And who's sessions regarding the English translations, communication skills, all those sessions are doing well. And then when we speak of polishing grammar. And once there is the platform of Beyond Law CLC more for the professionals as such, but this session. Because polishing grammar, not only helps the professionals, but also the students, the teachers teaching faculty, and everyone else. And they say that the polished man creates his own niche, he stands out. And same way Mr. Vasant, when he takes a session, he stands out. And that's why we take his sessions at 9pm, which normally we don't do. But we know that he's a crowd puller and it's himself. And therefore, at any point of time, we can do that. And it also gives us a different flip to think about a session on a different time as to whether people are able to latch up on that. Because ultimately it is the knowledge which we intend to decimate amongst people at large. And an interesting facet with Mr. Vasant is that he takes his sessions, not only in Hindi, as well as in English at ease. He's like Glenn Maxwell that he can play with ease at both strengths, without taking much time since we are in the late hours of the day. And we are also approaching the end of the year. I request Mr. Vasant to take things forward. Those who have missed his sessions, I just missed it out. They cannot also watch it on Beyond Law CLC. They can like it, subscribe it, and share it. And his sessions are already there. Over to you, Mr. Vasant. Thank you, Vikas sir. Good evening to all of you. I am thankful to Vikas Chathwajji for his kind words. But what I sincerely feel is, it is the English language or rather importance of English language in our day to day life to all the aspirants who want to reach the pinnacle which pulls the crowd, if at all. It is pulling the crowd. I sincerely feel that we should be able to gather knowledge from all the possible sources irrespective of whether it is Vasan Patwardhan or XYZ, anybody else. So, as Vikas Chathwajji was telling you that it is both required as an academic requirement as well as a professional requirement, we have decided to go from the scratch from the grassroots. We will not compromise with a team or with all the important points which we are going to share regarding the grammar. And polishing the grammar itself is a job of a life limit. You can say it is a lifeline job. But here we want to emphasize on all those important facts and matters from the basics. So, we have started today from the parts of speech. Please bear it in mind that parts of speech are very basic in themselves. And as a new, we say it should be strong so that we can construct something very big on it. This part of speech is very basic and very important. So, once we have the clarity in these parts of speech, we can really build the whole communication part of it. When I say communication, it is always learning and expressing. And parts of speech play a very important role in both the aspects of communication. So, let me tell you that parts of speech are the parts of language. Speech is nothing but a language. We call it as vice, V-O-I-C, vice sometimes, or speech. It is a language after all. Parts of language is parts of speech. What is that parts of language means? The whole language which we use verbatim in our conversation or when we put it on paper, we can divide it into eight main categories. Means we use the sentences and sentences are made up of words. All the words in a sentence either used verbally or in writing can be divided into these eight parts of speech based on the usage. Please underline this that we have to name the particular word or categorize a particular word to a particular category of parts of speech. We have to first consider its usage in that particular sentence. In isolation if you ask me, what is water in the eight parts of speech? You all know by this time there are eight parts of speech. I just want to brush it up. They are noun, pronoun, adjective, verb, adverb, preposition, conjunction and interjection. Some are of the opinion that articles are also parts of speech. We have already covered it in our last lesson under the title articles as determiners. In very good detail we are able to cover it. Today we will try to cover up the main eight parts of speech. We are not in a hurry. If we are able to cover up only noun or pronoun or the first two, we are satisfied. We will restrict our timing and we will see that we are not compromising with the matter. So I was just wondering that I can't answer your question if you ask me in isolation that what is water out of the eight parts of speech? No, I can't. Please show me the use of that word water in your sentence then only I can categorize it whether it is a noun or a verb. You may be astonished, surprised to know that water is a noun because it is a name of a thing. At the same time water can play a role of word. If you say I want water to drink, here water is a noun. If I say my father is watering the kitchen garden then water is used as a verb. So I stress upon the point once again that words in a sentence are to be taken on the virtue of their usage in that particular sentence and then categorize them as noun, pronoun, verb, etc. So let us start with a noun first. Noun as we all know from the high school level that we know a very fixed definition that noun is name of a place, person or thing. And really it is so simple only because we name everything by one or the other. We name everything in this world. We have a name for each and everything in this world. Be it a tangible thing which we can touch, which we can touch, which we can see, which we can feel. Do we have any word for all of these? So whoever you have given a name to will be called a noun. The one we are talking to right now, the one we are connecting with is a network. This is a network noun. These mobile or laptops, these are nouns. So whatever you see, you touch, they are all nouns. So we say name of a place, person or thing. Let us see what is the definition of a place. The place is called world. Then we call it country, India, America, England. They are all nouns. Your city's name, Chandigarh, Bangalore, Badami, all of them. Even in that, if there is a place, a neighborhood, that neighborhood itself is a noun. As well as if you name that neighborhood, Ram neighborhood, if there is a name, it will also be called a noun.  So while moving forward, we have to see what else is possible. The name of a place is, come inside the house. The different rooms of the house, which we know, bathroom, kitchen, all, they are all nouns. To the extent that the corner, where there are two walls, where there is a place where we usually put some stuff on it. So that particular corner is also a noun. The name of a place comes, temple, court, bank, post office, all are nouns. Why am I explaining this to you so much, that you should be aware that this particular noun is used as a subject or an object in a sentence. In a word, noun is used as a verb or a verb.  What is that subject and object, so that in our further discussions also it comes handy. The easiest thing is to recognize the verb of that, that Rama is a fruit. In this, say that what is Kriyapad is food. If you are able to recognize the verb, then just ask a question, who is the doer of that? Who eats? Who jumps? Who sinks? You have to go and ask Kriyapad, who? Who is the doer of this action? So whatever you get, that is subject and always this will be a noun or you can say noun will be a compulsory portion of that subject. Because there are adjectives in the subject, there are articles as well, but noun will definitely be in the subject. So that is why there are adjectives in the noun. I say object. Again ask Kriyapad, what eats? What helps? Rama helps his brother. So if Kriyapad is like that, then ask him who? So there are two words, what and who? If you get an answer for this, it is the karma or object of the sentence. Again you will find a noun there. It is compulsory. Maybe an adjective will be there along with a noun if it is there required, but a noun will definitely be there. So if you can recognize nouns, if you can understand properly the nouns, you can understand the positions of the nouns, you can recognize them as that and understand the meaning of that particular sentence properly. So once I say name of a place, I quoted you so many examples. When I say name of a person, we all know, we all have a very wonderful name. We all have names. So all those names which we possess are nouns, our surnames. Sometimes we like Vasanth Patwardhan, Patwardhan is a surname what we will say, family name or so, they are all nouns. In addition to that, the names of the positions we occupy, like judge, lawyer, professions, positions in society, manager, puns, clerk, they are all nouns because they are the words which are given to a person. Again a person exists in relations. If he has got any relations, like father, mother, brother, sister, they are all nouns. So when we categorize them, so if it is a classical grammar, say I want to go in depth, there is a lot of scope in that which we avoid rather, because it is more of literary sense than a practical use. So let us rather take up the practical importance of that particular noun. If you want to know about the noun, there is a problem or say a challenge in English that we should note the spelling of it because spelling is a very big hurdle. As there are no set rules or spellings, we have to by heart them to learn them. So it applies to nouns also. Again, when we come to noun in particular, see that you know the singular and plural of a noun because once we discuss about the things, after the person, the things are all made up of those which are not, which rather which are neither person nor place, like pen and some are abstract, some are not visible. You can only feel them like pain, happiness, joy, sorrow, all these are nouns. So once you know these things, there comes the importance of knowing their singularity or you can say numbers. What is the world when it is one and what is the world when it is more than one? Singular and plural. Why I am stressing this again is English has got a very peculiar difficulty in understanding these singular and plural forms of the nouns. Again, there are no set rules. Most of the nouns take yes or yes to form their plurals, which we call bhahu-achan. In our language, bhahu-achan is also a matter of honor. In bhahu-achan, as you say, I am not talking about that. I am talking about the numbers. Like pen, once it is one, if it is more than one pen, book, books, it was an easy one. Like a box. Its box is es. Once I say datum. Datum is a singular of data. Data is a plural word. Datum is a singular of it. So a singular plural has a circle, which we call a circle. I am just taking you through this quoting some examples. Then comes the gender. In all of our languages, there are three genders. Pulling, stealing, nappusakli. But in English, there are four genders. And these nouns exist in or categorize in these four genders. Like musculine pulling, feminine, stealing, neuter gender, nappusakli. But in English, there is common gender. Musculine pulling is known as men. If we talk about men, it becomes pulling. If we talk about women, it becomes stealing. All of this is general knowledge. What is the difference between neuter gender and common gender? Neuter gender is where it should be neither musculine nor feminine. Whether it is men or women, it is called neuter gender. But common gender is what can be a man or a woman. We have categorized it as common gender. In English, it is an additional gender. So here we come into a little trouble, make mistakes. As I give you an example, usually we say cousin. The cousin who is like a brother or sister is called a cousin. The one who is not a brother will be called a brother.  But a cousin is sister like and brother like in relation. So if someone is with me, I will say that my cousin is a sister. It is wrong. Cousin itself is in common gender. So say she is my cousin. He is my cousin if he is a man. But what do we make mistakes? He is my cousin brother. She is my cousin sister. Because we are stuck to that arrangement of only three genders. Common gender concepts cannot be caught quickly. So look at this. We commit mistakes in this. The judge is a common gender. Like I said before, chair is the mind. Today chair person is a common gender. It can be a lady or a gentleman. If you want to know more about the nouns, we should know the exact gender difference between that. Like man, woman. What is the feminine gender of sir? Sir, we say teacher, most of us. If you don't say, it is very good. You know the things. Teacher comes under common gender. Sir, when a man teaches, he is called a woman. So we should know the exact opposite always and always the right opposite. Then the biggest difference is the countable nouns and uncountable or non-countable nouns. Countable nouns are simple. We can count one, two, three, four. I have five pens. It is a countable noun. Pen is a countable noun. One, something which I cannot count is uncountable. Like say knowledge. Knowledge is a noun. Knowledge is power. So knowledge and power are both uncountable. We cannot count it. For example, this is money. Money, it is an uncountable noun. We can do anything from it. Money. No. What is the specialization of countable and uncountable? What is the specialization of it? See that the pure uncountable noun does not have a plural. We make mistakes here. Sugar, sugar is not there. The most surprising thing is the luggage. You may have 15 bags of luggage. It will remain luggage. If there is one, luggage is heavy. If there are four, luggage is heavy. It cannot be luggage because it is uncountable. Furniture is uncountable. The house was sold with all its furniture. Furnitures, luggage. There is no word like that. There are some words that are uncountable. Like luggage. It is the same as luggage. Baggage is uncountable as well as uncountable. So luggage and luggage are both existing. So pay attention to this. When the noun comes, you should be very particular about this. Right? So there are some nouns that you will always see in the plural. You cannot use them in singular at all. They are always in plural. Means say scissors, gobbles, tongs. Tong means chimta. You can say they are this kind of nouns which are always available only in plural. Like we say trousers, pants. They are not trousers. Because they have two legs. Shirt can be shirt. Trousers is always available in plural only. So we used to see these nouns only before definition. So now we need to go inside a little bit. And we have to recognize and realize the importance as well as the challenges in learning the nouns. So the next one after noun is pronoun. Let me see whether I can make justice to this subject or this topic too. Pronoun is a word used in place of noun. Because we cannot use noun again and again. If I told you earlier about Gandhiji, Mahatma Gandhi ji was born in Gujarat. Mahatma Gandhi ji was born on 2nd October. Mahatma Gandhi ji fought for our freedom struggle. If I keep saying this, then my full existence will be filled with Mahatma Gandhi ji. Which is not expected. So I said that I will say Mahatma Gandhi ji for the first time. I will say Srimati Indra Gandhi for the first time. Then I will say Shee. So we categorize the words used in place of noun by pronoun. This is the second part. So there are totally eight pronouns. We, you, he, she, it and they. When we categorize them in two ways, one is the horizontal, that is first person, I, we, I and we.   T-H-Y, die. You will get many times from the Geetanjali, the Geetanjali of Ravidranath Tagore ji. Die. Di. Die. Di was the word. So we just changed it in the new English. Singular is also U, plural is also U. He, she, it. This is called third person. Pratham Purush, Vidya Purush, Tritya Purush. Singular me, I, you, he, she, it. Plural me, we, you, they. Jab inki baari aarti hai, pranam seekne ki. To iske aage hume seekna hai ki, iske forms kya hai? Jaisa mai kahoon ki, I hogeya mera. I mean, me. Agar kahoon, mine. Agar kahoon, me. Agar kahoon, mine. Kya difference hai isme? What is the difference? I is the subjective form of that pranam. Why I am stressing again because we make mistakes. We interchange them. No, out of ignorance also and out of a new way or a fashion. People you may hear speaking. Me and my wife are attending the party. It is a wrong sentence. You can never say me in subject. Me is always a object word, object pronoun. It is an objective form. I, my wife and I, people say myself and my wife. No, myself is a reflexive pronoun. Totally different. So we should take a very careful step in usage of these pronouns properly. Don't go by fancy. Grammar doesn't allow it. When grammar doesn't allow it, the people you address cannot understand you properly. It is not that they are pointing out the mistakes, but they can't understand because you are on the wrong foot. Once I do a mistake, people cannot understand what I am saying because they are not on that same page. They are expecting you to put I and you are putting me. There is a norm in English. Whenever you use me, the third person, the second person comes first. It is a decency. It is a politeness. Like my wife and I, she and I, never say I and she are friends. Say she and I, my sister and I, my boss and I, always keep the I in mind later. Just like between me and I, just like I said, I listed the other eight, look at their different forms. So I think we can finish this chapter in another 2-3 minutes. There is a problem in the pronoun, because our culture is bad. When we say that you came to our house, we usually translate it as a P.H.E.Y. It is out of respect. No, English does not do this. English only looks at the sign. It is only based on numbers. He, a man, is one. And De, a man's sign, is more than one. She, a woman, has more signs than De. If a man is the headmaster of your school, even if he is the principal, he will say the same thing. Just like your grandfather, he is 80 years old. It does not matter. If he is a man, he will be addressed as he, irrespective of his age, position. Even if he is the prime minister, he should keep this in mind, because there are big stages, and mistakes are made. There are big invitations, they have agreed over to preside over the function. No. By saying he, you are not insulting a person. That is not their culture. They do not use it. De uses it only in signs. So keep this in mind. We make a mistake here. Last but not the least, is self. Myself. Himself. We make a mistake here. His self. Their self. I say they use it. It is always themselves. Ourself. Yourself and yourself. When we use ourselves, S-E-L-B-E-S, then it will be used with God. It will be themselves. It will not be themselves. Similarly, it will not be himself. It will not be himself. Please remember this. No. 1. And when myself, yourself, and herself use it, they use it in two ways. One, it is called reflexive pronoun. It reflects the subject only if the object is used. Like I saw in a mirror, and I could see myself in the mirror. I or myself, Okay. Reflects. It reflects the subject only on its own. The second is emphasizing. Emphasizing means giving strength. Like I was walking in the garden. Oh, I myself saw a snake. I myself when I give strength, I myself I myself help the lady. I myself saw the snake. When we say, we emphasize it. Use it. And its difference. Know a little so that when you use it, in your words, you never go wrong. And you understand also properly. When you come across us, you say this when you read, when you listen to lectures. So, just say, I say, I say, I say, I say, I say, I say, I say, I say, I say, I say, I say, I say, I say, I say, I say, I say, I say, I say, I say, I say, I say, I say, I say, I say, I say, I say, I say, I say, I say, I say, I say, I say, I say, I say, I say, I say, I say, I say, I say, I say, I say, I say, I say, I say, I say, But let us keep, as I told you, our discussions to the practical usage of it. So here I stop and in the coming lectures, we'll discuss about the next six parts of speech. And I just request Vikas Ji to take over and proceed further. Yeah Vasan Ji, I was just checking it out. On the group, I didn't get any message. Because you have told me so much about your clarity. I was just checking out if there's anyone on YouTube. Anyway, you have polished the grammar in such a way that it can only give the shine and no sheen. So we are all happy that the way you have taken things. And so good night to everyone. And before we leave for today, kindly join tomorrow. We have a session. Tomorrow, we will be having a short scale session on a mental health approach. The introduction will be by former justice, Justice Rajan Dalvi, a former judge from Bombay High Court. But the speaker would be Dr. Shetty, a resource person, a renowned personality has looked after many famous celebrities. One can Google around about Dr. Shetty. So do stay connected with us tomorrow at 4pm. That will be two parts. Next time, short skills will be on the legal perspective and that introduction will be by Dr. Shetty. And the legal perspective part will be taken by Dr. Rajan Dalvi. Thank you, everyone. Stay safe. Stay blessed. Thank you. Namaskar. And good night. And thank you.


This is torture! He has to keep experiencing that! Oh my god! We are five operate, I'm daddy outta daddy outta... What are these bells jiggling, man? Just please let them walk through. Don't even say anything, bro. What do you do? He just looked at him. Is he better like go to sleep?  Imagine your essence?  It's way too quiet. The next arc begins. Lord Okage dies, and the next enemy arrives. Is he already fighting again? Oh, he's looking at himself. Back when he was a pussy.   Do not! Do not! He killed his old self. Wait till he finds out. Oh god. Naruto's back at it. He's ready to take Lord Okage's spot. You got another show to do that, bro. Hopefully music. We're back. Alright, nothing dark is gonna happen until like the end of the episode. What's he doing? Oh, he's looking at his grandpa. He's not hiding on the fences anymore. Look at him. He's serious now. He's crying still. No! Oh chopper. Say it. Say it. Say it!  I love this concept of loneliness in this show. There's no time to be feeling lonely, yeah! His voice just makes me smile. Funny, bro.  You had to graduate from the academy. That was just obliterated. My phone number? Oh. Thank you, Naruto-chan. This kid still has a wife's nose. Maybe the school needs to be knocked down again.  Like older, with the same voice actor. Back to Ichiroku. Bro. Don't tell me the fight has yet to begin. What they find?   Before the Shunin exam? Oh my god.   This is supposed to be a cartoon network. You were thoughtless, you dumb-it. Oh, we're in Narouchi Maru's lab. I thought someone holiness was happening. All these Easter eggs, man. The three snakes when Mika's a scarf. Please kill Kabutox. Make him a fossil. Look, mentioning Hitachi now.  Mentioning Hitachi now because he's here. We got like two name drops already.  Bro, what are they doing to me? It's like right when I think of Rouchi Maru's the problem. Here comes Hitachi. I can't wait to see Hitachi and Sasuke. Eye to eye, man. Stuck, stuck.  And he's still looking at titties. He doesn't stop. He didn't even put black on. He didn't go to the funeral. This is all these girls do when his village is bathed. Why is he so dirty to begin with? I think he needs an advisor. That smug look. That was a scary face from Jiraiya.  Is this Hokage's wife? No it hasn't. Oh yeah, now that Hitachi's there. The unpredictive crisis is here. We're gonna see Jiraiya versus Hitachi.  Jiraiya versus Hitachi. Lee? Guy? I mean guy, not Lee. Gathering materials. What kind of materials?  Let him look at some titties. Jiraiya with a girl. She's not gonna be Hokage. Jiraiya the Hokage imagine? The Hokage.  It can't be the guy we're about to see.  You're giving free food? You see what he just did? Why does money even matter in his village? Jingle bells, jingle bells, jingle all the way. Oh god. Is this guy about to pass out too? He's still reading it. How good is that book? What are you doing here? I'm here reading porn. Kakashi doesn't feel anything! Oh Hitachi has the coolest look, man. Oh my god. Look how close they are! Why do I feel like they have the force to make a sense each other? Oh my god. Remember the last time you stripped down naked in a ramen shop, guys? They knew it. They knew they were there. Sasuke had no clue, so Kakashi knew. They knew.   That's it. Just do it.   That's all he had to do. Finally, I get to see what he looks like fully in color.  It's like a cooler Sasuke. Why are they playing this OSD right now? How do they play something darker? Ugh. Yeah. Kisami Hojikaki? What is this, Arlong? I guess Atachi's traveling with Arlong for some reason. Kisami. Kiss on me. A resolution.   Oh my god, it's that number one sexy game.   Major S criminal. Nice! He has to cover his little brother. His little Oni-cho. He has a cool voice actor, too. We're gonna find that Atachi never killed his, um, mate. Who's a Rochimaru all along. So now I know Sasuke gets it in the family, bro. Oh, that's sick. He even has Arlong's big sword. We are not doing this right now. We're not seeing Atachi in a battle.  Don't, don't blue ball me like this.  We're just fighting on a random sidewalk like this!  Shark skin.  Oh, dude. Oh, dang. I like Kisame. That sounds, here we go with the Naruto sound effects. What does she think she's doing? You've got his legs weak. Atachi still just standing there, bro.  Uh-uh, that's the stance you don't wanna see your enemy take. You could go through any tree you want. You are not touching him. Look at him. He's staring at you. He's bored. He looks soulless. He looks like erin. He swapped. What is it? Oh go? Oh my god, that's dangerous, bro. Don't do it. He's not gonna do it. I'm gonna do he's not a killer.  That's it. Oh my god. He's a badass now He wants to get her wet. Nice.    I'm gonna be nice. What's going on?  It sounds beautiful. There's a woman who's data. I want to collect There's a lot of women's data. You want to collect Jiraiya? Every woman's beautiful, bro Maybe I'll take Sasuke it's all you have to say he's really a cute kid stop it Just go back to the waterfalls What do you think they would be like I've heard Full names I can't believe it. He knows full names That's a buzzer kid. I told you we knew him Stop it Tachi smart nice. I already love a touchy I'm looking for what you call Sasuke What's he doing? Why is he so edgy right now, man?   Why do you take that turtle with him? Wait a minute wait a minute yo stop What is that?  What did you say? No, she's nice Why does he want Sakura to like him please tell me why Look how cool. He is man. I want to be like him when I grow up 13 years Oh my god No, he's not is he actually gonna do it. This is just for now the power of the Don't look at him. Oh god.   Oh my god I wonder who that is.  Oh my god.   He has to keep experiencing that This is like what's his name me you would us from Bleach's move we used to do it in slow motion But I don't know which one's more tortures, man 72 hours.  Yeah, bro. Just imagine it doesn't exist. It's not real Maboroshi the pain is not an illusion. I don't believe Wait, no, I believe him. I believe him He's fine.  This is like a music video man.  Wait, how much that way?   What are they just standing there? That was one second. I can't man.     She's a baddie man. The legacy of the Porto Kage. Oh my god. What's going on? Wow, Jirai is gonna look over No, I'm rich on now. That's beautiful man.  Yeah, it's hockey shark, man And Boruto Bro That's his destiny to hear that from Jirai is insane All right, I got to get used to Naruto Jirai together and then Sasuke and Kakashi had a perfect team up right now Cuz Jirai can't teach Sasuke anything. They're here for Naruto. That's why Jirai is taking him away without telling him I can never tell if he's saying this out loud or not.     Yeah, he better have brought a change of underwear, bro


Confusion puts the brain in a state of neutral so that an outside source can actually be the driver of your vehicle. Just say no, start to question, have discernment, feel what feels right to you, question all motivations. This does not mean become paranoid, but it does mean that we need to go deeper inside so that we can reestablish that connection to undo confusion because it's just a habit. It's just something that we learned in order to get by from another time. Listen for watch words in yourself and for others and question, why am I doing what I'm doing? Is it healthy? Is it good for all living things?


Hi, my name is Megan McNich and I'm a preservation planner with the City of Columbia. Today we're going to be talking a little bit about the history of the Whaley Street Protection Area. Whaley has a unique character and it's associated with both the Granby and Olympian mills and the houses within the district were used to house supervisors for the mills at varying levels. Some were lower level supervisors, some were higher up in the hierarchy. There are several historic house types located within the Whaley area. There is the Type D one story bungalow, the Type E two story side gable structures, and the Type F two story hip roof structures. In addition to the residential buildings located within the district, there are several historic commercial and religious buildings as well, including 701 Whaley Street, which was the Mill Community Building, the Southside Baptist Church, and Trinity Chapel, which is now the Cornerstone Baptist Church. So some important dates throughout the history of the Whaley Street area. In the late 1890s, the Granby and Olympian mills were constructed. In about 1900, the first supervisory structures were constructed on Whaley Street. That's the first housing that comes into the district and really continued along with the supervisory structures that we find on Whaley Street in the Granby district. In 1916, the Granby and Olympian mills were sold by the W. B. Smith Whaley Company to the Pacific Mill Company. And when Pacific mills purchased the mills and the associated housing, they began to develop the Whaley Street area more intensively. So beginning in 1916, and up until about 1920 construction, you continued within what is now the Whaley Street district. In 1939, Pacific mills saw costs associated with the housing that they had built and other mill villages within this area begin to rise. So they started to sell off individual houses to property owners. At this time, as individual property owners began to take ownership, they made small changes to their homes to make them more distinctive and unique and more personal to them. Fast forward several years to 2010, when this area was locally designated as a protection area. And within the last few years in 2018, it was listed in the National Register of Historic Places as part of the Olympian mill village. So the first housing type we're going to discuss today is the Type F style house. These structures are found predominantly on Whaley and Wayne streets and are among the first were constructed in the district. They share some similarities with the supervisory structures that we find in the Grand B district. The next type is the Type E structure. These are side gable structures that have a sort of saltbox style roof. And this these structures are found predominantly on Whaley Street and yet again as I mentioned earlier, sort of tie the Grand B and Whaley districts together. And the last historic house type is the Type D structure. These were the more recent additions to the neighborhood. And they're more commonly found on the side streets north and south of Whaley Street. They certainly have enclosed front porches and are more of that bungalow style that we see in both the construction by the Pacific mill company in the Whaley and Grand B districts. So that's a brief overview of the Whaley Street protection area. Hope that's been informative. If you have any questions about the Whaley area or about any other historic district in Columbia, please feel free to reach out to us at preservation at columbiasc.gov. Thanks.


Okay, welcome back everyone. The clinical genome research or ClinGen knowledge base is an important collection of information that seeks to link information about genetic variants to the phenotypic effects and functional changes that are observed and brings in other important clinical data into that knowledge base. The current grant is about halfway through its current funding phase, and we figured this was an opportune time to give counsel an update about ClinGen, and here to do that is Erin Ramos, Program Director in Genomic, the Division of Genomic Medicine. Thank you, Rudy. I first have to thank counsel. He came to my rescue at about 2.45 this morning. My seven-year-old, well, I felt someone hovering over me. I opened my eyes. It was my seven-year-old. We walked down to his room, and he said, Mom, I checked out a book from the library from the nonfiction section he emphasized. It was on UFOs, so he was extrapolating to aliens, and I said, well, UFO is a generic term. It could just be something in the sky, we don't know what it is, and I said, that should be nonfiction, but if it's about aliens, the librarian should have put it in fiction. This went on and on. He was getting more upset, and then I said, I clearly was like a rookie parenting mistake, and then I said, look buddy, I have to give a presentation to the NHGRI National Advisory Council, and he said, oh, okay, Mom, and he rolled over and went to sleep. So I am calling on all of you, it'll be like every two, three weeks. Just pretend that I'm giving a presentation to you if you run into him. Thank you. Thank you. But in all seriousness, I'm grateful to give this presentation an overview and an update of the ClinGen program. Sharon and I originally planned to give this talk together, but we decided it might be more efficient for me to go through the slides, and then Sharon will give her reflections as both the ClinGen PI and the clinician before we jump into the discussion. Giving this talk on behalf of the NHGRI ClinGen team, which includes Lisa Brooks, Robert Fulham, Nicole Lockhart, Terry, Manolio, Natalie Pinot, and Ken Wiley, and especially want to acknowledge Natalie and Rob, who are the two ClinGen analysts that are very dedicated to the program. So I just wanted to set the stage for the rationale for why we launched the ClinGen program. Some council members may be more familiar with it than others, but if we go back a couple years, here I have 2010, 2011, we're at a point where obviously we are detecting hundreds of thousands of variants. It's greatly surpassed our ability to interpret their clinical impact. From a paper from the 1000 Genomes, there's an estimate of over 88 million known variable sites in the human genome that's a lot of variation to deal with. Of course, we know not all of it is going to be relevant to a clinical disease, but it's a big problem and it takes a community to curate this information and put it together. So this is sort of the state of where we were at at the time. There's a number of databases that were stood up to organize this data both on genetic variation and phenotypes impact on disease, research databases, locus specific databases, there's over a thousand of them that might be a low estimate, or they were focused on organizing information on a specific gene or disease. Population databases like exact, 1000 Genomes, OMIM, and of course the biomedical literature and others. These are all really important resources, but they often stood up without common data standards allowing for interoperability and they weren't necessarily applying the same approaches to interpret the impact of variation. And then on the other side, we've got clinical testing lab databases which are becoming increasingly important. There's a wealth of information in each of these databases from testing companies. And they were at the time largely absent from the public domain. So that's where we were at. We had a workshop called ClinAction, some of you attended that workshop and that led us down the path of issuing an RFA and standing up to ClinGen program. So the main goal of ClinGen is to increase data sharing and build an authoritative resource to define the clinical relevance of genes and variants for use in medicine and research. This is the website. The program was launched in the fall of 2013, so ClinGen phase one. This is a consortium of three multi-PI cooperative agreements. Jonathan Berg, Katrina Goddard, Mike Watson, and Mark Williams are the PIs on one grant. Carlos Bustamante and Sharon Plon on the second. Heidi Reem, Krista Martin, and David Ledbetter on the third. So in total for this first four years, we've invested $33 million. This includes about $5 million in co-funds from NCI, NICHD, and supplement funding from the Office of the Director, so directly from Francis Collins. And then in phase two, as Rudy alluded to, was launched four years later. We're roughly at about $39 million for this phase. It's the same constellation of PIs. And we have co-funding from the LC research program. The All of Us program provided supplemental funding last year. And then I'll talk about this later, but at the same time, NICHD stood up research opportunity announcement to provide funding to use the ClinGen frameworks to curate diseases of interest to NICHD. We'll touch on that in a minute. So these are the faces of the ClinGen leadership and coordinators. So there's 48 people on this slide. The PIs are on the top. This is all of the members of our steering committee, the co-chairs of many of our key working groups and the project coordinators. It's an incredibly fun bunch. They're very committed to ClinGen's mission. Some of you have seen this before. This is a graphic. It's meant to describe at the highest level. Very broad strokes, ClinGen's mission and aims. So first, across the top, you'll see, I'll use the pointer here. So this is our emphasis on data sharing. So the idea is to get researchers, laboratories, clinicians, and also patients to participate in the data sharing process. And then with that data and data from the literature and the other databases I mentioned, ClinGen is asking a few critical questions and setting up our curation ecosystem to help address these questions. So the first is looking at clinical validity. Is this gene associated with disease? The second is then within the gene, is this variant causative or pathogenicity? And then lastly, is this information actionable or clinical utility or actionable? All the curation, the evidence is assembled together into the ClinGen resource and distributed out to the broader community. So I'm going to start here looking at clinical validity. And this is just a quick overview of all the information, the protocols, training materials for each of these elements are available on the website if you want to do a deeper dive. So the ClinGen gene curation working group, which is co-led by Jonathan Berg and Krista Martin worked for at least the first two years of the program to develop this semi-quantitative framework to classify the strength of evidence for the role of genes and disease. This is at very high level, but essentially this framework includes matrices to score genetic evidence and experimental evidence. Putting that information together, it leads to this classification system of clinical validity. So we've got definitive and strong. This area of moderate evidence are limited down to disputed and refuted. So here there's evidence against a real relationship between genes and disease. The team at Stanford built our curation interfaces. So the idea is we want to make the curation process as efficient as possible. So this curation interface has all the elements of the curation frameworks using standard ontologies, data models, et cetera. When the curators are finished with their curations in the system, they can just publish and the results go directly to the website. So this is an example of a gene MSRB3, which was curated for non-syndromic genetic deafness and it ended up with a classification of moderate. If you click on the report, you can actually see all of the elements of the matrices and the publications and underlying evidence. So the first phase of ClinGen, the first four years, was standing up this framework, piloting, validating, and doing our first sort of first round of curation. In phase two, we've really ramped up curation. The network has done 670 gene disease pairs to date. And I just wanted to walk through a few examples to give you a sense of what we've covered. So this paper was published earlier in summer of 2018. It comes from our Brugata syndrome gene expert panel. And they essentially applied the ClinGen framework to the 21 genes that are typically on Brugata syndrome clinical testing panel, so multi-gene panel. When they applied the framework, only one of those 21 genes had evidence of clinical validity. The 20 of them actually were at the lowest level of refuted or disputed. SCN5A is the gene that had definitive evidence. This work was led by Michael Gollum, who's a cardiologist and researcher. So if you look at the data another way, this is just a pie chart, gives you a sense of, you know, that little slice of the one gene that was definitive. And there's actually been testing laboratories now that have removed those other genes from the clinical testing panels, so demonstrating the impact of this work. And then I'm just showing you a couple of other examples. These are all recently published from our different gene expert panels. So colorectal cancer, hypertrophic cardiomyopathy, and hearing loss. And you can see, if you kind of look at the blue slices, so that would be strong and definitive, in none of these examples are we looking at more than about 55 percent of the genes on the testing panels having strong or definitive evidence of clinical validity. And we do have a sense from the community that they're paying attention. So we know, like I mentioned with Brugata syndrome, that companies are paying attention to the ClinGen curation results and modifying their panels based on what the community produces. So then looking at, is this variant causative or pathogenicity? This is a multi-pronged effort. And I'm not going to go through all of it, but essentially public sharing of varying interpretations via ClinVar is the first step. It's really important when we get a sense from the different testing labs, what their interpretations are, assembled in ClinVar, they can use that information to work through conflicts between the testing laboratories and improve the curation in ClinVar. Engaging experts, just like we did with the gene curation, we do the same thing for the variant curation. We stand up expert panels and they work on the particular gene of interest. And I wanted to mention this covers both sequence variants and also we have a number of groups looking at copy number variants. Before I launch into ClinVar, we do get this question quite a bit. What's the difference between ClinGen and ClinVar? So we think of ClinGen as the consortium of people that are sharing data, they're developing the standards and curating the knowledge. ClinVar, as far as the variants go, is the repository where ClinGen and other labs around the country share their assertions about a variant in disease. So here's the ClinVar database. Excuse me. Here I just did a quick search just to give you a sense of what it looks like. So I searched CDH1. There's a number of variants that are returned. You can see this is a likely pathogenic variant for diffuse gastric cancer. If you do sort of a deeper dive, you can see which labs submitted evidence to ClinVar. So Ambri, Genetics, and VTAY. And here's the ClinGen CDH1 variant curation expert panel. And this work has been recognized by the FDA, which we'll talk about in a minute. So as I said, thinking back to our infographic, data sharing is one of our main goals of ClinGen. We have a really close working relationship with ClinVar to get the community to contribute data. So as of this past month, there's over 760 variants with interpretations submitted to ClinVar from over 1,000 submitters across 67 countries. Natalie Pino put this map together in 761,000. That's not what I said. That's 261. Oh, okay, thanks. Yeah, a lot more than that. In the past year or two, we've seen an increase in the number of submitters from South America, Australia, and Asia. And this is just showing you the growth. So if you think about sort of the second phase of ClinGen, Heidi Rehm's lab in particular works really closely with the external community to help them share their data via ClinVar. There's been a really nice uptick in data sharing. And if you think all the way back to my first slide, we had the clinical testing labs kind of siloed. Where we're at now is the top five ClinVar submitters are those genetic testing companies. So over 470,000 variants in ClinVar with interpretations representing 62% of the submissions come from these top five companies. So we think we've definitely sort of broken through there. ClinGen relies on the ACMG AMP criteria for sequence varying interpretation. This matrix you don't need to pay too much attention to if you haven't seen it, but essentially it's just the different components of varying interpretation that get you to a place of being able to say whether a variant is benign, likely benign of EUS up through pathogenic. So ClinGen has a sequence varying interpretation working group that is co-led by Stephen Harrison and Les B. Sicker. And their goal is to refine and improve these guidelines as they're continued to be deployed and tested by the community. So in the past year, in the second phase of ClinGen, they've come up with a couple of publications focused on specific elements of the ACMG criteria. So adding value, clarifying these different elements of the interpretation framework. They also are hoping to move this interpretation guideline towards a more quantitative framework. So they've published an analysis where they're modeling this framework as a Bayesian classification framework and have a sense that they ultimately would like to be able to move this interpretation to sort of using the a priori Bayesian approach. Just like with the VipGen curations, Stanford set up a variant curation interface. And there's all these different colored tabs across the top, and they reflect the different elements of the ACMG sequence varying interpretation guidelines. Again, this is just the way to try to pre-populate the curation ecosystem with publications, with data coming from exact population databases, functional data that's in the community, and getting into a place where the curators can jump in and get started. Once a curation is complete by one of our expert panels, it goes directly to ClinVar. And one tool that's been incredibly useful for this variant curation process that was developed actually by Sharon's lab at Baylor is the ClinGen allele registry. So if you're thinking about you want to curate a particular variant, well, it could, depending upon which build it's coming from, could have different HGVS identifiers, ClinVar ID, DVSNEP ID, EXACT ID. So this allele registry generates a canonical allele identifier or a CAID, which then rolls up all those other identifiers into one element. So the ClinGen allele registry has identifiers for over 900 million variants so far. And if you are seeing a new variant off your sequencing pipeline, you can quickly register a new CAID, either sort of a one-off or you can do it in bulk and register thousands of variants in a few seconds. So the CAIDs are being used by key resources that I've mentioned on the slide, Civic, ClinVar, and the EBI resources. This is just giving you a sense of where our ClinGen variant curation expert panels are. On this slide, there's 29 ClinGen panels, and then four panels on the bottom, actually three on the bottom corner here, where ClinGen has been shepherding them through this process, but they've done their work outside of our consortium. So this is basically, if you're thinking about groups that are just getting started, there's a group that's looking at coagulation factor. And then groups that are further along, like CDH1, those variants are already deposited in ClinVar. So I mentioned this NICHD curation effort. So that funding was used to stand up curation groups in monogenic diabetes, brain malformations, and mitochondrial diseases. They're into the various stages of progress. And then we've had a collaboration with the American Society of Hematology. They provided funding to stand up curation groups looking at platelet disorders and myeloid malignancies. And as we alluded to in Eric's director's slide, the variants that have gone all the way through the ClinGen process have achieved this recognition from the FDA as part of their human genome database program. I just want to say a few more words about that. So what does this recognition mean? It means that the data and the assertions from ClinGen that you can access via ClinVar are considered valid scientific evidence. So a genetic or genomic test developer, they can use these assertions to support clinical validity during the FDA's regulatory review. So instead of having to submit information on all these variants, they can just point to the ClinGen or ClinVar resource. The FDA hopes this program will increase public sharing, reduce regulatory burden on test developers, and advance the evaluation and implementation of precision medicine. It's not just the curation results, but this program also covers the people and the process. So there's an expectation of curator proficiency. So ClinGen has had developed training modules. Our SOPs have to be transparent and available to the public. And we have to, every time there's a new version, make sure all that information is documented and publicly available. So this was a ton of work for the ClinGen program. And they actually sort of thought we might spread this out over the next year or two, but decided they wanted to be the first to set a really good standard for the community and worked really hard to get their application in and approved. Just earlier this last winter, December 2018. So we showed you this in the director's report, but this is some of our variants from the MYH7 curation panel. And you can see they've got the FDA recognized tag. One thing that this program really helped us with led to improvements in transparency and access of our underlying evidence. This is something we were working on in ClinGen and setting up our curation interfaces to be completely accessible. But one of the tools that came out of this program was the ClinGen Evidence Repository. So all of the codes, the underlying evidence that goes into a classification of whether or not a variant is pathogenic or not is all available through this ClinGen Evidence Repo. There's open API access making it as available and transparent to the community as possible. I just wanted to say a quick word about ClinGen's involvement in GA4GH. We are a driver project, primarily participating through the genomic knowledge standards work stream. So there's a lot of effort focused on the variant, the data models that we're using. We're trying to leverage the SEPIO model. Just organize our data in a way that can make it transparent and interoperable. And then moving to is this information actionable or clinical utility? Similar to our other efforts, ClinGen, they work the first phase of the program to come up with a transparent and systematic evidence base for prioritizing genes based on their clinical action ability. This work is led by Katrina Goddard, Jim Evans, and Bradford Powell. We, clinical action ability, the definition that they're using is there needs to be well-established clinical interventions. The interventions are specific to the genetic disorder under consideration and leads to disease prevention or delayed onset, lowered clinical burden, or improved clinical outcomes. They haven't focused on personal utility, but they're sort of thinking about incorporating that into the model. Similarly to our other efforts, there is sort of a classification matrix. And these are the elements, severity of disease, likelihood or penetrance, the effectiveness of the intervention, and the nature of the intervention. So if you think about surveillance versus mastectomy, those have different levels of risk. This is just an example of some of the work that this action ability group has produced. So this is looking at genes, ATM and CHEC2 for breast cancer. And they apply this framework based on the intervention. So they look at it both for surveillance as the action and chemo prevention. And then you get a sense of what the scores look like. And you can view the detailed report. There's been a nice trend in, steady trend in growth in producing the action ability reports. And we started a pediatric working group in phase two of the program. And another area to emphasize impact is that the process and the results from the ClinGen Action Ability Working Group are integrated into the ACMG Secondary Findings Working Group. So all the evidence review and the results are passed on to the ACMG Secondary Findings Working Group. And they're using that as the base to add additional genes to the ACMG59. I wanted to say a quick word about how we're engaging patients. So ClinGen has a patient registry called Genome Connect where patients can go through a consent process. They often learn about Genome Connect through the physician or the testing laboratory. And they can enter health information through this portal and also upload their genetic test report. Those test reports are then curated. And if the patient consent shared with ClinVar, so to date, we've got about 1,800 participants enrolled, 805 ClinVar submissions. And it's interesting to note that almost 50% of the submissions to ClinVar, there was no previous record. So the patients are adding quite a bit of value to the ClinVar database. We do have an ancestry and diversity working group led by Alice Pope, Joy, and Carlos Bustamante. This also got off the ground in the second phase of the program. They're exploring how race, ethnicity, and ancestry are used in clinical genomics. And we have a survey jointly with the CSER program surveying the clinical lab directors, geneticists, genetic counselors, and researchers involved in varying interpretation and variation to get a sense of how they're collecting or if they're collecting information on race, ethnicity, and ancestry and then how they're using it for varying interpretation with the hope to put out some guidelines to the community. By the end of this phase of the program, we have an education and training working group that spends a lot of time getting this material out to the community. There's a maintenance of certification model that they built, which is available through the American Board of Medical Genetics and Genomics. And it's basically a module learning how to interpret variants in ClinVar and resolve discrepancies between assertions in ClinVar. And if you go through that sort of training exercise, you can receive MUC credits. One thing we've done to leverage the community that's a ton of interest in ClinGen is launched a community curation committee where if people are interested in participating in ClinGen, they can go through a survey. There's a lot of training that's available online. They kind of get assigned to a curation group of interest with oversight, and then they are starting to participate in the curation process. ClinGen has a YouTube channel. So there's a wealth of information here. Some of those videos have over 1,000 hits, so we know people are looking at the training material. And then we've got a number of other ways where people can get involved in ClinGen. We have a monthly consortium call, which usually gets over 150 people attending to learn about the latest updates in ClinGen. So when winding down, this is, I think, my second to last slide, if you think back to the faces of ClinGen, there was 48 people on that slide from the three grants that we fund. But through all these expert panels that we stood up, we are now at 850 researchers and clinicians from 27 countries just participating in various ClinGen working groups. So I feel like we've achieved our mission to make this an international community curation effort, and it continues to grow. There's new people being added every day. And I feel like we've elevated the community. They're thinking very carefully about what's the best approach to use for doing curation, for adding genes to testing panels, thinking carefully about data models, data annotation, et cetera.  I didn't say much about our CNV work, but ClinGen is partnering with ACMG to update the CNV interpretation guidelines where they will likely move towards a model very similar to what we use for sequence variant interpretation, so adopting the pathogenic VUS benign categorization. That work is still underway. I think it's going to go in front of the ACMG board soon, and then out for public comment. We have two variation in function disease, variation function and disease supplement. So the ClinGen investigators are thinking about how do we structure all this data that's coming from functional assays and get it ready to pull into our curation environment? We have a complex disease working group led by Carlos Bustamante, where we're evaluating approaches for measuring clinical validity and actionability frameworks for polygenic risk scores, sort of taking what we've learned from ClinGen already and applying it to PRS. The Bustamante group has some efforts in machine learning methods to improve our curation efficiency, and then Sharon and Jonathan and a few other, the PIs have been working hard to stand up new disease curation groups and looking at hemostasis and thrombosis, ophthalmology, neuromuscular and a few others. And my last slide is just to announce that ClinGen holds a meeting with decipher every year called curating the clinical genome, and this next meeting is coming up this May in Washington, D.C. So Sharon, I'm gonna turn it over to you for a few reflections, and then we can take questions if there's time. Great, and I'll just be a minute or two because I wanna allow questions. So first of all, I wanted to acknowledge Erin's incredible work as a leader of the consortium and our facilitator, whatever the right role is. She's been amazing with a really wide-ranging group. And I also just wanna acknowledge the work with NCBI, Melissa Landrum, and the staff at ClinVar really get on a lot of our working group calls and really try to make our tools interact appropriately. I do think one of the things that we evolved was trying to develop structured frameworks for how to do things. At the same time, we developed web-based tools to implement those frameworks. Has actually been a pretty successful model because people read papers, but then they wanna try it so then you can go online and get a login to the gene curation interface or the variant curation interface. And I think, especially moving forward, we're now having online training sessions for how to use those tools has been actually a pretty effective way to engage, not just our own working groups, but to get people to join us. And then I do, we just wanna emphasize something Erin said. She talked about the clinical laboratories, many of them being commercial entities submitting to ClinVar. Not only do they submit to ClinVar, they're extremely active members of our working groups. It's really been amazing to see the uptake by people that work full-time in diagnostic laboratories and academic laboratories and clinical centers all working together on these working groups and sharing data. So I always give this example from CDH-1 that when they were trying to analyze a troublesome variant, among the members of one working group, they had 850,000 tests on that one single gene that they were able to compare data across to come to a conclusion. And then I think Erin's already talked about some of the things we wanna do moving forward. I would say that our tools are now being used by their labs. I do wanna say that the allele registry comes from Alex Molosevic's lab at Baylor, not from my lab directly, but that's an example where now the Jackson Laboratories is looking at using that framework for mouse variants. So I think we are getting wider distribution of our tools. And with that, I'm happy to take any questions or comments. Yeah. Thanks, that was a great overview. So one question I had in relating to future directions was what's your thought on the status of functional testing of experiments in saturation genome editing? Do you think that that's ready for primetime to incorporate into this sort of database? Yeah, that's actually part of our functional supplement. We've been working closely with the group of the University of Washington, for example, as well as a group doing that for the LDLR gene. I think it's ready for primetime, but not in the way that I think people always think, which is we view it as one set of evidence. We don't feel like it alone has to be able to curate the variant. And I think that's where there's a difference. If you look at the ACMG framework, we're combining functional data with a variety of other data types. We don't require that the functional data alone be able to predict whether a variant's pathogenic or benign. And I think that may be where sometimes the errors occur when you're saying, I just want this one CRISPR-based assay to do it all. You're very likely to miss variants that are pathogenic for reasons totally unrelated to whatever function you happen to be testing, mislocalization of the cell or something like that. So we are working hard to be able to upload that data more easily into the variant curation interface. That's what part of our supplements designed to do so that we could pull bodies of data. It is actually something that variant curation expert panel spent a lot of time on. They're literally, so for example, for BRCA-1, they're 24 different published functional assays. And so the curation panel has to decide which of those assays do they really think there's good enough evidence that they actually are predictive of disease. They may be very good for that biochemical function, but that may or may not predict disease. You mentioned that ClinVar's trying to work towards being more quantitative. What do you think the timeline is for that? I mean, in an ideal world, it would be that this is a probability of pathogenicity with a confidence interval and it would be very transparent and really easy for clinicians and patients to understand. Yes, that is the ideal world. And the hereditary cancer world in some ways is closest to that because of the amount of data. And that paper, Sean Tavagene's done a lot of work on making predictions for BRCA-1 and 2. ACMG, so I should say that ClinVar is an aggregator of data. The ACMG guidelines right now are not, quantitative, are not calculated that way, although part of the point of the paper was to show if you actually look at the relative likelihood of pathogenicity of supporting versus moderate versus strong, it actually is pretty close. And so one of the things we're trying to do is they're members of ClinVar and ACMG does have a committee that is now looking to update those guidelines. How far they'll get towards a really statistical approach, I think it's hard to say because there's such variation in the amount of data. If you look at genes like CFTR or BRCA-1, there's just a huge amount of data and you can really do it. If you look at rare recessive syndromes, whether you could ever get enough data to say this is a 95% and this is a 56% is, I think, harder. So that's how we use these more qualitative assessments. I actually think you just answered my one question I had which now that I've heard Wendy's, I realized was way too simplistic to ask. My second question, though, is I'm very curious about how patients are getting their data in, well, I also wanted to say, fantastic presentation.  I think that'll go well for both of us or all three of us, but I'm very curious about how does that even work? That was very interesting, but I'm curious. It's been a very interesting process and it's not one that I've worked directly on, so I'm talking about other people's work. So Genome Connect is an IRB-approved registry where patients literally can, if they have like a hard copy of their test report, can upload the PDF. There's a team that actually then interprets that variant. They look it up in ClinVar and the patients are essentially giving permission to upload not only their variant, but their phenotype. So it's an access to better phenotyping. It's led to some very interesting issues, which is that there are people submitting test reports where that variant's already been reclassified in ClinVar. So we had to then have a whole discussion about how do we handle that. So we now let the lab know that their patient has submitted and sometimes that own laboratory has updated it. Sometimes another lab has updated it. So we do let the testing lab know that we're gonna be contacting the patient back and letting them know there's an updated interpretation of that variant in ClinVar that they may wanna talk with their physician about. So it highlights the reclassification problem. I will say that we've had a large number of participants, but maybe not as many as we might have hoped, and we are now targeting also other disease support groups, particularly those that have registries that use the same platform, because we can provide the genetics piece that a lot of them don't even collect. They collect phenotype or medical information, but not genetic information. So we're trying to work with them. So in fact, I was talking with the CDH1 group actually as a registry, but uses this platform but doesn't collect genetic results and they might be interested in that kind of collaboration. I had a related, I mean, hearing your explanation of the last question, but then also hearing some of the statistics, which I wasn't familiar to the immense number of people that are now sort of within your network, country-wise, investigators, and so forth. I'm sort of trying to imagine how this has scaled as well as it has. And is it on the back? Was it out of control? Yeah, no, I mean, is it, is it, and it's, and there's- Scale is a question that comes up. Right, but it must partially relate to NHGRI staff and NCBI staff, I mean, sort of program staff. It must be the grantees. It must be also NCBI staff. Is this on everybody's back in some way? Because just even managing and adjudicating and coordinating, is it just everybody doing it? And is it scaling? Well, it just seems that it can't possibly be scaling linearly, so how are you doing this? Right, well, so one of the main goals of the second phase was scale. And so we're actually, we're really at the point now where we've got tools where you can go from a variant to the interface to the website, all working. Now what we're trying to do, oh, there you go, thank you. Now what we're trying to do is really build tools that will allow us to scale even better. So we're, we've been building a variant prioritization tool which allows you to pull like every variant of that gene and exact. It'll tell you what its population frequency is, what is it called in ClinVar. You can do all these filters. So then the committee can say, okay, here's 200 loss of function variants that are rare in Nomad that we now want to curate as a bulk because that's what it's really going to take. So right now it is more manual and we're really, to get approved as a panel, you only have to take about a hundred variants. What we have you do is take a hundred variants of range from benign to dispute, to uncertain to pathogenic, and show that you can apply the specifications and to classify those variants. And then it's really a question of now, how do you scale that to all the other variants we know about that gene? But I understood the concept of needing this phase, needing to scale in terms of dealing with the tsunami of variants. But I was actually asking about it as the tsunami of different people around the world you're interacting with. Because it's one thing to get a bazillion variants from two or three labs, another thing to get a bazillion variants from hundreds of different people. So that's a lot of emails to answer and a lot of that right now. Yeah, I think we have the social interaction. Yeah, I mean, we have an exceptional set of coordinators, a core group of coordinators. We have, these are funded, those are the grantees, yeah. And so, sort of that exceptional group of people, they've been very smart about the training materials that they have developed by setting up, for example, a bio curation working group. So as all the curators now from around the country, they wanna get up to speed, make sure they understand what the changes that have been made to our curation ecosystem, there's just a very streamlined way for them to get that information and it to be distributed across the network. That doesn't mean it's perfect, but I think it was just very smart choices as we were setting up the various elements of the program that is making at least the social part more scalable than you might have thought otherwise. It's a lot of conference calls. But I would say the coordinators are a key group. So what's the vocabulary used for phenotypes? Are you using an ontology for that? We generally try to use HPO and we will try to create HPO terms if they don't exist. We also have a working with Monarch. So we try pretty hard, it does get difficult as you get off to these highly specialized disease areas. But we've been doing a lot more work with the Monarch Initiative as well, trying to use consistent terms. And we also work with OMIM as well. Can I say something? Yeah, yeah, please. And then we have a group affectionately called the lumping and splitting working group. So for the expert panels and the curators to make choices about whether or not you're gonna roll up a couple of phenotypes and curate at the sort of macro level or you have to do a curation, like in epilepsy's example, right, where you have to really parse out the different phenotypes and curate that particular subset of epilepsy. So we're trying to develop sort of structured approaches for that as well. So it's not subjective choices, but people are following a set of roles to decide how to curate these complicated syndromes. Other questions? Okay, Erin and Sharon, thank you very much.


John, your update on what's happening in the uranium market and your last results was phenomenal. How about we start there? Can you tell us what's happening with uranium? Yeah, it's a very exciting time in the space. A lot of geopolitics being considered here, Russia is a major supplier, so is Ukraine. And so what's going on there in that part of the world is putting a lot of pressure on the space. So we're seeing a bifurcated market where Western supplies are being valued more than global supplies, and we see that in our discussions with the utilities. They're willing to pay more now for Western supply than they are for the global supply, particularly out of Russia and Ukraine or out of Kazakhstan. They want that security and they're after it and they're willing to pay for it now. So let's talk about geopolitics and let's start with the USA first. The Department of Energy has altered some legislation to make it even more beneficial for shareholders to be involved in uranium. Can you tell us more about that? Yeah, you bet. So Congress in a bipartisan manner, they established the uranium reserve and they charged the Department of Energy to set up the program and go out and acquire and process $75 million worth of domestic uranium. And so the Department of Energy has initiated that process. They've got the program stood up and have gone out for bid. We've got a great inventory. We've bid a portion of that inventory into the reserve and we'll know by December 15. DOE has had a couple of delays, but the new deadline is December 15. So we'll know if we've prevailed on that. But yeah, it's a great way for us to take some of our inventories and to turn those into cash by selling them into the reserve. And DOE will then use those pounds to backstop utilities in case there is a supply disruption. And speaking of supply, of course the financial market doesn't like to miss out. There were a number of ETFs that came trotting after the uranium market when we saw that uptick. Can you give us an update about why we haven't seen ongoing and continued rising? I had people call me all the time, John, and I'm like, let's ask an expert and a global leader, what's going on? We should continue to rise, but it hasn't. It seems like it is somewhat found a new normal spot and long term hovering right around $50 a pound. But I guess I would convey that that may be a published price and that may be the price that some global players are seeing. But again, in our discussions with utilities and with US utilities and European utilities, they really are feeling the impact of Russia and Ukraine and are very nervous about their future supply. So they are not paying that published price. It is a bifurcated market. And unfortunately, the Western price is not published. So I think the global price has reached a plateau. But other pricing, Western pricing has not. And we've seen that in our contracting discussions and I think we're going to continue to see that right now. Congress is contemplating cutting off the supply from Russia. If that happens, that's going to be a tremendous, tremendous earthquake in our industry because both Russia and Kazakhstan are such big suppliers. So we're expecting to see further increases because of geopolitics, but also because just increased demand going forward. There's a big gap right now between supply and demand. And I just want to clarify for our audience, when you talk about it becoming a major earthquake, you don't mean negative for uranium shareholders of North American uranium companies. You mean positive. I mean positive. Yeah, there are so few uranium producers globally that when a major supply like that gets cut off, it'll have an immediate and overnight impact on pricing for basic uranium primary supply, but also conversion and enrichment. So throughout the fuel cycle, it'll be a very positive for the suppliers in each of those arenas. One final question. Will you be able to ramp up if this potential earthquake actually occurs, which from all indicators it will? Can you handle the production demands on you? Yeah, so we've got two flagship properties, Lost Creek and Shirley Basin. Lost Creek is built out, it's actually producing right now. So for us to ramp that mine up, we can get up to very meaningful production in less than six months. And we continue to shorten that timeline because we're drilling and constructing right now. Shirley Basin, our second property, it'll take us about 18 months to get it ramped up to a very elevated number because we need to build out that facility. But the answer is yes, we can ramp up very quickly, especially at Lost Creek and we're very well positioned.


Right guys how we doing welcome back to yet another reaction video today. We look at the most savage and Emotionally charged sports moments Ever I'm lead to believe this is a video with over two and a half million views It was created and published by our good mate Joseph Vincent I mean when we look at the the spread of five athletes here, we've got we've got porter now that's not That's not porters that's porter. I absolutely know no idea who he is. I mean we know Tiger Woods We know the most savage of all time Mike Tyson The bad man Aaron Rodgers. I mean, I look I haven't I haven't seen too much of his career, but I do know that in the In the moments that count he really does become a real savage and Low and behold Michael Jordan either way guys It's 20 minutes long the most savage highlights on YouTube the most savage and emotionally charged sports moments, and I'm just wondering What if any of these moments I actually recognize so let's get into it Who's that Roy Jones, Jr. Oh Bit of a right hook. Oh, well, what would you look at that? I've never seen that footage before that's for sure That's a boxer that I've actually never really watched to be fair It was just before my time, but what is the most savage moment of his career? Nobody Bro hit some of the right and then hit some of the left.  So let's uh, let's Light heavy waves Round 11 what a performance who's next I don't mind a bit of that. I don't know Three will be better Rg3 now, that's the name I do recognize What was his what was his name it was um clay Geez, I I should know this he doesn't want it doesn't want to be named a white man's name I've never seen that interview before that's for sure. So he's converted to Islam and gone with Muhammad Excuse the language guys, but oh my god, he's laid out for the count legacy That was ten punches within two seconds That is absolutely ridiculous Anybody in the world the guy can hold court and the poorest of the poor right up to the what a tragedy the way that his life Can you imagine if he had of heads if he if his brain if his mind had have been pristine until His death can you imagine the amount of entertainment? We all would have had you know in his later years it would have been incredible and unfortunately that was that was ripped away from us Just not right man, damn he was fast. Yeah, look at this.  Let's be fair So if you can defend if you can get around those swift punches, then you might be in with a shot But I guess he was just too fast for his generation Too fast too strong Like in 67 Oh He's doing a snow angel Cash is clay. Yes When how of course selling everybody's calling you Muhammad Ali now why you got to be the one of all people whose color to keep saying cash is clay Why don't you call me my name, man? What's your name? You told me your name was cash is clay a few years ago You my name was cash is clay. My name is Muhammad Ali and you will announce it right there in the center that way after the fight If you don't do it now, so ladies As the two contestants Yeah, we were we were robbed actually we were robbed of years and years and years of of entertainment Um From this guy severely robbed. What's my name? You all know exactly who I am He bounces around like no one else I wonder what his defense is like that screaming at him. What's my name? What's my name? What's my name that is savage that is extremely savage We're talking about the most savage and emotionally charged sports moments So we're talking so that the pre-fight interview was was the was what charged this up As much as it was What's my name? Compliments him, but not a perfect. Well, it ain't Cassius Clay anymore. That's for sure What do we got magic Johnson vs. Michael Jordan And we got out on about well what I do know and I don't know too much about basketball What I do know is that Michael Jordan never lost a final series. So well the two and I said, I'm gonna I'm gonna really Rather exchange so I went over there tapping on the shoulders. So hey man. I mean Jordan six six Johnson six five similar physics If you don't turn in the air Jordan, we're gonna blow you out to that Jimmy his eyes got big Oh My lordy Lord gets around the block and slams at home. That's it. That's fucked. That's incredible Yeah, Jordan, all right, yeah, Jordan, what do we got top of the three? Michael has a streak in him competitively that I've never seen in anyone before Yeah, look if I was watching Michael Jordan for the first time I'd be impressed. Oh Everything was perfect Michael Jordan in 1991 came down on us with the right hand turn out That's incredible. That is so crazy. You gotta have some real control over that ball You got to be able to palm it at the very least that's You got to have some real some real hops about you It's almost as if everything slowed down for him, isn't it? And that was that was his first championship you should not talk trash to Michael Jordan Longest return or the longest play in Super Bowl history a hundred yards This is a bit more up by Ali. What do we got here picked off by? What's the context? What is the context of the game? I'm not quite sure but he's gone a hundred yards That was to me. That's the game winning play Arizona scoring Don't tell me that's big Ben Rothersberger Jeepers Creepers This could be back in the early 2000s. It looks like it. It does actually look like it But you play a mega try I know a mega try to do we are here at Ford field getting set for the 12 all-time meeting between These two franchises featuring once again. So Megatron is Calvin Johnson who played for the Lions Would that be right you just don't have the nickname Megatron just to have Megatron, man If anybody just been growing up on the transformer things man Megatron is a beast. Look at him Look at him. He's DK Metcalf of the 90s and 2000s. Well, I wasn't expecting that I was not expecting that That's many years difficult for oh, this is a young tiger woods. Look at him Do you do you ever feel under any kind of pressure or any kind of prejudice every day We heard all the hype about the 18-year-old who could hit it further than most of the tour pro Yes, boy till the US Ammoner get in some you think in some ways that you can help change that if you be He dominated the way no one ever has and I'm pretty sure no one ever will Look the first golfing game I ever played was Microsoft golf nine Windows 95 it was an already installed game, you know somewhat like the The pimple game and in Windows 98 and and so forth. What have you Microsoft golf? 1995 Prior to the PlayStation one actually and prior certainly prior to Tiger Woods PGA golf Whatever year you may have bought the game. I'm lead to believe it. It spanned over 20 20 years But the first golfing game I ever played was Microsoft golf 95 if anyone's actually ever played that Let me know in the comment section below because that was an incredible game The masters was the way blacks have been treated there Everything it takes to win so you know what you guys do when he gets in here daddy want a back Thank you. Congratulations. Enjoy it and tell him about the certified chicken next year What okay, that's even younger I Didn't see this I was just I was just just that little bit too young to really you know Get behind this guy and really understand exactly what he did in the world of golf But I suppose we're seeing it now All right, here we go Look the first thing I wanted to say I knew Mike Tyson was going to feature here somewhere But what I do want to tell you is that that the the biggest tragedy for me being a New Zealand boxing fan Is the fact that Mike Tyson never fought David Tuer they never fought and That my friends is a fight that would have absolutely gone down and fucking History it would have been incredible. We never saw it. Unfortunately. It is what it is Let's go big Mike have to intimidate opponents a lot of them seems to have been beaten before they got in the ring Almost or when they caught your eye when they got in the ring you aware First punchy through Mike Tyson when the bell rings he conducts himself as if someone stole something from so short And he had this crazy style of bobbing and weaving and ripping ridiculous power and speed Oh mate from both hands right or left Could you even call him a Southpaw or an orthodox you couldn't because he's bouncing he's bouncing in and out every single Geez, it's yeah, that wouldn't be easy I Honestly don't even know if I've seen a Mike Tyson jab Boxing that's what they want to see I want to see people get knocked down every fight is a 32nd assault those 80s Fights with Tyson or he would just show up and look at people. They would know I'll tell you what that first punch from from old mate in the blue shorts actually looked all right, but unfortunately Tyson slipped Dipped moved got out of the way and just yeah made him pay for it I thought he was going okay to be fair Geez those early days really were just something else 30 second fights if you're lucky If you're lucky That's insane Oh He slips about 10 or 15 punches says you know what I've seen everything everything every single thing you can throw and Now it's my turn One punch Only do it to the body to all my No, oh no, oh Look I laugh, but it's really no laughing matter.  Oh no. Oh Oh And again, he didn't need those extra two he didn't but Mike Tyson gave it to him anyway And he just he almost you almost gave him another one for good measure Mike Tyson didn't just finish people he Flatlined them. Oh my gosh Such What have we here Do they actually thought I knew a few soccer stars, but I don't know this guy Last round of games in group C if United States when they are through Algeria do anything but when they are definitely out And USA playing soccer playing FIFA World Cup football qualifications in the late 90s and they've done it So I'm assuming USA vs. Algeria is is that that that last hurdle You know to get to win the qualification to the FIFA World Cup And I'm assuming Algeria almost always got it over the US until now And it was done through a bicycle kick like that. All right, here we go on the football field What do we got Green Bay vs. San Francisco? Hmm. What year who would know first quarter? No, no What do we got his ability to throw on them? Well, it's Aaron Rodgers. I know that much Outside the left still dancing now to the end Remarkable Aaron Rodgers and utter ballet of Not bad last play So we're talking most savage and emotionally starts charge sports moments But really in this case we're talking about an athlete and that's the bad man Aaron Rodgers What do we got three seconds on the clock? In fact make that none no seconds on the clock down by two Who's gonna score untimed play someone's got to go long. That's for sure Unless Aaron Rodgers rolls out Runs it himself, which I Well, he's he's going long. That's He is going long and high and it comes down in Would you believe? Big number 82s arms Now if that's a tight end that is that's that's that's probably the most I'm gonna say that's the biggest tight end I've ever seen in my entire life They'll be disappointed year after year haven't they and it hasn't got any better for the Detroit Lions What do we got? Within his in-zone rolls out he loves that he loves that fires again fires long once again. Who's that Jordy? Okay, but they're still down seven points. What's gonna happen here?  Packers team can they get it to overtime? Here we go. Just like the Motown miracle the Packers hoping They can He just launches it doesn't it Hey, that's a that's that's a that's a bad throw, but it's also a bad catch bad as in good I'm going to ask you point blank back in the boxing ring. What do we got here? I Don't recognize anyone just yet of a better word almost miserable Yes, one sense is in reading this article that the both of my life was spent in the family No, not quite the world champion just yet, but ranked number five in the IBF and ranked number two in the USB a Trying to do something trying to do anything that would win the approval of your father big Roy Well, I'll tell you what that's a counter-strike So quick so oh my How unfair is it the guys already knocked out but he's still on his feet and I guess he's still fair game So you hit him with as many punches as you can that that seems unfair to me, but that's boxing for you When one man is just that much quicker Than the other I reckon that's happened right there. He's knocked him out. He's on his feet still, but he's gonna give him another one No, not in this not in this case Okay, now let's go to the biggest punch you ever delivered who was it? Art so Wano Oh, no, oh No, what are we gonna see here the biggest punch he's ever delivered He had a seizure he had a seizure no no that's the type of that's that's That's the kind of thing that I'd actually look away for to be fair I'd shut the TV off right there right now Vicious savage would you believe? Savage is that Drew Brees Manning versus breeze Hang on this must be after Hurricane Katrina Invest in played on the road The entire season didn't have a home stadium. I'm not quite sure what happened to be fair But I'm assuming New Orleans came back one. Why can't sandwiches be dropped to the to those people that are super though In the wake of the storm one of the worst on record a new storm has loomed in the form of how to rebuild and resettle the area You have the strength of not only a city in the community, but I feel like We cannot stress enough the danger this hurricane poses to Gulf Coast communities I'll take it all the way mate take it all the way and he does He doesn't puts them out by two touchdowns, okay What a result that is savage That's emotionally charged. I'll say that much I reckon if there was one Super Bowl manning would be willing to give away it'd be that one For the bulls a win would be a championship for Michael Hang on is that is that Morpheus in the background? I think it might be Jazz versus the lake My bad, what did he say for the bulls a win Game six For the bulls a win would be a championship Jazz versus the bull Jordan never lost a final series, right? So I guess this is kind of Well, let's continue Always took his game to another level Jordan pulls up like we've never seen before Six titles six finals in BPs that mean it was all about you each series.  Peppermint he still leads the field he became the most dangerous man alive How the how could you concentrate? I'll tell you what those needles are actually the noodles Sorry are doing their job. I must admit the noodles do look extremely distracting, but It ain't nothing That Michael Jordan can't handle John Stockton coming back with the big three Those two didn't make a difference Those are hard Those are hard to compare anything to none of us ever saw what he was going to do And we thought it was gonna be great Hang on what do we got fourth quarter 83 86? What's he gonna do?  Drives to the brim Okay, what do we got here 37 Jazz are up by a point They need to control the clock, but Jeepers that was a That was an oversight So He scored the two he's gone and got that the possible game-winning still and he's about to win the game Off of his own back absolutely no help from anyone else. Let's see what happens Don't tell me he shoots a three Oh He almost broke his own ankles He certainly broke the broke the oppositions and he's gonna bring it back in shoot the mid-range jumper and Winner, but there's five seconds to go You'd call a time out wouldn't you and I feel like the jazz have it's not it's not all over mate. Oh It is all over. They've done it Was that his sixth NBA championship Wow, that was the way to finish it. You're kidding me.  What what does that mean? I have absolutely no idea It was created by none other than than Joseph Vincent and I'd love nothing more than to bring it to you guys and give my reaction So in the next one we look at Kobe Bryant today. That was the I'm gonna say probably six seven eight Maybe even ten of the most savage and emotionally charged sports moments of all time. Thank you and I'll see you soon