Today we are at Ozele and Crystal River where it is a Zella Park and boat ramp We're gonna do some night fishing, but there's signs all over here. It says Park is open from dawn to dusk and No camping Well, here's the thing. I'm probably gonna be up until four in the morning fishing. I don't know how they can stop me From using the Gulf of Mexico to fish So, I don't know we're gonna check it out. We're gonna do a little bit of fishing and I'll be back with you Okay guys, so sorry about the wind. We are on the coast So we parked right back there and Shoot there we go, but right over there from us. This is the ramp part right here They got a tent and stuff set up there.   I'm gonna try squid first I'm just gonna try to cast out here Monkey says beautiful over there, but yeah, I see they got a tent set up.  Sorry about the wind. I'll kick you back on Once I get out here, I know you're on the wrong side of me, but if I put you over here, I'm afraid the sun I don't know Looks like it's dark in this camera right now, and I don't know why I might be able to lighten it up here Hopefully that's not overexposing you so alright guys. I'll be back with you shortly hang tight But hopefully we'll get to sleep in the car. Hopefully they won't say anything We're not far from the house, but It's a 10 mile drive just to get to the main road and then it's only like 18 minutes after that to the house so But this is a long windy route. It's really it's really nice back in here. So I See a couple kayakers All right, I'm gonna get get my bait cut up and get a line out in the water Okay, guys, so I am getting some bites here, and I think I just got a snag. There's a fish on it The wind is blowing my line to the rock that's the way the wind is blowing that way So no matter how hard I cast out here to my left still blowing it back Push me into this coral They're biting. I'll leave you all for a minute. It's blown it that way even I cast it that way I'm gonna have to get a heavier weight heavier sinker. You can see my line Just went over into these rocks again. Now. Let's see if we get the black max out here There is a manatee right out in front of me Monkey seen a couple over here behind me where she's at catch a couple them I might keep them for some bait at in the truck Don't mess around a little bit. I'll kick you back on if I catch something.  So I went over to check on monkey and came back I got a friend. I ain't sure what that thing is.  We're glad I didn't touch it. Okay guys monkey's getting hungry. So And they took the grills out last time we were here there were Two or three of them maybe even four over there. They took them all out Though they did put a new picnic table in but they took the grills out So some food cooked up here so Let me get a knife. Let me get this open and Then We'll start cooking Okay And it's still a little breezy, but the mosquitoes are still out. They don't care. They don't care one bit Okay, I know what I need a glove. I'm not sure where I put my gloves But anyway, that's what we're doing. We've got some ham or hot dog buns in there Just gonna cook a couple of these up there. I'm on a hot dog bun Okay, so we ate I made monkey first I made mine and then I ate an extra piece because I had a piece left over Well, there's a lot of it there. I don't know if you've seen it, but I just cut them in half So she ate half I ate half and then I Cut up half of a half for Bruno when I eat the other half of that one. So Time to do some more fishing Okay, there he is guys number six. I Don't know if I was recording a minute ago, but Yep, that's number six right on So there we go Monkey has caught none, but that's okay guys I Catch plenty for both of us anyhow, I Got to get this hook out of him and get him back in the water. All right guys number seven. No What that's my fix?  Thank you. I'll get him in the water. Okay guys. So monkey has gone to bed It's after two. So I'm gonna step a little bit fish a little longer. She uh, she got another catfish Little bit bigger than the last one pound and a half going on two pounds. So yeah, she's got two fish so far So that's that's good. I Don't know how much fishing we'll do in the morning, but we'll see but I'll kick you back on if I get something here Trying out my Got this green light. It's pretty cool but Yeah, so but I like that. It's not so bright It is still windy, but it's keeping the mosquitoes away and that's a nice cool breeze but Every once in a while you feel this real hot breeze come in but like right now. It's really cool. It's a cool breeze but Yeah, I'm gonna since she's not fishing I'm gonna spread my rods out a little bit We'll go from there and see what happens stick around. Okay guys, so I don't know what time it is. It's late I think I'm gonna crawl in the truck get a couple catch a couple z's I've only had one bite since I caught that catfish and that was right after that catfish I haven't had a bite since try different spots right in here and Nothing so try different, you know, try Shrimp and chicken liver. It's not biting. It's low tide too. So I guess that's what I'm gonna do I am going to go ahead and head to the truck pick my stuff up Catch a few weeks and then I'll see you guys in the morning. Good night Good morning, everyone. It is 642 a.m So I'm getting ready to rise the The tide has come in So I'm gonna throw a line out here and see what See if we can get something Got a boat coming in there Looks like kayakers over there So We'll get some bait on my line We'll throw it out there and see what happens Good morning, Crystal All right guys, that's it for this trip. Sorry didn't get to bring you along with me on that last catfish I caught Excuse me, but I just walked over there just Real quick to give it a shot and I caught the fish Monkey was clear over here. My camera was over here. So Yeah Monkey's getting her camera. She's gonna do an outro. So thanks for coming along with us guys It's been great. It's been real. It's been real fun. I loved it.   I know I told you last night I was gonna go in and get some sleep, but I didn't so anyway Monkeys going over there to do her outro and I'm doing mine right now And I'm gonna leave you with some beautiful drone footage a couple hundred feet up in there we're gonna drive around the drone and Hopefully enjoy it. Thanks for watching guys. Appreciate it. Enjoy the drone footage We'll see you in the next one. Shea bear the myth of man legend gone for now. Bye. Bye guys. Take care


The United States Army presents the Big Picture, an official report produced for the armed forces and the American people. Now to show you part of the Big Picture, here is Sergeant Stuart Quinn, coming to you today from Canada. 100 years, Canada and the United States have shared an undefended border. The Canadian Army and the American Army have long been partners in the defense of two free nations. In Europe and in Korea, Canadian and American soldiers are fought side by side shoulder to shoulder in keeping with a proud heritage. Today, the Big Picture salutes the Canadian Army and brings you a report on its distinguished past and its dynamic present. With me here at the historic Citadel Fortress at Quebec are two of Canada's soldiers. Regimental Sergeant Major McManus and Company Sergeant Major Don Saru. Sergeant Major, you're with the Canadian Guards, aren't you? Yes, Sergeant Quinn. I am a member of the regiment of Canadian Guards. The regiment was formed in 1953 and became Canada's first national regiment. Its motto, a maria yusquie at maria, means from sea to sea. And what of your assignment, Sergeant Major Don Saru? Yes, Sergeant Quinn. I am with the premier battalion, Royal 22nd Regiment, quarter at la Citadel. We are a French-speaking unit. Most of our men are French descent and come from the province of Quebec. I am told that the Royal 22nd Regiment is frequently referred to as the Vendous. What's the story behind this? Yes, we are known as Vendous by the English-speaking people. They have difficulty to pronounce 22e Regiment. Now, come along and we watch the changing of the guard. The traditions of Canada's regiments have been nurtured by the older British customs and provide added luster to the parade ground. One of the most famous summer sites in Quebec City is the daily inspection and changing of the guard at the Citadel by the Royal 22nd Regiment. These 19th century uniforms belie the modern professional soldiers who wear them. The regiment is led on parade by Baptiste the Goat, a gift from Queen Elizabeth. These ceremonials are an important part of a proud military heritage. They are very much a symbol of Canada's modern fighting force, highly trained to assume the military responsibilities of a growing nation, although the Royal 22nd has carved a special reputation of its own in war and peace. And it is typical of many units in Canada's present-day army. At this colorful show in the Citadel, even Baptiste has his horns gilded for the officer of the guard. Canada's army man is only, incidentally, a ceremonial soldier. His primary function is to fight, if and when necessary. How well he has done it in the past is written on battlefields from Cardenburg, South Africa to Seoul, Korea. The solitary sentinel in front of the Citadel's historic entrance waits to be relieved by the morning guard mount. In the show window of the army, the new sentry takes over his post, stiff and impassive, standing well over six feet tall in his great bare-skinned busby, embodying a tradition of duty as old as Canada. On the nearby plains of Abraham, in 1759, British General Wolfe lost his life and won Canada for Britain. The English victory over General Moncombe's force marked the destiny of Canada as a British Commonwealth nation. French and English Canadians were united, and by 1885, when the Governor General's bodyguard crossed the ice of Lake Superior to help quell the Northwest Rebellion, Canada was fast becoming a nation. The Canadian army received its baptism as the Indian lands in the West were settled. Although Canadians fought in South Africa's Boer War at the turn of the century, it was not until the outbreak of World War I in 1914 that Canada was called upon to put a large modern army into combat overseas. During these war years, many of Canada's finest regiments came into being. Some were raised and equipped with private funds. They learned how to soldier, and they went to France to the tragedy and victory of a great and terrible war. Montserrel, Busson, Amiens, Festubelle, Ypres, Vimy Rids. Germans launched a gas attack at Ypres in April 1915. The Canadian First Division took the brunt of it, but more than once across the vast and bloody front, Canadian soldiers paved the Germans back. In 1918, the Canadian army emerged from the mud of the French battlefield. The Black Watch of Canada alone was awarded 23 separate battle honours, and the Queen's own rifles, 21. The Germans had been beaten, and Canada shared the sweet taste of victory. Four years of struggle and a crucible of fire, the Canadian army left 60,000 men behind when it returned from France. Today, a simple monument in Ottawa pays silent tribute to their memory and to the spirit they personified. Sixty-eight Canadian soldiers were awarded the Commonwealth's highest decoration, the Victoria Cross, upon which is inscribed with simple eloquence for valor. In 1922, the Canadian Parliament passed the National Defense Act, which provided the peacetime blueprint for Canada's armed forces. The regular army numbers approximately 49,000, all volunteers. Between World Wars I and II, the regular army dwindled, seldom numbering more than 4,000. When war broke out in 1939, the National Defense Headquarters had to draw heavily from local militia units. Canada's first troops embarked for Europe in December 1939, and a continual flow of soldiers was channeled into the Allied war effort over the next six years. Most of these early troops, comprising the Canadian First Division, were volunteers from militia units. Not until August 1942 did the Canadians make their first combat assault on the German stronghold in Europe. The objective was a small port on the Channel Coast, the French resort town of Dieppe. The Dieppe raid was to serve as the preliminary experience for the main invasion of France still two years distant. Though the raid itself was a tactical failure, Dieppe proved that the new Canadian army could fight as well as that of 1918. Few of the combat objectives were realized on the beach, but the many lessons learned by the Allies paid off in future amphibious operations. Of the 4,900 Canadians who went in on the Dieppe beach, less than half returned to England. At Buckingham Palace, many of those who came back were honored by the King and watched in silent admiration by the English crowd. The Canadian heroes of Dieppe represented all ranks and a cross-section of units from the army. They represented, too, a cross-section of Canada. The courage and the fighting skill they demonstrated was not simply the army's story. It belonged to the nation. Christmas of 1943 found many Canadians celebrating in the picturesque Italian village of Ortona. Germans disliked giving up their quarters just before the holidays, but the Canadians could not wait. For cautiously ingenious technique called mouse-holding, the loyal Edmonton regiment and men of the Seaforth Highlanders leveled the town one room at a time. By the end of the Italian campaign, nearly 100,000 Canadian soldiers had seen service in Italy. Troops went ashore in Normandy. The Canadians carried their share of the assault and subject to repeated German counterattacks. In a great pincer movement during August 1944, Canadians, British and Americans effectively sealed off and cut down a formidable German force deployed in the Falaise area. When the fighting ceased around Falaise, the battle had turned into a major German military disaster. The Canadians alone took more than 12,000 German prisoners. At least eight enemy divisions were destroyed and 16 more suffered disastrous losses. At the end of the war, General Eisenhower lauded Canadian troops for their valor and determination. Responding to the United Nations' appeal for troops in 1950, many Canadian soldiers volunteered for duty among the barren Korean hills. Fighting side by side with American and other U.N. soldiers against the North Korean communists, the Canadians brought a matter-of-fact military professionalism to their work, which was a model for all. These men knew their jobs. They remembered the reputation their fathers had made at the Somme and Vimy Ridge. They remembered Dieppe and Ortona and the Falaise pocket. And before they were finished in Korea, the communists remembered them. The First Commonwealth Division provided recreational facilities such as they were. For the hard-fighting Canadians, the chance to relax over a glass of ale was always welcome. The Canadian Army has maintained a brigade group in West Germany since 1951 as part of Canada's NATO obligation. Headquarters is near Zost, handy to terrain well-suited for the constant training activities carried on by the formation. Some regular regiments are rotated periodically for service in Germany. These men stand next to the American Seventh Army, unguarded at the outer perimeter of free Western Europe, ready for any emergency. When the United Nations was confronted with a Suez crisis in the fall of 1956, the Canadian Army was called upon to provide personnel and material to assist in policing the area. Serving under the UN flag, Canadian units helped bring about a successful prisoner exchange between Egyptian and Israeli forces. In the troubled Middle East, Canadian soldiers still represent the interests of peace. The fighting history of the Canadian Army is a proud one. And nowhere is it more revered than at the Royal Military College at Kingston, Ontario, where future officers are trained. At a modern army camp near London, Ontario, the oldest regiment in the Canadian Regular Army makes its headquarters. Royal Canadian Regiment has been a part of the Regular Army since 1883 and carries battle honors from the Northwest Rebellion of 1885. Today, the regiment continues in a state of combat readiness, providing highly trained men for duty anywhere Canada requires them. Already, members of the regiment have had experience as international policemen and as UN observers. The unit has also served with NATO forces in Germany. These fellows comprise a special group of soldiers called pioneers, similar to our Army engineers. The axe, the apron and the beard reflect time-honored tradition when the men parade. Every Canadian soldier learns the basic tools and techniques of his profession early in his career. Famous for their precision on the parade ground, members of the Royal Canadian Regiment polish their drill under the guidance of experts. The Sergeant Major's pacing stick marks the step and his experienced hand times the slow march. The same serious attention which these men bring to their close-order drill is carried over into all phases of their work. Most members of the RCR are qualified parachutists who maintain their proficiency with frequent jumps. There is only one member of the regiment whose combat effectiveness might leave something to be desired. But he makes every jump anyway. Canadian regiments display their colors in a solemn and moving ceremony. At Edmonton, the second battalion of the famous Princess Patricia's Canadian Light Infantry troops the color. Hamilton Galt, founder of the Princess Patricia's in 1914, was this year's guest of honor. When Brigadier Galt first organized the regiment for World War I service, he spent a personal fortune training and equipping his men. General! Salute! The most junior officer in the unit receives the color from the regimental Sergeant Major. The ceremony is derived from the age-old battle practice of rallying around the flag. The color is displayed so that all might be able to know it well and recognize it on the battlefield. With slow reverence, the regimental color is paraded between the ranks of the patricians. Patricians wear their honors proudly. Among their most prized regimental decorations is a United States presidential unit citation awarded to the second battalion for its gallant-fighted Kapyeong Korea in 1951. Since the end of World War II, the Canadian Army has maintained a mobile striking force specially trained for continental arctic defense. In early post-war operations such as Sweetbriar, United States forces participated in joint maneuvers with these Canadian snow fighters. Such forces may someday be needed to protect our arctic radar warning centers from enemy attack over the north pole. Defense of this due line is one of the many cooperative responsibilities of American and Canadian troops. At Gagetown, New Brunswick, typical permanent facilities are designed to accommodate all the needs of a busy army. At Camp Gagetown, regular army and militia units which convene here each year for maneuvers can march to some of the world's finest band music, including the pipe bands of the famous Canadian Black Watch, a at summer brigade concentrations. While the bands rehearse, the artillery is busy on a softening up operation to be coordinated with armor and infantry units. Men of the militia have an opportunity to train with duty-toughened regulars. Innovation 578 gets a chance to show what it can do. Settle action, traverse right, steady, on, 800, tank, fire! Crouching in the low grass awaiting the signal to move up, men of the illustrious Black Watch Royal Highland Regiment keep their eyes on the objective. Hello one, hello one, enemy section in farm, I'm taking them out, over. Taking them out. How many times in two world wars in Korea did that simple message spell the end for an unfortunate enemy? Say again, exercise cease fire. When President Eisenhower spoke before the Canadian Parliament on his recent visit, his words underscored the role of the army in Canadian American cooperation. We stand together at a pivotal point in history. All that we Canadians and Americans and those who went before us have built. All that we believe in is challenge as it has never been challenged before. The new horizon of competition ranged from the polar areas and extend to the infinity of outer space. One of the most successful endeavors of English-speaking allies is the tripartite standardization board made up of high-ranking officers from Canada, Britain and the United States. Ideas are exchanged and new weapons evaluated by these men working in Washington, Ottawa and London. Frequent troops maneuvered with live nuclear weapons at desert rock-proving ground recently, Canadian units participated, thereby gaining valuable experience on a simulated atomic battlefield. Far from the nuclear testing ground, retreat ends the day for the garrison at Quebec. Canada's modern army embodies a living tradition begun long ago, nourished by the many soldiers who contributed service and sacrifice, who led its regiments and filled its ranks on the battlegrounds of the world. To them and to the men who follow. To those who stand guard over their country today, Canada and the free world are indebted. Proud of its past, dedicated to a vital role in its country's future, the Canadian army stands beside our own, serving the common purpose of free nations everywhere. Now, this is Sergeant Stuart Queen, your host for the Big Picture. The Big Picture is an official report for the armed forces and the American people, produced by the Army Pictorial Center, presented by the Department of the Army in cooperation with this station.


Essentially, what this course is what I wanted to accomplish during my sabbatical, and some of my introduction to the course here, I think hopefully we'll put this into perspective about where the epidemiologist is in terms of a field that is moving as fast as genetics. And that is, it's kind of like two ways to interact with a steamroller. You can either be under it or driving it. Certainly prior to this, I felt like I was under it. So let me just give you some perspectives, just to say, in terms of conflicts of interest, the I don't have any or Dr. Monoglio has no interest in many of the genomics companies, et cetera, but we do make aches. So let me just put this into perspective. And some of you have been editors of journals and some of you have been on study sections and some of you have been in the audiences at meetings, and this is what happens, okay? This is a genome-wide association study of Crohn disease. It looked at 300,000 SNPs in 540 patients with Crohn disease and 928 controls. This is an epidemiology study, okay, classic case control study. The analysis confirmed two genes that they'd previously seen, one in chromosome 1 and one in chromosome 15 and 16. And then there was this other region on chromosome 15 with multiple SNPs associated. This was replicated in another study with 1266 cases and 559 controls and 428 trios. The SNPs that were then associated, these new SNPs, were located in a gene desert, 270 bytes, proximal to a prostaglandin receptor gene, whose expression looks like it was controlled by this. And there you are. Are you comfortable yet? Certainly as I sat on or chaired study sections, there was a whole lot of words up there and a whole lot of technology that got them to those words that I didn't have a clue about. The last time I took a genetic course was 1971, okay? And I think our geneticist's friends would probably suggest there's been a little bit of activity in genetics since 1971. So this is where I think I'm a classically trained cardiovascular geneticist, an epidemiologist, sorry. And so this new genetic epidemiology, population genomics, obviously we want to, for this course, is filling some of the questions you might have about what all of this means, what are the strengths and the weaknesses of this kind of research. So who's the target audience? Bummer of a birthmark, Hal. Well, the target audience really is for investigators, epidemiologists or population-based investigators who really would benefit from being familiarized with the developments in the theory and methods of human genetics and genomics. In your handout, you'll see the learning objectives for this course. This will be eight lectures, there will be a number of case studies relative to some of the papers in the literature. As I'll mention in one moment, hopefully we'll have plenty of time for discussion. And this is being webcast by the NHGRI. And we want to thank Larry and Maggie for joining us for that, so that it will be archived if in fact there were other needs to go back and look at the material. Let me just say is that as a teaching tool, this is also a research tool, one of the things that we've relied on as a repository is something relatively new over the past few months. This is the NHGRI catalog of genome-wide association studies. This is an activity by several of our colleagues in Terminalio's Office of Population Genomics. And this basically takes all publications reporting genome-wide association studies being in March 2005 in which the platform used at least 100,000 single nucleotide polymorphisms, the density of that magnitude. And these were your typical search of the literature in terms of these studies. And you can see a variety of types of data that are all cataloged there. So we put in the website there for you, but this is a real asset if you want to go and really see. Now I always am dangerous to say how many there are in there. I will tell you, as of September 30th, there were 109 studies. If you count all the Framingham and a couple of others, there were multiple studies in one. But again, now it's probably closer to 150 or something as this field moves along very rapidly. So what I want to do for this first lecture is to provide an overview of the course, which I've just done. I'd like to also review the structure and function of the human genome just so that we can get some of those words and terms right. Review the patterns of inheritance, which are obviously going to be thrown around and will be models for some of our epidemiologic investigations in terms of genetic causes of disease. Talk about some types of genetic variations or mutations, which we would consider as potential causes for disease, and then at the end identify some online informatics resources, which talk about the genotype and phenotype of human genetic variants. And a couple of them, I think, should be certainly on your favorite button on your computer. So let's start with talking a little bit about the basic genetics, and genetics is the science of inheritance. It's about 100 years old. The genetic code, of course, begins with Watson and Crick describing the double helix, and that is a little over 50 years old. And the field of genomics as coined by Roderick is perhaps a little bit over 20 years old, which is that field concerned with the structure and function of the entire DNA sequence in a population or individual as defined by Roderick. You can see some of the variations, but the idea of genetics, the science of inheritance, the subfield of genomics being part of that, of looking at the whole genome. Now what we're really involved with here is taking an immensely complex biological system and trying to hone down to really identify those variations in the system, which are important in causing disease. So of course we have 46 chromosomes. We believe that there are 20 to 25,000 genes in there, functional genes in terms of producing a gene product or a protein. There are about three billion case base pairs that's haploid, six billion if you count each base. And of these, 99.9% of them are the same between all of us in this room. However, if you've got three billion base pairs, 0.1%, one in the thousand still leaves a lot of variation. And so that's where the money is in terms of identifying those variants that may be related to disease. So we really have, according to these figures, Simmons, your department has lost another number two double N and I want you to find it. So there's the haystack and looks like it's a number two needle. And so this is essentially the challenge is finding within the entire genome those issues which are important for human health. Well here's the haystack and we had a little conference this afternoon and we decided that there were about six feet of DNA in every cell. So can you imagine how many cells you have? So each of you have enough DNA to go from here to Bethesda or maybe further. And so here it is, all of this DNA pulled out from the chromatin pulled out and you can see these literally feet and feet and feet of this genetic material which is made up of, of course, a chain in which the two helices are cooked together by these base pairs and adenine, thymidine, guanine, and cytosine which are hooked on to a deoxyribose sugar with a phosphate to it and then these are linked together. And what you will see is when they say the three prime and the five prime end is to orient you which way the DNA is going for purposes of say transcription, etc. The five prime end here is where the phosphate is and the three prime end here is where this hydroxyl group is. And here you can see the deoxyribose hooked together with phosphates and these form a chain and then these bases are coming off and then they link with these hydrogen bonds to another chain and then wrap up in the double helix at Watson and Crick described. And the importance of these hydrogen bonds obviously is that these are relatively weak bonds which can separate and go back together and as obviously that's important because that's how DNA replicates and so this is what we're talking about is little variations within literally a single base pair unit affecting the structure of what they encode and that in fact going on to cause disease. So that what you'll see in the literature, certainly in the genome wide association gene study literature are a variety of terms, exons, introns and a whole bunch of regulatory elements, promoters, the polyate tail, enhancers, silencers and the control regions. And the point is that each of these have a meaning. Exons are the part which actually encodes usually in several different segments of protein. The actual parts of the gene product or the protein introns are between these exons kind of spacers which are then spliced out during the whole processing of the genetic material and then there are a variety regulatory elements which turn on and turn off the gene. So what we have here is this promoter which is a place can be acted upon to really start this transcription which occurs here and then these blue bars are the places within the gene which are actually coding the protein of the gene. In between these are these which are transcribed and but as you'll see later then spliced out and then you have a codon which says stop and this poly A signal here at the end which tops transcription with this whole region back here. And these are a variety of genes. So this is the breast cancer gene beta globulin. And you can see that the structure of these is really quite variable and part of the truly elegant variation in how the genes are structured. So the story does not get any simpler with transcription where you have your gene transcribed. It's an initiation sequence, a promoter sequence that starts, so this transcription starts and RNA is formed. The RNA then goes along and is a process where these intron areas are then spliced out leaving then your RNA ready for translation out into the cytosol where the ribosomes then make the protein products. So the point is that you have a lot of places to start and to finish and the structure and the splices a lot more than just a little code that is read out in some way but a lot of other elements that could be varying that could alter how that gene product is produced and we're going to talk about later with, for example, the GWAS study that I showed you on Crohn's disease, there's a gene out here in the gene desert. Well, there doesn't seem to be any known exons out there that encode anything. What is happening with this polymorphism? Well, again, you can see that many of these regulatory elements, et cetera, may be where that gene is acting and just important to understand that some of these other things act there and could be targets for variation. So the genetic code then attributable to Watson-Crick are those sequences of the four DNA pairs that are translated in triplets. So what you have is the triplets as 64 codons each which encode an amino acid with the exception of some SOP codons. So this is a genetic code, the 64 variations of a triplet, each of which could be one of four bases. Some of the 20 amino acids there for, there are only 20 amino acids that make up proteins which are encoded by this. So obviously, you have 64 and 20, there's more than one codon will encode some of the amino acids. And then three of the codons are stop codons which basically terminate translation of the RNA. Now there are a variety of opportunities to have variants in there. One could argue some of these variants are deleterious and may be called mutations, but this could occur at the level of the whole genome at the level of the chromosome and at the level of the gene. And you can see here examples of, obviously Trisomy 21 is actually having three, chromosome 21, so you'll have chromosome segregation. Chromosome rearrangement frequently occurs in cancer cells and we're going to talk a lot about single nucleotide polymorphisms today which is a single base pair of mutations but there's a lot of others that both I and Terry in the next lecture are going to talk about in terms of variables. So the whole thing becomes extremely elegant but also extremely complicated and I think it's our job really is just to provide you with some of notion of the level of variability we have here. Now when we talk about single nucleotide substitutions, there are a variety of terms you'll also see in describing the results of the study. Synonymous or silent mutations are one where you may change a base but the base that it's changed to also codes for the same amino acid. So even though there is a variability, there's no change in the amino acid produced and so there's really no effect on the amino acid sequence. It is a variant but it doesn't do anything. There's this missense or the non-synonymous in which that one base pair in fact changed the code for amino acid and that amino acid sequence change then can have of course effects on the protein structure and function etc. The nonsense mutations encodes the termination code on and obviously changes the way that the gene does or does not turn off and the termination mutation destroys the termination code on and so it continues to transcribe into the next gene and so it may not only affect the gene being encoded but also the adjacent genes perhaps encoding other things. So these are some terms you'll hear and so when they say we believe that the defect here is a missense codon and such and such you'll understand what that means. So obviously this is the genetic code. This would encode a series of amino acids which would be translated into protein. You can see where you could substitute a single substitute so your SNPs, single nucleotide polymorphism will be related to this. You can also have deletions or insertions in which of course this would cause a frame shift so that since these are in triplets all of them will be different and of course then the protein and the amino acids translated here will be obviously totally different than the amino acids translated here and obviously cause a perhaps a dysfunctional protein. So the deletions and insertions when they're talking about that's what they're talking about. Now Terry's going to talk more about these indels, the deletions and insertions. Some of them are simply only involve a short segment of DNA and perhaps only affect two alleles where the deletion or insertion occurs. Some of them are much more complex. One term would be the short tandem repeat polymorphisms where you have a variety of repeat units, nucleotide units repeated over quite a number of times and this could affect a number of alleles. Variable number repeats are larger nucleotide repeat units again can be repeated hundreds of times. And Terry's going to give you some practical examples of something that we in cardiovascular epidemiology for example study lipoprotein little a. Something that I think is perhaps the next area of particular interest in concentration are the copy number variants. These are larger segments of DNA which are duplicated and affect a few of the alleles and the important part here is that some of the newer genotyping technologies are going to be able to start measuring these and being included in genome-wide association studies. So currently we're particularly doing a lot with SNPs and I think this is one of the next areas that we're going to be able to measure. I want to briefly talk a little bit about inheritance. This is something that you should have had from your basic biology or human genetics course but just to say that it is important to just go over the terms again as we go forward. The Mendel's principles of inheritance obviously is segregation is that a pair of alleles, a pair of genes for any particular trait of variants in coding the trait, they separate and only one allele passes from each parent to the offspring and which allele passes is random so that goes back to Mendel's experiments with his peas and that these traits are encoded by different pairs of alleles are inherited in the presence of each other unless they're genetically linked and we're going to talk about that because this is important part of our ability to measure quite a bit of the human genome without measuring each and every base pair is the concept of linkage. We're going to talk a little bit later about OMIM the Mendelian traits catalog online Mendelian inheritance of man and at least of last summer this was the number of autosomal genes that are listed in that catalog there's x-link genes there's a few y-link genes and mitochondrial genes we'll talk about the inheritance patterns of each of these but you can see obviously most of them are autosomal and x-link and each of these would have inheritance patterns. So what classically we've been talking about say up to what would you say the late 1990s perhaps would be more of a Mendelian disease pattern perhaps maybe earlier than that would be conditions which are caused almost entirely by a single major gene so when we talk about a Mendelian disorder it's one of those major gene disorders and they look they express themselves as manifesting only one or two of the three possible genotype groups and so when we test for Mendelian inheritance obviously the diseases are being inherited in this way which is a predominant forms and we all know about our favorite Mendelian disease of familial hypercholesterolemia, Marfan syndrome, a variety of the classic described diseases with dominant recessive patterns. More current in terms of the questions of the day are this common disease, common variant idea in which you have common diseases so diabetes, cardiovascular disease, the cancers, etc. are not caused by a single major gene but rather attributable to a limited number of variations which occur in say 1% or perhaps 5% or more of the population. So you have multiple forms which occur in relative frequencies are not rare variants but relatively frequent variants which then when put all together would explain the genetic basis for some of our most common afflictions and I think this is where the genome-wide association studies and a variety of our current activities have focused on for the last 20 years or so. So I think you're all familiar with autosomal dominant inheritance and this is obviously what it looks like about 50% of the offspring are affected. There can be male-to-male transmission. A person who's phenotypically normal does not translate to their offspring because should be of penetrance and men and women are affected equally so this would be the autosomal dominant pattern and again you all have I'm sure the diseases in your own area of specialty of interest. There can be complete and incomplete dominance just a couple of terms they're used. Complete dominance is where the phenotypes whether they're heterozygous or homozygous, one or two copies of the gene are present are indistinguishable. An example of that would be Huntington's disease whether you have one or two genes doesn't matter. You are affected by this debilitating late onset neurologic disease. Incomplete dominance is that the phenotypes are more severe in the homozygous than the heterozygous state. I run a lipid clinic, we see a lot of patients with familial hyperclesterolemia, those are almost all heterozygous with cholesterol in the 300 to 500 range. The homozygotes we don't usually see because they show up as children with very high cholesterol, 1,000, 1,500 they're very rare and they also do poorly unless they're treated with liver transplantation or other heroic means. This is an example of incomplete dominance whereas the homozygotes really are even more severe than the heterozygous although the heterozygotes everyone is affected there as well. A couple of other terms. Autosomal recessive of course are the genes that frequently will be seen in inbred populations. I did my training at Johns Hopkins and Victor McCusick did many studies in the Amish community there. You'll still see in the literature a variety of other founder populations studied because this is where some level of consanguinity will have occurred and this will allow the the recessive trait to occur. So if it appears in one family member it's most likely to appear in a Sib ship because there's obviously there are two carriers each with heterozygous for the recessive gene up here. Male-female is equal. The parents of the affected children are asymptomatic. Again there are there is increased consanguinity and this is why some of these inbred populations are particularly involved with these these disorders. And so the offspring of two heterozygous parents such as here these are are likely to be 25 percent affected. 50 percent of these are carriers and 25 percent of these would be non-carriers just on chance. So your autosomal recessive pattern. X-linked has to do with both male and female offspring of female carriers would have a 50 percent risk of of inheriting the again this is X-link dominant. So this this affected person about half of their children this woman would be inheriting phenotype.  The number of women affected is much greater than men because obviously there's two X chromosomes and they will obviously have to get the X chromosome from their father there and that means all daughters would be affected and there can be some variation in the severity in the women because of course that X chromosome can be deactivated. There's the lion hypothesis the lionization the inactivation of one of the two X chromosomes occurs and vitamin D resistant rickets is an example of this. Thank you. X-link recessive is that only males are affected. So here we have the carriers identified so you have a male here and the all of their daughters would be carriers and then of this carrier woman they're related through the carrier females you would have the the male cases with the one X chromosome that they have coming from this this particular parent and hemophilia A or red green color blindness would be an example of that. Y-link inheritance again relatively less common only the males are affected obviously all sons but no daughters of affected men are affected so as to rule out other kinds of inheritance it's not X-linked since male to male transmission occurs and it's sex limited because it cannot occur through unaffected females and then the final kind of of inheritance and something we're not going to have a lot of time to talk about is obviously inheriting another kind of of genetic material particularly from your mother and that is mitochondrial DNA this has been a great interest in the tracking of of ancestry and particularly through the maternal line the origins of of of racial groups etc this inheritance is matrilineal so it it does not go through the even though this individual would be affected with mitochondrial DNA from his mother he does not pass it on the mother passes it on to all of the all the children both men and women so having said that one might say that the rules of inheritance look quite tidy in fact it's it's not really so we have sporadic mutations obviously you can see no evidence of there being any genetic issues in the family and all of a sudden she'll have a case and so the suggestion would be that this would be a sporadic mutation there is heterogeneity in the in as you'll see with many of these disorders there will be several gene defects which can can be causative of them and each of them can have some differences in their severity and familial hypercholesterolemia for example there are literally dozens of forms of this probably six or eight mechanisms in which the the individual has the same phenotype so within that phenotype there actually is some variability in in in the disease there can be non penetrance where a disorder simply isn't isn't expressed familiar combined hyperlipidemia is a good example quite a common lipid disorder for example but it's the person gains weight or diet exercise issues much more likely to express that gene than otherwise you can also have late onset conditions like huntington's Alzheimer's disease which may have a strong genetic component but may not look genetic because of deaths etc prior to their age of onset and you can have sex limited and sex influenced phenotypes in which you'll have differences in in the phenotype so there's a lot of the point here is is that the autosomal dominant x-linked recessive etc obviously are general rules of inheritance but there are these other things that that affect what's happening so just to comment on this common variant common disease hypothesis so what you can have is I've just shown you the the various issues that could be going on genetically with single nucleotide polymorphisms in exons in regulatory elements in several genes in several exons the important part of this though is is that their prevalence is common enough to start to explain a common disease and then put on top of that of of course is that these all could be interacting and I think Terry's going to talk a little about gene-gene interaction which is of another whole kettle of fish and the other problem is that all of these could be obviously interacting with environmental exposure so you end up with a disease model which which which is very complicated and obviously this I think should be part of the bailiwick of the epidemiologists who are generally used to teasing out these issues and alls we now have is a lot more complicated data in which to tease out some of these other complex associations and just to give you an idea this is a study of lupus systemic lupus rheumatosis looking at a genome-wide association study 720 women with lupus with 2,300 plus controls over 300,000 single nucleotide polymorphisms assessed across the genome then almost by really by requirement there have been two replication studies which constituted in total 1846 female cases and 1825 female controls this was as I said study all of women and what they found was at least 17 single nucleotide polymorphisms which were associated at the p lesson 2 to the 10 minus to the minus seventh power level of probability so what you have here is then obviously each of these would have a gene frequency of five to say 50% and when you put them all together then in the logistic regression model looking to see how many of these really are independent of others maybe one's just the neighbor and they're all just kind of co-associated you come up with these six models which have independent either a susceptibility or protective relationships all significant at somewhere between the 10 to the minus seventh and 10 to the minus 18th level of significance the C statistic is 0.67 and apparently would account for about 15% of heritability and so what you're now talking about with lupus and those of you who have clinicians who have taken care of lupus patients obviously many times you'll see a family history you get the idea and we'll talk about heritability I think of lupus a little bit later and now what we're seeing is really quite a number of gene variants which look like they play a role in this disease and and act so independent of each other so many of these genetic models I think to least my eye are very complicated and obviously are a challenge to to fair it out the last couple of minutes what I want to do is just to say that that was kind of a semester long genetics course in in about 30 minutes one of the important aspects of some of that basic genetics is now is that our informatics resources which have then taken all of that complexity and now is accessible online I think I've used the wrong colors here but basically are now all available through the National Center for Biotechnology Information of the National Library of Medicine and Terry and I took a day long course on bioinformatics I think we were the geriatric sets in that that course there were I think everybody was more facile with computers than we were by a long shot but the NCBI has a variety of resources and particularly OMIM and perhaps gene bank are something that you can very readily then go and identify the polymorphisms etc there were maybe in a paper maybe identified in one of your studies or maybe something that you would like to have measured in one of your studies in which you've had the wherewithal to collect DNA and form consent etc and so we just wanted to list those and we're going to talk a little bit about each one of them so OMIM is an outgrowth of of Victor McCusick's catalogs of the Mendelian inheritance of man and it was it was always a lot of fun to go to clinic with with Dr. McCusick his all of his patients were average height unfortunately they were either four feet tall or seven feet tall because his two areas of studies was achondroplastic dwarfs or Marfa on syndrome so so on the average everybody was about five and a half feet tall but they were all in between so OMIM is a is a catalog of human genes and genetic disorders and I think Terry and I would agree that if you want to know one online resource this is the one it's got concise information on most of the human conditions which have a non-genetic basis pictures full citations etc other materials are available in the gene bank and some of these I think for at least so in my simplistic computer skills are truly amazing collections of all the publicly available DNA and protein sequences not only in humans but down to the the roundworm etc again a huge number of records description of the sequence the references and this is all generated by the submitter who basically it's kind of like a a wiki Wikipedia kind of activity where each of these is put in by a submitter this is a little bit different than RefSeq which is that each molecule in the in the sequence is described again this is non-redundant whereas the other one is redundant it's linked to the nucleotide protein sequences in gene bank and it's updated by NCBI staff dbSNP identifies the 6.2 million currently known single nucleotide polymorphisms and this is obviously changing every day we believe there's up to 10 million of them available and over 200,000 of them are within genes so these are related so another resource for you so finally um from 1900 to the present human genetics benign disorders still current some of the things I talked about are still obviously relevant to the practice of clinical human clinical genetics etc 1953 obviously molecular genetic structure and function human genome obviously building on really what we're talking about 1980 the present would be really description of the gene variants and candidate gene studies including in the epidemiologic literature and about 2003 to the present sequencing of the entire human genome and now more recently human genome they all build on each other they all build on the on the structure and function of the human gene and at some point certainly in the possibility parts of your discussions you're going to need to talk about but in the end here's the problem you're drinking from the fire hose concept that has come up in the genetics quite a bit is too much data and obviously one of the things we need to tell you about is how to measure some of these things so you can boil the data down to something that we can all study on our study populations okay I think we have time for questions which is what this says actually we want to the questions question or should maybe Phil why don't you ask the your good question again so what's thought to be the purpose of introns I guess is this a religious question nobody quite knows it used to be thought they were just sort of junk DNA that's in there and and it just has to be spliced out it probably has to do with the stability of the messenger RNA and how it is sort of moves from the nucleus out into the nuclear you know out of the nuclear membrane and into the cytoplasm to be transcribed translated because it seems as though changes in the introns actually are not silent and they do affect both the way that the exon splice as well as the speed with which the translation transcription occur so it probably has to do with folding of the the DNA transcript essentially but I don't know and I don't know that that there are many who know you know exactly what it is I think it is interesting to look at the intron structure of some of the known genes it's really quite variable you know if you looked at that BRCA gene you know there's just so you know that the exons were very small and there's a whole bunch of them there's a lot of introns are you just wonder if had also something to do with perhaps the the evolutionary fastfulness as well in other words the ability to to over to have variation because you can then mix and match and these all these little little bits of protein rather than really relying on just one big chunk but I don't I don't know the answer either and they also clearly that the introns allow for alternative splicing so that you can you can take out different pieces of of the you know the of the exon so maybe you'd have the first five exons and then you might skip six or seven and then go to go to eight and the and the way that the cell knows to do that probably has a lot to do with the molecular structure of that molecule that the introns help to define you know having read all these G1s I mean it was almost like in the beginning as it was kind of an apology if someone found a gene in an intron and like it was or this can't be real and I don't by the time two years went on it didn't seem like they were saying that anymore that they'd seen this so often that it was really something that was very important in terms of variation another question some of the snippets in current genome-wide studies come from the the coding region not from the intron or exon region uh it it actually varies the answer I think is that they come from both and if you look at them I haven't seen a study which has taken say literally hundreds of steps and classified them maybe you know about that but there are substantial numbers actually actually the DB snip has done that and there are some as you say substantial numbers in exon but there's also substantial numbers in in introns and coding regions as well yeah so the early platforms everybody believed us as I think you know you're suggesting that that the only thing who possibly be important is the exon so let's just focus on on coding snips c snips as they were as they were often called and there actually were platforms developed that were just coding snips and nothing else um 10,000 or 20,000 of the of the coding snips the current platforms are developed in a different way and we'll talk about it a little bit in a minute um to in order to capture the breadth of variation regardless of where it is in the genome basically you know based on on how many other snips are associated with the particular snip you're measuring so so what the hat map did was to sort of define those patterns of association among the snips and and ask the question if you you know if you only had to measure one which would be the best one that would describe maybe 10, 15, 20 other snips and so those can be in coding regions or non-coding regions they're anywhere in the genome um depending on the on the chemistry of the particular platform um some of them are are in places where um endo-ribonucleus is actually chop the DNA the afymetric platform is built that way others are are just you know assays that are developed for the best coding snips essentially but if you look at one of the uh the the snip platforms a small minority of the snips on that platform will be to exons and and of all those listed in db snip um one of the smallest groups is the exons


From DailyDoseOfWeirdNews.com, I'm Darren Marlar, and this is your Daily Dose of Weird News, the show that makes you want to sing, laugh, dance, shout, cry, call the cops, defect! This episode is brought to you by the audiobook Bed Bugs by Jason R. Davis, narrated by Darren Marlar. If you love horror but hate bugs, this is the audiobook for you. Here, a free sample and support Marlar House by downloading the audiobook for yourself at DailyDoseOfWeirdNews.com. Fox News is officially no longer fair and balanced, as the network will drop the slogan it has used for more than two decades. It was the late Roger Ailes who came up with the slogan in 1996 as cover for the network's right-leaning news. Moving forward, Fox News will be going with the slogan, Most Watched, Most Trusted. However, an unnamed source says that while fair and balanced is out as a slogan, it will continue to be a kind of editorial mantra for the network, because that has been so effective so far. Attendees at the annual Southern Baptist Convention have voted to condemn alt-right racism along with every other kind of racism. Last Wednesday, they approved a resolution to denounce and repudiate racism, including alt-right white supremacy as antithetical to the Gospel of Jesus Christ. Congratulations, Southern Baptists! Welcome to the previous century! Hillary Clinton appeared in a video last Tuesday in which she compared herself to Wonder Woman. Some call her Wonder When She's Going to Go Away, woman. A traffic stop in Texas led to deputies discovering what they thought was nearly half a pound of methamphetamine. As a result, 24-year-old Ross LeBeau of Houston was arrested and spent three days in jail, but then he was suddenly released and the charges were dismissed because a forensic lab showed that the substance in question was not meth, but kitty litter. Embarrassing themselves even further, the Harris County Sheriff's Office has already put out a press release touting the fact that deputies kept our children and loved ones free from being introduced to drugs. The kitty litter was inside a sock, which granted is a little odd, but LeBeau said it worked at keeping his windows from fogging up. If you're a police officer that is unable to tell the difference between meth and kitty litter, do you have any business being a police officer? Come to think of it, do you have any business being a cat owner? According to the book The One Device, The Secret History of the iPhone, Steve Jobs never really wanted Apple to make a phone. Not only was the Apple CEO wary of dealing with mobile carriers, he was worried smartphones would only be popular with the pocket protector crowd. After increasing pressure from employees, Jobs finally agreed Apple could make a phone, and well, you know how that turned out. A study released this year shows that more than 50% of Californians ages 18-29 are substituting cannabis for alcohol. It has been proven to be less dangerous than alcohol, but it is harder to drink. Starbucks is teaming up with Lady Gaga to release a line of summer drinks. They should call it the baby it was brewed this way blend. We're only barely at mid-year but have already found the dumbest criminal of 2017. Police had very little trouble tracking down the guy who stole 100 GPS trackers along with other items from the Santa Clara offices of tech firm Roombie. While he apparently thought that they were cell phone chargers that he could resell, the devices he stole were actually designed to help producers track goods as they are shipped around the world. Company co-founder Vidya Subramanian said, �We notified the police and equipped them to track the devices, and at about five or six hours it was done. It gets worse for our burglar boy. He also managed to cut himself while taking a beer from the fridge during the burglary, leaving DNA evidence behind on a napkin he used to soak up the blood. Police say that when they arrested the suspect, they recovered Roombie's goods along with other stolen property, including an album of World War II photos stolen from a veteran's son in a break-in earlier this year. For some reason, his name has not been released, suggesting he might be a minor. Well, if he keeps being this stupid, he may never make it to adulthood. Yoko Ono is going to get co-writing credit for John Lennon's Imagine. Actually, I'd rather not imagine. Wow, that woman is still screwing up her husband's career. Sarah Jessica Parker and her husband Matthew Broderick had bought adjacent townhouses in the West Village and are currently combining them into one huge mega mansion. Personally, I would have kept them as separate townhouses, so I'd have some place to go when my wife tosses me into the doghouse. Vladimir Putin has sarcastically offered political asylum to James Comey. And Malania. In Sacramento, Lee Caldwell has decided she wants to be the world's newest billionaire and is looking for Chipotle to make that happen. She is suing them for $2.2 billion all because of a single photograph. While Caldwell has very little chance of collecting that kind of money, she is still moving forward with her suit nonetheless, saying the popular restaurant chain used a photograph of her in promotional material for years without her permission. Allegedly, photographer Steve Adams took a picture of her at a Denver Chipotle back in 2006 and asked her to sign a release, which she refused to do. Eight years later, she says she saw the image hanging inside a Chipotle in Florida, then in two different California restaurants in 2015. In fact, the lawsuit alleges that the chain first used the photo in advertising in 2006. It also says the image was doctored to include alcoholic beverages, which she says cast her in a bad light. So why the massive sum? Caldwell is seeking $2 billion, $237 million, $633,000 because that is precisely how much the company reported in net income for 2006 through 2015. And once the chain announces its figures for 2016, well, she wants that tacked on to the total as well. The lawsuit names Adams, the chain, and CEO Steve Ellis. Okay, let's think about this for a moment. She had her likeness used without permission and she wants every single dollar the company made while the photo was being used. So she obviously believes that it was her face that prompted people to buy food at Chipotle. And that was the only reason people bought the food. If her photo had not been used, then they wouldn't have made a single dollar. Therefore, she is entitled to every single dollar they made. I don't think that kind of arrogance even exists in Hollywood or Washington, D.C. Here's the kicker on this one. Her likeness is so ubiquitous and powerfully effective, I can't find it anywhere in a Google search. A new survey shows that men are four times more likely than women to take their cell phone out during a wedding. Well, yeah, because we're hoping for some kind of news to get us out of sitting there for the rest of the ceremony. The Ellen DeGeneres and Portia de Rossi divorce rumors flaring up again. Good news, fellas. She might be single soon. Ellen on the market. There are several reasons you may overeat in restaurants, but this might be the oddest one yet. When a heavy waiter or waitress works your table, it can prompt you to order more food and alcohol than you otherwise would do. That's the word from researchers at Cornell University's Food & Brand Lab in Ithaca, New York, who found that diners are four times more likely to order dessert if their server is heavy set. In addition, those same diners consume 17% more alcohol, and this effect is strongest on the skinniest diners. So whatever you do, at all costs, stay away from cracker barrel. Unbeaten boxer Floyd Mayweather is going to fight UFC lightweight champion Connor McGregor in a boxing match on August 26th in Las Vegas. Obviously, it's Mayweather who is strongly favored to win, so bookies are only taking bets on how McGregor will lose, judging, knockout, or beheading. In Scotland, an alleged car thief had his vehicle stolen while refueling it at a gas station. Officer Karma always on the job. Never miss a single episode of The Daily Dose of Weird News. Download the free Marlar House mobile app. In the app, you can find links to my Facebook, Twitter, and Instagram, watch other Marlar House YouTube videos, sign up for the Marlar Sheet newsletter to automatically be registered for giveaways, purchase Daily Dose of Weird News t-shirts or mugs, download audiobooks I've narrated, see my latest blog posts, and more. The Marlar House mobile app is free for iOS and Android users. Download it now by clicking the mobile app tab at DailyDoseOfWeirdNews.com or search for Marlar House in your phone app store.


Microbial inoculants have been used in agriculture for over a century, with impressive advances made in recent decades. The availability of quality products and elite strains at competitive prices has led to increased adoption among farmers, who now prefer them to chemical fertilizers due to their lower costs and improved crop yields. Microbial inoculants can also reduce environmental impacts from agrochemicals, while further research is needed to expand the use of these products to new crops and regions. This article was offered by Mariana Sanchez Santos, Marco Antonio Noguera and Marangela Hungria.


It's not get status, right? So where is the where is the MD file I can't see the MD file Yeah Let me see what else. How do you see what you're pushing? Let's see what's in the repo All right, I go to file here, right? Yeah, I think it's okay. Just stop it and it's okay There is not a picture Just it just pushed all the way. All right, but we don't need the html Yeah All right, so here everyone So welcome to the majority workshop We prepared something. Yeah, try to build a module. It will be It's because it's not ready yet. So I Mean the project is not finished, right? So we're only doing a lot of stuff by hand and maybe we come up with some ideas to build some better tooling for that But it would be not that hard to build a module So I guess I want to explain first how does it work like in current Fedora and maybe How we wanted to work later so I thought I'll be Figure white was so I need to use this one. I have it up ready. Oh No, I just wanted to talk about the branching and stuff. Okay. Sure So, yeah, I don't have any slides. I thought like I can use this. Can I use this? I think so. Yeah, yeah We can get rid of Wi-Fi Only these No, I just want to draw something so Yeah, it's an official So, how many of you know Fedora How many packages A lot of you. Okay. So, you know how the branches work and everything like you have a repo for package and it's got branches for example f24 f25, etc And then we take all the packages for example from branch f25 and build a distro out of it So in modularity, it will be a bit Messier because we'll get branch for I don't know version of the package and then we have a module and D Where we select the packages and the respective branches to build the module so you can choose and Mitch makes a match the branches as you like so Yeah, basically that's it So So, yeah Yeah So if you prepare Which you wanted to use so Python over with scripts and stuff, but the Wi-Fi is pretty slow here So we bought a virtual machine for you. We can SSH to that and try to stop that. So Yeah, we need a repo No, it's fine. It's working. You can see it here as well Yeah Should we play the video which video I put a video in here, so you don't know what it is. What our module is You can play a video They can watch if they want to then Okay, if you like, yeah All right, so we have a virtual machine where you're going to build the modules. So it's on this IP address 35 Right, yeah, that was like for the original plan But yeah, the Wi-Fi is pretty slow. So we have generated the file for you It won't be just interactive and It's only Because we will be using SSH and we don't have to download like packages Yeah Yeah, that's everybody know Do you know SSH, right? So there is thing called Marsh, which is like faster SSH, right? That's transparently So this So you can use SSH or Marsh to connect to this machine and we have users called student from 01 to 30 Yeah, and Password is I think Password is DefconnCZ with three instead of the V and for security purposes, yeah, it's much more safer So Who's got a laptop? So let's try for example, here you go one That's creepy, because I think we have you You can All right, so two, three, four, five I think six, seven, eight Five Nine, ten I don't see a laptop there. Eleven? No. You? No, eleven, twelve, thirteen. No So twelve No No So thirteen, fourteen No, so fourteen Defcon Defcon Yeah, security Can you open the repo? Oops Yeah Maybe we can we can show the login Here's the wrong one That's going to do the end goal. We'll start here, so this one So could anyone connect? No. No, no, no, okay Can you read? Actually, or should I just sit on the screen? Okay So it's like three five one five six two five three four three, okay Four three, thank you Student zero one two thirty Yeah What really? It's Langdon's fault What Defcon scissor Yeah, so this guy's Alright So could anyone connect? It's usually not the case with a warship Someone have to have troubles So next thing we need to do is to Open this URL. I can copy it here as well So on the URL is a guide and That's the machine where we're going to build it It should be beefy enough for everyone to do all the stuff and Yeah So I can just go through the so do you want to go through the guy sure. Yeah I suggest you to make sure that everyone is like was able to connect because it's usually the case that Some people are not and then they will be lost during the whole workshop. So all right better ask Yeah, so can I help everyone is that working for Yeah So we can try to connect here and Two screens really So It's like So it was the wrong you are What did it open this file just about other people. Yeah, we go how we want to get people to this file, right? Oh my god That's the wrong one No, it's the wrong one We need to put the file there No, this file I guess yeah Sorry got the wrong URL We'll try it again. Oh my god. Yeah, sorry. It's a different URL. It was wrong one soap Well, it's still there. You can just go to the files and find the d file or you can use this URL We realized the Wi-Fi was so bad yesterday, so we were then going to do it in containers. Yeah Yeah So do we have the links to the moduland d I We could just you know guide through the thing This one all right You want to run this after it's pretty fast now Is it yeah, it is we don't need to do that you can go over what a module MD is Yeah, right. I think I need to use it. I have a notebook though No, because you need to print out with a module MD Do we yeah? All right, so we can just display that one. Yeah You Sit Yes, we will yeah You can do just so do so and become a route. Yeah, yeah, we are on the machine So please just I don't know don't do anything Yeah, we will kill it after the workshop. So that's fine No, please don't kill the machine at least you can kill it in the big in in the end, but yeah So I like the picture it was there, so can you open yeah this one Yeah What is the test module right Does it all right, so oh my god, okay, so So do you put prepped EP leader? I did in there Should be in there Yeah, oh it is okay No, but we should have the This module right yeah So why is productivity here? What I didn't run it No, but okay Yeah, I guess so All right, so the correction would be we need to download the Testing module, I don't know why it's not here. I guess it's some kind of different version of something just broken So should I just do like them? So I'll just look into the thing Yeah I don't think there is like anything I will put it there. I just need to prepare it. I guess because Yeah, yes What's this? Okay, so it's 35 Soon as you are copying it to the home directories, okay. Oh, that's great Yeah So there is like student one and student zero one Okay, so should we try? I don't know. I think it doesn't matter. So Yeah, you should have This built modules directory in your home. All right So you can take it from I all right. Let's let's do it. Let's do it together. So Yeah Yeah All right So let's try to get the let's try to get a directory with the build script and the module and these so it's in home Fedora, you need to be rude to access it. So so those two You will need to type your password and then It should be in home fedora built module so we can copy it to home fedora built module to The home like this Yeah, we know All right, so into your own home. So yeah So home student. I don't know what So like this so Niels, you don't have to do it some of the some people can have it already there some not so If you don't have anything in your home, please do this command Yeah What what's doing 25? Oh Like all right. Oh I know what I mean. Yeah All right. So for me, it's already there. Oh, thank you All right Then I need to go to my home directory. So it's like home student. I'm for example 25. I get to the built module directory and there is a Pref CPD module which is a One of the modules we can build So let's have a look at the module MD. You got to start No, oh, there's a dog running this one. Yeah Okay, okay, okay. Yeah Or I can just Make it smaller. Yeah. Oh my god. What just happened. So it crashed Yeah, the process what? No, the terminal crashed. So I have to run the terminal again. All right. Sorry guys Okay, so let's try again. We can view the Build module preft PD YAML Yeah, I know So Okay Yeah, just use PI So, yeah, this is the module MD. So there is a summary description license of the file Dependencies so we need the base runtime and also we need for runtime There are some references about I don't know where the project lives, etc So there is an install profile, which means if I install the module the prep tpd package should install and an API which means This is the only package I guarantee will stay unchanged or like Yeah, actually, it's like that and I have components. This is these are all the packages in the module so there is the for prep tpd prep tpd and also the dependencies and I'm taking all the packages from 25 here. So There is a name of the package there is a git branch in this kit And also I can specify a build order of the packages. Oh, sorry. So it's Yeah, so it's in the build module directory. There is a prep tpd and prep tpd YAML Yeah, you can still it for me for example, or it was in the It's in home Fedora Built module copied it. That's why you can copy it from here Isn't it So just copy it from student at 25 Yeah, what student 25 works, yeah So does everyone have in their home This so that's the example module we can try to build here, but it's got a lot of packages. So I don't know To this model before instead of Hmm Okay, I just started looking for you I think it was Mm-hmm Yeah Oh The test module because this is just too big, but I have no idea how to Play yeah, the plane will do it. All right because we shouldn't do the pro of tpd one Yeah So is it there yeah, that's fine Mm-hmm What Yeah Okay, so let's try to build it, but I realized the private tpd might be even Big so I just created a new repo in my home. So There is this test module thing, which is a much simpler So it's in what all right longer. We copy it for you And it will find it in your home. So if we do This module yeah, yeah It's in student 25 home on Langdon will compete to to your home as well So this one got like I don't know just three packages, which should be pretty easy to build so You will have it in a moment and to build it We need to use the script from the build module directory. So I can do build module like this and I can specify the Yeah, okay So I can specify the test module I want to build so it's like that and the results. So for example just results and this will This will run a Dr. Container with module build service in it and I put it into container because it could like this much dependency so I don't want to mess up the machine and It will build the module in mock We're like mock next to docker, but yeah, no No It's different What All right Yeah All right Yeah, I don't know well it's running inside docker, but Yeah Okay, sorry, yeah Yeah, so this will download all the packages from Fedora build them in the order we specified before And produce a repo so So yeah, the workflow we want to do is just for users to somehow generate the module MD file and Submit it to build it will be built automatically But to write the module MD file it can be a bit tricky because you need to specify all the dependencies of your package So we might want to come up with some tooling for that But in the meantime, for example, if you want to try we can do repo query and figure it out or I don't know. Yeah So we are using a fresh mock for each of those packages. Yeah No, no, no, we use the we use a mock with the base runtime When we build a package we'll take it back Well, it's kind of yeah, okay, it's been faked for you. So It's a fake base runtime actually All right So there so I think one source RPM from Fedora. Yes, it's being built in mock, right? And then what happens when another package is being built the same thing. Yeah, the same Oh, they do they do because they can provide build dependencies for themselves Yeah Yeah, yeah Oh in which order I mean, all right Yeah Again So in the meantime To So yeah the way to do right now you need to write a module MD yourself but If you want to for example try that, I don't know if you have some packages And even you don't know the dependencies or you want to Try manual builds like one package by another manually you can use copper. I don't know Does anyone do have you do you hear about copper Fedora copper? It's a community built service. Yeah, he does because it's his project, right? Yeah Mirko, you're gonna work on a copper. Hey Some All right, so writing the module and the Was one option and we will always use module and be to build the modules But if you want to try it first and you know, for example, not a federal package or just member of the community who's not contributed to federal at all you can use copper, which is a community boat service and You can do right now something packages to copper build it and use it by yourself But you can also build modules in copper. So If you have some builds, so if you have some Packages built in copper you can then go to here to modules and you will be able to For the record, this is dead instance. Yeah, yeah in production What's it have instance, but right and There is a bit different approach you just add the packages Before you will build it manually and then it will be able to select which packages you want to include so Then I can select some which will be the API. So for example, I care about just this one Yeah as normal project and copper will generate the module and before you based on this So you can specify the API the install profile for example default So I want to install just this one And I can have more Installed profile for example, I don't know like big one and I can install for example all these three packages and When I click here build module Oh Yeah, I also need to specify the name stream and version name is taken from the project's name Stream is like variant of the of the module. So For example, if I install a module, I will specify name and name and stream so it can be like web server and with this kind of database and this kind of An example, I don't know it can be if it's a one component that can be version If it's something more complicated like lamp, there is no such thing like version of lamp It's gonna be for example Adam's version. So I can just type Adam and Kind of like the major yeah Now I mean do I need to do when I change the API do I need to like bump it or I just change it So I can have stream number two Number one Yeah Yeah, in federalize will be like the name will be taken from the kids people name Stream will be taken from branch and version from the timestamp of the Yeah They can have or I can have Python and yeah Or can or even Python. I don't know 2.4. I buy that 3.6 and this So it's like yeah version of variant and the version will be taken from the timestamp of the build So it should be I guess it should be Automatically later. So Yeah, I just didn't feel these so I just type some version Yeah, it's to be the integer Yeah, I'll get to that So so when I get the module built in copper it will look like this I can open the previous version because it will be already done and It shows me how to install it on my machine I guess the workflow might be be different in the future when we are ready but right now I can test it with this we have a DNF plug-in for installing the modules and Yeah, I will enable the repo and I Can install it and there is the module and D Which I will be able to then take and submit Into Fedora for example if I want the package if I want the module reviewed and Available for everyone as part of Fedora Yeah, it's like upper generated the module and before you so you don't have to write it yourself You can just build the packages select API install profiles and this I Have All right, so that was the copper part and in the meantime we should get this ready on the yeah So this is ready and I should be able to in to see the results. So the results are Are here so I can just go there results something you need to have at least one. Yeah Yeah, for example default, right? I guess this will be also a policy decision or technology decision So yeah, if we decide what called default it will be default. So that's the that's the output What's not still fixed here is this When we build a module you want the RPMs what? Oh, I fixed it today. Okay, so I have an old version several hours old version Yeah Will get rebuilt Yeah Yeah Now it generates a module and he and copy those files to module and he and director Yeah, it's like not ready. So if you open the Directory on back-end there is the great repo for Vienna and module and the director Okay, so when I build package one and three like names And then I create module that they're only two years inside the one you If the one will be missing from the repo even if I build it in the same copper I guess you shouldn't even build the module if you don't have all the dependencies in there Yeah, so then you have to include it right yeah Yeah, so yeah, so You need to include all the dependencies which are not in the base runtime kind of yeah Oh in the future, I guess of course Maybe yeah So yeah, the copper part was like yeah demonstration of the workflow The technical side Yeah, yeah, it will it will give you instructions in the In the module section probably no Yeah All right, yeah But when it's fixed huh Yeah, so you can just All right So yeah, now we have 25 but they're later when it when it's fixed up. It's been already fixed there will be So there will be the module name Stream name and the version Yeah Yeah, but there will one extra step so when we build this module We just know it gets built. It's working at least for the build part. So we will be shipping that putting it into the next state when we Built an artifact that we will actually install so there will be a darker image No, right, yeah, it gets tested and then people to talk to image for example that you can install or even the or even the Repo, but I guess in the f-26 will be just the images, right? Versus repose Repose to yeah Yeah I need for this port and stuff like that. All right, I can show you So, let's have a look Yeah Oh A standalone container with ice in it is not good for anything except building on a container Yeah So Yeah Okay Like the no no no like should you create the basic Yeah, that would be But that would probably case like there will be You probably still have this you have to connect Because there is always Yes, you like it's likely it's likely that you will probably find a use case We want to generate a container for like every module. I was just gonna clarify that it doesn't currently at least Generation of those doctor And if you think about it, like sometimes it may not make sense from an author perspective Like you want to you know, the author needs to be thinking through what their kind of artifact outlets are Well, you need to somehow you need to somehow define The minimum legs to pull the package Yeah, so that we can do it's also but it's also the like What is the what's the module's intent great? What am I gonna maintain that module for right? And the thing is that there are really multiple cases of that So if you're doing a DNS server in a module, you may want to have two containers like if you want the Authority to be in a server of the user interface and a passion DNS server that you can figure that this drops into a system Not just the one-to-one You know it depends on the use case Part of this we're gonna try to capture in like that one's right like to you know, these are the best practices, right? Part of it's just gonna require people to think it through, you know, when you do that, please like what you call Multi-service inside of dinner. Yeah, that's just that you called your system. Yeah, even if it's just one server Yeah, I think that's the path We're Right now we're waiting for the infrastructure, right? So we're kind of writing a bunch of stuff over here that we're not what we need to then plug into the infrastructure one of the plans So there's some clean up Happy But for some stuff for example like web server or something which can run One option is to build Container automatically. So for example The built is then when I submit a module for built it will automatically produce Container with the module without the configuration and without the run statement, etc And then I will be able to use it as a base image To produce even more variants of the container in OSBS For example Yeah Right All right All right Can I have Python 36 module and part of Python 37 module both provided use of in Python Or not not on the same post Like so I do I can like have those module available at the same time Right, but I'm not be able to install them at the same time not as RPS only as containers But if I install them as containers then I require the user of this Python Do you have his application also as a container? Well, yeah In the or on the top of it You have module can your two modules can provide using in Python 36 using in Python 37 Yeah, so I can run it on RPS Yeah, it's no different. We're just encapsulating. You're acting that problem in a different thing, but it's the same problem Yeah, yeah, yeah, okay. I'm just making sure that it's the way I thought it is All right All right, so that was the Building part and We can try to do the I don't know the development part like writing the writing your own module MD But I guess that would be useful for just people who want to I guess help us with For example developing some kind of tooling because right now it would require to get the package query for all the dependencies and Filter all those join based on time So I don't think it's like useful for everyone so Yeah So the building part is like this. I guess that was all Now you have to do this, right? Yeah, well, I can do I Can try All right Yeah, that's it So yeah, when I was building the so right when I was building the module it just took all these Three packages and build them in the based on time build routes and I can see I have Built all the on this one specified. So you would first build these two parallel packages and then These these things Yeah, yeah I don't think it's useful Right, all right, so I guess That was it. So are there any questions or something? And dependency in both If you creating what you want to install as RPMs on the system You need to think about this. So one way to The same situation No, it's the same situation if you want them both run on the same system directly You need to package it in a way that they will install in the separate part. So for example, one of achieving is is No way, this is like an implementation, right? But you can for example the API packages will remain the same but all the other dependencies Maybe built in a way that we installed in a different part Yeah And Okay Yeah One of the reasons why we need to get the size of the base on time right to minimize that problem becoming unnecessary I think there's a difference in the base runtime and the common Minimal install which is small, but there's still to be some things every need they should be available across Some of this gets you into kind of a philosophical discussion about the entity where kernel Minimum space common user space and we have to sort that out What we call is we do have already Getting this company this trade-off right is very much We still have a lot of you to figure out all the options because right now It's actually today really not a problem for it's a challenge that we have to get right if we're gonna start If you so So you have a tree The more If you change the rule and say oh, I want a different g lip see But you did that then like that's great, but every way to run that on the same instance of The system is to run it in a container That's just basically the trade of business if you conflict to high in the tree then parallel or yeah parallel Install of conflicting stacks that will contain us all for us We don't want to force you to contain this but we're gonna apply a lot of the traditional constraints Basically as many to use the hard to use cases which are solved by the containers will solve only with containers We need to get the really common stuff I guess As long as it's easier than our Name the bind truth thing, you know So I guess this was a great Oh We still don't have the base runtime So we can try to I don't know install it in a container, but Yeah, right so we can run DNF install Yeah, pretty much All right, thanks for coming The lighting talks which will be at six at the D rooms and you can check In the application on the website if you click In the schedule on the lighting talks, you will see who is presenting and what


Following the standard group, the one that was just eating the same amount each and every day, a lot of them died, 13 of them died. They stayed an average of 219 days in the hospital. But the other group, just by changing that timing and how many calories stayed one day versus the other, only stayed in the hospital 123 days and he had six versus 13 deaths. I had the opportunity to be at the Personalized Life Extension Conference three years ago. One of my friends, a speaker there, Patrick Friedman, was also talking about intermittent fasting and he said, hey guys, let me ask you, what's your favorite theory of aging? Are we talking inflammation? Are we talking free radicals, instant sensitivity? No matter what your favorite theory of aging is, intermittent fasting helps with that. And it seems true, whether we look at the markers on inflammation, like the TNF alpha scores, if we look at the amount of free radicals that are being created, the amount of oxidative stress, fancy terms, but simply it means, pretty much when we look at the biomarkers, Scholar Tanner was talking about this yesterday, intermittent fasting helps in all those. We look at things like, say, HDL measurements, your good cholesterol. HDL ends up improving with intermittent fasting. Look at stuff with triglycerides. Three weeks of intermittent fasting on men, the triglycerides plummeted. A lot of benefits for not that much work. Same thing when we start looking at CERT-1 receptors. Let me just add pylon. He wrote Eat Stop Eat. He says that if intermittent fasting was a pill, then seller would make a billion dollars and win a Nobel Prize. And frankly, it's just that good. So why don't we hear about it? Well, a lot of times, let's think about it. How much money can I make selling you guys this magic, wonderful concept that, guess what? You don't have to eat as often.  You need to be eating every couple of hours, otherwise you're going to lose muscle mass. I get to sell you all sorts of stuff. I get to sell you meal replacement powders. Get to sell you protein. I get to sell you little boxes to carry your food in in your lean protein and chicken breast. And the thing is, it's not just from an anti-aging perspective, because I'll admit, that's my bias, but it's fantastic from the body composition standpoint. Airman fasting, particularly when he's starking the diet dial down a little, is one of the best ways to really shred your body for that extra bit of fat loss. We heard it yesterday. Abs are not built in the gym. Abs are built in the kitchen. And it's particularly true. So let's talk a little bit about some more of the details. How do you get started? Some of the regimens. The two that I hear about the most are the eat, stop, eat protocol and Martin Birkem and Lean Gaines. Eat, stop, eat. It's pretty simple.  He's usually advocating about a 24-hour period. And that doesn't mean that you wake up in the morning and don't eat all day.  That's now 24 hours of not eating. Lean Gaines ends up advocating more of a 16-hour fasting window and eight hours of feeding. The difference really starts being a question of what your goals are. In case your goals are predominantly like, hey, I want to build more muscle and bulk up, let's say more of a shorter feeding window like a Lean Gaines protocol would work out great. If you're looking more from an anti-aging perspective, I'd advocate up to about 36 hours, so a day and a half of not eating. So how do we get started? We've heard other speakers mention diet briefly. I end up telling people low carb paleo. Let me repeat that again. It's low carb paleo style diet and that low carb is really important and here's why. The thing is if you don't end up eating low carb, let's take a look at what would happen in your body when you end up eating a meal.   Ultimately, your body wants to maintain pretty tight control over glucose levels, so it ends up releasing a hormone called insulin which starts taking this glucose, starts trying to store it. It's basically a storage and growth hormone. So it takes this glucose, assuming your muscle glycogen stores aren't completed, you didn't just work out, it starts trying to store it. So now your insulin levels are raised. Guess what?  It doesn't have any way to do that. So what happens?  Don't do it that way. This is why I end up advocating a low carb approach. When you end up eating low carb enough, your body's mostly staying in a state of ketosis. In essence, your body's burning fat for its energy, not for carbohydrates. And now it means you can go so much longer without eating because your body's using what it should be using for its energy sources. It's fat.