I feel I'm here a little bit under false pretenses in a session that's entitled science and gaps but I'll do my best to be at least the modestly entertaining although I'm really depending on Mark to to carry the day. So I'm going to talk about into the lion's den my experience with third-party payers and molecular diagnostics something that I had really very little to do until a little over a year ago when I became a volunteer faculty UCSF and became CMO at Envite. So disclaimer disclosures I am a full-time employee and I get salary and stock options from this company and the opinions I express here are based on my own experience they're my own and they don't necessarily reflect those in Envite. I'm always interested in the following issue which is anecdotes as data. You can actually find both comments the plural of anecdote is data that was Raymond Wolfinger at Stanford Graduate Seminar in 1969 or the plural of anecdote is not data and that's a Bernstein metaphor cognitive belief in science paper that he published so take your pick but as of today I'm going to go on the left which is the plural of anecdotes data I'm going to tell you some anecdotes. So the first is the third-party payers are not monolithic and each payer creates its own policies and this has to be spread out among a number of different payers. I was spending a lot of time recently with Medicare but there are also large private payers as you know United Healthcare and Aetna. There are many blues large and small some were acquired and therefore belong to a larger umbrella blue but still retain some autonomy some are independent and you really have to deal with each of them on an individual basis then of course there's state Medicaid there's managed Medicaid there's the federal blues and it goes on and on so there's lots of different lots of different payers and they are very heterogeneous in their outlook on genetics on their knowledge and sophistication. So moldy X which is a very important component of this is a process that was set up and it's an organization it's a group that was set up originally about Palmetto which is one of the max one of the Medicare contractors and moldy X has been very much involved in evaluating genetic testing and making decisions about whether or not there is evidence that would make it reasonable to support diagnostic testing but moldy X doesn't dictate the most insurers but it does wield a lot of influence sort of like the Pied Piper here. So when it comes to molecular genetic testing most payers do play follow the leader with moldy X was moldy X do it reviews evidence concerning whether the coverage in a test is directed by Dr. Elaine Jeter who is a very knowledgeable person acknowledged in the field as as being an expert in this area but it's I find it sort of interesting that to have almost a single group like moldy X and even a single individual in that group to be so to so strongly personify what we view as being a sort of a national a national issue and it moldy X grew out of the work of Palmetto GBA which is a subsidiary of Blue Cross Blue Shield but it's also the Medicare administrative contractor in the southeast U.S. So when it comes to them most payers do follow the leader Noridian with another Mac took over the jurisdiction on the West Coast where I am California Nevada Hawaii Pacific Territories and Noridian tends to be a very close follower of what moldy X does other Macs also look there but they make their own local coverage decisions and so it's not necessarily a completely snap thing and many private insurers also look to moldy X for guidance but as I'm sure you're aware and it's an important point to make Medicare only covers affected individuals and not unaffected individuals at risk. So a lot of what we think about in the use of genomics for risk assessment for cascade testing in a family in addition of course to the age or disability requirements to be covered by Medicare you also also have to be affected and so no matter how good a job something like moldy X does it's still not going to cover the people that we are also interested in thinking about and that is unaffected people who are at risk. So for example when moldy X just recently looked at and approved a new for payment a new code for hereditary breast and ovarian cancer done as a panel by next generation sequencing as opposed to the previous coverage which was for a different methodology they looked we applied for our company we applied for Medicare coverage for this which was accepted and they asked us to submit a lot of analytical validity data they wanted to know that the next generation sequencing approach was going to work and was going to be equal or better than what have been done previously they wanted to know what the clinical interpretation of the data was and whether our lab had reasonable concordance with other laboratories and of course they wanted to know if we used ClinVar was an important component of what they looked at and they also wanted clinical utility information most of which has been published by a combination of some academic laboratories but some of it has also come from commercial laboratories in particular one myriad which had had the patent and the exclusive testing rights for a number of years and generated a fair amount of data on that one could use for clinical utility arguments and then when they put that all together decided they were going to do it they then had to put together some sort of a price and the price that they put for next generation sequencing for hereditary breast and ovarian cancer panel which they said had to include at least BRCA one and two but didn't specify how many other additional although genes although those genes had to be relevant to the problem and they priced it at $622 while continuing to pay for the on the old BRCA one and two code well over $2,000 and this is I think an interesting situation where you it's very difficult to find out exactly what the basis was for them setting the what I think most people would recognize as a fairly low price for the next generation sequencing approach to this and this still a preliminary price has not been formalized it's not finalized and likelihood is is that it's going to change but I just found this a very interesting experience to be working with this one designated component of one designated Mac and yet it will turn out to be probably the most influential and important contributor to the use of of next generation sequencing pay payments by Medicare and probably by a number of other payers as well if you do the testing by next generation sequencing. So the the other thing I've learned in working with insurers is that there's a very complex dynamic among the concerned parties between patients and providers on one hand payers on the other hand and the laboratory which is the rope there that's getting stretched in both directions. So the patients and providers they are driven very heavily by personal utility concerns you know as a practicing physician myself I don't always necessarily order a test just because I'm absolutely convinced that it has a total perfect beautiful clinical utility also sometimes I order a test because I'm trying to confirm a diagnosis or I'm just trying to understand and to be able to explain to a patient better why that patient may or may or may not have a particular condition without there being a clear alteration in management that's going to happen as a result of that test and patients certainly often feel the same way and they're looking to get their tests paid for by their insurance whereas the payers are driven by much I think much stricter clinical utility concerns as was said this morning they often repeated that they did not take economic issues as being the overriding concern they really are trying to provide good clinical care for the people that they cover but they do want good evidence such as clinical utility also many of the provide of the payers expressed a strong interest in some kind of utilization management similar to what has been done for drug treatment they also would like for genetic testing and often would engage with us about whether the laboratory could partner with them in some way to provide some sort of utilization management to make sure because they're quite concerned that many providers are ordering the wrong tests they're ordering tests inappropriately they're overusing tests they're misinterpreting tests and they would love it if somebody who had more knowledge and sophistication that they felt that they had would be able to partner with them to help them in managing the utilization of genetic tests and if they're also expressed a lot of concern about downstream costs I know this was mentioned this morning a couple of times in this afternoon as well that that the inappropriate interpretation of tests for example the extrapolation from variants on certain significance the expansion to very large panels with the number of genes that work that they considered irrelevant to the condition for which the patient was being tested that that would could own inevitably lead to excessive downstream testing which could potentially not only cost a lot of money but also be harmful to the patients and the laboratory wants to keep his lights on it certainly wants to get into contract with payers this is very helpful and the lab also has customers those customers are the providers and the patients and they want to keep them happy and so the lab is is is is working hard to try to be a partner with the payers but at the same time serve the needs of and keeping the patients number one and the providers that are ordering these tests number two at the top of their list of the people that they're really trying to pay attention to and take care of it because and insurers have a brief their previous experience with testing colors you know the others that there's that old expression about how the generals are always fighting the last war and I really felt that payers have been struggling with their previous experiences with genetic testing number one was they've just staggered under code stacking where their their laboratories that would generate stack codes for genetic testing that could go up into the tens of thousands of dollars for a test that really should only cost under a thousand dollars and that this is something that they really feel that they got burned they also feel they got burned badly by a lot of the toxicology issues that ever risen recently there's been a big boom of having in office tech toxicology testing which would then be which which would then be billed to third party payers and there's a whole cottage industry to develop for example you treat patients we take care of toxicology for you they are providers of a compliant turnkey in office lab for clinical toxicology in specialty practices they'll come in and install a toxicology lab in your lab and I think the many of the insurance companies have really felt that this has been a real problem for them with just escalating costs for drug testing it becomes even more complex dynamic when you now add drug companies as the fourth component of this tug-of-war and for example I've had some recent experience talking about LDL receptor mutation testing for hyperclesterolemia and the PCS K9 inhibitors which are new and powerful and expensive medications where the patients and the providers were looking to get their test paid for and express some resentment with the idea that a laboratory might quote side with the payers who are asking the laboratories to use genetic testing to limit who gets approved to get an expensive drug while the drug companies were not necessarily interested in having genetic testing that would limit the prescription of an expensive drug and so the payers and the drug companies are at odds and they're both trying to get the laboratory to side with them to either work to do the testing or not work to do the testing and meanwhile with the patients and the providers sort of saying look you know whose side are you on anyway so in summary I think obtaining third-party payer coverage for genetic testing is a chaotic and fragmented process some pairs understand the field others are clueless there's a theoretical bar of showing true clinical utility for the individual patient but this bar is arbitrarily and haphazardly applied or disregarded by different pairs I can tell you over again over and over again that there are many examples of tests that are done and sent to insurance companies and paid for even though those insurance companies have in their official documentation that this is not a test that they will reimburse for and yet they do sometimes and sometimes not and you can't predict when it's going to happen many payers are fighting the last war they're worrying about panel testing because of code stacking in the past even though there are most laboratories now have very very large panels and don't add additional costs if you add additional genes and the utilization management is a mantra for many payers but its implementation is very rigid is bureaucratic and it contributes unnecessarily to increased health cost health care costs mean our our prediction is that the cost of a test doubles or triples when a payer insists upon having stacks of documentation which they could actually save administrative costs by simply accepting a much lower cost for the testing don't demand all the administrative documentation and then for example did some sort of audit afterwards to determine whether in fact the laboratory was charging for what are medically appropriate testing so I think this entire idea that one is going to require lots and lots of clinical data in order to justify testing as the cost of testing comes down is going to become more and more more and more are really archaic and unnecessary in its view so we'll see what happens with that so the last thing I just want to say is that there are a couple real standout third-party payer efforts to try to really understand genetic testing and make it accessible to others you know there's something called evidence street from blue cross blue shield which is a proprietary database of evidence which is really really quite interesting what they tried to do and of course there's the blue cross tech assessment group which also I think has been very very tough very hard nose but also very evidence-based and so I think there are efforts but it is very variable in its applicability that I'm going to stop I think I may have taken up to mark thank you Bob next we have mark Williams and guys enter


des of the proteins and you can see how the space change as function of the number of chemical shift perturbation residue that you defined and you see at the end this is the location of the NMR structure so again when you put all the data there is a unique location in this case coming out for this particular example and the latest version of this is that we have can actually output all the solutions that are consistent with the number of restraints so this is the ensemble that you get you can refine those solutions give those to Haddock, refine them in Haddock so you don't do docking you just do refinement and you get two sets of solutions so again symmetrical solutions are popping up out here and the one that we find the best in terms of score is the one which corresponds to the average NMR structure so this ambiguous distance restraint analysis is not available in the server yet so that's something that we will implement later on so in conclusion we have a way of visualizing the information content of distance restraints from any kind of sources in principle it's important to realize that it's only based on geometric considerations so there is no energetic in that it allows you to identify a false positive and it allows you also to extract additional information by mapping the potential interface in your molecules which can be valuable to guide the docking process but of course it does not account for any conformational changes so it's not because a restraint is not satisfied at all in this kind of analysis that it is perceived wrong so the working version that we have now can handle ambiguous restraints as well and I didn't speak about that but we're also working, it could be that in your data set you have two binding modes and the question is could we distinguish those two binding modes then you need not only to calculate if a location is space is consistent with a number of restraints but you need to keep track of all the combination of restraints that are possible and monitor that so that becomes a combinatorial problem so you can do that with up to 20 restraints but after that the memory starts exploding but that's something hopefully that in the future we will also offer in a new version of the web portal so we have 15 minutes left make your choice some of these we already talked about so no need to go back to cryoEM or MS data because we already covered those and then we vote in a very democratic process protein ligand modeling who else is for protein ligand so one, two, three, well okay anyone else wants something else? Tax? Tax? Not very popular, sorry specifically riddle that's also an interesting one that's nature playing tricks on us again so that's yeah I think we should go to the ligand part because there is a majority and who knows maybe this afternoon depending on how far we go in a tutorial and how much we do we might come back to some of it if there is interest but maybe you are so fed up with Hadock by the end of the afternoon that you don't want to see me again okay so the ligand one let's do that where is the ligands here okay so here we go so I mentioned that's quite early on in Hadock developments we have been able to handle ligands because we build the ability to deal with ligands in the server early on so this is probably one of the first example of using Hadock to model a protein ligand complex so that was published in 2007 this was actually before we had the web server and this is also an example of a multi-body docking so this protein it's the chicken liver bile-acid binding protein actually binds two ligands at the same time and if you want to get proper results in terms of docking if you are going to dock only one ligand at a time I think you will never get a solutions where you can fit both because the ligand most likely is going to end up somewhere in the middle of your binding pocket and then it will be very hard to get a second one inside so what's the data that we had at the time so this was a collaboration with Lucia Zeta and Henriette Molinari for NMR people so they had chemical shift perturbation data on the protein site describing the binding sites they also had relaxation data basically telling us that some loops in this protein are re-gidifying when the ligand is binding so that's also information in principle proteolysis also comparing the difference between the free protein and the ligand-bound protein in terms of stability on the ligand side there were some STD data and also a few NOEs so this is basically all the information that we put in doing a free body docking docking two ligands at the same time to get them into the binding sites so this is probably the first example and you see the best cluster so it's not like it's a very nice very precise solution so there is still some viability in the solution but you can do a free-bodied docking at the same time here is another example and then I'm going to come more to some more benchmarking where we are docking now we are looking now at a protein which has antibiotic properties because it binds to lipid 2 which is this molecule here which is a critical component of the cell wall of bacteria and it's a complex molecule which has sugars it has amino acids here pyrophosphate group and then an isoprenyl tail which is inserted in the membrane so we did a modeling based on NMR data so the NMR is telling you that this protein is binding to the membrane so that's one piece of information and then there is also NMR data that are pinpointing the binding side of lipid 2 to the protein so from this we know that when lipid 2 is binding the tail this isoprenyl tail should be pointing down and not up so that's also a bit of information that you can use to filter solution because when you do your docking in principle the molecule could end up in two orientations so you're going to filter your solution based on this information and using all that we ended up with a model which has published in a nice journal another early example, sugars so this is a defensin binding to sugars so you saw now kind of a different docking here so the protein was flying in and just exploring the surface so again there were NMR data that were pinpointing the binding side on the protein side but because of the flexibility of the sugar in this case we decided to do the docking during the flexible stage of HADOC so we didn't do the rigid body minimization first but we gave more time to the molecule to sample the surface of your receptor so that's a flexible binding example and here is another example again oligosaccharide binding to a protein which is now involved in blood-specific recognition to guide the docking in this case so there was a crystal structure with only one saccharide born in a binding pocket and the question that was asked here was can we explain the specificity of this protein? so here we are looking at the tetra trisaccharide this one and they wanted to pinpoint which amino acids and these are mainly histidine and tryptophanes that are candidates are responsible for the specific recognition of an enacetyl moiety on the sugar so we did the docking drawing the sugar in the binding side that was defined by the crystal structure but giving full flexibility to the other sites so again the docking was not done on the rigid body but during the flexible refinement stage and you see your enacetyl group is here and it seems that this solution pinpoints that this histidine should be important for this specific recognition process so this is allowing you to generate hypothesis and now you can try to mutate this histidine and see if you lose this specific recognition in this case so there were different candidates here that were potential recognition sites but so our prediction will be that this is the right one which needs to be tested so this was 2006 we've been doing small molecules since a long time another example of such a case now a crystal structure solved in a group of peat gross in Utrecht the crystallographer I mentioned before where they managed to solve the crystal structure of the membrane protein, it's Pag-L it's a deacetylase that binds to a component of the cell wall of bacteria LPS but they could not get the crystal structure with the substrate basically so they knew the crystal structure they knew the substrate and the information that we had here to guide a molding process is actually the chemistry of the system because we know what this enzyme is doing it's cleaving a bond and the reaction of this cleavage reaction is also described so that's information so we have a catalytic triad actually it was not clear it was a glutamate or aspartate but we have the histidine serine pair and basically the serine oxygen is attacking this carbon here of LPS to cleave the bond so we put this information as distance restraints in Haddock to guide the molding process to guide the docking process so this is the molecule that we are looking at and actually what we dock is only Lipid-X which is a subset of this molecule so when you do that so we use the reaction mechanism basically the cleavage mechanism has restraints to guide the molding process and again we know which part of the proteins are in the membrane so these Lipid-Tales they should not sit out there in a solution but we should filter solutions that are compatible with the membrane orientation of the protein and this is the solution that comes out of the modeling and then you can analyze this solution and you get some nice insight for example surprisingly this protein in the middle of the membrane has an aspartate so you don't expect a negative charge in the middle of the membrane but now the model is explaining why is this aspartate there because it's specifically recognizing LPS so LPS has an hydroxyl group here in this chain and this aspartate basically is helping in positioning LPS in the binding site and then we can also answer the question of why is it the aspartate called Glutamate which is involved in a catalytic triad based on the model we predict that the Glutamate is the correct one so we have been doing also some recent benchmarking to go a bit more systematic about docking capabilities of Hadock so we took a number of complexes from the Aztecs diverse set which is a well recognized benchmark for small molecule docking it's also used by all the small molecule docking software so if you do small molecule docking with just the average small molecule docking software Autodoc, Autodocvina, Glide all of that they are not docking against the entire surface of your protein you define typically a box where the docking is directed so you put information in there it's not in a form of restraints but you limit your docking to a region around your protein so in Hadock we will do kind of the same but we define the binding regions which we define as active or passive residues so that's what is going to bias for docking in Hadock so we define the binding site on the protein as active only for the rigid body blogging part and during the refinement part we just request that the ligand should be contacting the binding site but it's free to explore the binding site so that's the protocol that we are using what is also different compared to the protein is that we change or we give more weight to the Van der Waals interaction in the rigid body docking stage one when we do protein it will be zero zero one so this gives better results and we also have typically depending on your binding site so if you have a buried binding site it might be hard to get in because in the way we docked the molecule are separate in space you do your rigid body immunization you might have to go through the protein to go in and our Van der Waals energies might prevent that so if we have such buried site we can change your settings a little bit to allow this interpenetration of molecule so this is the docking performance if you take what we call the bound docking so you take the crystal structure take it apart and just try to redock so there's no conformational changes here so this is the cluster based docking so we have 78 cases and we have basically a 77% success rate where we get acceptable solution in the top cluster if you look at the top three we get 87% success rate so that makes it quite competitive with over docking software it's not as fast as a small molecule so you don't want to use Haddock to screen one million compound it will be probably a waste of computing time but if you have data you can consider now if you start from the unbound docking set so this will be protein conformations that are not corresponding to the crystal structure of the complex you see that you take a hit in the success rate but the top three you are still at 77% which is quite competitive do conformational changes affect us a lot this is what you are seeing here so you see the interface RMSD of the best scoring cluster so we might have overcluster that are better but we are just taking the top cluster in this example versus the RMSD of the receptor that you are docking against so this will be conformational changes versus accuracy of your docking results and you can see so it's not like it's going up so it seems that we are quite robust in terms of conformational changes probably because we are guiding the docking with our restraints and we are allowing for a bit of flexibility so this is good news and this is an example of using NMR data now to guide the docking process so it's a phosphatase so we dock against the upper form of the enzyme the red colors here are the NMR titration data for this system so this is what we give to HADOC we also mimicked our binding site definition so this will be five angstrom this will be 10 angstrom in orange this is the kind of definition that we use in our benchmarking with the Aztec set and these are real data and if you do the docking with those data so this is the results that you get so in green you have the crystal structure so it's superimposed on the protein and then just showing the ligands so green is the crystal structure gray are our docking models so it's getting very close and this is the docking that you get with the 10 angstrom binding site which defines quite a large regions around the binding pockets so you see our clustering could be probably better here because we have two sets of solutions so we should reduce our clustering cutoff probably here but again you get a very nice docking results using these data so we also participated two rounds of D3R so I don't know if you have ever heard of D3R it's the design, it's the drug design data resource D3R, it's kind of the CASP capri experiment but for small molecule docking and it's run in California basically so what you get there are data sets from industry typically for a large set of ligands against one protein so it's a nice consistent data set which is nice so we have been participating two years in D3R in two rounds and this is mainly the work of ZNEP and PANOS so the first target that we did was a Farnesoid receptor so it's a pharmaceutical target and the data at the time I think were coming from Roche for this set so what are the challenges? so depending on the ligands there are large conformational changes on the protein side and the side that we are targeting here is quite buried inside the protein and the ligands that we are docking they are quite branched so this is not a small molecule, it's quite a large one so for this one we did kind of the protocol that I described you in a naive way defining the binding site we generated ligand conformations using open eye sample different conformations took representative clusters ensemble docking in Haddock and that's it for the receptors we took the receptors from the PDB different conformations of the receptor gave an ensemble of receptors for the docking and that was it I'm speeding it up a little bit so this is the ensemble of receptors and then we do a docking and you get some very nice results so this was the first one that we looked at so we say okay it's working fine so docking works well but if you look over all the ligands that we had to dock this is where we are okay so that was not so very nice but we learned a lot so the best ones are at one extra on average for all the models that we had to dock so we got some good ones we got some bad ones but we learned a lot so what limits our performance in terms of docking so you can do experiments using different so what happens if I take is it a ligand conformation that limits the performance so if you use the ligand conformation so these are our predictions the dark greens are our predictions if we use the bond ligands we improve a little bit if we use the bond receptor you see that we improve quite a lot in the top term so it seems that we have to be smarter in choosing the conformation that we're going to use for docking so that's one lesson here so the receptor limiting factor so we need to select receptors that are based on similarity to the target ligands that you need to dock and that's what you realize people are doing in a small molecule field and also the ligands we need to up sample the major cluster if possible so if you do that so green will be this new strategy you see that we have better results in general this is RMSD these are all the targets that we had to dock so this improves our results this is the kind of sampling that you are getting in the first stage what you have again the ligands and this is the top 100 models and if you see a gray or dark bars it means that we have an acceptable ligand so we generated ligands but they should be done there if our scoring function was good enough and you see that they're all over the place now if we do this smarter choice of receptor and smarter choice of ligand conformation this is the picture that you get you see you're increasing a lot of sampling you have more success rate in doing that and then came Grand Challenge 3 so having learned from our failures in Grand Challenge 2 we went a bit smarter here so these are the kind of ligands that we have so we did a smart choice of the receptor by comparing the similarity of the ligand that we have to dock against the ligands that are already in a PDB and the similarity is sometimes quite high for the ligand we also did select conformation that resembles the ligands that are already known from the PDB okay so we try to find a ligand in a PDB which resembles most the ligand that we have to dock we measure the shape similarity and we also measure the chemical similarity so we use open eye software for that which is free for academics so we're going to have a smart selection of ligand we're going to have a smart selection of the receptor and instead of starting or docking from random conformation we actually pre-position the ligand in the receptor and only go for the refinement stage of Haddock and this is what you get for those ligands so this is 2.5 angstrom you see that we are doing them much better than in round 2 of this Grand Challenge so we have learned from our mistakes so you should not be afraid to go blindly in those competitions because this is really a learning phase otherwise you always optimize your software thinking that you are doing well and if you'd never try to do the blind test then you don't learn much let's skip that one and this is not where we are in the last round so those results are not yet published the publication have been submitted but we are so this is 2 angstrom and you see that the top five groups are pretty much the same performance so now we are doing very well doing this kind of docking I think binding affinity I should not really so that was another part of D3R so we have to rank the ligands because they are experimental data on that one so we had a very simple model for binding affinity prediction and it did again quite well just to show you where are we so this was Grand Challenge 2 so this is only using so basically some kind of structure-based measure of binding affinity using contact and here you have all the fancy free energy calculation methods so we have a very simple model that does quite well and actually in Grand Challenge 3 what we did was to not even use the protein structure to predict the affinity but just train a machine learning model that compares the similarity so in Grand Challenge 3 there were a lot of kinases in there so there is a lot of data on kinases by simply measuring the similarity of the ligand that you have to predict with the database that you have out there and training a machine learning model we are doing much better than all the other energy-based model so in terms of conclusions for small molecules so yes we can handle small molecule especially interesting I think when you have experimental data there was a very nice paper in December from the Novartis group who has been using Haddock to do small molecule docking because they had measured NOE data and apparently what they were telling me there is no single small molecule docking software which can define a distance restraint so that's why they resorted to Haddock to do their docking because in all the popular small molecule ones you can simply not define a distance restraint you would think it's very simple but it's not there and then if you don't put a distance restraint they try to generate docking poses and then filter with the NMR data they had and this was not working so the NOEs that they had were critical to generate good models so that paper was published in Jack's it's worth looking it up because they show that actually they can use limited number of NMR data do generate docking models they could not co-crystallize those structures because the affinity was too low but based on the docking models then they can do structure-based drug design generate a new generation of ligands that then crystallize because they have improved their binding affinity and they can show that those crystal structures are matching with the docking models they are getting so it's a nice story of doing structure-based drug design using docking models using distance restraints so and maybe some perspective also just in terms of because some of you are doing fragment-based drug design so we also looked at can we do something like that and then I'm stopping see you so this was a project actually of high school students who use the web portal because it's simple to use to do this kind of fragment-based drug design so we went to do docking without any information just throwing the small molecule using center of mass restraints 18 different fragments this is near our mini-days and then you look at where are the fragments ending so these are the center of mass of the fragments and then you can look so here is an example of different fragments that end up in the binding site of this protein and what is interesting so this is the docked model in yellow is the crystal structure so if you were to do rigid body docking so without any flexibility so you see that here we are opening kind of a pocket which is not accessible in the crystal structure so there is an interesting potential there maybe to sample for small molecule okay so time to stop if I can find my mouse so we go here so to finish so I've shown you that information driven docking is useful to generate model of bi-molecular complexes even when you might think that you don't have that many data at hand so data are always useful the models that you are getting they are models so they have their limitations so even if they are they are not the most accurate one they are useful to generate hypothesis and the model again is not the end of the road the model is only the starting point for a new experiment so in that sense I think modeling and information driven docking integrative modeling is very complementary to the classical structural biology techniques like lmr x-ray crystallography and cryo-em so I'm not doing all this work by myself so this is that's almost two years old by now picture of the group in Utrecht we are funding from different European projects and also over the years different people have been contributing to the development of continuous development of Hadock so this was a retreat last year so some of them are still in a group some of them are on the world but they are still in touch so I'm also thankful to the team of people here and with that I want to finish and thank you very much for your attention


Welcome to this IT Ops Talk video. My name is Oren Thomas and I am a Principal Hybrid Cloud Advocate at Microsoft. In this video, you'll learn how to understand the role of ESU in supporting Windows Server beyond the end of extended support. Enable ESU on Windows Server with Azure Arc. Use multiple activation keys to enable ESU for non-arc enabled servers. Create and allocate ESU licenses for Arc enabled servers. The Windows Server 2012 R2 operating system is beyond the end of Microsoft's extended support period. Imagine that your organization presently doesn't have the resources to migrate the workloads hosted on Windows Server 2012 R2 to new servers running Windows Server 2022. As a stopgap measure, you'd like to take advantage of the extended security update ESU program for the Windows Server operating system. When you enable extended security updates, your organization will have access to several years of update support beyond Microsoft's existing extended support window. Enabling ESUs provides your organization with time to migrate workloads to a new Windows Server platform. Extended security updates ESUs for Windows Server include security updates and bulletins rated critical and important for a maximum period of time from the end of extended support, depending on the version of Windows Server. ESUs don't include new features, customer requested non-security hotfixes, or design change requests. ESUs are available free of charge for servers hosted in Azure, and available to purchase for servers not hosted in Azure. The extended security update ESU program is a last resort option for customers who need to run certain legacy Microsoft products past the end of support. Windows Server long-term servicing channel LTSC has a minimum of 10 years of support, five years for mainstream support, and five years for extended support, which includes regular security updates. When you get the extended security updates, depends on which version of Windows Server you're using and where it's hosted. The table on the screen shows the ESU duration and end date for a variety of Windows Server operating systems. After the period of extended security updates ends, Microsoft will stop providing updates. One of the aims of the ESU program is to get customers to migrate workloads to a newer version of Windows Server rather than to stay on older editions in perpetuity. How you get ESUs depends on where your server is hosted.  Virtual machines hosted in Azure or on Azure Stack HCI running versions of Windows Server where ESUs are available are automatically enabled for ESUs. These updates are provided free of charge. There's no need to deploy a multiple activation key MAK or take any other action. Extended security updates are also free of charge in other Azure products such as Azure Dedicated Host, Azure VMware Solution, and Windows Server VMs hosted on Azure Stack, Hub, Edge, and HCI. Customers in these environments should contact Microsoft support for assistance, as your Arc-enabled servers. If your servers are on-premises or in a hosted environment, you can enroll your Windows Server 2012 and 2012 R2 or SQL Server 2012 machines for extended security updates via the Azure portal. Connect through Azure Arc and you'll build monthly via your Azure subscription. You can also enroll programmatically at scale through as your CLI, ARM APIs, or Azure Policy, non-Azure physical and virtual machines. If you cannot connect using Azure Arc, use extended security updates on non-Azure VMs by using a special multiple activation key MAK and applying it to the relevant servers. This special MAK key lets the Windows update servers know that you can continue to receive security updates. ESUs are automatically delivered to Azure Arc-enabled servers if they're connected and enrolled for ESUs through Azure Arc. You can enroll in ESUs at scale by using Azure Policy or the Azure portal. Once enabled, you'll build monthly via your Azure subscription. When you use this method, there is no need to activate special product keys. Customers who cannot connect to Azure Arc to apply ESUs can use multiple activation keys MAK through Microsoft 365 Admin Center. With some versions of Windows Server, you may need to install the servicing stack update and extended security updates licensing preparation package that are available from the Microsoft download center before they can be enabled for ESUs. Activation occurs over the internet. For computers that are unable to directly communicate with the internet, you can activate ESUs using the volume activation management tool VAMT in conjunction with event ESU configuration file. ESU updates can be delivered through Update Manager, Windows Server Update Services, Microsoft Updates, Microsoft Endpoint Configuration Manager or third party patch management solutions. Windows Server 2012 and 2012 R2 extended security updates are available at no additional charge on Azure Stack HCI. Windows Server 2012 and 2012 R2 servers running on Azure Stack HCI can be enrolled in extended security updates using PowerShell. You use the extended security updates section of the Azure Arc page of the Azure portal to create ESU licenses that you can then assign to Arc-enabled servers. The licenses tab of this page is shown on the screen. This page shows two different licenses, standard edition license and the data center edition license. There are also a different number of license cores and core types visible on this page. To provision an ESU license, you select the create ESU license option on this page. When performing this step specify the Windows Server SKU either standard or data center, type of cores either physical or virtual, number of 16 core and two core packs. If you choose to license based on physical cores, the licensing requires a minimum of 16 physical cores per license. If you choose to license based on virtual cores, the licensing requires a minimum of eight virtual cores per virtual machine. Licensing virtual cores is appropriate for scenarios where you may be running the VM on a third party host or on a third party cloud. Virtual cores are also an appropriate choice when running Windows Server 2012 and 2012 RA2 VMs on versions of Windows Server that are still subject to mainstream or extended support. If you're licensing a server used for virtualization, the standard licensing can be applied to up to two hosted virtual machines whilst data center licensing has no limit to the number of VMs it can be applied to. Depending on the number of VMs hosted on the virtualization server, it may make sense to choose the data center license instead of the standard license. You have the option of provisioning extended security update licenses in a deactivated state so that they don't incur billing from creation. You can then activate these licenses when you're ready to provision them. You are also able to modify the number of cores associated with the license after provisioning. To link an existing ESU license to an Arc-enabled server, select the eligible resources tab in the extended security updates section of the Azure Arc page in the Azure portal. This page is shown on the screen. Select the Arc-enabled computers for which you wish to enable ESUs and then choose enable ESUs. On the enable extended security updates page shown on the screen, choose the ESU license that you wish to allocate to each computer. If you haven't already created the ESU licenses, you can also create a new ESU license when performing this step. The extended security update program is a last resort option for customers who need to run certain legacy Microsoft products past the end of support. Virtual machines hosted in Azure or on Azure Stack HCI running versions of Windows Server where ESUs are available are automatically enabled for ESUs. If your servers are on-premises or in a hosted environment, you can enroll your Windows Server 2012 and 2012 R2 or SQL Server 2012 machines for extended security updates via the Azure portal. Connect through Azure Arc and you'll be billed monthly by your Azure subscription. If you cannot connect using Azure Arc, use extended security updates on non-Azure VMs by using a special multiple activation key MAK and applying it to the relevant servers. This special MAK key lets the Windows update servers know that you can continue to receive security updates. You can find out more about managing ESUs on learn.Microsoft.com by following the links in the video description. My name is Oren Thomas. Thank you for your attention and I hope you found this video informative and useful.


Over a quarter of a million Minnesota seniors were told in October that their Medicare plan would no longer be offered and they would need to find a new plan for 2019. Many seniors were able to make the switch easily, but for some families the switch has been more complicated than they could have ever imagined. Our Anthony Scott has more. There are three major types of Medicare plans available in Minnesota. A Medigat plan, a cost plan, and an Advantage plan. In 2019, the cost plan will only be available in 21 counties. So the government said that when enough people enroll into the Advantage plans, two or more Advantage plans, so a certain number of people are in those plans, then that triggers this event where the cost plans go away. The cost plan has been available since the early 2000s and offers seniors a relatively inexpensive full coverage plan which has been very beneficial because he's had a lot of major illnesses that have picked up the cost where we haven't had to pay hardly anything. Meet Kathy Frank. Her and her husband Gilbert have lived and paid taxes to Aiken County ever since they moved here in 1980. The cost plan is not being taken away in Aiken County, but the Center for Medicare says the Franks live in Crow Wing County, where the cost plan will no longer be available. We've never lived in Crow Wing County. Right now, we're not, we're hitting dead ends. All you can do is stay at the lower level. You can't reach anybody at a higher level at this point. The Franks have gone to the Social Security Office and the Post Office to get their address straightened out, but the Center for Medicare still does not recognize the Franks as living in Aiken County, so they have turned to their Senator. We're hoping that Senator Klobuchar will come through and tell us that CMS has straightened the database out and that we live in Aiken County, which we do, and that he will get a letter stating that the cost plan is still available to him. If the issue can't get resolved, the Franks would have to enroll in either an Advantage plan or a Medigap plan. The Advantage plan typically comes with high copays, and the Franks are not eligible for the Medigap plan because they live in Aiken County, which is keeping the cost plan. If he were to change on his own, he would have pre-existing conditions, and they wouldn't cover that. So we need to stay in the cost plan until they drop the cost plan in Aiken, and then we could get into the Medigap without pre-existing conditions being considered. Medicare plans are already confusing enough, and the Franks address issue has only made the process more stressful for them. Reporting from Aiken, Anthony Scott, Lakeland News. For anyone losing their cost plans, you have until the new year to enroll in a new Medicare plan. If you enjoyed this segment of Lakeland News, please consider making a tax-deductible contribution to Lakeland PBS.


I've been talking about making this resistive speed control for one of my boats and it's basically a thing where you got the batteries and the motor and wires connect them and then you just put different size resistors in the way to slow down the electricity to the motor and that's how you do your speed control and some of the energy gets wasted and people are pointing this out to me a lot that it's wasting so much energy but it's not as bad as you think and I'm going to show you some math in a second first I'm going to show you my resistive speed control isn't that awesome that's it that's the whole speed control it replaces so much stuff like this is I think this piece of wire this is a nichrome wire cost like I think it was like around ten dollars it replaces like a five or six six hundred dollar other thing anyway let me show you why it's not as bad as you think say you've got a battery here right and then you've got a motor here and let's say it's a hundred watt motor and when you connect the battery directly to the motor it runs at 100 watts now say if I want to run the motor at 50 watts I stick a big fat resistor in here to slow down the electricity a lot of people are under the impression that 50 watts are being thrown away wasted on the resistor so you're only getting half the energy and you're wasting the other half however let's let's just check the math on that all right we've got our battery here now let's make the numbers really simple so this is easy to do let's make this a 10 volt battery and over here we've got a motor that's 100 watts so you connect it direct there will be 10 amps going through here because 10 volts times 10 amps equals 100 watts which makes the resistance on this motor one ohm and that one ohm is going to make the math really easy for this and the reason the way you know this is one ohm is because let's see voltage equals current times resistance so the resistance equals let's throw that down there equals voltage over current so the voltage 10 divided by 10 equals one so the resistance on this motor is one so let's say we want to run the motor at not 50 watts our battery is still 10 volts now somehow we have to figure out how to slow down the electricity so only half as much is going in here now let's connect our one wire that's going to be the same and this wire we're going to throw a resistor in here that's going to slow down the electricity and it slows down the electricity by throwing away part of the voltage and to get 50 watts we know the voltage and the current is going to be the same because the current is one i mean the resistance is one so i'm not going to be able to get exact but like seven times seven equals 49 that's close enough to 50 so let's go with seven volts seven amps okay so we need seven amps running through this whole circuit and we want seven volts to be hitting the motor that means we have to waste three volts over here so we make this resistor three sevenths of what this resistance is so since this is one this ends up being three sevenths of an element which is not important at the moment but whatever okay so how much energy is actually being wasted by this resistor well let's see how much oh wait we know 50 is going into the motor right let's see how much is coming out of the battery we know that the voltage is still 10 10 volts and the amperage is seven times seven amps equals 70 watts so only 70 watts are coming out of the motor and uh 50 are making it to the motor that means we're wasting 20 watts we're not wasting 50 watts we're only wasting 20 lines of being like 21 or whatever but this is just rough numbers to give a give you a rough idea so technically this would be 49 watts and you'd be wasting 21 from right uh let's let's do another one so this is a lot better than than wasting 50 watts all right let's do another one here uh let's say we've got our 10 volt battery still and we still got our 100 watt motor that we want to run at 80 watts okay i'm picking 80 because nine times nine equals 81 which is close enough so we're just going to call that heat so technically this is 81 whatever so we connect that and then we connect this through a resistor that's going to waste one volt so that nine volts make it to the motor nine volts um since the resistance on this motor is still one nine volts is going to have nine amps going through and so 10 volts oh let's just check what's coming out of the battery 10 volts times nine amps is 90 watts coming out of the battery and 80 well technically 81 are making it to the motor so we're not wasting 20 all right let me just make this actually 81 okay we're not wasting 19 we're wasting nine so so we're wasting nine nine watts to get the 80 watt speed control so uh yeah you're not actually when you when you use a resistive speed control to reduce your 100 watts to these others you're not actually wasting 50 50 watts to get down to 50 watts you're only wasting 20 21 to get to 49 whatever and you know to get down to 80 you're not wasting 20 you're only wasting nine okay so there is another reason i really like this speed resist this resistive speed control actually two other reasons one i i kind of already mentioned that it's this costs ten dollars and it replaces like a six hundred dollar thing it's also super simple and uh here's the thing it replaces this complicated piece of electronic stuff and it's got like a solenoid you have to have with it and it's just all this extra crap you have to have it's got a that doesn't matter this is like a pretty expensive speed control so it's expensive it's uh you know hard to repair if it if it breaks like basically can't repair okay so that's this that's the second reason i like this resistive thing the third reason has to do with overall efficiency now this bit of reasoning is a vehicle specific thing this is the boat that i'm using it with and this boat only goes like 10 miles an hour top speed so almost always i'm going to be driving full speed so the only the only two circumstances i can really think that i'll use the slower speed controls or the slower speeds is when i'm starting the motor so instead of just jamming it into full speed i'll go uh first speed second speed go full speed so it's like a second right the other time is maybe if i'm parking at a dock and i need to come in slow so for a few seconds i'll run the motor slow other than that if i'm driving i'm just going full speed so like 99 percent of the time i'll be driving full speed now this fancy speed control thing is a very nice speed controller it works great and everything it boasts something like 98 percent efficiency or or something i don't remember what the efficiency is but it's it's pretty high high efficiency that means if i want to run the motor at 50 watts i'm only going to be wasting a couple watts not 20 right so the the lower speeds on the other speed controller are definitely more efficient however if i'm running full speed that other speed controller is still going to be using some energy it's going to be wasting some energy however with with the resistive speed control i just bypass the resistor completely connect direct this is more efficient than the fancy six hundred dollar super electronic mega speed control and if i'm going to be running full speed 99 percent of the time the resistive speed control is going to be more efficient overall it's going to be more efficient more robust cheaper everything about it is great and you know after i start using it i may eat my words but on paper it's all looking great and the funny thing is i originally wanted to do this because it was cheap and simple but then once i started doing the math on it i realized how good this actually is it is really really good particularly if you're driving full speed most of the time and with any luck three months from now i will not be making a video saying oh i was wrong


That was the concluding presentation for the layer, ladies and gentlemen. Can I please call up on Professor Divi Farid to address the gathering now? It's a midnight test with destiny. Very interesting. I had promised all of you that I'll keep myself short. But the only way to ensure that I keep myself short is never to give a mic in my hand. When should do that, I'm sort of provoked to speak my mind. I'll still try to keep myself short. I'd like to begin by congratulating all of you. I think you have spent almost two months, eight weeks of six to eight weeks or whatever. Fairly rigorous activities here. And I hope you enjoyed that time. I also hope that you learned a lot of things which ordinarily you would not learn. You would notice that under pressure you would have learned faster than what you normally would. Ordinarily, as students, you would learn very fast when you are preparing for exams. But ordinarily, the adrenaline does not flow. Whereas when you work here and you work in teams, and you work under time constraints with the kunnas to actually produce some good deliverables, you do learn fast. I would suggest that you write down these learnings, contemplate on those and spread the news. I, you see, IITs have not fallen from the sky. There's fundamentally no difference between the people in other places and people here. All of us come from the same stock, students, teachers or whatever. All right, there is a performance requirement so the J.E. rank decides. But I have learned over the years not to give a damn to the ranks and marks because individuals can actually do wonderful things independent of how they work in academic performance. This internship itself is an example where when we started several years ago, this is all Professor Avinash out his idea, we used to select people based on only their academic performance. Then it dawned on us that creativity may exist in large number of people who are unfortunately not able to translate that into high academic performance. And that is where he came up with the idea of software quota where people who can demonstrate their creative talent are welcome here as interns. I wish the IIT system for regular educational admission also does something like that. It's not possible to individually interview over 250,000 learners who give the advanced J.E. So be that as it may, but that is how it is. However, what is fundamentally important to understand is that the ethos in IIT system is significantly different than the one which obtains in other institutions. I hope you have had a glimpse of that ethos. By the way you work, just take the simple example of making the departmental lab available throughout the summer vacation. No other institute will generally do that. No other institute will actually permit such large number of interns to descend on you. No other institute will be able to provide tens of mentors who will actually spend time with you, try to make you understand something different. The projects on which you have worked are all related to activities under the national mission of education through ICT. So let me tell you something that has happened very recently. We had a project review committee meeting assessing our projects here. And I don't know what they went back and reported, they were obviously very happy with this. Out of about 150 projects which have been executed or which are still being conducted under the national mission by many institutions, different PIs and so on, they shortlisted 10 projects which will be presented to an audience of all vice-chancellors of the country. There is a mega event that is happening in Delhi, about 1000 people are likely to participate, all directors of central institutions, IITs, NITs, all directors or equivalent deemed to be university vice-chancellors of autonomous institutions and all vice-chancellors of the university. And that 8th, 9th and 10th is the event, on 9th the President of India is going to inaugurate that 9th event where these 10 projects will be dedicated to the nation. So as I said, out of 150 they selected 10 and out of those 10, 4 are being conducted at IIT Bombay. Now that's a great privilege. You did not know it, we did not know it at that time. But the work that all of you have done is actually going into one or more of those 4 projects and that is the continuation. We have always held that while what you contribute is important, the fundamental objective of this entire exercise is to ensure that you return back more empowered than what you were when you came here. I hope that objective has been achieved.  Try to spread that ethos, try to talk to your colleagues, try to talk to your teachers. There is absolutely no reason why every institution in the country cannot actually emulate and establish the same ethos of an IIT. There is no reason. People cite rules, people cite whatever systems, whatever, whatever. One fundamental system which comes in the way is the standard university system where you have set syllabus, where the syllabus does not change, teachers are often not adequately prepared to guide. These are the problems. But it does not mean that students, if they work collectively, cannot bring about this change in ethos. I would charge you with that responsibility of going back to your own institutions and start talking about things. Start changing the mindset of people. Tell them that facing hard problems may lead to frustration and may lead to a lot of hard work. But at the end, the enjoyment that you have of having learned something and having contributed something is so beautiful that it's worth fighting for. Many of your colleagues and students and teachers in your colleges would not be interested in doing this kind of, this is a different kind of. So I would like you to spread that ethos as far as possible. I would like to leave with you a few tips for your professional lives. Although you are a couple of years away, you are just completed third year, right? So most of you will be completing your undergraduate studies in one more year, some of you in two more years. But then you will face the world outside. And when you face the world outside, believe me, the professional activities of the 21st century are going to be significantly different than what they were earlier. In the 20th century, most of the engineering students after finishing their degree course would take a job and do that job formally. Today we do not even know what is the nature of the job vis-à-vis the degree that you are. Particularly computer science, IT and electronics people will have to contribute to solving large and complex problems belonging to all other streams other than computer science. Except those of you who actually end up doing further research and studies in computer science itself. But your job mostly will be to build applications ranging from Internet of Things to other embedded systems, to sensors, to networks, to commercial applications, to financial sector applications, all kinds of things. And you will find that you will have to learn a new thing very quickly, absorb it and actually produce a good solution. So treat this as a glimpse of a training. If you thought that these two weeks or two months were full of hardship, lot of hard work, etc., etc. Please note that rest of your life you are going to work like this only. There is no difference. And therefore you will have to find time in that busy schedule of yours in your professional life to enjoy life as individuals, as families and so on. Balancing the act is not very easy. Many of us have been doing it for like 45 years. You will also do that and you will learn to enjoy, learn to mix business with personal pleasure, family trips, whatever. But more important thing is that as professionals you have to discharge certain responsibilities and acquire some trades which are not necessarily built in you when you do your conventional courses and pass your degrees. For example, the amount of rigor that is required in your activities that you do is very slip-shod in terms of the conventional education. I will just cite one example of rigor. It is a mathematical rigor. If you want to talk about three variables or three values which are unequal to each other, you say the values are A, B and C. The typical notation that you use is A not equal to B not equal to C. This is not rigorous enough because A not equal to B not equal to C does not guarantee that A is not equal to C. So the correct representation is A not equal to B not equal to C not equal to A. Even in mathematics books you do not find this kind of rigorous representation many places. I myself learnt it when I came here to do my m-take having done my undergraduate studies in a college elsewhere when a teacher not in maths but an electrical engineering professor told us this. Curiously, instead of teaching electrical engineering in the first lecture, he started by asking a question, prove route 2 is irrational. All of you would have come across this proof sometime or the other. But if you have not, it's not very easy to prove it by induction. You have to apply your mind, do something. So rigor has to be maintained in every activity that you do. Metaculousness is absolutely essential particularly when you deal with large segments of software. You remember I was asking questions on testing, version control. These appear to be simple names but they become lifeline. I'll give you an example of testing in real life in our own project that has happened. I was talking to Abhilash who is our senior administrator. You talk about Git by the way. How many people have used Git for version control? Several people. So have you learnt to use Ansible? No. So Ansible is actually a tool which is used to manage a whole lot of configurations. It is not really a tool for version control. That is one part of Git. The point is why is it that you have not heard of Git when you are studying in your colleges? What is so special about Git? Now that you have used it, you know how to use it. Why is it that it is not becoming part and parcel of learning? Git is not a matter of any syllabus in our courses also. But we have labs. We have labs called software engineering labs where you have to learn to use Git and you have to use it. Otherwise you don't pass that lab course. It may be just a three grade course. Go back and try to impress upon your friends and colleagues and teachers that such learning are useful. It is not Git. Today it is Git. Ten years later it may be something else. Ten years earlier it was something else. The point is regular rigorous mechanism of version control, regular rigorous mechanism of testing are very critical. So I was telling you about how testing can impact production systems. I was talking to Abhilash the other day and he was telling me, so we have actually the IIT Bombay X which is the open source platform. So there is a team called development team which is led by Aparna and others advised by Abhilash. There is a team which is building MI software for blended operations. He said that we launched IIT Bombay X on 26 January 2015 and till then he has had at most two or three problems. That was the rigor with which release is tested before it is released to production. On the other hand the MI system which of course has more functionality and it is outside the main core had umpteen problems perpetually. Reasons because there were perpetual demands on change in functionality and genuinely the team did not have sufficient time for testing but the team never put its foot down and said that unless I get two weeks for testing I shall not release this version. So this is the importance of testing particularly when you build large systems and you will be building large systems in life and building large systems does not mean writing 50,000 lines of code yourself. Building large system means discovering a million lines of code written in 100 different modules and then selecting them meaningfully connecting them with small lines of code that you write. This is the API method of building systems and that is what you will have to learn and do in future. It's not an easy thing. Thoreau understanding of basic concepts is absolutely essential. Saksint articulation is very important. I was very happy that the glimpses that I had people who were making presentations were making good presentations. Can you say the same thing about all your colleagues in your class back home? I have noticed that in most colleges in India the ability to articulate is not developed. Again, because there is no course in the syllabus which says except I think all of you had some communication skills course. First year taught by Humanities Department, neglected by everybody. And that is because you don't realize the value and importance of articulation. It's your ability to articulate both in written and verbal form which will permit you to communicate very succinctly to others and you will be communicating with thousands of professionals across the world and unless your written articulation is perfect you would have tremendous problem. Make sure that you develop that ability and retain that ability. Professional ethics is the last point that I would like to talk about. There are a lot of conflicts. Each generation has greater aspirations than the previous generation and this has been going on for 4,000 years of recorded human history and possibly for 10,000 years of all. That is the reason why people take competitive exams, people go to one institution over there, people choose CS over other disciplines, etc. It's a competitive world and therefore you choose this in the hope that individually you and your family can do very well or better than others by following this dream. Unfortunately these aspirations sometimes lead to short changing yourself in the long run. You may compromise this. You try to put your own aspirations of generating material wealth over your own long term interests and the long term interest is a professional life spanning 30, 35, 40 years. There are people in the computer science branch who have joined as professionals and in the first three years they have changed three jobs because somebody was offering better salary than the earlier one. There are people who actually sign a bond and break a bond as easily as possible. These are trades which are contraindicated to long term good professional life. Don't make a commitment easily but once you make a commitment even if sky falls on your head you shall not waver from that. That is the first fundamental professionalism, no matter what. So value systems, these are part of value system. I don't care if your value system is completely different from the one which is professed by your own family or professed by teachers like us. The point is do you have a value system? Do you have 1, 2, 3, 4, 5 principles which are principles? Once you call something a principle it is invalid. If you change that principle, if you compromise with that principle it is no more a principle. It was always a matter of convenience. You decided on these four principles to be your value system because it appeared convenient at that point. But five years later you suddenly find no, this principle is coming in the way of your progress in material life and then you are tempted to scratch that saying Oh, I thought it was a mistake. I will replace this principle with that principle. That is not a principle. So please develop your own professional ethics in an extraordinary fashion and this is the time when you can start doing it. You cannot do it later. Of particular importance is the fiduciary ethics or ethics related to money because money is the greatest character of thought. If I am not very careful I may be tempted to take some shortcuts which will violate some very fundamental principles which you yourself will not like that you have done it but you will do it because of that temptation. First time you fall to that temptation second time you will be encouraged Third time you will do it more and that is a guaranteed do. You may succeed in fooling a large number of people for 40 years of professional life but after 40 years when you retire will you be able to look yourself in the eyes in the mirror? Forget 40 years later. You will be able to do that even next week after you have done something wrong and that my dear friends you have to guard against the temptations because temptations related to money are enormous. There are people who will fudge bills you might have heard of so many gory stories people submit TA bills which are wrong TA bills. They forget that a TA bill is a reimbursement of the expenditure incurred and not a mechanism of earning money. There are senior corporate people who laughingly tell me that they have a car because car is the earning member of the family because their company gives them allowances. They do not have the truthfulness to say that I spend only so much money on my car and therefore I will not accept this. It does not happen. I will give you couple of examples of the poor example of what kind of should I say practices we are setting. So this is an example of a father who is shouting at his son. His son has stolen a few blank answer books from a school. He wanted blank papers to write rough work, whatever. He had some notebooks but these blank papers are a bunch. He stole it from the school. Specifically the school watchman caught him, reported it to the principal and principal reported it home and the mother was shouting at him and when the father came in she told father see your son has done this. Father was really mad with rage. Why did you do that? Are the papers which I bring from my office and give to you are not sufficient? What kind of role model are we putting in front of children? I think children are not sensitive enough to understand this. They make their own judgment and unfortunately they form a value system element in their mind. We say this is alright against this. Consider extreme examples. I don't know you all have heard of Sir Vishweshwariya who built the great dam and he was the divan of Mysore. He was on a tour and he was staying in a dark bungalow in a small town. Those days there was no electricity. So he had a laltin. In that laltin he was reading something and writing something. A friend of his came late evening to meet him and he greeted him and when the friend sat down he said just one minute. He went back, took out another laltin, lit it and extinguished the first one and the friend said why there was oil in that it would have still worked. He thought that oil is about to finish or something. Vishweshwariya laughed and he said that was government oil. This is my personal oil. Can you think of any better example of fiduciary responsibility than this? So please ignore any number of cases that you may see around you where people constantly fall to the temptation of taking shortcuts and compromise. Ignore that. Learn to establish a fiduciary responsibility to yourself and remember you must not only do correct things but they must also appear to be correct. Here is an example that I learned from a colleague of mine Professor Sinha was a warden of hostel 7 and during one summer I found him frequently going to hostel 1 to eat his lunch. So by the way hostel 1 food was known to be the best because it was the post graduate hostel at that time which means all rich people. Only post graduate students got scholarships. Others had to depend upon the money sent by their parents. So the mess bill in other hostels used to be 92, 94, 95 rupees per month. In hostel 1 it used to be 106, 107 and so on. But hostel 7 food was also known to be very good food. So I was just curious and one day when I met him on the road he was coming back from hostel 1 and I was coming out of the old computer science building and moving towards my home and I said Sinha sir, he was known to visit his hostel twice a day. It was that meticulous. So I said Sinha sir, you get good food at hostel 7 why are you going to hostel 1? And you know what he smiled and said Patak sir, everyone will see food in my hostel but no one will see it giving money. See he would pay for everything that he would eat. He would do so even in hostel 7. But he is concerned that 100 students will see him eating in hostel 7 and many of them may presume that because he is warden he is eating free here. Contrast it to several wardens who actually enjoy free lunch and dinner. Now this is an example of amazing correctness of the fiduciary behavior. I would strongly suggest that since you have not yet been tempted by real life you know for all 30, 40 years you will have such temptation. Right now try to form some principles around these and keep these in mind. And remember once you define a principle you have it is invalid. I have built my own life on three simple principles which have not violated. It has not violated till the end of my life. I think you should make such principles. And the last thing I would like to say is my favorite. You all heard of the word dew. You have seen dew drops. They look beautiful on the petals of trees or flowers. I have a special interpretation for the letters of the word dew. For me D stands for dreaming big. As late Dr. Abdul Kalam said you dream small your achievements will be limited. You dream big. You may not achieve the biggest dream but you will work much harder and go to much higher high. So dream big in everything that you do. For example attempt to become an entrepreneur is considered very risky and is not tried by most youngsters either because they themselves don't want to take risk or their parents don't want them to take the risk. Going forward in this country we would require a much larger number of entrepreneurs to come up. The city of Bangalore today is full of startups and what are those startups? They all have some interesting queer ideas. They want to build business on it and they are working hard on it. Sometimes they may fail, sometimes they may succeed. But ability to take risk and doing something is a different flavor. So I would like you and your friends to think about those things. But dream big in any case. The later E for me stands for enjoying life. You must enjoy every moment of life. Whatever you are doing, you are working, you enjoy that work.   You are fighting with a friend, enjoy that. You are arguing with your brother, sister, father, mother, enjoy that. Enjoy everything. Why? Because every instance that comes goes away and it will never return back. Time is extraordinarily different from any other commodity. Any other commodity you lose, you can reacquire it. You lose money, you can re-urn it. But time once lost is gone. It will never come back. So every instance is precious. And therefore don't ever let any kind of frustration that hits you on any day to prolong. Because when you prolong that frustration, that frustration results in hurt and aches in your mind. And you may spoil not one moment, not one day, but one week or maybe a month just getting frustrated. It's not worth it. I've had a simple principle which has helped me. Whatever calamity happens, I feel like crying. I cry, I shout at the world whatever, whatever that day, that evening. I go to sleep and next day morning when I get up and I see the sun rising, I say, ah, a beautiful day. You must not permit more than 24 hours to elapse before you have recovered from any failure. Failures will happen. Failures will happen. Life is not hunky-dory. Not everything will work. But recovering from that failure very quickly is important. So remember this. Enjoy life.  And the last W is for working hard. People smarter than us have attempted for 4,000 years to find a substitute for hard work. None has succeeded. If you want to achieve something great because of your great dreams, if you want to enjoy every moment of life and yet make those achievements, the only way you can do that is by working hard. So dream big. Enjoy life and work hard. And this is an IIT style question paper. Any two of the three is not an option. Why I say this is because I've been saying this year after year, about 15 years ago, there was a student, a batch of students who had joined different jobs. And they used to regularly come and say hello or something like that. And one of them I said, hey, such and such fellow is working in that company. Where is he now? Oh, you don't know, sir. He was thrown out of that company after one year. I was quite surprised. He was a smart fellow. He said, sir, he took your advice of dreaming big, enjoying life and working hard very, very seriously. Except that he did only one of the three things. He enjoyed life. So anyone or two out of the three is not required. You have to dream big.  And please remember this. Every one of you, every one of 1.2 billion Indians is capable of creating history. You just have to say that I will do something extraordinary in life and you will do it.  It does not matter. It's just your mind which says that, okay, our next 30, 40 years I'll do something extraordinary, something big. And you will do it. That's all I have to say. Thank you so much. And once again, congratulations.