Ynweud nhw'n oedd gennym ni'n gweld o gael gweithio gydyddiannau o'r mynd i gwrthodol, gyda'n cymryd yn cynnwys y lleol y drefprwyl yn hanes Fyryd ffrwyl natrefnt, maen nhw'n ei wneud o'r oed o simbnado'r ffordd 2015. Mae'n gwybod i'n gwaith yw fod yn cael y bydd gyda'r ffordd 2015. Felly rwy'n yn ni'n gallu'n gweld ffordd 2015 i'w gweld. Wrth i yan, os mae ddechrau'r s Puerto가�u ddau, a'r ystafell yn y cyfnod yn y byddol i 1990. Rwy'n dweud yw'r ffactor o'r ddweud yma yw'r ddweud, mae'r ddweud o ddweud o'r ddweud. Mae yma yw'r ddweud yw'r ddweud, ac yw'r ddweud yw'r ddweud o'r ddweud. Felly, y ddweud yw'r ddweud yw'r ddweud, mae'r ddweud yw'r ddod. Mae'r Ues, y ddweud i'r ddweud, The Russians, the Chinese essentially worked with their ideological partners, they supported their development programmes on the basis of their ideology. So aid policy was essentially an extension of political policy. That doesn't mean at all to say that all aid projects were bad, but to the contrary, many of them were extremely good. But the basis for entering into an aid relationship was a political one. And also there were commercial objectives as well. I remember well the 1980 paper when Mrs Thatcher came into government in the UK setting out very clearly that political, trade, commercial and defence objectives were to stand up there alongside aid objectives in determining aid policy. And then the second factor of course is the decolonisation process for countries like the UK, France, Spain, Portugal who had significant colonies left particularly in Africa but also in parts of Asia, continuing their support through maintaining the infrastructure which they had largely been responsible for delivering. So aid policy was about supporting roads, about supporting hospitals, schools, developing the capacity through technical assistance of those countries to be able to continue with that themselves. This was in many ways a good thing to do as those countries gradually took on those responsibilities but was disrupted by the first factor which I mentioned before which is the Cold War. And the 70s and 80s I know people describe as the lost decades of development. That was largely true because what mattered above all was the nature of the political relationship. There is a story. I don't know whether it's true or not of the US Secretary of State taking in an African leader, let's call it Mabutu. I don't know who it was to see the president. And they had a half hour conversation and after they'd had that conversation the American president asked his secretary of state to come in and see him and he said, and forgive my American accent, gee, Mr Secretary of State, that guy was a real bastard and the secretary of state said, oh yes, sir, but he's our bastard. And I think that kind of sets the tone for what aid policy was about. It was about supporting your friends and it was about confounding your enemies. Issues like human rights, how much aid reached the poorest people, really didn't feature very large in that set of equations. Everything changed with the fall of the Berlin Wall at the end of 1989 and driven by the model of Eastern and Central European countries wanting to become parts of the European Union, different factors began to come into play. So those countries who wanted to drive their own development, they wanted better democracy, they wanted better governments, they wanted to take human rights into consideration, became factors for determining whether or not they were able to enter into the European Union. And so in that period in the early 1990s, people began to ask the question, well, if we're having these considerations taken into account in our programs towards these countries in Eastern and Central Europe, shouldn't we be thinking the same way in our aid relationships? Shouldn't we be taking issues like rights into account, democratisation, better governance, all those sort of things, more into account in our aid relationships? And I remember very well running DFID programmes in East Africa in the 1990s. When I went to our regional office in 1993, I think I had three engineers and three natural resource agricultural advisors. And by the time I left four years later in 1997, I had one of each. But I also had these strange new people called governance advisors and social development advisors. I think the only thing that remained constant through this period was the large number of economists. So people began to think about who is aid really targeting? What should aid policy be really about? Who are the people we're trying to reach here? Is it heads of government? Is it ruling elites? Is it governments? Is it the people? And gradually those ideas began to coalesce into the international development targets, which in turn transmuted into the Millennium Development Goals. This audience needs no reminding of what those are, the overall arching goal of having the proportion of people living in absolute poverty by 2015 and a number of subsidiary goals essentially around primary education and basic health. So here we are now 15 years later. The period of the Millennium Development Goals about to expire at the end of the year. Far more successful in making progress towards those goals I think than almost anybody had imagined 15 years ago. Why has that happened? Largely because of very strong economic growth in certain parts of the world, above all of course in China, but other countries in eastern Asia too in South Asia and actually in a lot of African countries as well. So that economic growth has driven progress towards the MDGs. Two or three years ago people started to think about what should come after the Millennium Development Goals and there's been a really interesting process I think, a very consultative process over the last two or three years of thinking about what should come next. And those thoughts and ideas and consultations widespread both within governments but also within civil society have led to this new set of sustainable development goals which will be formally signed off in New York next week where many people in this room will be. Now many of us will have problems reminding ourselves what those 17 goals are let alone the 169 targets that come underneath them but the document transforming our world very helpfully sets out five P's which is the way that I find it quite easy to remember what these sustainable development goals are all about. So the first P is prosperity, economic growth. The second one is planet. You mustn't have this growth whilst destroying the environment on which we all depend in the process. The third is people.  If you reduce the number of mothers dying in childbirth you still have too many mothers dying in childbirth. So it's about those and about thinking about who are the people who are being left behind. Who are the people who have been left out? It's possible to take a very economic approach to that but it's also possible to think maybe disabled people are the people who are being left behind of this. Maybe it's ethnic minorities. Maybe it's the people because of their sexuality. These are things that kind of go beyond economics and perhaps more intuitive. The fourth P and it's very important is peace because I think we all recognise that unless there is reasonable security and peace and reasonable governance in the country you're simply not going to make the progress that you need and then the fifth P of course is partnerships. What does all this tell us then about the exam question that we've been asked which is aid policy post 2015? I think we have to remember that the world is a very different looking place in 2015 from 2000. 2000 the paradigm was still very much about there is a group of developed countries and there is a group of developing countries. There is north and south and it is the responsibility of the north to support the countries of the south in their development programmes and essentially explain to them how they should do it. Although that notion of country ownership was becoming increasingly strong in the 1990s. I think the important thing about this is that those changes need to be reflected in that whole paradigm of aid policy in 2015. Perhaps particularly the changing world after the financial crash of 2008. What we all describe as the global financial crash which I think if I'm right the Chinese describe as the North Atlantic crisis. So the power structures in the world now look very different. The G8 simply doesn't matter as much as it once did. The G20 is much more important than it was. Many developing economies the bricks of course China perhaps above all but India as well. Brazil are developing different sorts of relationship with what we have traditionally thought of as the developing countries. How does that play into the development of aid policy? How are those countries going to feature? What are the experiences that developing countries can learn? Is aid in future all going to be about grant support or are the different mechanisms that we can look at to stimulate South South cooperation? We've always been very against the notion of aid tying for example for very good reasons because that was traditionally used to support Northern companies, Northern goods and essentially to subsidise some of their goods and products. But if China ties at aid is that really such a bad thing because it may help to increase the resources which they're prepared to make available to other countries but the difference between the price of tied aid and untied aid is much lower than it would be otherwise. So those are some of the questions that I think we need to be looking at as we move into this post 2015 agenda. How are we going to achieve this overarching objective of reaching zero absolute poverty by 2030 whatever that means and we've had some interesting discussions about that this morning. I know that some of the economists who I've been talking to are nervous about the STGs because they're not sure which of them are going to be measurable and whether we can really judge progress against all of them. There is as you know a process of defining some indicators which is not yet complete which will be complete by March 2016 some of those will be measurable some of them won't be measurable some of these targets you simply will have to take a judgment about progress but this is why it's equally important to look at the politics as the economics. At the end of this month all the countries in the world will sign up to these new sustainable development goals. These are not just goals for the south. These are universal goals. These are goals which are as binding on countries like the UK as they are on the countries of Africa. This is a compact between governments and their peoples and the fact that governments have signed up to this compact means that the peoples of those countries whether in the UK or countries in Africa have something for which they can hold their governments to account and I think that is a fantastically important development. I think I've perhaps left one or two hooks for the two Richards to hang their comments on about where this all goes in future but I hope that provides a framework within which they can make some of their remarks. Thank you.


Oh You're done. I'm Corbin as with me as always is Rick.  It's brought to you by one of our patreon. Thank you. Thank you so much to everybody Yes, yes, yeah a certain tier you are allowed to pick Anything something you want us to react and we will react to it. So this one. I'm glad he suggested it because it looks quite interesting It's Amir Khan's most exciting and extreme stunt. Now. Let's talk about stunts for a minute here first of all Does he do his own stunts all the time when he does stunts? No, so this guy gave me a little background. All right What's the story about the stunt work here? Stop, Sev. Yeah, it's my dog. It's his dog And then now they're like we want to see your dog. This is a scene Doesn't play a major part in the film However got famous for all the wrong reasons Amir Khan performed the stunt by himself and got really famous for stupid people Have actually hurt themselves while trying to replicate this stunt Well, that's like people who hurt themselves after they watched us eating Hajmala Hurt your colon Amir has lately told publicly that he was foolish of him to try the stunts. Okay, I can't wait to see this thing Oh, I don't know what it is. It's from a film that we have not reviewed the trailer for you. Okay It involves a train He's gonna do it for the girl And just show the guys you can do it I know I know look at him Oh, yeah, go get it Amir. What's he gonna do? I don't know. It's gonna involve a train. He really does It's gonna involve a frickin train. I I Didn't expect that He's not gonna make it There's another train gonna come like right after that train because I don't think that's realistic He's not gonna make it. I can feel it in my bones. Oh, oh, that was see that was like grease, too But we've already gone past the stunt obviously Charlie's not gonna make it was the second stunt also as equally what we saw where he had to go and pull him before the train There were two stunts there. Yeah, so I'm guessing he did both and the second one's a little bit dicier Well, because you have to pick somebody up and he could trip or the dude on the ground is like that was dicey right there Now that I got to be honest that first stunt didn't really Deliver what I thought it was gonna. Yeah in terms of me being mind blown I'm guessing it's because he actually did it like he was running at the train right and obviously that's idiotic. Yeah It's not a crazy thing to do. Yeah, but I was anticipating you know I was anticipating kind of the same kind of things that Tom Cruise does. Yeah Yeah, yeah, it isn't saying you shouldn't do that. Yeah, no, please And so I think there's videos on YouTube of people trying it as well and I don't know I think that goes against YouTube's terms and Conditions true, but it could be that there are reports of people who did this and didn't make it It's just like the people with bird box Oh, yeah, all the people watch bird box on Netflix and then they started doing all these things where they like are driving Their cars blindfolded guys guys.


Welcome to the journey! Today we're gonna talk about how to time block your calendar so you can get more stuff done. Remember when multitasking was all the rage? Yeah? And you know you thought, hey I'll multitask, do a little bit of this, do a little bit of that, I'm gonna get so much done and it's not the case. Not at all. And actually multitasking has the opposite of fact. You take away the momentum of actually getting things done when you switch tasks and it's not going to be as efficient as just sticking to one thing. So one way I combat this is through blocking off time in my calendar. This is really going to reveal the nerd in me, but I also color code it. So do you want to know about it? Sure. Okay so I think about my day from like 8 30 a.m to 5 30 and I think about what's urgent. If it's urgent I color code it red. If it's a meeting I color code it green. And if it's like this should happen today but like if it doesn't get accomplished today NBD blue. And then from there I do little time blocks at certain times a day because in the morning my brain works differently than the afternoon. So maybe writing a webinar script, block off two hours for the afternoon whereas in the morning I would do something else like create social media slides. Like a little bit more vibrant cup of coffee creativity. Interesting and I like how you mentioned certain times of day because I know some people work better at night. Others work better in the morning. Myself I am a morning person. Give me the hardest things I need to do. Get that done first early in the morning because after lunch like now I'm not feeling too enthused to keep up. But I do the same thing. I do block off some things on my calendar. I am all about technology so I use Google. Google calendar on my phone. You may, some people may find it easier to just use a actual tangible calendar where you just write it down and you have to remember to look at it. That works for you? Sure. Another great thing about time blocking your calendar is it helps you from overbooking yourself. You can really stay structured with your time. I even include a lot of people don't do this. I feel like but in my work calendar where I just told you about the color coding and the time of the day I also have for the color orange my social life because you guys do balance whether that is the work that you're doing or the social life that you're leading or your exercise schedule. So I literally block off time for all of those categories. And I do the same thing. Like when you say exercise in the morning I'll have a little block where it says hey you got to get up 6.30 or so. Get your exercise in. I've been working out my eyes closed. I'm getting back to it. If my wife is watching I am getting back to it. But things that you actually schedule so that you know hey I'm going to take this time for me self-care. My wife is big one telling me about that. It's important just like Emma said good balance. You can't just be about work work work work work and you have not so much left in the tank to keep giving out. And it's a commitment too I feel like if I say I'm committed to getting this work test done today at this time it helps it's that extra step of commitment. Same with I am going to go to yoga at 6 a.m. tomorrow. Another cool thing about time blocking is it makes tasks harder to ignore. Say you write things down and you have all your tasks in a list. It's easy to jump around in that list and say oh I'll do this one then I'll jump to this. But if you have that specific time blocked off for that one task you know you're going to be dedicated and focused to it and you'll be so much more efficient. Treat the task like you would a meeting right. This is a time don't be late and wrap by the end of the hour. And it's funny because you wouldn't be in one meeting and say hey by the way halfway through I'm going to take this other meeting. Y'all just hold on. I'll be right back. You wouldn't do that. Alright so we're going to tell you how to get started. First evaluate your task list. I think this is really important because it can help prioritize what you do. Also think about how much time does this task take first this task as well. And then also what's more important like in a week I know I'm like I have got to get these tasks done by Tuesday or by Wednesday and that really helps me to prioritize and then also like we talked about a bit ago what do I how do I perform in the morning with certain tasks versus the afternoon versus the evening. And also sometimes it's better to get those harder tasks the ones that you may not enjoy out of the way out of the way first. And like Emma was saying if you work better in the morning like myself get that hard task right there a.m knock it out so that the end of the day you can take that momentum of actually accomplishing that and going to your other task. I had this friend who brought up recently she's like do ever just put tasks in your calendar that you know you can get done that day just so you can delete it and feel really good. I was like do I maybe I do do that and then I noticed that I do I add things in there that are just like get me started in the morning where I'm like oh that's done I want to roll. So think about the time of day when you're actually blocking off the time for the task because that's really important with you know what makes sense does it make sense to maybe start your day with Pilates and then go into your work day depends where do you need to be do you need to be across town for a meeting logistics matter or are you going to have a zoom call that's a big one for me like if I have to be on video I'm not going to go do work at the coffee shop today that's just annoying.  Yeah so think about what that is you need to be done where you need to be for it and then what comes before and after. So all of this is good at the same time you want to be able to be flexible so it's good to have some checkpoints some review time to see how things went or during your day or during the week and see how you may adjust it as you go along because you don't want to be so rigid and set in stone to where you can't be flexible.  And it's also good to have that kind of communication with your customers it's okay to say no in my role in customer success dealing with client facing interactions I have to tell customers at times I don't have time right now but I do respect your time and what you have to get done is important to me so let's do this I have this day and this time or this time available which one is good for you that just shows that you do respect their time and you do want to make that effort to take care of whatever their concern is that you respect your own time exactly I mean that was a big thing I know as on sales for GoDaddy is they were like you know don't just say you're available anytime that comes off to a prospective customer like well what do you have anything else to do you know nothing else to do yeah but if you show hey I got you know one o'clock or three o'clock today what works best for you you just learned how to time block your calendar so you can get more stuff done comment below like this video and make sure you subscribe to our channel and ring the bell so you're first be notified when we have new content coming out this is The Journey see you next time


The FEI Titan G280-200 Krulli is a powerful transmission electron microscope capable of investigating a wide range of solid-state phenomena on the atomic scale. It features a shocky type high-brightness electron gun, a CS probe corrector, an in-column SuperX energy dispersive x-ray spectrometer, a post-column energy filter system, an angular dark field scanning TEM detector, on-axis triple beam detectors, and a 4 megapixel CCD system. This instrument can be used to study materials such as semiconductors, nanostructures, thin films, and other materials with atomic resolution. This article was authored by Andres Kovacs, Roland Schierholz, and Karsten Tillman.


so the time of it is really sure I think I think that you know we these days people need it like so small to be digestible or you know they'll lose their interest there's something really quick yeah so that's why I'm doing one problem one problem one problem you know yeah yeah it's almost better than some people all of them be that for them yeah and they'll be like oh I have to sit there are three these three problems to do this okay so let's do this next one one million argon atoms is blank moles of argon atoms okay so you know already right what how many one mole is right how many things one mole is how many is that talking about the I've got his number you're 6.00 to 222 222 23 remember I told you that's just it's just like saying if you think think of this is like to chemistry then you're losing the battle with chemistry you know what I'm saying it's like you saying like doesn't only is talking about donuts I cannot apply that to eggs you know what I'm saying yes so I can have a dozen eggs I can have a dozen donuts I can have a mole of donuts eggs anything so okay so this is just whatever items you know it's just one big number yeah it's just a huge frickin number you know that's it in this case since we're talking about argon atoms what we really should write just to be not confusing is to say one mole of argon atoms right equals 6.0 222 times 10 to the 23rd argon atoms does that make sense okay so that's the best way to and then we know it says one million argon atoms is the number that we have so the number we have of argon atoms is one million so one that's written now so what is that I guess they want this to two sig figs okay so whatever only reason I know that is because we've got a number of argon atoms and we've got a way to convert that number to moles so that's all we need to do you know so how many moles do we got moles okay so we go one mole so our one million and you want to get argon atoms out of there right so one mole of argon atoms equals 6.0 222 times 10 to the 23rd argon atoms argon atoms cancel out and you're left with moles of argon atoms all you got to do is so would you expect this to be a number smaller or bigger than one just looking at it straight away so this is like 1.0 times 10 to the 6 right this is 1.0 times 10 to the 23rd it's gonna be bigger right well is this so this is dividing by this one this one's big and this one's small so that's like saying a small number divided by a big number is that bigger or smaller than one that's bigger this number is bigger or smaller than one no that's smaller okay I'm not don't make me get my orders out again okay so whenever you see a big number divided our small number divided by a big number right this is much bigger than this right this is six this is 23 right it's gonna be less than one okay so if your answer isn't less than one you've done something wrong okay so that makes sense okay so one million she wanted to do 100,000 divided by we stick it with three six fix let's see the answer is gonna be in two six six yeah that's the so our options are either one or two six fix and I from the answers I would assume that it's going to be 1.7 times 10 to the negative 18 yes are gone are yeah all those is that numbers bigger smaller than one that's smaller how do you know that negative on the 18 so you want to always check yourself right before you go on to the next problem so if you get something that's like to the 23rd or something like that doesn't make any sense you know this isn't even one mole right yes one mole is this many you know so this is 1.0 times 10 to the 6 that's not that many right that's not even close you still got to multiply that by almost four to get that right yeah okay so you want to think about it that way go with that one


Get out of my game! Woo! Get out of my game. I love making them quit. We got this guy shook right now, champs. We got this guy shook. There it is, man. Jesus. Got to do tippy-tap toes, man. Little tip-taps everywhere. Ah. All right, Ronaldo. Feels good to be the best. I got to press this button. I got to press this button. I got to press this button. I got to dial this thing down. I got to pull these knobs down. I got to calibrate this one. I got to press this. I got to turn this monitor on. I got to type in a code. Nice ball over the top to chase. Still possibilities. That's just, that's this beautiful touch, man. It's all starting to come back a little bit. Just a tad.


I will try to give you an overview of the current state of structural bioinformatics and specifically in what we are doing right now in my team. As most of you may know, we just had a revolution in structural bioinformatics. It all started around CASP 13 with a few models including Alpha 41 and around CASP 14 it became very clear that the problem of protein structure prediction is essentially solved. So what you see on this slide is the accuracy of structure prediction with respect to the difficulty of particular targets. Difficulty means if we have structural templates in the protein data bank or not. So you may see even that even without the templates, the accuracy of protein structure prediction became a near the experimental. This is measured in very strange units which are global distance test but the accuracy of 90 corresponds to about one 1.5 Angstroms of RMSD from the crystallographic structure. So these are very well known examples from DeepMind to targets with near experimental accuracy. And why did it happen because of multiple developments mostly in data science area. And if you'd like to learn more about the progress which led to these discoveries we co-authored as a review for the special CASP 14 issue in the proteins journal. So this was during CASP 14 which was already two years ago and we just had to the conference for the CASP 15. So the differences you may see the slide from Dan Rigden who was the evaluator of the protein structure prediction during CASP 15. And you may see here that the most of the top performing methods were used in one or in other way alpha 42. So it's still alpha 42 which dominates protein structure prediction. The best to the top rank non-alpha 42 method was the one from David Baker's team here somewhere in the middle. And very interestingly we had multiple models that didn't use multiple sequence alignment at all. They were based on protein language models based on a single sequence. But unfortunately these methods so they are marked in violet. These methods are not yet performing so well. Okay, a bit of history. Why do we need, why do we care about protein structure prediction. So protein structure is rather simple because most practically structural databases contain only about 0.1% of proteins discovered across life forms. The protein structure prediction problem became known and popular quite a while ago and the first attempt to predict protein structure started back in the early 70s. There were multiple attempts using molecular dynamics or Monte Carlo simulations but we had to wait until 1998 to see the first truly nearly one microsecond long molecular dynamic simulations of a short peptide. It was conducted by Peter Coleman and it took them two months with fully occupied to craze to the computers. And it was not a true protein it was a 36 residue short peptide. Shortly after, many more folding molecular dynamic simulations followed, including all different types, for example, GPU accelerated simulations and also simulations using very specialized hardware. But very interestingly, the success in protein structure prediction didn't come from molecular dynamics. So let's look at the problem of protein structure prediction from a different angle from a slightly different angle. We may notice that the shape of a protein is preserved much more than the sequence. For example, in this slide you may see that all different but homologous sequences would result in nearly the same three dimensional structure. This motivated the researchers, the researchers to use so called homology modeling. So we may model new proteins by comparing individual sequences we may model proteins, comparing the multiple sequence alignments also called profiles, or we can also substitute three dimensional fragments for homologous sequences. For example, if we look at the sequence profile a bit closer, we may notice some conserved regions so they are marked here and also regions that would co evolve together. It turned out that couplings between the square wall position myself as a very good estimate of 3D protein contacts. To estimate these couplings were made in the early 90s followed by routine estimation of protein contacts with the developments of so called thoughts or direct coupling analysis models. In these models, the probability to observe a certain sequence depends on the conservation coefficients and the coupling coefficients. And these coefficients can be estimated from the sequence profiles. Later on around CASP 13, these models were additionally supervised using deep learning by the observed protein contacts, and in the last generation of structure prediction models. There is no any statistical model at all. These models would use the multiple sequence alignment directly and to estimate protein contacts without any statistical models just using deep learning. So, we believe that the classical protein structure prediction problem is essentially solved. But there are still many developments around protein representations. There are many more exciting developments in using protein language models and also applying protein language models and co evolution models to other types of molecules for example to RNAs and DNAs. We also believe that molecular dynamics will be used in some areas less specifically for protein structure prediction, but the so called protein coding problem and also involves protein kinetics, and the structure prediction problem is not the holding problem so holding connected ticks yet has to be predicted. There have been some progress specifically around CASP 15 around protein docking so there have been many attempts to predict it at a much higher accuracy. And we still need to predict protein multiple states and protein flexibility. Then, we need to predict or simulate protein behavior at physiological conditions. And finally, there are many exciting developments around the inverse problem, the protein design so if we know a certain shape, which serve a certain protein function then we can design a specific sequence that would fall into this three dimensional shape. And these are the current exciting developments in this field. So, I will start by introducing the algorithms developed in our team around protein interactions in solution. We've been interested in protein, protein, protein ligand interactions for quite some years, and we've been specifically interested in symmetrical assemblies. And we care about protein symmetries because most of the high order assemblies are symmetrical and if we look into the protein data bank we will see that about 30 of the assemblies are would satisfy, would satisfy some, some type of a point group symmetry. So we introduced a specific formalism based on rigid body operators that would include rotation translation and symmetry operator. And so we designed an exhaustive search algorithm based on these operators, we would project all of these operators into the free space and we demonstrated that the shape complementarity or the docking score can be formulated in the free space using all the symmetry constraint constraints implicitly. And this allowed us to exhaustively sample all possible symmetries in just a few seconds on a personal laptop. We can formulate the dual problem. If the protein assembly is known, for example, if it's solved by its recrystallography or cryo microscopy, we can basically look at the same problem and the estimation of correspondence of one unit with respect to another unit. Here, however, we would know in advance the rotation and translation operators, and we can estimate the symmetry operator. So this problem can be solved analytically with respect to the best matching, meaning that we would estimate the best rotation and the best translation for each of the symmetry axis. And the estimation would give us a list of all possible symmetry axis with their accuracy. We have also developed, I believe, the fastest calculation of small angle. We have the sketching profiles, both for x-rays and for neutrons, which is based on the past multiple expansion, which scales linearly, linearly with the size of the system. So in this example, I simulated the sketching profile of the largest particle I could find, which consists of 160,000 of sketching centers. And the whole simulation of the sketching profile takes only about three seconds on a personal laptop. So the speed and also the accuracy of the model allows to interactively refine the molecular shapes. And here you can see a couple of examples of the shape optimization, which was also a part of the CASP 13 exercise, where our model performed the best. Finally, the same rigid body formalism can be combined with the small angle sketching calculator. So we can analytically apply rotation and translation, rigid body rotation and translation operators to one of the partners. For example, to simulate a protein, sorry, a sketching profile from an assembly. So we can apply the rotation and translation operators to one of the partners, so we can project it into the free space, and we can apply some additional averaging to obtain the sketching intensities. This, for example, allows to scan many thousands of docking solutions very rapidly. So it takes about one minute to scan 100,000 of docking solutions. And if we look at the performance on a standard docking benchmark, we see that docking with respect to the sketching profile provides a much more success rate compared to only the energy based docking. So this is one of a particular examples where the energy based docking does not really find the right solution. So if we look at the RMSD to the solution with respect to the classical Z-Dock energy, there is no funnel. So if we zoom in, we see that there is no correlation between the predicted docking energies and the distance to the crystallographic solution. But if we do the same experiment and measure the accuracy of the sketching profile, so the chi-square to the experimentally measured profile, then we may see that the correlation of chi-square with respect to the distance to crystallographic solution is much, much, much better. So in this case specifically for some elongated shapes, SUCKS or SUNS profile can be very good proxies of the right docking positions. And which exactly the same formalism applying rigid body transformation to the sketching particles can be used to analytically compute protein, crowding or aggregation effects. The formalism is absolutely the same, but then we apply some additional averaging in the angular space which allows to analytically treat structure factors for complex particles and this allows to analytically compute crowding effects. Here you may see the sketching profile for a single particle in black and for a particle with crowders in purple. And finally, recently, very recently, we have extended the same formalism to simulate crowding particles. Altogether, so this was our first attempt towards self-simulation. What did we do? We have pre-computed individual interactions of crowders with respect to each other using the fast Fourier transform, and we used this pre-computed energy in a Monte Carlo simulation. These allowed us to perform very fast simulations on a personal computer which scales from milliseconds to seconds. And there are many more extensions of these simulations, for example, we're planning to also run Brownian dynamic simulations, and we can also do sequential or replicate change simulations. So in the proof of concept experiment, we simulated several systems, the largest would be composed of five different proteins, and this was our simulation box. As you can watch, the simulations allowed us to measure, so they allow us to measure, for example, the diffusion constant of one particle with respect to the concentration of the particles and the simulated values fit very well with the analytical predictions. We also measure the diffusion constants with respect to the volume of the particles. So these simulations didn't follow the analytics that well, and we're currently trying to extend the model with more physics. The method also allows to run many more simulations at different temperatures and different concentrations, so here you may see the evolution of the energy of the system with respect to the temperature at different concentrations and you may clearly see the melting temperature or we can measure the same way the diffusion constant with respect to the temperature and again, here you may see the melting regime. So these was the proof of concept study and currently we're extending it by adding hydrodynamic interactions and also flexibility because so far all our particles were rigid. So let me switch into protein flexibility. Why, why flexibility because proteins are flexible, and many of them perform their function by interacting with other partners. So flexibility can be very efficiently simulated by adding just a few additional collective coordinates or degrees of freedom which can be computed using molecular dynamics, or the so-called normal mode analysis. So why is it interesting, because we can explain experimental observations, for example, my colleagues have measured by x-ray two structures of a membrane complex, one in the active, and the other in the non-active forms and the normal mode analysis allowed us to simulate the rotation from the non-active to the active state using just a few collective coordinates. So here you can see that these collective motions involve a rotation in the membrane patch and this is a light motion in the extracellular patch. So what is the normal mode analysis and how is it linked to molecular dynamics, both technique aims to solve the Newton's equations of motions. And what normal mode analysis is doing, each assumes that our system is not very far from the equilibrium position and the potential energy in such an approximation can be expanded into the Taylor series. The first derivative vanishes and we can very efficiently represent the potential energy using just the second order term which is also known as the Hessian matrix. Now if we plug this back, it turns out that we can solve the Newton's equations of motions analytically, and we get the transition from the so-called normal space into the Cartesian space using a linear transformation, which is the diagonalization of the Hessian matrix, which has links to the very popular technique currently in tri-electro-microscopy, which estimates the latent variables for reconstruction and conducting the spectral heterogeneity. So if we look into cryo-spark or cryo-dragon, they both currently estimate the encoder part and the latent variables, or the latent variables would correspond to the normal space and the encoder would correspond to the linear transformation from the Cartesian to the normal variables. The idea, very frequently, the normal mode analysis is not performed on a very sophisticated force field, but in many practical applications we can use a much more simple model, which very often is the elastic network model. The idea is that we can link all our atoms or residues or bits or particles by harmonic springs. And in such a model, we will have only a single adjustable parameter that will be the cutoff distance at which the particles or the atoms are linked together. Historically, there was a bottleneck, how to diagonalize large matrices, how to arrive to the linear transformation from the initial space to the normal space, there have been many different approaches proposed. And one of the most successful was the cost-growing technique, where we would split the initial system into a set of rigid blocks, such that each rigid block would contain only six independent variables, three would correspond to rotations and another three would correspond to translations. And effectively, the diagonalization problem will be simplified because we will multiply it by the transformation from the initial space into the rigid block space that would produce a much smaller rigid blockation, which is much faster to diagonalize. Our contribution to this field was to notice that diagonalization in this space also leads to the estimation of angular and linear velocities applied to each of the rigid blocks, which allows us to effectively extend and extrapolate the motions to very large amplitudes. So here on top, you may see the classical normal mode analysis where at large amplitudes, the initial protein structure, well, actually it's a complex here, is very much distorted, and if we apply the non-linear approach, as we do, then it can be extrapolated to very large amplitudes without the distortion. Also, our method is very CPU and memory efficient. We can simulate very large structures at nearly interactive rates. So we can simulate the largest ribosome complex that I could find in the protein data band. And this simulation took me about 10 minutes on a personal laptop. So, how can we use this technique? There are many possible applications. For example, we can interactively flex the initial systems. We can open binding pockets. This is an interactive simulation that allows the user to open a pocket of a protein. So what do we do? We compute the normal modes, some of the lowest normal modes of the protein alone, then we specify automatically or by the user a possible binding pocket. And after we project the pre-computed normal modes on the pocket, and the algorithm estimates the best combination of the normal modes that would deform the pockets the most. We can also computationally simulate large transitions, for example, from the unbound to the bound state. So this is a classical protein-protein benchmark, where the goal is to predict the bound state if we only have the knowledge of the unbound protein. So here we show the success with respect to the number of normal modes involved. And we may see that if we use only 10 normal modes, then we can simulate about 35% of the transitions. In some cases, just a single mode provides already a half of the required transition. For example, this particular case shown on the next slide, here a single mode can very accurately simulate the transition from the unbound red to the bound blue structure. On the right, you may see another example where, again, just a few normal modes can predict the normal mode analysis is the estimation of the protein-riching domains. So what do we do? We compare the flexibility of different parts of the protein and then link those parts that behave similarly together. This allows us to automatically identify rigid protein domains, and we can also compute normal modes in the rigid domain approximation. So here you can see the estimation of mode one, mode two, and mode three for membrane protein in the approximation of seven rigid domains. I must say that by default we're using the elastic network model, which has specific limitations. For example, if the elastic network is too dense, we cannot easily simulate large structural transitions. We are trying to find walkarounds about this problem. For example, what we have recently introduced was an automatic removal of some of the artificial links in the elastic network model. And so these links are detected from the contact map as those unconnected patches, and if we remove them, then the success to generate large motions is much higher compared to the original elastic network model. And finally, there is a very nice analytical connection between molecular dynamics and the normal mode analysis. This is known as the quasi-harmonic approximation. For example, if we know a molecular dynamics trajectory of a protein, so here it was a coil-coil system simulated with a very sophisticated coarse field with explicit water for about one microsecond. And having this simulated trajectory, we can apply and talk with the principal component analysis. And what you see on the right is the principal component one and the principal component three, estimated from the MD trajectory. The MD trajectory took us about 60,000 for hours. So here you might also see the normal mode analysis from a static structure using the elastic network model. Essentially, the motions are the same. So here you may see normal mode one and normal mode three. So the first mode is bending motion. The third mode is a twist motion. So this estimation is much, much, much faster. So this estimation took me less than one second, and the speedup is 10 to the power nine times. So one of the take home messages is if you're only interested in near equilibrium dynamics, there is no need to run expensive molecular dynamics simulations. The normal mode analysis can do it much faster with the same accuracy. Another message is that there is a nice connection between molecular dynamics and the normal mode analysis, and if we know estimations of the poses we can also compute the normal mode subspace, which brings me to the last part of my talk. Thanks to the elixir European project with many European partners with the aim to chart and analyze the structure heterogeneity in the protein data bank. The project consists of three different packages. So in the first package, the goal is to cluster similar structures by sequence and by structure. In the second package, we aim to characterize all types of flexibilities. And in the final package, we aim to provide biophysical and functional characterizations all the absorbed flexibilities. We already compiled a master benchmark from what is observed in the protein data bank, starting from very simple cases where all the protein chains can be clustered to just two stable clusters such that the structure heterogeneity can be effectively described with a single motion One PCA or one normal mode is sufficient to cover 95% of the absorb structural variance. We have more difficult examples where three modes are sufficient, or even more sophisticated cases. For example, in case of car modeling we have about 500 different protein chains in the PDB and we need about 15 principal components and modes to explain 95% of the variance. So we may have even more difficult cases where many more components, many more modes are needed to describe the structure heterogeneity. And finally, we are using this benchmark to learn the linear and non-linear motions observed in the PDB. Another idea is that all the observed protein conformations can be mapped to linear or non-linear but low dimensional manifolds. And having several states, we can compute some linear or non-linear transitions from one state to the other stage. Here is an example of the ITPS cluster. If we compute linear transitions from start to the end, all the atoms, all the residues will be moving along straight lines. But if we try to estimate the non-linear transitions, non-linear manifolds, the atoms will be moving along the curves. We do we aim to to estimate non-linear transitions because watch our experiments demonstrate us, the linear transitions are often not sufficient to interpolate or extrapolate the motions. For example, here the goal was to estimate the motion manifold based on two unconnected clusters and then to predict a structure which lies somewhere in between. So if we use just the linear interpolation for one cluster to another cluster, then the linear PC reconstruction would be situated rather far from the intermediate structure observed in the protein data bank. However, if we assume that the manifold is non-linear, and we would use only two distinct clusters for the estimation of this non-linear manifold, the estimation of the intermediate is much, much better. So this is still work in progress and on the next stage we will do the same experiments on the whole protein data bank. This is my time to draw the conclusions. So protein structure prediction problem, the classical protein structure prediction problem is essentially solved. But this is far from the end of the structural bench mathematics. There are many new challenges, which include prediction simulations of proteins in solutions. The interactions with other proteins with DNAs RNAs and small molecules. Similarly, simulations on the whole cell level. And from our experiments on the structural heterogeneity in the protein data bank, we may conclude that learning motions from experimental structures are definitely possible but tricky where very often pro to overfitting. On the next step, we aim to learn the motions on the whole PDB ones. So if you're interested in our software, we have many packages on our team's website and also our server that simulates sketching profiles from x-ray. And from New France and also it allows you to do flexible fitting of initial models into the sketching profiles structures. And finally, I'd like to shamelessly advertise the upcoming workshop on interplay between AI and mathematical modeling the post structural genomics era. So we still have a few slots available. So if you're interested, please contact me. And I'd like to thank my collaborators. Hello delaying publisher complementary knowledge and share my students. And thank you very much for your attention.


signal gasoline let every traffic signal remind you you do go farther with signal gasoline yes you do go farther with signal the signal oil company and your neighborhood signal dealer bring you another curious story by the whistler tonight murder will shout the whistler and I know many things for I walk by night I know many strange tales hidden in the hearts of men and women who have stepped into the shadows yes I know the nameless terrors of which they dare not speak murder is born in many places most of them quite ordinary sometimes it's born in a smoke-filled hotel room sometimes around a nightclub table but more often it begins in a small secret place because murder is a secret thing at first take for example a small unobserved telephone booth in the back of a chain drug store the one in which a small-time racketeer peanut marola is talking yeah yeah I got all that dope it shouldn't be a tough proposition to swing the garage is out in the suburbs in the Oakdale district where the houses are far apart and everybody minds his own business nice place to work but said yeah yeah this guy who owns the place George Kramer is single lives by himself out in the little house on 71st Street yesterday I counted only three cars that stopped in that ain't enough to buy him a good breakfast right now the place is plenty big but empty hey here's an interesting angle I got on it seems that some small-fribe businessman named Albion if I got the jerk's name right he's got some kind of a mortgage on the place it might give us some trouble yeah yeah I'll get busy on it now call you when I got something definite don't worry it'll be easy picking yes that's the way murder is born in an ordinary way nothing unusual about it a small time racketeer makes a phone call to talk over a business deal and that's the beginning maybe if George Kramer had known things might have been different but he didn't in his little garage in the Oakdale section he was sound asleep slumped in his office chair Kramer Kramer wake up what's that oh Mr. Albion you were asleep asleep in the middle of the day how do you expect to make any money like that well Mr. Albion I was up half the night last night doing a hurry up ring job on an old school never saw an old small be last night and the last ring job you did was probably six months ago probably out carousing around last night now you know I don't go out nights Mr. Albion anyway you haven't got a single car in your garage to work on and you fall asleep in the middle of the day because you're tired why don't you go out and stir up some business hello care Mr. Albion you stick to your business and I'll stick to mine right now this happens to be my business I'm trying to tell you the things are tough in the garage business these days look you know I'm having a tough time of it why do you come in here every day and burn my ear can't you leave me alone I'll leave you alone for the next week but let me give it to you in black and white I've loaned you in various amounts a total of two thousand dollars which is more than I've come to think this place is worth you agreed to pay it back with interest of course one week from today you owe me two thousand dollars but what I thought you were going to carry it along until I get back on my feet I've been waiting six months for you to get back on your feet and you show no signs of ever making it oh I'll pay the interest I'll pay it faithfully haven't I always paid what good is the interest if I lose the principal or you you won't lose it honest Mr. Albion I promise you you won't lose it I think I've already lost it unless I can do something with this garage myself all I have to be going along now I have business to do I'll see you in a week Kramer wait a minute you you wouldn't take the garage away from me wouldn't you you've got a lot of money you you don't need it that's beside the point a debt is a debt but what what would you do with the garage if you haven't I'd sell it to someone who could run it profitably oh you wouldn't I'll be back in a week have some money for me Mr. Albion yes I I could kill you with a prologue of tonight's story murder will shout the signal oil company brings you another of the strange tales of the whistler but first I know you whistler fans will be interested to hear of the growing popularity of this program the whistler is now tops on the coast the latest program popularity survey of all radio program shows no other single Pacific Coast program has more listeners than the whistler yes people do know a good thing when they see it and when they hear it too and that goes for gasoline and auto lubrication too for 14 years so many drivers have been switching to signal products that today signal dealers serve six western states from Canada to Mexico but what's of most importance to you is the reason for this swing to signal what the signal products and signal dealers have that accounts for this growing popularity well throughout 14 years the name signal has stood for the absolute top quality in gasoline and auto lubricants even now with certain ingredients reserved for war signals famous go farther gasoline is still the finest gasoline that can be made today with the emphasis still on mileage and experienced signal dealers being in business for themselves have a real reason for giving your car more thorough more conscientious service that will keep you their satisfied customer there you have it two genuine reasons why signal service cars do go farther two reasons why when today's cars must last out the duration your neighborhood signal dealer is a man you should know to and now back to the whistler murder gets its start in simple and ordinary way for instance this murder in the heart of George Kramer and once the thought occurs the next step is easy if the opportunity presents itself and in this case it does very soon and in the person of peanut Marola you George Kramer that's right something wrong with your car I can fix not exactly got a couple of minutes time is all I've got good mind if I sit down well what do you want I want to talk over some business oh well and sit down sit down by all means thanks things kind of tough in the garage business these days oh they're not what they used to be but I managed to get along but not in the way you used to get along hey not exactly look what are you getting at can you use a little ready cash no references cosigners very little collateral who couldn't on those arrangements my name is Marola peanut Marola I'm glad to meet you now where does this ready cash come in you sound like a smart man Kramer mind if I talk turkey oh go ahead I can't lose anything listening is mr. Albion been bothering you lately how'd you know about him and I kind of looked into things and found out that Albion holds some kind of a mortgage on this place that right that's right how much $2,000 it's a nice little sum keeps you awake nights doesn't it awake at night and asleep in the daytime and if you want to let me I can fix it so you can sleep at night and spend your days buying expensive clothes what sort of a proposition is it if you hear the black market you mean where you buy meat without giving any ration points now the black market in automobiles I didn't know there was one well there is and it's big time and there's big money in it oh where do I fit in now look pal you have a nice big garage in a quiet neighborhood where nobody bothers you we get the cars as any way we can and then we sell them for anything we can get and it's always a lot we need some place to keep them until the soul you just want to store them here sure it's a cinch a guy drives into your garage with a car and ask you to fix it up see when it's ready the same guy calls for it again looks like a legitimate business nobody knows that anything out of the ordinary is happening or how much fixing up is there to do and that much it changed a few numbers switch a couple of wheels and maybe splash a little paint on them what about the police nothing to worry about pal when they get suspicious we just moved to another garage but while we work here there's plenty in it for you how much a hundred on a car good enough sounds too good to be true is it a deal it's a deal if you advance me two thousand dollars to pay off Albion with this is strictly a cash and carry business chum we don't advance nobody nothing well then it's no go in a week Alvin will have this garage and you will be able to use it yeah getting tough on you yeah we wouldn't want our plans upset now would we pal there's a cheaper way of paying off the debt than by me giving you the money yeah how simple maybe Mr. Albion just disappears someday do you mean yeah sure oh oh no no I I couldn't do that now maybe you won't have to maybe we'll do it for you you'll you'll do it for me sure my business is nothing to it and all your problems would be sound well I don't know but well if I said okay what would we do first well the first thing you do is just so that we can sort of pass a buck back and forth in a nice way you understand in case somebody starts poking his nose into our business we've got to have at least two partners in this garage what do you mean well what I mean is this you got to make me a 50-50 partner in this business establishment you mean you want me to sign over half of this garage to you that's the idea on our way wait a minute I'm not getting into anything that's going to end up with me losing this garage no sir all I want to do is make some money and in a hurry now if that's what you're in slow down Kramer don't get all excited nobody's trying to cut you out of your garage this business the more partners you have the better it is I'm not going to move in permanently soon as the racket wears thin we dissolve the partnership and the garage goes back to you oh well in that case everything's all right I'll make any sort of an arrangement you want I thought you would well I'm going to skip downtown I get in touch with a mouthpiece who will draw up the papers I'll bring him back this afternoon for you to sign see you later Marola just a minute yeah aren't you forgetting something forgetting what mr. Albion well what do you know I almost forgot about mr. Albion well don't you worry pal we'll take care of him in due time look I know you know your business but I know mr. Albion I've been doing some thinking I've got an idea yeah okay spill it well this guy Albion has a lot of money but just the same he's too tight to buy a car of his own so he always rides the bus everywhere he goes now the end of the Oakdale line doesn't quite reach his house and he has to walk a half mile along the highway from the end of the line in order to get home it can't bump a guy in broad daylight on the highway all you you don't have to every Saturday night he always stays in town and takes the last bus home at 2 o'clock at 2 o'clock in the morning that half way half mile of highway he walks is deserted and I get it quite a setup all we do is run over him and make it look like a hit and run case the easiest thing in the world but an automobile leaves a lot of clues behind who's worrying about clues we just pick some car up off the street use it in an abandonment somewhere but some other sucker worry about taking the wrap well I I don't want to know too much about it you just go ahead and handle it in your own way wait a minute today Saturday yeah mr. Albion takes the bus tonight okay don't worry about a thing now I'll take care of all the little business details it'll be a sin you heard what the man said he said it's a sin he ought to know because he's an old hand at this business of getting inconvenient people conveniently out of the way it's an art the way peanut Marola does it the art of murder yes and since it's going to mean so much to you you should be here to see it those two cars parked at the side of the road waiting for the bus to stop drop it loan passenger turn around and head back for town and when it does there's a quick flicker of light and the first car driven by a friend of Marola's starts down the road is headlight pick up mr. Albion walking along the right side of the pavement then Marola in the second car the stolen car walking along the highway Albion here's the first one come up and pass the noise of the first one hasn't died down before Marola roars in the rapid succession of sounds confused as Albion just enough he doesn't step off the road quite fast except for a slight bump there's nothing to it I'm George Kramer by identification Lieutenant Clark headquarters precinct oh yes Lieutenant you hear about my car yes yes the car that's right you reported it stolen yes last night I left the park in front of my house like I always do I don't have a garage on my property yet and when I came out to drive to work this morning it was gone it was a green Chrysler sedan license 6g 4537 yes that's right I just finished putting on that paint job two days ago yeah had at the shop a week fixing it up I reported the theft as soon as I could hit you right over here in telephone yeah I came right out when we got the report funny we were just checking up on the ownership of your car when you're called you know you mean you found it already yeah yeah we found it even before you reported it do you ever drive out around Miller Highway Mr. Kramer milk Miller Highway why no no I haven't been out that way for months you weren't driving out there last night around to well no no of course not I wasn't fed and my my my car was stolen yeah sure sure well well you may be telling me the truth Mr. Kramer and maybe you're trying to be pretty smart I don't know which but either way I think you'd better come down to the station with me get your hat and lock up a place oh but wait wait a minute you mean you're arresting me let's say we're going to hold you for questioning but why for what for hit and run maybe you can explain to the boys down there how your car happened to be found part 300 yards from where a guy was run over and killed and the front of it was covered with blood stains well George Kramer that's what happens sometimes when you think about murder it doesn't come out just the way you expected it you don't know what this is all about yet but you do know that there's only one person who can explain it to you so when you get to the police station and after they booked you and taking you to yourself you asked him to call peanut Marola and pretty soon I have minutes Marola okay I won't stay long hi Kramer Marola what is this they've got me in here for man slaughter my car was the one you used to run down I'll be in get up you fool I want somebody to hear you well before I'll take the blame for this I'll make sure somebody hears me I'll tell them you were driving that car not me listen small fry what do you want to go flying off the handle for more than one way to beat the record but you used my automobile why I was an accident one of those things that happens once in a century doing just like I told you who's going to come out here into town and stole the first car I found on a dark street I was I don't know you lived on that street and it was your car I was taking good Lord you expect me to believe that look all you got to do is tell them that you weren't driving your car last night and get an alibi tell him you were someplace else that's what I told him told him that I was home but they don't believe me and I got no proof okay look tell him you were mistaken about the time telling you spent the night until 2 o'clock at the Lido nightclub down on Foster and Green Street get a dozen people to swear that both of us were there until 2 tell them I drove you home in my car well is that any good they can't do a thing to you they gotta prove you were driving that car they won't be able to break an alibi like that but it's straightener yeah I I was at the Lido nightclub until 2 with you and some friends you'll you'll back me up now sure I'll pick you up get nothing to worry about that's right Kramer you don't have a thing to worry about that is under spending the rest of your life in prison worries you amateurs like you shouldn't get mixed up in murder George but of course your friend Marola your good friend Marola has everything figured out Marola's an old hand at this business he doesn't seem to be excited so don't you worry about a thing oh you're not Marola speaking yeah I'm at the Hall of Justice I just up to the jail talking with him listen to this he believes that I took his car by mistake how can you lose when you work with characters like that let him talk all he wants to what can he do this I got an alibi that he couldn't break if he talked a year besides the cops of an open and shut case against him now give him about two days to clear it up and we'll have the garage to ourselves and it'll be easy sailing yeah he signed the papers all right yesterday yeah everything's great that's not all of tonight's story the whistler will return in just a moment with a strange ending of tonight's tale meantime a question have you forgotten anything lately just anything well of course we all forget occasionally and suppose you had 32 different things to remember like the service station operator who lubricates the average modern car it'd be mighty easy to forget one of those parts wouldn't it and you know what that means going without lubrication might wear out some vital parts some part you can't replace today that's why signal gasoline dealers don't trust to memory when they lubricate your car instead they use the famous signal check chart on which the maker of your car lists each part and the exact lubricant it should have and your dealer isn't satisfied with checking each part against the chart just once no sir he checks each part twice so not a single part can be overlooked and go without lubricant and when I say lubricant I mean the nine specialized lubricants that signal dealers use to assure all parts the long trouble free life the maker of your car built into them it's just another example of signal gasoline dealers more conscientious service to help your car go farther another reason why a good man for you to know today is your neighborhood signal gasoline dealer now back to the whistler well George Kramer now you know what murder is like how it starts a fleeting almost meaningless wish in your mind and builds into a noose around your neck you're in jail charged with manslaughter and Marola the man who actually did the killing who double-crossed you with a frame up is going scot-free or is it everything's great he said a minute ago to someone on that telephone but now as he hangs up and steps out of the phone booth well what do you know he nut Marola huh nice to see you once in a while when you're not in trouble if that's possible yeah Lieutenant Clark you ought to quit the police force and go on the stage you are so funny so long wait a minute Marola yeah aren't you being a little unsociable step across the hall here to my office where we can talk come on I got nothing to talk to you about the down I think you have for instance you know a guy named George Kramer sure I know he's my pot in the garage business that's sort of a new one for you isn't it Marola maybe and maybe I like it yeah maybe you were just in talking to Kramer weren't you sure naturally my partner gets in trouble naturally I'm going to see him see what I can do you figure anything to do seems like there's not much I can do he got out of line you've got him looks like an open and shut case but can I do I was wondering if you'd say that yeah what else would I say knowing you nothing I just wanted to be sure this was the way I figured it what do you mean the way you figured it how else could you figure it you got the guy red handed I think maybe we have you say you went into partnership with Kramer in his garage sure he needed some dough so I bought in I figured it might be a good investment I'm sure you must have but didn't you know that Kramer already owed another investor some money sure I heard about it but that was Kramer's own personal affair had nothing to do without you after you talked to Kramer one of my boys went in to see him he's changed his story about where he was last night says he was with you down at the Lido nightclub until two then you drove him home he says that he's nuts you know the Lido's been closed for two weeks pulled it up because of the curfew and I didn't see Kramer last night I can prove who I was sure I'm certain you can you always were good at alibis hey listen clock take it easy just a couple of questions more one that you ever drive Kramer's car why those I did nothing I just wanted to check you see we found some fingerprints on the steering wheel it weren't Kramer's I just thought they might be yours away yes a matter of fact they might be I did drive it when well about a week ago think again Kramer's car was in the shop being fixed up until two days ago yeah I guess it must have been later a couple of days ago yeah it must have been the tenant Clark yeah okay thanks now it's nice you told me about driving the car Marola that was a file room those were your fingerprints when I heard you talk to Kramer I had them pull your prints and check okay so they were my prints I just got nothing on me I just said okay so I'm getting sick of this I told you what connection I got with Kramer it's strictly business my potency I got nothing to do with him going out and bumping off a guy he owes money to some through answering questions you get me wait a minute just one more answer this one Marola if you can how did you know mr. Albee on the guide Kramer owed money to was the one that was killed hey read the paper the only paper that carried the story was the morning Harold here read what it says hit and run driver early this morning hit and killed it go on read it unidentified man yes Marola until 20 minutes ago even I didn't know who he was so how could you have unless you had something to do with it listen Clark I tell you I didn't Kramer Kramer told us yes well maybe Kramer will tell us a lot more when he hears how you've been trying to frame him this is one time Marola when you depended too much on an alibi you forgot too many other things important things like the fingerprints on the steering wheel you forgot to find out that it would have been next to him too impossible for George Kramer to have driven that car last night you see he has a very advanced case of night blindness rare but very real and it prevents him from driving after dark now with his help our case against you won't be hard to prove the whistler will bring you another strange tale the curious story of checkmate for murder the whistler is broadcast for your entertainment by the marketers of signal gasoline and motor oil and fine quality automotive accessories and by your neighborhood signal dealer this program directed by George W. Allen with story by John Hayes music by Wilbur Hatch is transmitted to our troops overseas by the armed forces radio service Bob Anderson speaking and suggesting you let every traffic signal remind you you do go farther with signal gasoline yes you do go farther with signal this is CBS the Columbia Broadcasting System


Hello everybody. I just wanted to take an opportunity to inform you around some initiatives that are coming out of the urban area. You all know when we attend fires in structures that there are a number of inherent risks. One of those is that sometimes we're required to get on the roof to do work. And another is that nearly all buildings that we attend that are on fire have electricity connected to them. Now there's a number of things that you all do and have done for many years to mitigate that risk and ensure our firefighters are safe. You know you conduct a dynamic risk assessment. You know you adjust your tactics and strategies based on the risks that you have at hand. But we also recognise that there are other things that we can do or other training we can offer that will help mitigate that risk. In that regard we've developed low voltage shoes removal training that's training to ensure that people are appropriately equipped and trained to remove electricity or isolated electricity where it enters the building, not just at the switchboard. So the target for delivering low voltage shoes removal across CFA ultimately is to 9,500 firefighters across around 479 brigades. So that's a significant undertaking not only for the training team that will be delivering it but from all of you that will be participating in those training courses. In the short term for the financial year that's just started we aim to deliver this training to 420 members across 84 brigades. So we're starting it in a rolling approach. It will need to be phased as I said it's a significant undertaking. There will be more detail on how that training will be delivered and where it will be delivered from an update from DCA Greg Patterson very shortly. So keep an eye out for that one. So we intend to deliver safe working height training across brigades based on risk. Clearly OMs will work very closely with OOs and brigades to identify where the most appropriate areas to put this capability is. In the financial year commencing now 1819 we have funding and equipment to train 160 personnel across 32 brigades. So again a phased approach and there will be more to come on that shortly. As I said keep an eye out for DCA Greg Patterson's update on the specifics of that training. The other related issue with working at height on electricity of course is the prevalence or the increasing prevalence of solar panels and battery storage units around structures. We recognise that this is an emerging hazard and emerging risk for firefighters. So immediately we've identified some funding to conduct further research into the best ways to mitigate that. We will have the opportunity over the next 12 months to research what the risk is around PV and solar arrays and develop training that's specific to deal with that. And I'm sure there are many people across CFA that have experience around solar panels that will be able to provide input into that research. So we look forward to that as well. And the final initiative I wanted to talk to you about and which we're all very excited about is the latest version of the Field Emergency Response Guide. Known as FERG to many of you we've had this response guide in a pocket handbook format for several years and periodically it gets reviewed. It's just been through an extensive review and the latest version is now at the printers so that will be issued shortly. But the exciting thing from my perspective about this version is it's the first time we've been able to make it completely interoperable. It's done in partnership with the Metropolitan Fire Brigade. So this version will be the first time that we've got a Field Response Guide that's for all firefighters across the state of Victoria. So we're very excited about it and it will be issued shortly. As I said it's in the printers, there will be a number of hard copies come out and also an online version. Stay safe.


training run, Sunday long run, except it's not Sunday, is it? It's Saturday. It's all right, we can edit that bit out, it's fine. This is my last long run before Brighton Marathon. So I'm doing, Victoria's doing two loops. I'm doing the second loop with Victoria but she's already done nine miles and this is our second loop. What are you hoping for? I've done more than nine miles. You did nine miles and now you've done the second loop. So now we're on, I don't know, 16 miles. We're walking along Worthing Seatfront. Listen, this weekend is all about celebrating inspirational women in running and I've been running today with two of the most inspirational women I know. Oh, you weren't talking about me. So my daughter, Elsa, has been training for the past... Our daughter. Sorry, our daughter. Elsa has been training for the past month or so to beat her parkrun PB, which is over... She said it a few years ago. Yeah, over six years old her parkrun PB. My arm's aching, let me swap over. So Elsa lost the love of running. She has found her love of running. She has been working steadily over the last few weeks. She's been taking herself off to the gym. She's been doing parkrun each weekend. She did a Zwift run last night with me. She's been focused. So she's been training for the past four or five weeks, I'd say, deliberately to try and beat her parkrun PB. And she's using it as part of her Duke of Edinburgh Bronze Award. Oh yeah, she's doing Duke of Edinburgh. So this morning we set off, although we were a bit late, because we planned to get up early and leave early and do a nice warm-up and thrills and all sorts of stuff. Like all teenagers, she went to bed late. And like all middle-aged men trying to create a video at the last minute, I went to bed late as well. So we got up late, but we did make it to parkrun by the start. And Elsa just absolutely focused and said, right, I am on this. I know I got up late, but that's in the past. We are going for this. We planned for it to be today. Let's do it. And we went for it. And she was amazing. It was quite windy here this morning. So running out on the parkrun course, the first two kilometres were quite windy. But she kept to her guns. Look, here's the parkrun sign. This is our turning point at parkrun. So that's about 2.3K into parkrun.  And she absolutely smashed it on the way back. And she crossed the finish line of parkrun with a PB of 26 minutes and 40 seconds. Black 11, 819. 20 seconds. So absolutely fantastic. Blown away by her determination to achieve and blown away by what she did today. She really is awesome. And she literally can switch her brain. Very similar to how it feels like I can just flick a switch.  I'm going to swap over again now. I can only hold the phone for like a few seconds before my arm hurts. Amy Green says, well done, Elsa. Kingsley says, where are you running? We're taking a walking break because the last time we filmed alive whilst running, it was very, very wobbly. So I said, let's walk while we do the live.  Worthy seafront, worthy promenade, which is our local running. And we only live a couple of miles, a mile or so. A couple of miles, a couple of miles from here. So we're just on our way back home. Victoria is going to do 20 miles today. So by the time we get home to be 18 miles, I'll go in and make myself a nice cup of coffee. Victoria is going to carry on and do another two miles. So yeah, the other inspirational woman in my life is Victoria.  The OCC race in Chamonix, three marathons in three countries. In three weeks last year. So a phenomenal year for Victoria last year. This year we've been ill, as you all know, but Victoria is now on it training for the Brighton Marathon. She's had a couple of weeks of getting some long runs in. And this is the last big long run before Brighton Marathon on April the 7th, which I'll be running as well. Victoria is going to be trying to pace it around five hours. I'm going to try and pace some friends of ours on Zwift for about four hours. So that's our plan. A huge thank you for all of your support. It really does mean a lot. And of course, the reason we're celebrating, you know, one of the other reasons that we're celebrating inspirational women in running is a phenomenal achievement. If you haven't seen it yet, go and check out the video I released last night. Jasmine Paris, one of the UK's foremost ultra runners. Last night, created sporting history, running history. It was now biting stuff, truly, truly inspiring. If you don't know about the Barkley Marathons, it is the only race where there's no live coverage, there's no regular updates on Instagram, or, well, there are, but it's like, there's no regular video updates or anything like that. Runners are not allowed GPS watches. Yeah, and there's a little bit of mystery and secretiveness to the whole thing. Huge amount of elevation. Oh yeah, the elevation is basically twice up Everest. So, what Everest is about 8,000 metres, so 16,000 metres of elevation gain. Putting that into context, the UTMB run that I did last year, one of the most famous and arguably one of the most popular ultra running events in the world, has 10,000 metres of elevation gain. The Barkley Marathons is well over 100 miles, five loops of frozen head state park in Tennessee, organised by the very famous Lazarus Lake.  And they have to find, to make sure they've been to various checkpoints, they have to pull out pages from a book and bring them back to LAZ at the end. And if you haven't got all the pages from your book, you are disqualified. It's an amazing event, and the only way that you can find out what's going on is by checking out Twitter. Because there are regular... It's telling you what position the run is in, how far they've got to go, et cetera, et cetera. And it's just a hilarious fest of constantly refreshing Twitter to find out what the latest updates are. Let me just have a look at the comments here. Kingsley says, ah, it looks beautiful. I'm on the Lancashire coast. Hello, Kingsley. Thank you for popping in. Amy says, well done, Victoria. And oh, Kingsley is now mentioning Jasmine Paris. Yes. So this race began in 1986. I mean, not the... You know, it hasn't been... They haven't been running it since 1986 constantly. I mean, once a year since 1986. They'd be very tired if they'd been running since 1986. Once a year since 1986. And in all that time, only 17 people up until yesterday, 17 individuals had completed the Barclay Marathons, all five loops. And none of them have been women. So no woman had ever completed all five loops of the Barclay Marathons until last night, when, with 90 seconds to go, Jasmine Paris touched the famous yellow gate at the end of the Barclay Marathon loop and completed the fifth loop of the Barclay Marathons. And it was a monumental moment. This, you know, really feels like, in our small community of ultra runners, it really feels like an absolutely monumental moment. There were very excited people all around the world. Really, there were. And it was just, you know, Twitter went absolutely crazy. The BBC have finally picked up on it. There is a story on the BBC website now all about Jasmine Paris completing the Barclay Marathons and completing the first woman to do so. So that is why we are celebrating women's, inspirational women in running this weekend. Go and find out more about Jasmine Paris. Jasmine is also the first person to have won the spine. Outright, the first woman to have won the spine race. Outright, if you don't know what the spine race is, that is 268 miles along the Pennine Way. And, yeah, so Jasmine won that in 2019. Beating all the men and breastfeeding her child, or no, expressing milk for her child on the way round. So, another incredible achievement from Jasmine. Making her just one of the UK's super ultra runners. So, alright Victoria. Yes, thank you. It was raining and cold and windy here until we got onto the seafront and now it's beautiful sunshine. And we had a beautiful double rainbow. Oh yes, which has now disappeared. Paul Haywood says enjoy your afternoon run. Thank you very much. Kingsley says you have to write an essay and say why you shouldn't be allowed to enter as part of the entry process or why you should be allowed. I think it's why you should be allowed to enter. I'm not, maybe it is why you shouldn't be allowed to enter. Yeah, part of the entry process to the Barclay Marathons, you have to write an essay to last saying why you should run it. I think it's why you should run it. Here is the park run 3K sign, look. Is that on? Yeah. So when you get to there you know you've got two kilometres left to run. So that is us. We'll end the live stream there. Thank you very much for watching everybody. Thank you. Bye. See you soon. Yeah, we'll be back. On Zwift we'll be back on Tuesday. I'm going to the track tomorrow. We have Bright Marathon on the 7th of April and then I've got London Marathon on the 20... 20-something of April. Thanks for watching, take care. Go and have a look at the video I released last night all about the Barclay Marathons and Jasmine Paris. It's an amazing, amazing run. Take care everyone. Bye. Tina says, Well done you two. I'm hiding from the showers. Oh yeah, yes. It's been on and off showers all day here. Kingsley says it is definitely why you shouldn't run. Okay, alright. I'll roll with that. Quite happy to accept that. Okay, we're off. We're done. Thank you very much for watching. Take care everyone. See you. Bye.


Hello and how are you all today? My name is Priyanka and I shall be helping you with the following question. It says in each of the exercises 1 to 6, find the coordinates of the fukai and the vertices, the intense eccentricity and the length of the latest rectum of the hyperbolas. Now, the equation which is given to us is x square by 16 minus y square by 9 is equal to 1. Before proceeding on with the solution, we should be well versed with what a hyperbola is all about. A hyperbola is the set of all points in a plane. The difference of whose distances from two fixed points in the plane is a constant. Now, here we have this as a standard equation of a hyperbola which is x square by a square minus y square by b square is equal to 1. Here, these two f1 and f2 are the fixed points which are called the fukai. The line through this fukai is called the transverse axis. The line through the center and perpendicular to the transverse axis is called the conjugate axis. The point of intersection of parabola with the transverse axis is called the vertices. Now, in the figure given here, hyperbola is shown, fukai are on x axis with f1 and f2 having coordinate plus minus c comma 0 and the vertices that is plus minus a comma 0. The general equation has been discussed with you before that is x square by a square minus y square by b square is equal to 1. Also, the eccentricity that is e is equal to c by a whereas we can find the length of the latest rectum is equal to 2 b square by a. Now, here the given equation of the hyperbola is this is the given equation of hyperbola. x square by 16 minus y square by 9 is equal to 1. Now, on comparing it with standard equation that is x square by a square minus y square by b square is equal to 1. We have a square equals to 16 that means a is equal to plus minus 4 whereas b square is equal to 9 that is b is equal to plus minus 3. Now, we know that we can obtain the value of b that is the square root of c square minus a square. Now, we know the value of b and a so with this the help of this equation we can find out the value of c that implies we will take the positive values only 3 is equal to c square minus a square is 16 on squaring both the sides we have 9 is equal to c square minus 16 that further implies 9 plus 16 is equal to c square that is 25 is equal to c square that further implies the value of c is plus minus 5. Now, since we know the value of a b and c thus we can see that we know that foci is plus minus c comma 0 right. So, we have it as its value is equal to plus minus 5 since c is plus minus 5 comma 0 vertices are plus minus a comma 0 and the value of a known to us is equal to 4. Now, eccentricity that is e is equal to c upon a that is 5 upon 4 and further we have the length of latest rectum is equal to 2 b square b is 3 by a that is 4. So, we have the answer as 9 by 2. So, let us write down the answers once again we obtained the value of foci equal to plus minus 5 comma 0 vertices are plus minus 4 comma 0 that eccentricity is 5 by 4 whereas length of latest rectum is 9 by 2. So, these are the required answers to the question that is given to you. Hope you enjoyed the first session and understood the concept of hyperbola as well as the standard of equation of the hyperbola well. Have a very nice day ahead.