scientific principles. Another is that recent decisions of the Supreme Court have imposed new duties on you, gatekeeping and decision-making duties that require an enhanced understanding of the scientific methodologies at issue in your cases. The series seeks to help you fulfill these duties in several ways. First, by providing you with an understanding of the basic principles governing three discrete fields of pure science, microbiology, epidemiology and toxicology. Second, by examining methods of evaluating the reliability of evidence from those three fields of science. And third, by considering scientific evidence from these fields in the wider context of making rulings and management decisions in specific types of cases that is patent and toxic tort cases. As you know, after Markman v. Westview Instruments Inc., a patent case can turn almost entirely on your conclusions about the meaning of scientific terms in the patent claim. Because patent litigation increasingly involves questions of microbiology, the first three programs in the series will be devoted to an examination of the fundamentals of microbiology in the context of a patent case. The first two programs will be pure science lectures. In the third program, a panel of judges and attorneys will examine the Markman and related issues presented by microbiology evidence in the patent case. The series then turns to a consideration of scientific evidence in the arena of toxic tort litigation. As far as you're well aware, the parties often seek to present evidence from toxicologists and epidemiologists on the issue of causation, and Daubert and Joyner and Tkumo Tire require you to make rulings on this evidence that may determine the outcome of the case. As such, the fourth and fifth programs of this series will address the basic principles of toxicology and epidemiology. The sixth will be a discussion by a different panel of judges and attorneys focusing on methods of evaluating toxicology and epidemiology evidence for purposes of resolving Daubert and other issues in toxic tort cases. The goal, of course, is not to turn you into scientists. Still, as you encounter terms like recombinant DNA, antisense, or nucleotides, and phrases like no observable effect level and cohort study, you may find yourself thinking you were on a longer and more arduous journey into the realm of scientific inquiry than you'd like to take. I can only respond that I think it is a journey you must take, indeed that we all must take, to be effective judges in this day and age. Why? Because it will increase our knowledge about the science we can expect to encounter in our cases. And as such, increase our chances of achieving justice in them. And so, in the spirit of scientific inquiry and in the pursuit of justice, let us begin. Science in the Courtroom, Program 4, Basic Principles of Toxicology. This lecture is presented by Dr. Bernard D. Goldstein, Chairman of the Department of Environmental and Community Medicine at the University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School. My goal today is, my objective is to try to provide just the basics of toxicology, particularly as it relates to toxic torts. Most of what I say is going to be right from the Federal Judicial Center's Science Manual. There's much more detail there if you'd like to follow up on this. Toxicology basically is the science of poisons. It's an ancient science, an understanding of the toxicity of natural chemicals has been a part of human evolution, a successful human evolution. Toxicology has been practiced through the years, not only by scientists and by physicians, but also by government people, considered Lucretia Borgia, for instance. And a lot of toxicology has developed in terms of worrying about poisons and the potential for poisoning. Modern toxicology is really an interface science. We're sort of stuck between chemistry and biology, and it's exciting that way. We have to keep up with the newer advances in biology, which is just such an exploding and scientific field now, and of course with chemistry. The chemistry is particularly important to us because we have to understand the intrinsic basis of how chemicals react and how they fit into the niches that biology produces. And it's that interface which is really the challenge to toxicology. I will actually show you a few chemical structures, but only really to make you feel good about having entered what for most of you I know is sort of dangerous territory, and it's in a sense to appease my conscience that I really shouldn't give an hour lecture on toxicology without showing at least a little bit of chemistry. We can roughly divide the field of toxicology into three. Forensic toxicology is a field that has long been associated with the courts. Its practitioners are well aware of their role in the criminal justice system, and you are well aware of what they do. The complexity of the field has been greatly increased in recent years by DNA and other advanced approaches, which can be brought to forensics. And I emphasize this distinct nature of forensic toxicology because it is not necessarily true that expert toxicology and the other two, toxicologists rather, and the other two fields of toxicology will necessarily be expert in forensic toxicology or vice versa for that matter. These other two areas can loosely be called pharmacology, pharmacological toxicology, and environmental toxicology. Well, pharmacology is in many ways the parent discipline out of which toxicology has evolved. Therapeutic drugs always have some associated toxicity, which must be understood if the benefits are to be achieved and to be calculated. The toxicity of chemicals can also be a basis for development of a therapeutic agent. For example, there's an effective class of anti-cancer agents that came out of studying a West Indian tea. It was a tea that was made from a bush in the West Indies, and people believed there that it would help in cutting down on diabetes. And so it was tested to see if it decreased blood sugar in rats, and it didn't have any effect on blood sugar, but it destroyed white blood cells. Well, that isn't good for an anti-diabetic drug, but it's very useful for an anti-wukimic drug. So again, testing the toxicity of chemicals is a way to not only be careful about therapeutic agents, but it's a way to develop agents which can be of value. Environmental toxicology is the newest field of emphasis for toxicologists. It arises in large part from the need for experts to address concerns arising out of the use and abuse of chemicals, which is so prevalent in our modern chemical era. And it's concerns that often lead to toxic tort suits. My first overhead, and I'll be showing you lots of them, tries to list for you the three major laws of toxicology. I'm going to keep coming back to these laws, but let me first focus on the first one, the idea that the dose makes the poison. This really was developed, stated very clearly in the 15th century by Paracelsus. He's a bit of an alchemist and a bit of a fraud, sort of a bombastic renaissance type who was always one step ahead of the laws he wandered around Europe. But he very clearly pointed out that everything is poisonous. It's only a matter of dose. Even water can kill, it's a question of dose. And so we really have enshrined that as if you will, a law. Now, I don't mean a law in the sense of these are really scientific laws, and they're certainly not laws of the type that you're familiar with, but they are basic principles which govern our understanding of toxicology. Let me first define dose in terms of the dose makes the poison. Dose very simply is concentration times time. There's a related concept which sometimes gets confused with dose, and I will through this lecture be talking about areas which, in my experience at least, there seem to have been some confusion in legal cases and with the hopes of setting these straight. And that related concept is called dose rate. And that's the speed at which dose is delivered. So, but it isn't dose itself. And let me give you some examples, or at least one major one, which is let's assume that we were breathing 10 parts per million carbon monoxide for one hour. That's exactly the same dose as breathing one part carbon monoxide for 10 hours. But the dose rate is obviously greater in that first dose in the sense that we're delivering the dose much more rapidly. A dose rate can be very important in terms of toxicity, but I won't really discuss it in too much more detail beyond this. There are two major types of dose response curves, dose response relationships that we discuss in toxicology. This is a gross generalization. It's a simplification, but I think it's a very useful simplification because many laws are based upon this, and it does help in understanding these relationships. The two major types of dose response curves are one that has a threshold associated with it. And this is a dose level below which no adverse effects are observed or expected. It's believed to be applicable to all chemical impacts other than certain mutational effects. And it's the mutational effects that we are concerned about that we believe have a non-threshold relationship in that every molecule, at least theoretically, has the potential for an adverse effect. Further, the risk is directly proportional to the number of molecules in the dose. So even one molecule has some threat, some risk associated with it. There is no threshold below which there is no effect. And the mutational events are particularly believed to be important in terms of cancer, and I'll go through that in much more detail. Well, what do we mean in terms of a threshold and non-threshold dose response curve? And I thought what I would do to try to help explain this in more detail would be to go through and actually draw some of these curves. I hope that, in fact, if you'd like to, you might want to draw them along with me. It just is a pedagogic technique to help understand them a bit more. And what we're going to do is we're going to draw, we're going to plot two axes. The vertical axis is going to be the response. It's going to tell us how much response occurs. And this response can be anything. It can be the number of animals that die. It can be the amount your blood pressure goes up or down for that matter. It can be something not measurable in the direct way, but subjective. How much pain are you in based upon something happening to you, a scale of 1 to 10. 10 is the worst, 1 is the best, and you've got to give us some numbers. And we can plot that as a response. The other axis, the horizontal one, is going to be dose, where the greater the dose, the further the right we get. If we start over here, we start with a situation in which there's neither dose nor response. We're starting with zero with both. Well, as an example, let's take sulfuric acid being poured on your skin. If we start with pure sulfuric acid, there's no question that we will burn a hole right into your skin. We'll destroy the tissues. Let's call that the maximum response at a dose that's over here, and this is the maximum response, and we'll put a little mark there. But what's the minimum response? If I take some pure sulfuric acid, if I take one drop and I put it in 100 gallons of water, and I mix it thoroughly, and I take a jigger full of that and pour it on your skin, nothing's going to happen. That's too dilute. It's just simply no effect whatsoever. The level of acid in that would be far lower than we have in our body naturally, certainly much lower than you'd have if you eat some vinegar on your salad. The acid level is too low. You won't feel anything. That's a dose where nothing happens. There's no response. And I can keep doing that. I can put two drops in 100 gallons or four drops. I can get up to a gallon in 100 gallons, one gallon of sulfuric acid, 99 gallons of water, mix it well, pour it on you. Do you feel anything? At a certain point, you're going to start feeling something. At a certain point, you're going to get a burn there. At a certain point, as I go higher and higher in dose, I'm going to get more of an effect. But we start with what is a threshold. It's at this level where we first start seeing an effect. And as we draw these curves, we get what's generally seen as an S-shaped effect. In that, as you adding more and more sulfuric acid, higher, higher doses in that jigger-full, higher concentrations in that jigger-full of water that we're pouring on your skin, each time there's going to be a little bit more. And each time, we're finally going to get to a level which is an effect. And that's what we would call the threshold. Below that, there's no effect. Above that, there is an effect. There's a maximum level.  And you can do this with just about anything that affects people, affects animals. You can take a lead pipe. And I could just softly put it on top of someone's head in a way you can't feel it. And there'll be no observed effect. Till we finally get to the strength of putting that lead pipe on someone's head, we'll finally get to a threshold to feel it, to have pain. And then as we keep doing this, we'll end up with a level where we'll crush the skull. Now, what this does, what I've described to you, hides a little bit of something that's very important, which is that people have different susceptibility. Obviously, a baby's skin is going to be more susceptible to that acid than an adult's skin. If you've got a cut, so you can go from a time where you're more or less susceptible just by having a cut in your skin. And obviously, pour a little weak acid on that.   People change in their susceptibility. I'm going to go through susceptibility to a large extent later, because it is a very important issue having to do with understanding toxicology and having to do with what happens in toxic tort suits. Who is susceptible? Why are they susceptible? And how important is susceptibility in these situations? One of the issues that we come up with as we look at these dose response curves, and actually, let me use the same one all over again because I think there's room to write it, is to understand how we go about making standards. And that's an important issue in terms of understanding whether or not people are particularly been affected. What is a standard for, say, a level of sulfuric acid in the skin or in air? What would you permit to have happen? And traditionally, in toxicology and in regulatory toxicology, we have taken this threshold level and put what we call safety factors. They're really protection factors. They don't make you completely safe, but they do protect. And these are protective factors that are based upon extrapolations from the laboratory animal where this study was done. We haven't really done this study in humans. We've done these in the laboratory animals. And we try to understand what would protect a human. So traditionally, the standard as it's been applied in the workplace and the general environment has been one which has been 1,000 fold lower than this particular no observed effect level. And that's the number which you may sometimes exceed. And we don't want people to exceed that number. We don't want people to be exposed to it. But just because you are, just because one day you happen to be exposed to a level that's just above the 1,000 fold safety factor, doesn't mean you are necessarily affected. It doesn't mean you are more likely than not affected. If we've done our job right as toxicologists, as regulators, just barely exceeding that allowable level, should we view completely safe? And we should be no harm whatsoever if we've done our job right. So that's where that standard comes from, and that's the general approach in toxicology. Well, I said there's two types of dose response curve. And the other we usually use for cancer. I want you to consider that we have a situation in which this dose causes this response, and the response is a 10-fold increase in cancer levels in a work group. I'll talk about benzene. Benzene causes acute leukemia in adults. Workers exposed to benzene at high levels of benzene have been found to have elevated levels of acute leukemia. So let's say this is a 10-fold increase in acute leukemia. That's the response at this dose. That's very high levels of benzene. There's benzene in this room right now. What's the effect? What's the implication of the level of benzene in this room? Benzene's a component of gasoline. It's in some ways a natural product. It's almost impossible to be anywhere in the world without some measurable level of benzene. The level of benzene in this room is very low compared to the level at which workers had an increased risk of leukemia. That was demonstrable. But how do we know it isn't causing an effect at this lower level? And the thing is that we think it might, theoretically at least, it could. And we say that because we don't think there's a threshold for the leukemia, for the cancer that's caused by a chemical. We think even one molecule has some risk. Well, why is that? It's simply because of the way we understand mutations. If there's a mutation that causes cancer, it can occur with just one change in the DNA bases that is basically our genetic code that codes for the information that the cell has. And if we change just that one base, that theoretically at least can be done by just one molecule. Now, there's a trillion molecules of benzene in every breath you're taking, roughly, right now. Don't stop breathing. The chance that any one molecule will do this is incredibly small. But we can't rule it out as being zero because if we think of cancer as being a single mutation that leads to a clone of cells that just keeps on dividing and dividing and dividing, well, then it could be done by any one molecule of a cancer causing chemical, at least theoretically. Basically, what we've done in our society from a regulatory point of view is to put the burden of proof, I'm using your language now, on the industry that's making the benzene or making whatever chemical it is to prove that the chemical has a threshold. And in some cases, you can. In some cases, there are good reasons why a chemical does not cause cancer in any one molecule. But the burden of proof is on industry and it's not easy to prove. And so what we have is a situation where we just assume that it's a straight line down to what we call the intercept. So that if this level of benzene causes this much leukemia risk, well, that level of benzene will cause that much leukemia risk. I'm going to go back to this because it's so key to so much of modern toxicology and so many of the arguments about it. Let me now talk about our second law of toxicology. And that's the law that says that toxic agents have specific effects. That I like to think of was first described by Dr. Paré. Dr. Paré was a very famous French surgeon from the 15th century. He's considered to be the father of modern experimental surgery. And the king of France, once came to him very excited because he had just purchased this very difficult thing to obtain. He'd gotten it from a Spanish nobleman who was something called a bezzouar. And a bezzouar is a concretion of the fact is a concretion, it's sort of a soft stone that comes out of the stomach of goats, particularly goats from Persia. And somehow this has been smuggled out of Persia. And the reason the king was so excited is this was supposed to be a universal antidote against all poisons. And Paré said to the king of France, nonsense. There is no such thing as a universal antidote against all poisons. It can't be because every single poison acts individually through a specific pathway. And each of these is different. And so no one antidote can help against all of these. Well, the king, of course, having invested all this money, decided he would do an experiment. And what he did was there was some poor cook who had been convicted of stealing the king's silver and was about to be hung. And they went to the cook and they said, well, instead of being hung, would you be willing to take this poison? We'll give you the antidote if it works. You'll go free. The cook took the opportunity. The cook died. Paré was right. Every chemical has a specific effect. There's a specific pathway by which it works, more or less based upon its own inherent chemistry, but also on pawn biology. Let me give you a couple of examples about specificity. And these come from being just basically going to a gasoline station and filling up your car. Gasoline's a mixture. It's got lots of chemicals in it. One of the chemicals, for instance, is benzene, which we just talked about, which may at low doses, perhaps even cause cancer. It's also got other compounds in it, which can cause effects. I'm going to talk about two different types of specificity related to this. Let me, in fact, talk about, since I've talked about benzene, let me talk about hexane and other straight chain alkanes. It's a very fancy word. It gives me a chance to show some chemistry. And really, I'll anchor it for you by pointing out that one of the straight chain alkanes is called octane. And we all know that octane is in our gasoline. And this is actually the end, stands for the fact that it's normal octane. It's a straight line of just eight carbons. These are hydrocarbons. I haven't shown you the hydrogens on there. And what I've done is I've drawn for you the pentane, which is five carbons, hexane, which is six, heptane, which is seven, octane, which is eight. The approach to metabolism by the body of these kind of compounds is similar to each one of these. You oxidize the internal carbon in each end of the chain. So this is an oxygen being added to these carbons. They were all added one carbon inside. And so you've got, in this situation, with eight carbons, you've got four carbons inside. You've got three carbons inside. You've got two here. You've got one there. It all looks the same, except this specific product of n-hexane causes peripheral neuropathy, causes damage to your peripheral nerves. None of the others does. And that's simply because of the fact that there's a niche in the peripheral nerves, which allows this particular size of four carbons with the two oxygens at the end to slip in there, cross-link that nerve in such a way that it stops functioning well. Doesn't happen if it's more, doesn't happen if there's less. See, here we have a very specific result, which is due solely to the fact that there's a biological niche, which allows that chemical to react and cause the effect. Well, that happened at the gas station. Absolutely not. Won't happen because there isn't enough n-hexane there. There's a threshold for this effect. Without getting to this level of n-hexane, it simply isn't a worry. We don't worry about the hexane that's in gasoline. We do worry about the benzene that's in gasoline. Now, as I pointed out in the previous overhead, benzene, the example of benzene is one in which there is a central nervous system effect, and the example of hexane in other straight chain alkanes is one in which there are central nervous system effects. You can get to high enough levels, very high levels, of these compounds in the pure sense that can make you drowsy. They're anesthetic-like. They can put you to sleep. In fact, people have died over vats of benzene in the workplace by just basically falling asleep and drowning. So these all have that same type of an effect. I can get a toxicology graduate student to give a very learned, at least the student better be able to do this, very learned discourse as to all the different alkanes as to which one will put you to sleep faster, which one you will recover from. The same thing with benzene and alkylbenzene. Alkylbenzene is a toluene, xylene, a whole bunch of other compounds, which are basically the benzene ring with just a small change and additional carbon added to it in various places. These compounds also have central nervous system effects. They'll put you to sleep. And again, the toxicology graduate student should be able to tell which one will more rapidly put you to sleep as compared to the other. Easily predictable. What I showed you about the n-hexane is not predictable in that way. It doesn't fall into what we call structure activity relationships that we could understand. We could not predict the peripheral neuropathy caused by n-hexane from knowing what pentane did and heptane did. It simply would not be predictable. And the same thing is true for the benzene toxicity. We cannot predict the bone marrow damage or the leukemia caused by benzene by understanding what happens to toluene and xylene and the other alkylbenzene. I can predict the central nervous system effects to some extent, not completely, but pretty well. But I can't predict the bone marrow toxicity. What I've described to you are two different types of toxicity in terms of direct acting or indirect acting. The central nervous system effects of benzene or of hexane or related compounds is a direct acting. It depends purely upon the actions of the compounds themselves, benzene, toluene, xylene, hexane, heptane, octane. The toxicity that I described in terms of the peripheral neuropathy due to n-hexane is not a direct effect of n-hexane. It's an effect of its metabolite. The same thing with benzene. It's not a direct effect of benzene to cause leukemia. It's an effect of its metabolite. Anything that changes metabolism can change the extent of these effects. So metabolism is something that we have to understand in order to be able to deal with toxicity. Well, I've talked a fair amount about these first two laws of toxicology. One of the reasons I did want to spend so much time on about it is that we see a fair amount of obfuscation on the part of defense and plaintiff's attorneys and sometimes confusion and judicial opinions between the two. And particularly when it gets the issues of general causation and specific causation. In essence, that first law of toxicology, the dose makes the poison, refers to specific causation. The second law, the specificity of effects, really refers to the general causation. It's almost the opposite. Specificity in specific causation refers to the dose responsible specificity in toxicology has to do with the general causation questions of whether or not a chemical can or cannot produce a specific adverse effect. You'll come across this, I'm sure. Let me talk now about toxicology methodology. How do we go about doing toxicology? We have three major approaches. One is that we will look in a test tube and try to develop what we call in vitro techniques that will allow us to predict what adverse effects might be. We would very much like to be able to replace animal toxicology with test tube studies, at least certainly in safety assessments so that we don't have to test as many animals to see whether a new cosmetic, a new drug, whatever is safe. So far, we've been not very successful in developing in vitro tests, developing test tube tests, which will really be predictive of animal effects. Animal studies are a major part of what we do in toxicology. I'll come back to them. Controlled human exposures are something that also occurs. People think of toxicology as not dealing with humans. You can, in fact, ethically expose humans to, for instance, to levels of compounds that are present when you go into a gas station. So as you understand what the metabolism and the effects are, many of the Clean Air Act rules and laws come out of studies in which humans are exposed in a controlled way to levels of pollutants that you might get outdoors anyhow. And this way you can understand which one of the pollutants might be responsible for an effect. But animal studies remain the major part of what we do in toxicology. As you saw in my first overhead, the third law of toxicology is that humans are animals. Toxicologists really do believe that. We really believe that we can understand so much about humans by understanding what happens to animals. We do know that there are differences. There's almost a bias built into the scientific literature about this. And I've seen this in legal documents or in the legal literature, where people have reviewed this and pointed out how poor animal studies are to be being predictive. You have to understand that I can write a paper and publish it. I can get a graduate student to do a PhD thesis on a difference between species. I can't do it on a similarity between species. Almost everything is similar. If something is different, though, it gives us an opportunity to understand why, to understand mechanism. For instance, we know that mice are more sensitive to benzene than our rats, in terms of the acute bone marrow toxicity. If we can understand why, that would help us understand which of the metabolites, which of that big list of chemical structures I showed you, is responsible. So it becomes something that's publishable. There's a mouse that's different than other mice in terms of its sensitivity to benzene. That's a publishable difference if it's different than a rat, if it's different than a hamster. But if it's the same, it just doesn't make any difference. I mean, we're not going to publish that. So there's a publication bias that sits in the literature having to do with toxicology in that you will find lots of examples that we really look for to show where species are different. So we can exploit this in understanding toxicology. Toxicology, this methodology, obviously, is different from epidemiology. It has the strength, as compared to epidemiology, of being able to carefully control the complete situation, except for just modify one thing. And that's the variable we're interested in in that variable. We usually be the dose of a chemical. So we can put an animal into a situation in which we have complete, the animals getting exposed are the same as the animals getting not getting exposed. They control animals in just about every way imaginable. As I said before, they're very often the littermates, they're identical twins, identical sex tuplets, and they've been carefully randomized to the different groups. They've also been brought up in a situation in which they had the same food, the same light, the same environmental issues for them. So they're really identical. And if you expose one group, you're really can deal with issues of causality. And I thought I'd talk about one aspect of a multi-year animal cancer study. And that's something called the maximum tolerating dose. This is routinely used in lifetime rodent exposure studies. It's usually the highest dose tolerated by animals in a short-term study. It's controversial because it uses doses much higher than those usual for human exposure and because it may lead to physiological changes that cause the cancer that wouldn't be applicable to humans. You may have heard of this in relationship to saccharin, where it was basically equivalent to 8,000 bottles of soda pop a day worth of saccharin was given to rats. And how relevant could that be? I want to describe in a simplified way why that's done and to some extent what the support is and what the problem is. Really, the reason for supporting this use has to do with statistical power and the goal of doing these tests. Let me give an example. Let's assume that there's a regulatory objective to protect the public against the chemical, which in its usual use, its usual exposure, we would be exposed to it, would cause cancer in one out of 1,000 individuals. That's not an unreasonable regulatory objective. In fact, sometimes we go much more stringent than that, one in a million or 100,000. And assume that there is this compound. I call it HMCW. That's a favorite toxicology compound. It stands for hexamethyl chicken wire. And this really would produce pancreatic cancer. So we've got a chemical. It's going to produce pancreatic cancer if we let it out there. And it's going to increase the, if we use the expected dose, which I gave initial white to over a lifetime, that cancer will occur. And let's assume that rats are similar to humans in response and that the background incidence of pancreatic cancer in humans and in rats is 20 in 1,000. And that it's going to cost about $2 million for this usual study where we're exposing 100 control rats and 100 exposed rats. And the question that comes up immediately is, well, OK, how many rats need to be exposed lifetime to the expected environmental doses to observe a statistically significant increase in pancreatic cancer incidence in these laboratory animals? And obviously, you can ask the question, well, the routine study is done with 100 animals in the expose and 100 in the control group. Could we expect to see this? And the answer is no.  You do 100 rats. Sometimes it'll be 3. Sometimes it'll be 1. But the average will be 2. And 1 in 1,000 increase just brings it up to 2.1.   But you're not going to be able to see that won't be any difference. Even if one time you got a 3 and the other time you got a 2, which would only happen one time out of 10, it wouldn't be statistically significant. You wouldn't know what to do with it. You really would not be able to say that this causes pancreatic cancer. What if we went and increased the number of rats in the study to 1,000? Using the usual expected dose, couldn't we find that then? It's a still no. What we would get, on average, is 20 out of 1,000 in the control group and 21 out of 1,000 in the exposed group, because there'd be a 1 in 1,000 more increased risk of cancer. That's not statistically significant. If you found that once, you'd say, well, maybe next time we'll go the other way. So you can't possibly protect the public using this animal cancer test if you're worried about a 1 in 1,000 risk. Well, you can if you make some additional assumptions. And then you make two. One is that, as we showed before, that the cancer risk is linearly related to dose. That's basically this curve over here. We're linearly related to dose. And the second assumption we're going to make is that rats can tolerate a 50 times higher than the anticipated lifetime dose with no real change in their health. And what we usually will do is we'll give a dose response study for 90 days in rats. We'll give lots of different doses. And we'll pick the dose where there's no weight loss. There's no change in the animal's life that we can tell through using a series of tests. And then we will go back and start all over again and use that as the maximum tolerated dose for two years in these laboratory animals. Well, if we do that, then we ask the question of can a statistically significant increase in pancreatic cancer incidents be observed with exposure of 100 rats to a lifetime dose 50 times higher than the anticipated dose? And he says yes. Because what we would see in those 100 control animals, again, it's two out of 100, but in the exposed animals, we do expect to see seven out of 100 to have pancreatic cancer. That would be statistically significant. It would say to us, well, if we're right about that being the cause of that if we're right about the linear response, again, if we're right, then we can just basically go down 50-fold on this and say, OK, here's the amount of cancer we would expect from 150th of that dose that we used. And that's an increase in 1 in 1,000. Of course, we get an increase in 50 in 1,000 out of the 50-fold higher dose. So what we have is a situation where, again, assuming linearity and assuming the rats like humans, we can make some regulatory approaches. But these are regulatory approaches. In doing toxicology, we focus a lot on the chemical pathways in the body. The chemical has to get into the body. It has to distribute within the body. It has to be metabolized within the body. It has to be excreted. These are important pathways, important to understand for each chemical what happens. Absorption is obvious. It can come through the skin. You can inhale it. You can get it through ingestion, through coming through the mouth. These are the major pathways. They all have different implications as to how rapid things will come up. If you breathe fine particles of lead, basically 100% of what you breathe comes into the body. If you eat lead in your diet, sometimes 10%, 20% will depend upon what you're eating with it, or what your basic status is, and I'll talk a bit about that. We'll only get into the body. So different pathways have different implications as to uptake. Distribution means how does something get around the body? There are certain chemicals which, because of their chemical structure, will pass what we call the blood-brain barrier and get into the brain. Others will not. Iodine in the body will go preferentially to the thyroid because it's thyroid hormone, which is really about the only major constituent that the body has, which we have iodine. Iodine's necessary for it. Well, when you get iodine into your blood, you take iodine into your body, the thyroid gland has a very specific pump which basically sucks out all the iodine or almost all the iodine that will go past the thyroid. Other tissues do not, so more iodine will distribute to the thyroid than to any other area. And again, understanding this is important to understanding toxicity. Metabolism, basically, how does the chemical change within the body? As I pointed out before, some of the changes are, if you will, good in that they detoxify, they get rid of the toxicity of the agent. Other changes actually make the agent into a toxic agent. And excretion is important to understand as well. What are the pathways of excretion? Some things come out through the urine, some through feces, some through just exhaling, some through our gallbladder. So there's a variety of different approaches that need to be understood. The responses can be acute, can be sub-acute, can be chronic. These responses are very often the time pattern of response along with the understanding of absorption, distribution, metabolism, and excretion can tell you a lot about toxicology and about toxicity. One of my favorite questions to toxicology graduate students is to tell them about the newspaper article about someone who had chronic headache for about five years and it decided that it must be coming from the mercury in their dental amalgams. And had the mercury removed from the dental amalgams and got up from the dentist chair and said, my headache is gone. And the question to the toxicology graduate students, what are your problems with that? And there's a couple of problems. First of all, mercury in the brain will build up in the brain if a high level of mercury exposure and can give you symptoms like headaches. So no question that can occur. But I would expect the toxicology graduate student to be a little concerned about, a little skeptical about how mercury in an amalgam gets up to the brain. I'd expect the toxicology graduate student to be, even if they could come up with a pathway while maybe some of it vaporizes and somehow gets through the pallet into the brain to say that, well, the dose won't be high enough to be equivalent to the kind of dose which we've observed in people who are mercury miners or gold miners using mercury and roasting mercury and getting lots of mercury exposure, high enough to cause chronic headache. But most importantly, that student would have to point out that the level of mercury, whatever level of mercury you have in your brain, the time at which it turns over, that kinetics of its turnover is such that it will take months for it to leave the brain. So you can't just get out of the dentist chair, immediately after having the mercury removed and say that the mercury got out of the brain and therefore the headache went away. If the headache went away, it had nothing to do with the mercury. These are the kind of decisions you can make if you understand the toxicology, if you understand the pathways, if you understand the time frames of these issues. Some chemicals stay in the body for lots, for a long, long time. Other chemicals basically get right out of the body. Understanding that and knowing that is very important. We also have to understand toxicological responses. What these responses can be for everything from altering the cell function or cell death, you can just basically kill a cell, but the cell can mutate and lead to cancer. If you have mutations of germ cells, you can end up with fetal changes, which are obviously very important. Scarring is a kind of long-term process. You can get scarring of the lungs from asbestos. You can get scarring of the liver from cirrhosis from drinking, that's what cirrhosis really is, is simply scarring of the liver from drinking too much alcohol. And again, dose response considerations are important. Alcohol, obviously, the dose rate is important. One drink every day for a month is not gonna be harmful, while 30 drinks in one day will cause a lot of acute damage to your liver and the healing process will very often be with scarring. And if you keep repeating that, you will end up with a lot of problems. And again, target organ toxicity. If there's radioactive, I mentioned iodine going to the thyroid. If there happened to be a nuclear power plant releasing a lot of radioactive iodine because something went wrong, it would put you at an increased risk of thyroid cancer because the radioactive iodine would go preferentially to the thyroid just as any other iodine would. If it was not radioactive iodine, it was radioactive C-zema, it would go somewhere else. In considering toxicological responses, we always have to remember about adaptation and repair. The body is able to adapt. Sometimes the adaptation is very good for a short-term problem, but very bad for a long-term problem so that an adaptation response to smoke, presumably developing from the time of living in caves with smoky fires, is that we produce more mucus. And that makes sense. If you breathe in a lot of smoke, the lung airway starts producing a lot more mucus. The mucus sort of cleans, gets rid of some of the smoke particles which gets on and protects the lung. What too much mucus production over a long period of time is the basis for chronic bronchitis and emphysema. So what we have with cigarette smokers is a situation where cigarette smokers make more mucus than non-smokers. What I started to say, you and I, I hope you're all non-smokers. And that cigarette smoke does manage to produce that, if you will, it's a protective response. But over time, you end up with so much mucus being produced by so many cells, it changes the characteristic of the lung. The mucus gets stuck down in the airways and you end up with chronic bronchitis. There's a lot of situations like that where acute responses, good acute responses, turn out to be the basis for chronic disease. These have to be understood. And certainly the mechanisms of susceptibility are increasingly important in toxicology. Obviously some reasons for differences among people are the inherited factors. We're genetically different and some of the genetic basis for this is being understood more and more with our new science, with unraveling the human genome. We will understand even more of this over time. I'll try to get back to that. Age and gender, I pointed out before about a lead pipe in the back of my head. That's an age-related change. Obviously male-female differences are great. Lifestyle factors will change dramatically how much at risk you are to chemicals. The benzene example I gave, benzene, we know that if we increase benzene metabolism, we will make things worse. We do know that alcohol induces, basically increases the amount of the metabolic machinery that's responsible for the metabolism of benzene. So we will end up with far more metabolite of benzene if we have alcohol at the same time. And health status factors, if you've already got emphysema and you're exposed to an air pollution, you're clearly gonna be at greater risk than if you have a normal lung function. So obviously these all play a role in toxicology. I thought though I would go back specifically to the toxicokinetics to basically the absorption of distribution metabolism and excretion to discuss with you a little bit more about susceptibility, about the things we're learning. The way susceptibility will often develop is through changes in how the kinetics of chemicals go through the body.  That's carbon monoxide toxicity. And the reason the kids are more at risk is simply because children breathe more per unit body weight than do adults. It's partly because of their metabolism, it's partly because they just don't sit as still as you do.  They simply will breathe more. So they breathe more carbon monoxide. So respiratory uptake is just one example of increased absorption. Another for susceptibility is the fact that lead uptake in through the stomach will increase if you're iron deficient. Inner city children who tend to have more lead around also tend to be more iron deficient. They just don't get as much iron as they should. So the very children who are iron deficient are the very children who are more likely to be exposed to lead and who are at higher risk because they're gonna absorb more of the lead. Simply because lead and iron have a similar absorption pathway and if you have not enough iron, you make more of this absorption pathway and so if there's a lead around more it gets taken into the body. Distribution, I mentioned the iodine going to the thyroid is a classic example of something that could make you susceptible. In the Chernobyl incident a lot of radioactive iodine came out and it came out into an area in central the old Soviet Union where there isn't much natural iodine and so these are relatively low iodine diet. Well the more iodine you have that's natural the more it's competing with the radioactive in terms of being taken up into the thyroid. In fact the way we've stockpiled around the country around nuclear reactors, we've stockpiled iodide. And if any time anything ever gets loose and there's radioactive iodine coming your way just grab some iodide because what you do is you put so much into your system the thyroid won't take it all up and it will take up much less of the radioactive than it would if you had very little iodine. Well these people were more at risk, these children particularly, because they had very low levels of iodide in their salt and in their natural food and so they ended up with being more susceptible to thyroid cancer and now are having a high level of thyroid cancer. Metabolism as a cause of susceptibility. We have inherited all sorts of different pathways of metabolism, there's differences among individuals. These are very often genetically determined as we learn more about genetics we're going to learn more about why people differ from each other. Why is it that only one out of every eight lung cancer, cigarette smokers gets lung cancer? To what extent is this determined by genetic predisposition? Have to do with metabolism of the chemical or other issues as well. Excretion obviously the same type of thing. If you've got kidney disease you are going to be much more likely to retain within the body a toxic chemical that otherwise would be excreted in the urine that will lead to higher levels and more likely to have an effect. So all of these things affect susceptibility and are going to become more and more important in understanding whether people have been affected by toxic agents. Let me switch now to talking a bit about how we go about practicing toxicology and what we really do. And to do that I thought I'd start by giving you the distinction between drug and environmental toxicology. As I mentioned these are two major parts of what we do in toxicology and just trying to understand those differences might help understanding what we do on a day to day basis. First of all, when you're looking at a drug if you're the manufacturer of a drug you really want something that's got a biological effect. I mean it's gonna decrease blood pressure it's gotta do something to the body or it's a placebo or it's a chivalroid. I mean it's no sense making it. If you're manufacturing an industrial chemical you got a new color of paint you got something to make the color of my tie a little sexier, you're hoping it has no biological effect at all. You just want it to do, you know, just change that color please, nothing else because you don't want any effects in humans. Now there's an in between thing. There are things that are sides, C-I-D-E-S those are the pesticides or odenticides. You're trying to kill, herbicides we're trying to kill something that's living whether it be a plant, that dandelion in a backyard or whatever. But we don't want to affect humans. So again, they're sort of in between things. But basically that's a major distinction. And that leads to also a distinction in exposure and dose. Exposure to a drug is limited to the individual using the medicine, we hope. And the appropriate dose is well defined. On the other hand, if you've got an industry or a consumer chemical, you're never quite sure where it's going to end up.  You have to be really concerned about these things rather than assuming that it's really predictable. The other, another difference is that an individual exposed to a pharmaceutical agent presumably has some potential for a direct benefit. So if there's toxicity, it's unfortunate, but at least it's related to the hope that there was some benefit. There's no reason whatsoever we should have any toxicity from painting something in our home or doing something with a consumer product. Or any effluent that comes out of an industry. If they're making some money on it, it shouldn't be contaminating the neighborhood. And this leads to a difference in the amount of information we have available, which is what will very often appear in a courtroom. How much information do we have available about this chemical?  For a new chemical that's going to be used again for color of my tie, we really require a very minimal amount of information and that minimal amount of information is hardly enough to be able to predict what is going to happen. The way we get this information is by two means. One is through understanding mechanism, the kind of basic toxicology that I've spoken about to try to understand and predict how chemicals act. Another is through something we call safety assessment. This is a routine testing that is done in response to regulatory requirements. They range from prescribed tests in a test tube to see if say something might cause mutations in cells in a test tube to multi-year animal cancer studies. So let me stop here and again refer you to the Federal Judicial Center's scientific manual if you have other questions about toxicology. Thank you.


The three key tools to keep your TEFL class managed. The way a teacher manages the classroom has a profound impact on the success of the class and the ability for students to achieve their learning potential. Successful class management is made up of multiple different facets that all work together to achieve a positive learning environment. When executed correctly, the use of body language, the way the class is arranged, and the maintenance of discipline work together to create a successful class. Body language. In the classroom the use of body language is incredibly important in effectively managing the class. There are several different ways a teacher can utilize body language to manage the class. One of the most obvious of these is the use of eye contact. Eye contact can be used to show students they're involved and encourage them to contribute to the class. This in turn helps hold their attention as well as allowing the teacher to ensure that everyone is participating. Conversely it can also hurt the class if used inappropriately, such as during not teacher-centric activities. Like all classroom management techniques, it is important to strike a balance to manage the class effectively. The same can be said of the use of gestures in the classroom. Gestures can be very helpful as they help convey meaning visually, whilst reducing the need for verbal explanations. The addition of visual gestures is something that naturally helps keep students in the class attentive. Similarly to the use of eye contact though, unclear gestures can have a confusing and negative impact on the class, so to maintain a well-managed class, it's necessary to make sure they're used correctly. The final major tool a teacher has at their disposal in this area is the use of their voice. A teacher with clear speech who sounds enthusiastic is going to have a much easier time holding a class's attention than a teacher who speaks in a dull monotone and isn't visibly enjoying being in the classroom. When used effectively, all these techniques can come together to provide major help in managing the classroom. Grouping. Another incredibly important way a teacher has control over the management of the classroom is through the grouping of students in the class. There are numerous ways in which this can be done, and they all have their pros and cons, depending on several different factors, such as class size and the student's English level. For example, whole class groups can help build rapport amongst students, and all the teacher to easily monitor the whole group. However, on the other hand, these large groups can reduce individual student talk time and also be intimidating for shy students. So it is important to take into account the class dynamics before deciding on a preferred method of grouping students. As a ground rule though, a mixture of whole class grouping, pair work, and individual work helps maintain students' interest in a well-managed class. Once a teacher has gotten to know a class well, more effective groups can be made, such as seating strong students with weaker students. This allows students to help and learn off each other, rather than solely relying on the teacher's input. Discipline. Possibly the most important form of classroom management, is the maintenance of discipline. A poorly disciplined class is incredibly hard to manage, and has the potential to quickly descend into chaos. Whilst some factors that lead to poor disciplines, such as issues at home, are outside of the teacher's control, there are several ways that a teacher can create and maintain discipline within the class. The first of these is to establish rapport within the class, both between the teacher and the students, as well as amongst the students themselves. If the class is comfortable with each other, then the students are much more likely to be confident, and willing to contribute to the class, as they are within the safety of a positive and comfortable environment. The appearance and presentation of the teacher, are also very important in this. Always being on time to welcome the students into the class, and maintaining a professional appearance, goes a long way to helping maintain discipline within the class. Always providing simple and clear instructions that students understand, is also of vital importance, as obviously they will not be able to complete tasks, likely to get distracted if they're unaware of what it is, they're supposed to be doing. In every class no matter how well managed, there is always likely to be at least occasional problem behavior. In these situations, it is critical that the teacher remains calm, and is fair and consistent in their response. This along with all of the preventative measures, helps to minimize any problem behavior, and provides an example of a well managed classroom. Effective management of the classroom, is the most important factors in a teacher being successful with a class. Through the use of body language, class grouping, and discipline, the teachers give themselves the greatest chance of achieving this. An effectively managed class through the use of these methods, provided the best possible learning environment for students, and gives them the chance to maximize their learning potential in the classroom. Subscribe by clicking that button down here, and click on any of the videos here on the left, for more interesting teaching tips for getting certified to teach English abroad and online.


So we're here in Parkesville today for the opening of Family Plays, which is a fabulous community project that brings together services from the Ministry of Health, the Ministry of Children and Family Development, Education, and Bank of Brown Health Authority, all into one place for families to come, so they can come for immunizations, they can come for early childhood learning programs. We've just toured Munchkin Land, which is a strong start at BC, center where kids can come and play and learn with adults, and it's just it's just a fantastic example of what we can do when we bring everything together. This is an incredible facility. It's one of the reasons that it's such a great place to be at MLA. All the communities working together getting things done for the benefit. In this case of families, we have the school district, the Ministry of Children and Families and Bank of Brown Health Authority coming together to provide facilities for families, to help support families with health needs, early education needs, and children and family counseling and other needs. So it's a great facility to have all in one place. Family Plays has been built in a way that allows us to have a variety of kinds of spaces to be with families in a way that's welcoming and friendly and respectful and encourages us to work closely together with families. It's built to be with families in a very fun, respectful way where we learn together, we play together and we grow together. It's a real asset for the community and we're so excited and so proud to be able to be here together.


And I feel like with a lot of this, teaching them how to flex and drive and do all that, I feel like you get a really good feel for that horse's personality as far as how they react to pressure, how they deal with pressure. When they're a little bit confined or they're in a little bit of a tight spot, maybe close to the wall and you're asking them to turn and asking them to do things, do they get a little gives me an opportunity to just work on my start working on some of my half turns and being able to use some forward motion sources really fine and a good balance uses himself well behind when I release the pressure of my body driving him forward I really want him to I want him to take that time that's his time to stand there relax whether it's a cutting horse rain horse you know our cow horses a horse backing up is probably one of the more unnatural things for them to do it's not something that comes instinctual to him and so I feel like that's something that I've really tried to concentrate on is is these cults learning to back up softly and changing things up you know whether we're working a cow and we back a circle on them or whether we're actually asking them to back up straight I'm asking them to stay in between my lines so wherever I go in the pen I want them to start finding their way to me and if they can do that softly then I to me I have I have all four corners starting to work in the right direction moving their hind end while they're stepping with their front feet they're not leaving their front feet out there dragging and pulling on my hands they're just softly backing up with me so if I can and be able to and be able to kind of follow me where I'm asking him to back I have to have control of all that so if he wants to push that hip over there a little bit when he moves that hip back up underneath him in order to follow me


In this set of slides, we will have a look into a real attack against the DNS infrastructure. The DNS infrastructure can be in itself a target of attacks, for example, a DDoS attack. DDoS attacks aim at hindering or stopping the functioning of a certain service. What would then be the effect of degrading the performance of DNS? The easy answer is that any application that has a dependency on DNS will suffer. Unfortunately, nowadays, this means a large portion of the Internet as we know it. To give some examples, the web, but also email, instant messaging, and the Internet electronic. DNS has a certain building resistance to attacks. First of all, DNS is highly distributed and redundant. Second, caching can get you a long way before a failure propagates. For example, assuming that a root server fails, it is likely that the local resolver has already cached the relevant IP addresses for some TLD servers, and the time to live for such a resource records is in the ordinary days for most zones. At another level of the resolution process, however, a failure can be not as much faster, ultimately resulting in failed queries. For example, the time to live for cnn.com is five minutes, which means that if all the authoritative name servers for cnn.com are down for more than five minutes, nobody would be able to resolve the name anymore. Caching is not the only consideration to be made, however. It is also a matter of number of queries. Considering that a root server might receive a number of queries per day in the order of billions, an attack to the root of the DNS is clearly a very serious business. In this lecture, we analyze the recent attacks on the DNS root servers. On the 3rd of November and the 1st of December 2015, most of the root servers experience what is suspected to be a DDoS attack. There is currently no agreement as if the event was a DDoS attack targeting the root of the DNS, or if the target was something else, but the net effect is that we have observed exceptional side effects at the root servers. So, in lack of more information, we refer here to this event as an attack. There were actually two separate events, one on November 30 and one on the 1st of December, but the modus operandi was the same. The root servers received an enormously high number of queries on IPv4 and UDP. Analysis of the traffic shows that all the queries were for only two domains. Researchers at VeriSign, who have analyzed the attack, report that 10 out of the 13 root servers received attack traffic. We have already mentioned that a root server might receive billions of queries per day. Let's have a look at how the root of the DNS is implemented. First of all, there is not a single root server, but 13 of them, named with letters from A to M. Each one of the root servers can answer recursive queries and knows how to reach the TLD authoritative servers. In practice, 13 servers is still a relatively small number for such a crucial service. Under the hood, for resilience and performance reason, most of the root servers are implemented using AnyCast. AnyCast is an addressing methodology that allows a receiving IP address to have several replicas. This means there will be several servers all with the same IP address online at the same time. Traffic to an AnyCast IP address will be routed to the closest replica, where typically we intend closest in a routing sense, but hopefully this is also consigned with a geographically close replica. AnyCast has the advantage of introducing redundancy in a service which is beneficial for resilience and performance. In case of the root servers, this means that hundreds of replicas are scattered all over the world. For example, Amsterdam hosts replicas for server E, F, I, J, K and L. Coming back to the attack, this is an example of how one of the root servers, the A-root, operated by Verisign, has seen the attack. In the picture to the left, we have the query volume in millions of queries per day. A-root registered total number of IPv4 UDP queries of $52.8 billion on November 30, 2015, against a general trend of around $3 to $6 billion per day. Verisign reports that for the duration of the attack, A-root registered a peak of $5.2 million queries per second. The attack is also clearly visible if we look at the number of IPv4 addresses contacting the servers on the right. This number spikes to $1.8 billion against a few million sources during a normal day. Verisign reports that about 895 million different source IP were involved in the attack for the two root server they manage, A and J. Finally, let's have a look at another characteristic of the attack. Most of the queries were regular, well-formed queries. This graph reports the response code for the query received by A-root. Most of the queries during the attack receive a non-error code, meaning that the queries were completed with success. The analysis of the query returns code shows that A and J-root succeeded in handling the attack, despite higher query load. Let's now have a look on how the other root servers reacted. This picture shows the percentage of unanswered queries for each of the root servers over IPv4 and IPv6 separately. Have a look at the y-axis. Each dot on the plot represents a time slot of 10 minutes. The picture has been generated by the DNS-mon server's RIPE using props generated by the RIPE Atlas platform. A green dot indicates that the server is reacting normally. An orange of red dot indicates that the server is not able to handle all the query it receives. In the plot, we can clearly see two red zones related to the two attacks. The picture shows that the root server reacted differently to the attack. For example, not all the root servers after query loss during the attack, as we already knew that was the case for A and J, for example. However, some root servers were badly affected, as for example B, C, G and H, and to a somehow less-degree E, F, I and K. Besides analyzing the event, VeriSign researchers also provide some example of how such an attack can be mitigated in practice. Other approaches to mitigate attacks against the DNS or misuse of the DNS are possible, but we will look at them in the next video. For the specifics of this attack, the following two mitigation strategies have been put in place at A and J root. First, response rate limiting. Response rate limiting is a mechanism recently embedded in DNS software that allows a server to slow down the rate to which it answers to queries that arrive in iVolume. In the case of the November-December events, response rate limiting was able to drop 60% of the attack response traffic. Response rate limiting has the advantage that it might already be deployed at the DNS server, as indeed it was the case for this event. So it is an automatic mitigation mechanism. The disadvantage is that response rate limiting only acts based on the rate of request. It does not distinguish between attack or normal traffic. Therefore, part of the attack traffic is unaffected. The second mitigation mechanism was filtering. To filter, you need to be able to create a rule to distinguish between malicious and normal requests. In the case of this attack, this was possible, and filtering was a very effective mitigation strategy. The disadvantage, however, is that it needed manual intervention, both for analyzing the traffic and defining a filter, as well as for deploying the filter.


Hey guys, welcome to Snowbreak Containment Zone. As you can see, I already have Katia. I spent around, let's say, around two hours just, you know, tinkering with her kit, running some scenarios with her before I give you guys my honest opinion if I'm going to recommend you guys pulling for her. I hope I'm not too late if you're still thinking about pulling for her but let's go first to her kit and give you guys a bit of a rundown on what she has. Okay, so my stats are actually for now maxed out based on how I built her and up to what extent. I'll do a separate build guide on how I came here but we're gonna be discussing more on the overview first on how is she going to impact your team, how are you going to be using her. Let's start off with her skills. So for her skills, this is related to her standard skills so she comes into a form which is called guidance 3 form. So this form basically is she can do a burst damage through the enemy but there's a energy bar to this one. So Katya use standard skill to switch to guidance 3 form and this form Katya cannot move. She's kind of, she isn't squishy in that pose but she'll take on damage depending on how much it goes your way. I would still suggest that you dodge and just activate this skill again, her standard skill and just shoot again. But more or less she is going to be kind of, what do you call this, kind of semi shielded. So let's move forward. So cannot move, tactical dodges will make her exit this form. So if you exit, if you dodge you exit then you just do the standard skill again. Okay, cannot restore S energy and each shot legitimately consumes 0.5 energy which is going to be quick but as you shoot in your regular shooting form you also gain this S energy back. Okay, so if you run out of energy you're going to exit the form as well. So Katya isn't affected by changes to rate of fire except when that happens to be in her manifestation which we'll discuss later. So and she gains increase in anti-interruption ability. This is what I'm talking about. She cannot be interrupted. However during this mode her shots have decreased, final damage, destructible object damage and you energy gain. So the trade offer kit is you get unlimited ammo but your damage is around half. It's half. Okay, so that is why you have to build her attack stat high so that you'll have, it's still gonna be 50% less or probably 48%. But again at least it is growing and you have consistent shooting and you don't have to reload anyway. So and also the energy gain is going to be decreased as well during in this form. Okay, in guidance 3 form Katya rate of fire varies based on the crossbow mode. So there are two crossbow modes. One is a singular shot and the other one is a wide shot which has five arrow shooting at it but obviously it's going to be a slower shot. So as you can see here there's a difference between the shots. I would highly encourage you to use a single shot because I think that is what she is made for. The spread shot is actually for me not as effective even though it's spread and the aim is way off. If you miss on the other bullets, if you aim on the middle and you miss on the other four then definitely it won't be that effective. So stick to the single shot I would suggest that. So final damage decreases to 48% of original value as I've said and the damage to destructible objects decreased to 50%. These are areas where an armor falls off where you can take off that armor and new energy decreases to 25% of the original value. Okay, so tactical dodge immediately resets death, traverse, cooldown which is nice. When equipped with a frost weapon not in guidance 3, shot hits, restores 2 energy. This is what I'm talking about once she exits and you just shoot the enemy with your regular shot then you gain S energy as well with this skill that we opened already. So moving on to her support skill. So basically her support skill is just a frost damage reflecting frozen to targets within range for three seconds. It's a short duration but it's a fantastic support skill to have especially if you're running her as a support. So that is it, nothing special. So these are just buffs. So basically this is just frost damage which gives you frozen for three seconds for your support skill and last is going to be your ultimate. So by the way the standard skill is Death Traverser. Explosive Envoy is going to be your support skill and your eloquent arrows is going to be your ultimate. Okay so you have the option of putting it on stay in which in she does her ultimate then she stays in the battle and this one is operative switches out the battle after a quick ultimate. It depends on you guys, depends on preference but for me I'd rather have it on stay in. So Katja shoots towards the sky. This is actually a nice ultimate to have. This has a long duration of 10 seconds. Target is a center target wherever the target goes that AOE fouls the target and also damages the other you know enemies near that target as well. So this one damage instant cooldown of Guileful Barrage decreases to 0.2 seconds and AOE increased by 50%. So the second one is also decreases movement speed which is nice as well for additional control and upon hitting 10 times additional inflicts frozen effect for another three seconds. Okay so these are her skills and for her um alignment index or day was alignment. So each of Katja's shots has a 30% chance to gain an aptitude effect. Shot deals 30% of attack as frost damage. So additional frost damage aside from the regular damage for Ballistic increases by an additional 7% for each of the alignment index. So I have now 400 so that's roughly 7, 14, 128 so 58 in total percent of frost damage. This will help you increase your damage output if you work on your alignment index. So that is how her kit at first glance looks like. We'll do a demo in a while um and I'll give you guys my thoughts on what um what her role will be in your team considering that you have enough characters I presume but that one was a nice shot. Okay so logistics these are the logistics that came with the shop this is actually obviously for her so this one increases attack by 20% if you have two for three officers when equipping operative shot hits but does not crit because your crossbow doesn't crit. So gains like Cyclonic Fisher increase frost damage by three for three seconds max 20 stacks so that's 20 times 3% that's roughly an additional one 60%. Each crit hit removes one stack dodging refreshes the effector so don't worry about the removal because you don't crit anyway so this will give you a consistent 60% but again it's only for three seconds but again it it counts again after the three seconds obviously. So this is going to be part of her kit anyway so it's going to be a standard in her kit we'll discuss more of it as we go to her build guide for her manifestation guys um she's gonna be she's gonna be good she's gonna require actually one copy for M1 this one is to increase her rate of fire okay in guidance form so this is very important we'll talk about the rest but again um just take care of the first copy then probably um probably mine the rest or farm the rest then you're good so for Neuronix we'll talk about more on the build guide I just want to focus more on why should you pull for her if you have that many ready why should you pull for her number one her dps for for what do you call this for even for this weapon even for this weapon this is going to be the weapon available in the shop this is actually a nice weapon because her ballistic damage scales up and stacks and increases in damage as you deal damage to a specific enemy so um it scales up and it scales up crazy so this one the weapon itself is going to be easy to get it's gonna be available in the shop and this is going to be good for her already you don't really need to splurge for the unique weapon that she has but if you have that then you could go after that but this weapon especially if you have this at tier five this is going to be a very very good weapon so again um why should you pull for her number one she is going to be a dps not a dps queen per se but she's gonna be beneficial for targets for bosses and if you could make the boss stationary you could really bombard with consistent damage especially if you time everything the immobilization the control plus you can time the standard skill for this girl and you just shoot away and again that meter just continues to drop because you don't have to reload take note all in all even though that she has medium damage but with the consistent damage and if you could control the enemy in not moving then you will be maximizing her so all you need to do guys is to increase her attack stat frost damage s energy recovery alignment index of course those are things that you need to improve with her again the unique weapon is actually good but it's not a must she's gonna be running for you even with the the weapon at the store again if you don't have a single target dps her then she's the girl for you if you have all the characters and you have a priority then if you still want to get her she really plays differently she's you're gonna get used to playing her because you don't have to reload and don't click on r because if you click on r it switches to the five arrow mode or cross cross bow arrow mode then it's gonna be you know you're gonna be doing less damage especially if it's only gonna be single target then you have to switch again so again her her play is going to be a lot of movement towards the battlefield so single target burst damage is going to be her best role if you already have a sniper and you prefer a sniper then it's really up to you but for me i usually prefer burst like for example life for example i have absconditus and now her then definitely i will be preferring her over a sniper because i prefer to use burst damage to gun down my enemies okay so ideally you you pair her with somebody who can support you with control stun freeze somebody who can incapacitate the enemy and you can pour on all the bullets then that would be good um life um what do you call this life five star is actually perfect for her because she does freeze as well um also if you can do the standard skill for freesia then switch to katia then it would also be good what else who else does a lot of control but anyway for those for for her to be good at a primary dps role you will need to have a good support that can hold enemies or that can freeze enemies or that can you know incapacitate them and not being able to move let's do a demo for this one your connection let's do just me as a single uh what do you call this single participant so she's gonna be you're gonna have a series of plays for her so standard skill dodge standard skill so again make sure that your standard skill uh if you can hasten that bar then it'll be good so so let's try this one so as you can see the shot varies in damage 3000 2000 4000 so let's do that that's for your basic shot so if you do your standard skill it would be smaller but again the damage is going to be quicker because of the speed once you have decreased in what do you call this decreased in your energy for your standard skill try to go back to your standard shot because it will recharge your standard skill quickly okay so it's gonna take you a while to use her or to be you know to be to be uh what do you call this to be proficient in using her so as you can see it's really quick how to lower down there what do you call this their hp so just gonna be doing basic shot the basic shots are not bad i'm shooting between 2000 something to 5000 so if you see that okay so she's like carrying a machine gun guys but it's more accurate than your machine gun of course so let us reduce damage taken okay i'll just uh go through the motions here so again standard skill is oh as you can see i forgot i reloaded and okay going back to the read to the this one has a little bit of a smaller damage but again it's really how hard to control the other projectiles especially if your enemies are not really in you know aligned with your let's do ultimate here it's to clear things out so as you can see the the projectiles actually are dipping down but you can still reach that far it's just have just have to you know just have to adjust because your crossbow ammo is are not bullets so it dips down the farther they go just have to get used to actually shooting them but the range is actually the range is actually respectable just have to adjust uh just uh just uh what they call this and tilt your crossbow up oops see just dodge and not bad damage right so basic attack would be around 2000 to 5000 then for your standard skill or your standard skill it's gonna be halved depending on what you dish out so if they're you know bunching up let's power up that standard skill first before we actually forgot as you can see they are reloaded and loaded a different type of bullet okay so we do need some hp here at this point kinetic again you have to get used to shooting because i don't have more anymore hp just have to be mobile here see how quick how quick hp goes down better have some hp for me by the time i cross dude again i forgot this guy is actually hiding okay don't reload i always forget the reload so as you can see guys it's not bad not really bad in you know carrying her max hp uh it's all hp so this is the boss who is the boss okay see how quick just have to be quick about it you have to actually dodge and do another dodge as you can see how quick the hp goes down just have to refill before you activate the standard skill again okay then we go see how quick is that okay guys i think you've seen it all and i haven't even you know i haven't even maxed her out so let's go back to her stats for that damage output i haven't really maxed out her neuronyx i haven't even maxed out her attack stat so as you can see neuronyx i still miss this one manifestation obviously i'm at zero logistics although i maxed out but the final stat line isn't freeze or or freeze damage or froze or frost damage weapon i still only have one copy so i am at what tier zero tier one so again there's a lot of work to be done for her kit and that is her damage output just want to show you guys a damage output because at first i was skeptical as well if she can deal that much damage and she can be effective but i find her kit very fun to use if you're looking for a different play style and if you're sick of using your existing characters be my guest pull for her if you really want her character design or her looks pull for her again pull for her if you need her if you desire to play with a different play style i would highly recommend her her damage output is actually decent it's not bad it's actually above average and her kit has a lot of promise i tell you so pull just one copy then mine for the rest of the copies you don't really have to mine a lot of copies for her i don't think that is practical at this point but again guys i'm recommending her pull for her especially if you though if you need a if you're not into a sniper and if you are into burst weapons that can take down single bosses because she's a single target burst damage dealer she's gonna be good at it and she is going to be better as i improve her kit so thank you very much guys for staying this far take care stay safe this is the warden and i'm out of here


So, we want to look at simple squamous epithelium now and we're going to use a couple of microscope slides to help us figure out what simple squamous epithelial tissue looks like and what some of its functions are. So again, simple squamous. And to think about simple squamous epithelial tissue, I want you to think about a piece of paper to start with.  But that's what we would call a frontal view or looking at the surface of the cell. But consider what the edge of the piece of paper looks like. And if you were looking at that straight on, you would just see a little sliver of the edge of the paper if I could hold it perfectly straight. Well, that's the way to think about simple squamous epithelial cells. So if we wanted to draw a simple squamous epithelial cell, we would just draw something that approximates the shape of a square. And we would draw a circle in there, maybe make it a little more oval shaped for the nucleus. So we've just drawn a simple squamous epithelial cell. But if we wanted to look at it in cross section or look at the edge of that cell, it would look something like this. This would be the nucleus of the cell.  And that would be similar to a simple squamous epithelial cell. This is just looking at it in cross section. So using the microscope over here, I have a slide of a lung. And we want to look at this lung slide. Now, of course, the lung is involved with gas exchange within humans. And we take oxygen in and we exhale carbon dioxide. So within the lungs, we see all of these little spaces. And if you look on this microscope slide, you can see all these hundreds and hundreds of spaces. Well, those are the air sacs within the lungs called alveoli. And the cells that make up these air sacs are simple squamous cells or simple squamous tissue is what the alveoli are composed of. And if you think could picture the alveoli, you just picture sort of a little cluster of grapes perhaps. You have an air passageway leading into each little cluster of alveoli. But instead of being made of grapes, they're hollow on the inside and the skin, so to speak, or the covering is made of these simple squamous cells, very, very delicate tissue. Of course, that's important for the respiratory gases to diffuse across the membrane. So we want to go up and look at this on a higher power. We can start to see the cells take shape when we look at it on 40X. And this is a pretty good microscope, and I was able to get away with oil immersion without putting oil on it a second ago. And so here we can really see the cells that make up the alveoli. And so here, for example, is an alveolus, and we could go around and sort of trace some of these cells that we see, and see there's a square shaped cell with the nucleus. Because these are all sort of mashed together in a hodge podge, it's hard to pick them out and just see cells where you're looking at them perfectly straight on, but I'm just picking out a few here that you may see. In this area, you can see no nuclei, and that's just because of the way the slide was made. Now one important function of simple squamous epithelial tissue that we didn't mention when we were talking about epithelial tissues in general is diffusion. Because this tissue is so thin, it makes it much easier for substances to move across that membrane by diffusion. For example, if this was the inside of an alveolus, and this was the outside, then oxygen could move across that membrane or carbon dioxide, could move in the other direction. So very thin tissue, good for diffusion.


So a Student's Union is essentially all of you. The Student's Union is comprised of students and we are 100% student-led. Ultimately, you are all part of what the SOAS SU offers and you very much guide and shape the direction. So whether it's a campaign, you get to have an input on that or if it's activities and events that are happening on campus, you get to input what we do in that regard. So very much, Student's Union is you. Depending on your interest and capacity, there's plenty for you to do. You can run to become a student officer, you can join the committee of a Society of Sports team or you can join the SU newspaper and radio. You can also become a student representative for your class and be able to raise your concerns to your convener or if it's a job you're looking for, you can always apply and work at the SU bar and shop. So every year we have an election season where we bring in around 15 part-time exec officers and then four full-time co-president sabbatical officers. And in every election season what they are doing is bringing their own manifesto and the unique set of priorities and that's what you get to vote on. So for example our women's officer this year has been focusing on putting the issues of women of colour to the forefront of the SU agenda and myself in my role as co-pres by activities have been working on initiatives to tackle social isolation and loneliness. But you can check out the full list of roles and responsibilities on the SU website. So we have over 200 societies and clubs and these societies and clubs are spread across numerous categories. I'm talking cultural, political, faith-based societies, all the way to educational and careers-focused societies. And then when it comes to sports clubs we have pretty much everything. I'm talking badminton, baseball, netball, you name it, we got it. And the beauty of SOAS SU is if there is a society that you want to join but we just don't have it then we will support you in creating that society. In addition to our elected officers we also have an independent advisory service to help you make sure that your time at SOAS is the best that it can be and help you navigate any sort of system in SOAS. For example the complaints procedure or mitigating circumstances because you've missed a deadline, any issues that you're having she can be there for a one to one confidential and professional support. You can find the SU here at the entrance of the JCR where our four co-presidents are based and operate on an open door policy so you have any problems you can always walk in and even if it's just to say hello you can do that as well. You can also find us on social media on Twitter, Facebook and Instagram at SOASSU.


Welcome to another episode in the 23 part series collection. This is 23 Michael Jordan videos in 23 days Today, we are looking at the trash talk story of when Magic Johnson for the first time ever Trash talk Michael Jordan and it went horribly wrong You may have heard this story before it's been well documented, but I don't think you've ever heard it quite like this We have all these NBA players and legends talking about this day and the trash talk that happened This is the story, and I hope you guys enjoy this video did take me a while to edit So I'd really appreciate if you guys could hit that like button Let's aim for 5,000 likes for the next episode tomorrow Be sure to hit that subscribe button and the notification button so you were notified when a new episode releases on the top right of your Screen you can click on that link and you'll find a playlist that has all the Jordan videos that we've done so far It's also in the description as well as the footage and content used in this video featured on the screen right now And in the description box as well I don't want to keep you guys waiting. So I hope you guys enjoy the video and enjoy Chris Mullin tells a great story about the dream team everybody getting out of the way You and Michael going at it. So all those great legendary players playing an empty gym in Monte Carlo You got magic and Michael just going at it verbally physically Very loud through curses put us there magic put us there My favorite dream team stories revolve all around Michael and magic over the years There's one basketball nugget that everybody talks about and I call it the greatest game nobody ever saw Can you just tell us a little bit about the back and forth between them? They were always competitive. I mean and no matter what I mean and it didn't just stop when we left the court I mean we go to practice. They didn't want to play with each other They always wanted to be on opposite teams and it took place during the dream team practice in Monte Carlo Chuck daily the coach said we're gonna get together really knock each other's heads out a little bit and To make sure that he was able to accomplish that he put Michael Jordan on one team and he put magic Johnson on the other team Those two guys were the driving force really to keep our practice and everything going they kept that competitive edge Peace in the West going at each other Everyone knew that Michael was the guy, but magic just would not pay he to that. You know, it was funny I tell you this story right quick because you really enjoy this so Michael Jordan was setting the tone for us and I'm winning attitude the greatest player when he came in the door It was all about business with magic and Michael. There was that little extra something there You know Something kind of to prove to each other I always challenge Michael every day and sometimes I will win and most time he would win, you know, we would play a Lot of shooting games a lot of free throw games a lot of three-point shooting contest I mean we were we're too competitive people and so I wanted to push him and he wanted to push me I took it upon myself to always shoot with Michael. Okay MJ free throws today. Who's the first one to 50 or we had little games who was the better shooter? He didn't want to relinquish that control of the 80s in a sense even though we were going into the night So it was gook and win who's gonna have the bragging rights by the end of this trip I'm the young guy with the old Elvis states me. I thought I was the most competitive person that I ever knew until I met Michael We went at it in Barcelona.  Oh, all right first ever time ever talking trash so we're with the dream team, okay and for three days in a row we had Came into a tie because what coach daily did he split the team up east versus west We had me Scotty Mullins bird and Patrick all played in the east Wow, and then we had the West guys myself David Robinson Malone Mullen Drexler and John Stockton. So we would play every day tie. So this is the fourth day Is that game in Monte Carlo? Was that as competitive as is anything you've ever done best game ever played in best game ever played in in the sense that No coaching You know, yeah, the referees but not really, you know, uh, and you had 10 Hall of Famers playing against each other First ballot Hall of Famers It was not even a question. It's not even a second third or fourth a first ballot and the way we competed And I desired a sweat and trash talking and all the beautiful things about the game of basketball Was illustrated in that one particular game you envision a game being played. That's how the game is going to be played Chuck says, okay, this is what's gonna happen. We're gonna play it like a real game. We're gonna play four quarters Uh, it doesn't matter what kind of a game he's competing in he's got a game within a game And uh, the competitiveness is in reality probably what drives him to be what he is Well the game starts out and magic's team gets way ahead And magic as is his one starts joining a little bit Michael Jordan came down the court and he made a jump shot and it was lucky magic got the ball He stopped at the three-point line. He took a shot and he said right back at you But it was very hard for magic to kind of surrender the Ground to somebody else. So I went over there tapped him on the shoulder and said, hey, man If you don't turn in the air, Jordan, we're gonna blow you out today. He broke the huddle He hit a three and he's looking at me This is what i'm gonna do to you Fallaway jumper good. What did I tell you? So he came down again hit another three So then I came down His energy is real high. He feels like he's in an opportunity to prove himself I'm still magic Johnson.  It doesn't take much to get Michael going Just a little something to tweak him and it's on the Michael magic dynamic would bring that out Jimmy his eyes got big Usually that tongue come about right here now it's way out When you see that look then, you know, just getting the damn ball to get out the way As much as it was five on five You can see in Monte Carlo that it was gravitating towards okay Michael and magic Magic was hesitant to surrender his place On the mount top and Michael being Michael He needed to say no i'm on the top of the mountain now Now this is the greatest shot I'd say he came down the right side took off David roberson took off and he said okay. I'm gonna sit here in the air Because I know David roberson is gonna go down So Dave roberson went to the ground he 360 tongue moving And dunked it in a practice game in a practice game. You ever see Michael Jordan? Well just in those commercials, maybe you see him do one of those 360 dogs And I was like oh my goodness Magic is saying look NBA is not yours yet I'm still here Michael's like now it's over. This is mine And the funny thing was Larry was sitting on his side. He's going it's his Michael basically took the torch in that practice session on our way to bust a long owner and Magic handed over not graciously, but he said, you know, you're the greatest Michael's team caught up and finally Jordan's team holds on to win and When it was all over you could really see that something was hovering in the air Magic's over there shooting alone and he's joining at Michael and Michael is joining back Finally Michael starts singing the Gatorade song be like Mike Rubbing it in a little bit as is Jordan's want To this day Michael Jordan calls it the most fun he ever had on a basketball court and that's what resonated with me We're in the uh restaurant and Larry and I sitting there talking so enters Michael Jordan And I remember Michael Jordan sitting there telling us remember this Larry and I were talking and Michael walks in We were sitting there He sits down and Larry and I going back telling stories with each other and just having fun so Michael says I just want to tell you guys I I really in college you guys were the two guys I looked up to so on and on and on And even in the nba you guys have been dominating But he said I'm just here to tell you both of you And he took a puff of his cigar And he said Larry and magic you had your run, but it's a new sheriff at town There's a new sheriff in town and that's me I announced it to both of us we both looked at each other and said you know what it is your turn So go ahead young man go ahead And we both hit each other like well, he's not lying And I hope you guys enjoyed the video if you did please help me out by hitting that like button Let's aim for 5000 likes for the next episode tomorrow here are two new episodes I think that you will also enjoy and I will catch you guys in the next one