So, I think we're ready to move on then to our last working group. Mark, you have the cleanup slot here, so. Oh, terrific. Since I had the... Since you had the opening... The biggest pleasure of leading off the meeting. Dawn is going to present the slides on behalf of our group. So, we're going to use the term integrated approach to describe any sort of situation in which we use multiple data types to assess the functional role of a gene or genetic variant and phenotypic variation. The types of data that one might use in the integrated approach are quite diverse, and here's a list of some things that have already been used in the past. Lists of causal genes or known associations, data from genome screening in unbiased fashion such as whole genome expression data or protein-protein interaction data, as well as genome annotation data from things like the ENCODE project, transcription factor, binding sites, epigenetic marks. We could also consider things like semi-structured literature such as PubMed abstracts that can be used as fodder and text mining applications, and model organism data such as the very rich mouse phenotype data curated by the mouse genome informatics group at Jackson Labs. There are quite a number of challenges one would face in taking the integrated approach, and our working group decided to highlight one particular challenge in this form, which is a challenge or perhaps even a danger depending on how you see it, and that's the new opportunities for storytelling that arise when you start considering extremely high-dimensional data. So one could imagine a scenario like this where you take a list of candidate causal variants for a disease, in this case Crohn's disease, which might have equivalent levels of statistical evidence just on the basis of the genetic data, and align those with the rich high-dimensional genome annotation data such as the ENCODE data, and using a strictly algorithmic approach, identify that SNP which has the most overlap with a relevant set of annotations and anoint that as the causal variant. I don't know if this kind of analysis has been presented yet, but one can imagine it happening in the near future if not. So I'm not disputing the fact that or we're not disputing the fact that functional annotation isn't relevant for prioritizing and identifying causal variants. Indeed, there's unequivocally an enrichment of functional annotation in disease-associated or phenotype-associated SNPs such as DNA's hypersensitivity sites, but this is a statistical observation, and we need to use rigorous statistical approaches when integrating those observations into our genetic analysis. It's not a black-and-white scenario. So for the purposes of this talk, we're going to frame the discussion, hopefully, by presenting first three use cases in which groups have used the integrated approach to identify new genes or genetic variants to be causally implicated in phenotype variation. There's not meant to be an exhaustive set of examples. In fact, probably not even necessarily the best set of examples that one could imagine, but those are examples that we are familiar with. The other thing that distinguishes them is that they do attempt to do data integration in a model-based framework which we highly applaud and would like to promote for future people that want to use the integrated approach. So our first use case involves using networks to implicate a gene in a complex and highly multigenic disease. The use of networks for doing this kind of analysis has been around for certainly five or ten years. It's a highly rich and prolific area with many contributors, and we're just using one such example today. So the paper that we'll present, it describes an approach called DAPL. It came out of Mark J. Daly's lab. The idea is pretty straightforward that we start off with a set of linkage intervals or, sorry, association intervals that were identified in a genome-wide association study or set of GWAS. We look down underneath those association intervals and pull out all the genes that exist in those intervals. We then turn to publicly available protein-protein interaction data and build gene networks on the basis of these PPIs, including not only the genes that are in the association intervals, but perhaps closely linked genes that fall outside of the association intervals. Of course, you give me a list of genes and I'll give you back a network. The fact that we have a network doesn't mean that it's necessarily appropriate for learning anything new about a disease. So what we can do is actually test for an unusual enrichment of connectivity between genes and different association intervals by comparing the connectivity of our observed network to a null distribution generated by something like a permutation strategy where we generate random networks. And if you observe a statistically significant enrichment of connectivity in the observed network, that gives you the confidence that there's actually useful information that can be used to learn new things about disease pathogenesis and genes that might be involved in these diseases. Having done that, you can then nominate candidate genes based on where they fall within the network. Those could be, again, genes that are in a large association interval or genes that fall outside of the association interval. And we can further narrow down that candidate gene list by cross-referencing them and their expression patterns in tissues of relevance to the disease that you're interested in. So in this paper, they apply DAPL to a couple of immune-related diseases, rheumatoid arthritis and Crohn's disease, and we see that the networks that fall out of these GWAS catalogs are highly enriched for connectivity compared to random networks with similar types of properties. You can define candidate genes based on those disease networks and see that they're highly enriched for expression in the immune tissues of interest for these two diseases. But the important thing is that this integrated approach actually has something useful to say about implicating new genes that weren't previously known to be involved in a complex disease. So 293 genes were identified in the Crohn disease network and also expressed in the relevant tissues. 10 out of those 293 at the time of the analysis were not associated with Crohn disease but were later confirmed by GWAS metal analysis as being Crohn's disease associated. So we actually learned something new about genes that are involved in Crohn disease using this integrated approach that we couldn't have learned strictly from the genetic data. The second use case involves using non-coding annotation to establish causality for non-coding DNA variation. Just a quick overview on non-coding annotation that I observed that it's a rapidly growing large body of data as we witnessed in the massive publications of the ENCOBE project over the last few weeks. Importantly, disruption of these annotations are getting to the point that they're interpretable from a sequence perspective. And also a very important point is that these annotations allow integration of germline genetic variation with the biology of somatic cell types and tissues. This is something I think is an underappreciated point by pure place statistical geneticists. So the paper that we'll discuss came out of the labs of Jonathan Prichard and Matthew Stevens of the University of Chicago. This is nominally a genome-wide CISI-QTL analysis in which they took whole genome expression data from 210 samples from the 1000 Genomes project, linked that up to the 13 million SNPs that have been identified in these samples and mapped gene expression phenotypes to these 13 million SNPs. However, we're presenting this today as a key example of how non-coding annotation can be used in a Bayesian statistical framework to form priors on causality to actually make statistical arguments about which SNPs might be causally associated with a gene expression phenotype. This modeling framework, which I'll call the hierarchical model, was first formulated in response to this thing that you might call the LD problem, which is this curious property that the population genetic property of linkage disequilibrium, which enabled the massive success and also confounds our ability to find map that calls a variant in a lot of haplitid context. This is a classic example of the NEGR1 locus. This is a haplotype that's associated with obesity and that in certain populations contains a dizzying array of types of variation that are in completely disequilibrium, including a large deletion and many SNPs nearby. It's impossible on the basis of some population genetic samples to disentangle the functional roles of different highly linked variants. The intuition behind the hierarchical model works out as follows. Imagine that you've done single point association analyses on a number of SNPs in the vicinity of a gene with which you've measured gene expression values for. This might be a one megabase window centered on your gene. You've unequivocally established the fact that there is an EQTL in the vicinity of this gene, but the extensive LD in the region confounds our ability to actually pinpoint which of the many variants is driving the association signal. However, we're doing this not in a bubble, but in a genome-wide context. There are many, many other genes which we've done the same analyses for, some of which might have more informative haplotype structures in which we can unambiguously pinpoint a single causal variant. Now, if we assume that there's some shared properties of bona fide cis EQTLs that we can measure in genome annotations, a reasonable strategy for arbitrating these more complex, sort of, uninformative haplotype structures is to combine our set of bona fide SNP EQTLs and identify which genomic annotations are predictive of EQTLness. So this is where the hierarchical aspect of the modeling comes in. So we have our first pass analysis gene by gene, pulling out individual cis EQTLs. We then lump together bona fide cis EQTLs and estimate weights on different genome annotations, which we might call lambdas, and these weights are telling us about the relative importance of different genome annotations and whether or not a SNP ends up being established as a cis EQTL. So the fact that we're assuming that these lambdas apply across the entire genome makes it hierarchical. That's the top level of our model. So once we've fit these lambdas, we go back to the original single point statistics, which we might represent as a p-value or a base factor, and we treat these lambdas as priors on those single point statistics, reweighting them with this new prior information. I'll say this again with a slightly different visualization to kind of hopefully drive home the point, the rationale here. So here's a gene in which we have two SNPs linked to expression which roughly the same amount of statistical evidence, and say the identical amount of statistical evidence. We fit the hierarchical model considering genes across the entire genome, some of which have more informative haplotype structures, and we learn about several annotations which are predictive of EQTL-ness. We can now see that SNP1 sits in three annotations which have strong effects on the probability of being an EQTL where SNP2 sits in only a single annotation. We can then reweight our prior, using this prior information, we can reweight our confidence in which of these SNPs is causal and find that SNP1 is much more likely now to be the variant driving gene expression variation at this gene. So this analysis was done with an earlier set of encode data. They tested over 50 encode annotations, and they found a handful of things to be predictive of EQTL-ness, including proximity to gene, a handful of histone marks, DNA1 hypersensitivity sites, core promoter motifs, and transcription factor binding sites. This slide is meant to drive home the fact that we're not just dealing with a simple algorithm that takes a set of SNPs and pulls out the one that has the most encode annotations overlapping it, but we're actually dealing with the proper statistical model which has predictive power. So what this is is a validation of the model using the following kind of approach. The authors took 100 genes from the genome in which a single SNP could be unequivocally anointed as the causal SNP in a driving gene expression variation. They removed those 100 genes and fit the hierarchical model to the remaining data. They then went back to each of these 100 genes and said, based just on the prior that we fit from the hierarchical model, what is the rank out of all possible candidates in the region, and since we're dealing with the one megabase region there's about 1200 candidates per gene, what is the rank of the known bona fide EQTL out of those 1200, just based on prior probabilities, and this histogram is capturing the distribution of those ranks. Let's just focus on the red histogram which is the fully specified model. Now remarkably for 45% of those 100 genes the true causal EQTL was predicted to be in the top 15 of 1200 of 1200 candidate SNPs just on the basis of the prior. So it has high predictive probability and you can compare that to how you would do if you were just randomly picking SNPs without a model which is indicated with this solid black line at about 2%, 3%. So I would call this kind of strategy perhaps building evidence by analogy. So what we're doing is taking a set of variants that we have a very high confidence in as being EQTLs, finding what the properties of those things share in common, and then identifying analogies between variants of unknown significance to prioritize based on these analogies. So our third use case is taking this paradigm of evidence by analogy and moving it into the rare genetic variation rare disease paradigm. This is a paper from Han Brunner and yours Veltman's group in which they did whole exome sequencing on 10 trios with sporadic cases of idiopathic mental retardation. The group identified 9 de novo mutations in these 10 samples and they claim that 6 of these are likely to be pathogenic based on gene function evolutionary conservation and mutation impact. This claim was made on the basis of a statistical model. They're taking unique mutations that have perhaps never been seen before in humanity and using a statistical model to come up with a p-value although I'm not sure the p-values are reported here to come up, you could potentially come up with a p-value on whether or not these things are considered pathogenic or not, it should be considered pathogenic. The modeling framework is pretty straightforward, it's easy to follow. They take two summary statistics of pathogenicity a Grantham score and a Philo P score and they use training data, they use dbSNP as a representation of benign variation and HGMD as a representation of disease variation and they fit basically what you could consider a classifier model, a two dimensional Gaussian mixture model using these two summary statistics to separate out benign from pathogenic variation. You can then take the observed Grantham scores and Philo P scores for the de novo mutations and assign them to one of these two spaces, pathogenic or benign, with some sort of statistical confidence. Now I'm not saying that I necessarily approve of the content of the model, but I do approve of the form of the model and I think it's laudable that we try to start to come up with statistical frameworks in which we can say something interesting and statistically rigorous about the n equals one scenario. So the take home points from this very whirlwind tour of the data integration world is that these model based approaches are essential for integrating secondary data. Networks are key data structure for integration which I think we should all get more comfortable with going forward. There's a wealth of non-coding annotation available for integration and maybe a potentially controversial point that n equals one may be tractable with data integration using large natural variation data sets like DB SNP and HGMD. I'll toss up a long list of potential discussion questions in case there's a lot of things to talk about. Thank you very much. All right. Comments. David. I guess one challenge with the, I think you're kind of alluded to this, one challenge with the Nova Paradigm paper is that the characteristics of the mutations tell you whatever they tell you and then you'd have to consider that alongside the fact that if those are mostly causal mutations we actually are missing the other expected mutations that we would get under control. So how do you weigh that in? The fact that there are in fact fewer mutations than we would expect if there were no causal mutations in the data set at all and surely that ought to be something pointed out when you're carrying out an analysis like that. Of course integral to this and I would say we discussed last night rather pointedly that some of us didn't actually think that that was a particularly valid example to use. Primarily because you absolutely cannot compare the properties of de novo variation to the properties of inherited variation they're quite different. The de novo variance in perfectly healthy people are very different than what's in dbSNP and there's no way around that. That I think leads to the false impression that more of those are relevant than they probably are. I was just going to say given our focus today of finding variants that we feel confident implicating do you think that we've implicated those six variants there? It doesn't seem like it's the kind of thing No, not those six variants in that paper I think what we think is that it is conceptually possible at least it's conceptually valuable to think in a very rigorous way about how one might integrate other sources of data into that. So if we're faced with our de novo variants where we have twofold excess of de novo loss of function variants, then certainly other types of information what we know about those genes whether they are, for example using some materials models to predict which ones are more likely to be haploinsufficient genes versus recessive knockout genes and so forth might be of value and in addition to the straight statistics if we can integrate them in a rigorous statistical fashion now what we have to be very clear on and I think what Don was emphasizing here are examples where you can see a path to integrating other data sets in a principled way to enhance the statistical analysis not to replace the statistical analysis or not to just present the data and then say oh and these ones are interesting because of such and such over here and distract from try to cloud or distract from the statistics but actually to supplement them and I think it comes back to sort of one of the things we were talking about last night and then we were talking about again this morning is that the statistics with small sample numbers may be challenging but we can't abandon them simply because it's hard to reach thresholds and similarly integrating other types of functional data into those statistics is not easy and has to be done very very carefully because there's biases in our genetic data in terms of what we cover in our data sets and what we don't there's biases in protein protein data that's available on the web, expression data but we need to be able to figure out ways of overcoming those and bringing those data together in a statistical framework Mark Gerstein I just like to amplify on what the two things just said and also respond I mean I think one of the key things about the last case study is that if we have really well worked out catalogs of natural variation then we can go to an individual case and we can think about it in a statistical way I mean the idea is not to just think of n equals one as n equals one but to think of n equals one next to this very large catalog of what we expect variation to be and so we can better appreciate that individual that one individual as long as you compare apples to apples when you do that and for you know for I mean just specifically I mean you know there is not strong evidence in that paper I mean because there's actually very compelling contrary evidence because there are too few de novo mutations so this is that you know in fact it's a good example of what not to do really but if you are going to make the comparison sorry there's no authors here that paper sorry sorry but in general if you are going to try to make an argument based on you know I agree with you by comparing the properties of mutations that you see in a single patient to others that you've seen you do have to make it comparable and you know and one limitation there is that we do not have actually a big collection of de novo mutations from individuals without specific diagnosis to work from right now we don't know we'll just shout Steve come on we can hear you to say about DB SNP in the thing we were just talking about integration and comparing to the the corpus of natural variation I think it's important to realize DB SNP does include variants with clinical significance that was mentioned earlier this morning but we do it export now which is a subset of DB SNP which is just the variants with no known clinical significance so I've sent the e-mail out to a couple of you earlier this is a new product DB SNP is doing it's in combination with ClinVar so wherever we have any kind of pathogenicity that feeds back into the database that's flagged and so we're doing a weekly dump that will be the variants of clinical significance and those without so if you want to do that kind of screening that's the proper subset to use not all of DB SNP just this seems the group that probably can best use that so did we want to talk a little bit about some of these discussion questions because there are quite a number of them where there's some that you guys were really stumped on Don and Mark or really split on they took the you know tack that we didn't necessarily want to present ourselves as having made firm conclusions about all these things but to have an open discussion about whatever topics in this area were of interest to people we presume too much going in then people have a tendency to end up defending their positions that they pre-stated rather than openly and constructively engaging well and one issue that probably people around this table would know well and could discuss is the key untapped data resources so and I think we've heard one of them which is all the data in clinical labs that are not being captured so I don't know if that's the key one it may be but perhaps Heidi or David could comment on that sorry the question is can we get this no no the question is they're asking what are the key untapped data resources today and it sounded as though one of the key and my question is is it the key untapped data resources what's in clinical labs so is that like the biggie and everything else pales in comparison or are there other things we should consider well it's hard to put things into relative perspective but it's certainly n key untapped resource I guess I would say but whether it's the best and I think one of the limitations of clinical labs is phenotypic information and so we will get interpretations but there will be a paucity of clinical data associated with them in terms of how this data is collected today and I think we can all agree that clinical data would be a huge advantage in these efforts we were kind of hoping as well from the integrated approach group that this is the time to start integrating everything today a lot of what we talked about so for example at the end we're talking about an integrated framework and this gets into what you guys talked about with the levels of evidence etc do we think that we can come out of here today with making recommendations about integration about some kind of framework that how we can wait different types of evidence is that too far are we willing to go out on that limb and actually assign levels I just want to say we did talk yesterday a bit about aspects of integration and I think there's two points that are relevant to raise here first is that it's just to integrate data especially from very disparate databases you really have to think about how the databases are structured, can you bring those together do they have are they on common cell lines are they on some type of thing that can fit together and so that really does require some communication and then the other thing that we talked a bit about was that once you can do that the whole point of doing it in a statistically rigorous way and trying to do more in integration than just simply overlapping something I guess maybe to throw a scenario which is similar to one that was raised earlier so if you had let's say that you had done a rigorous integration in a research discovery effort and there was a gene which just from the genetic data alone didn't reach the standards of causality but all of the other integrative stuff it was the most likely gene where there was clear evidence of excess of de novo mutations or whatever and then you have an exome sequence for a patient with the same sort of phenotype who then ends up with either a very rare missense variant or a de novo variant missense variant in that same gene for which there was good strong evidence what should the clinician who's ordered that exome sequence tell the patient is that a variant contributing strongly to that patient's phenotype or not or should they not report anything back what level of how does that clinician have access to that information has it been published that this is a there was a paper that came out and it says ABCD3 is the most likely here's 10 genes that we think are very strong candidates for causing autism whatever based on that they are presentations and they fit into the network and et cetera et cetera and now they're doing exome sequence and there's a very rare or de novo take your pick variant in ABCD3 in a patient with autism shift the question a little bit I think it's well posed but I think the answer is right now there's a standard for the type of gene that we report back to that we instruct clinicians might be useful to report back to patients and so forth so the question may be how do we advance genes given the enormous wealth of research that's going on of that flavor what's the standard we set as a community for advancing a gene into that set so if the original study had had five de novo hits in this gene and none were ever seen in the 20,000 other exomes that we looked at and the significance of that was 10 to the minus 20 then that is something which we would probably say we need to think about as a community a way to advance those into the pantheon of clinically interpretable things perhaps still not in the way that we have a set of really clear 100% penetrant things that we know about but that is a good thing I think this group could wrestle with may not be able to wrestle with it this afternoon as we start to fly but I think we heard from Heidi a very cogent example last evening of where this is incredibly important where in your example of the prenatal testing they were looking for a cardiac hypertrophy variant and had found one in the child who died and didn't find it in the prenatal testing and ended up having a severely affected child so clearly not that variant must have been something else so does that information get captured somehow that this wasn't the causal variant even though it really looked like it should be and we certainly capture that in the subsequent interpretation we write for that variant in the next case we see where we each time we add on our newest knowledge and some of that is supportive and some of that is not supportive and so we continue to keep that story going and it kind of sometimes oscillates back and forth as to what we think about a variant but that's a check against it it doesn't rule it out and it's still I actually think that that variant is still implicated in disease probably in a mild way but it's not the only piece of the story in that family and I think that's actually one really critical piece that sometimes doesn't get talked about is we say is the variant pathogenic or not but it's a separate question to say is that variant causing disease in that patient and an example of this is there are mild variants and when I do hearing loss testing and I find homozygacity for the M34T variant connects in 26 and the patient is profoundly deaf I say I don't think that variant is actually causal for their deafness but if I find homozygacity for that variant in a mildly hearing impaired patient I say I think that variant is causative they both have hearing loss they're the same exact phenotype but one's mild and one's profound and so I interpret that pathogenic variant two different ways and I think that's a subtlety that is sometimes very challenging to deal with okay I don't think anybody would mind if we if we ended a bit early so I think what we would like to do is take about a ten minute break just so that Daniel and I can figure out what we're gonna say and if you would come back in ten minutes so 20 of four and then we should finish off a bit early great


Hello, everybody. First and foremost, I want to thank the organizers, particularly Roberto, giving me the opportunity to speak here today. Actually, Tim Morris was supposed to speak, but cannot be here unfortunately today because of personal reasons. And I would like to present a series of three papers of Tim in collaboration with you indeed, and Zoe Slate is also here, which all deals with the question of what is the influence of demanding background independence to RG properties, particularly the notion and the existence of fixed points in the quantum field theory of gravity. And as a somehow simpler time model, we've been looking at conformally reduced gravity, and I will focus in particular on the second paper in the series. Yeah, so we've seen very good introductions, particularly on, and that's why I have only one slide, but let me just, that's probably the compensation of what you should take home, that first of all, whenever you choose to apply the background field method in quantum field theory to be able to carry out a particular calculation, you will split your full field in some kind of background plus remain the fluctuation. This does not have to be in this linear fashion, but it will be in some way. And whatever you get, the results of your calculation, they should not depend on the particular way, the artificial way and how you do the split, or the physical quantities or only a function of the full field. So this is true also, for instance, in Young-Mills theory, in any quantum field theory, but might be trivial. It's usually introduced through the gauge fixing sector and resulting in the ghost sector. But additionally, if you want to study quantum field theories of gravity, you have additionally the problem that when you want to use the functional RG equation, you have to define a notion of scale, and this is usually done by the spectrum of a similar plus operator, which you defined with respect to the background metric. So in a way, how you classify the fluctuation of your gravitational field depends on the field itself, namely the background part. So through this dependence, which will show up in the cut-off function, which depends on the plus operator, background dependence will be lost at least in intermediate scales k, and you will be able to restore this, however, by demanding that this modified split water density will be at least in the limit on k going to zero. So let me just clarify a bit of our notation. So we're interested in conformally reduced gravity, where the metric, the full metric with the twiddle, is expressed as some conformal factor, f, and some fiducial background metric, which we actually fixed to be a Euclidean flat. So the conformal factor field phi twiddle, which we split in the background, kai and the fluctuation's var-phi twiddle, which then, its classical counterpart will be denoted by just this var-phi. The background metric we denote with a bar on top. I note that the conformal factor is kept arbitrary in terms of the parametrization of the conformal factor field. Also note that this function f itself does not depend on the scale, and in this theory, no need any gauge fixing nor ghosts. So the first step is obviously to derive the functional RG equation, the Wetterich equation, which we have here. Note that the derivatives of the inverse propagator are taken with respect to the fluctuation field, and then the cut-off regulator will depend on the background field, and the RG time is just a lack of decay. So the demanding background independence is done in equivalent to imposing, in the case of the linear split, this split symmetry, where you just shift the fluctuation field with some field epsilon and the background in the other direction. And then you can derive from average action what we will refer to as the modified split water density, and this identity encodes to some extent how much this split symmetry is violated by the effect of action. Note also that the structure is quite similar to the flow equation. But where the time derivative acting on the cut-off is replaced somehow by the dependence on the background field, acting on R directly or on this inverse square root of the determinant, which includes this confirm factor. So the first thing you may want to ask, and also that has been said before, if the system is compatible, if the water density is compatible with the flow and what I mean with that I repeat it again, is given that the water density is satisfied at some scale and given that the effect of average action evolves according to the flow equation, the water entity should be satisfied in each and every scale. So rewriting the MSWIs we've just seen as left-hand side minus right-hand side is equal to zero, you can derive the flow of this water entity and what you get is this, and in particular it will be proportional to the water entity itself, so this is going to be zero, and then the water entity is a constant which is zero. This is somehow trivial at the functional level because you just do simple manipulation to the same partition function. But however this is not at all trivial anymore if you truncate your system in any kind of practical calculation and it's also not clear at all what is however I call the overlap of information, so it's not clear if either one equation contains the information of the other and in particular we see that that will depend at least in our truncated example will depend a lot on whether compatibility is satisfied or not. So then we wanted to study the system in the derivative expansion up to second order in the derivatives and assuming a slowly varying background field chi we can terminate the kinetic term effectively at the LPA and this is the most general action you can write down there. And then from the full functional flow equation water entity you get two equations at each and every order in the derivative expansion and I will just show the two equations we get for the potential here where q is the propagator to this order in the expansion and we have this very similar form as before so here you will have the flow you will have the time derivative acting on the cut-off here you have the background field acting on the... The first thing you can study in this truncated system again is compatibility and you can calculate again the flow of both water entities you have now here I just show you the flow of the water entity for the potential v and you see it gets quite a bit more involved so you will have something that lurks a lot as the identity we've seen before in the functional case and this is actually going to vanish assuming this is satisfied so the water entities are satisfied themselves but then you have this double integral which involves this commutator like terms of the regulator where for future convenience we abbreviate it with gamma this thing which is basically the variation of the conformity factor with respect to the background field Now one way to have the flow of the water entity to vanish is to demand that this commutator like term which is written out here is actually zero and this integral will obviously be zero and you can integrate this equation just noting that if you write it in terms of quotients this will actually be independent of the momenta and then you will see that this has to be linearly related to the time derivative by some function that is dependent on the background and maybe dependent on the scale as well The flow of the water entity for the kinetic term is much more involved, much more complicated and you will get additional commutator like terms as so with higher derivatives in the mentor but again it turns out that they vanish if this condition is satisfied so it is a necessary and sufficient condition to ensure compatibility is actually satisfied at each and every order this however I should mention is not necessary so they might not vanish but then this equation and all the others will give you additional constraints that are non-trivial and you have to satisfy so in a sense they are secondary constraints but then if this is not trivially satisfied you will also have to look at the flow of this object and so on so all the derivatives of the water entity itself and you have to demand that they are zero this will give you a tower of secondary constraints which you presumably cannot satisfy simultaneously so this compatibility condition can be satisfied it turns out that this is satisfied either if the anomalous dimension of the graviton is zero and then it is trivially satisfied by this being a constant or if this is not zero you get the differential equation like so with some constant and this can be solved by choosing the cutoff profile in the dimensionless variable with rescape of that variable p hat as so being power law okay now I want in a couple of five remaining minutes I just show you three results we obtained in the LPA and first of all you see if you rewrite the flow equation and the water entity in terms of dimensionless variables that you get a non-autonomous system in t so actually demanding you are at the fixed point where the time derivatives of the dimensionless potential vanishes then this equation is going to be independent of drg time t this however by the change of variables to dimensionless variables sorry you introduce a time dependence in the dimensionless conform factor which will show up through the gamma here you cannot eliminate and you can only and this will in general not allow it to have fixed points unless again you set either 8 to 0 because then this is going to be 1 or you have the parameterization the conform factor now to be power law not the cutoff but then again as I said if the equations are not compatible not everything is lost a priori but you can try to solve the system still but what we did is without including the additional constraints we just tried to solve in a particular case in what I mentioned with the optimized cutoff but then resulting incompatible equations and it turns out you can combine them and separate the scale dependence as so by the method of characteristics where you have this function v hat is then only dependent on some initial data and plugging that back into the flow equation which you have in addition to this combined equation you get then this form of equation and again this will depend explicitly on t unless you again set eta so you can only obtain solutions if eta is equal to 0 but then again the system was compatible in the first place third thing is what actually happens if we have this so what happens if eta is actually 0 and then again it turns out you can combine the flow and the watered entity and after some redefinition of the scale which will depend on the parameterization you end up with some flow equation that is manifestly independent of both the background field chi as well as the parameterization and it also turns out that the fixed points so there's a line of fixed points here I don't want to go into this too much here coincides with the fixed points you would have obtained by just studying the system without the watered entity but you have to demand this condition and it's very interesting that this under certain conditions is possible to formulate the flow combined with the watered entity in an absolutely background independent way alright let me conclude then so we investigated potential conflicts that can exist between a notion of fixed points and background independence in a quantum field theory of gravity we saw the compatibility of the flow equation and the watered entity is always satisfied at least in conformally reduced gravity at the exact level but not in the derivative expansion but however can be guaranteed when either eta equal to 0 or the cutoff is chosen to be power law we claim there are no solutions if those two equations are incompatible and confirm this with some example we also see that even if they are compatible fixed points, main general still be forbidden but however there seems to be well I don't know if always but at least in our case there is a way to actually combine the flow and this modified split watered entity to uncover some background independent description thank you


Welcome to Cleveland, Ohio where it's always sunny and seventy-five as you can see. Do you want an interview? No, no, no. Don't do that. He doesn't deserve an interview. Who do you think is going to be the best quarterback in this draft? Justin Field, Matt Jones. I agree with that one. Who's the biggest bust in the draft? Trevor Lawrence. Oh, what? I think, I wasn't impressed. Oh, Quiddie Pegg is from Mexico. No, Zach Wilson. I have to call whoever the Steelers pick first. Zach, can you compliment your rival? Give your rival like one compliment. One compliment, you have to give your rival a compliment. Give your rival a compliment. Oh, hard to say. Have you given one compliment to our rival? I mean, I guess I'll say that some of their fans are cool. Oh, that's stretch.


In here there's noise and everything anyway. Hello. It's been over a month since we have made a video How Jurassic World the game? Why is that? Well, well, I've kind of been on holiday. So for the past two weeks ish Just it's been schedule content. So and there's you know, you kind of need to record these the day of oh Oh, we've got something new a trade of multiple creatures at the same time to complete these exchanges get all your trades in Before time runs out and check back often for new opportunities. Okay. Oh Oh This is interesting. All right. Okay. Well hold hold on a second. Okay. It's two hundred thirty DNA Kind of need to have a look at this. Well, we'll just connect this thing. You can't those stager. It's actually quite interesting I think it's a kind of stager because in the trade hop, but that we've just seen they were you know, oh God You could get one of these by trading in their dinos Interesting interesting now. I'm expecting that the whole trade this whole trade dinosaurs for other dinosaurs is Not gonna unlock them. I don't know. I don't think it will. I think you'll probably just get one but That being the case it's not really worth trading in anything is it? Oh, no, ah So much for two hundred and thirty DNA one two three four Got hundred seventy Well as long as that incessant noise stops. Thank God, right. Give me that give me those I Didn't do anything with the terror dodo, but that's okay. Anyway, we also have a new event now last time I think it was the big one. I didn't make a video showcasing it because it's pretty much just a raptor I do have it though. I did I didn't get the season pass. It's interesting. Like sometimes Lydia They'll give me the season pass It was really cool and it kind of incentivizes me to do more and play more of the game However, they didn't with the last one. They still have it with this one. So I'm like, why why do they why sometimes do they decide? He's been a good boy. Let's give it to him and other times they go. Yeah, who cares? No, it's just pass it. It's weird. It's like all of a sudden they go Someone it whatever teams left to dress the world the game because it feels like it's very small in comparison. Just it will live Um, or at least, you know from updates and all that just feels like the few guys who are there, but oh wait, hold on Yeah, game beaver. How are we getting season pass? I completely forgot the last three months this time. We'll do it Anyway, anyway, so We'll see what we've got going on Also, it says times two Is there a special like bonus going on at the moment? So we'll have a quick look at the other trade We'll grab some of that Also, the trade harbor has changed. So it used to be 50 to refresh and now you can use an advert if you so wished I never do because I've just My time is worth more than a freaking advert Um, also, I don't know if I have We've got one hour left for that which we're definitely not doing I've looked in here to see if I have the apatosaurus statue. I don't have an apatosaurus statue My god, right. Okay. Wait, or do I? Place place place. No, I have one. I have one apatosaurus statue sweet Okay, we'll just quickly go make a couple of these My bad, I didn't realize I didn't have any of these Which means that when I do the trade harbor Um, I'm not going to have that as a thing to trade and that is one of the best things to get So we'll quickly go over here again Uh, I don't think there's anything in here that I really need you also notice. We've got 98 million million Uh food so we can definitely level up chromo spinal all the way Uh, sure. Why not? I'll trade that I need dna if anything Sure, I'll trade that um And unfortunately I didn't get any there, but I will trade the apatosaurus statue for dna It is better than nothing and they're not wasted. So there you go. We've got about like 600 dna ish For those which is a brilliant Um, just make sure I yes. Okay. I'm not live streaming. Good. Good. Good. So what do we get here? The feisty flock. I can't remember what these guys are called, but also the Sinner soropteryx, that's the one they are already in draca world live I think it was funny because we had something that was in draca world the game and not in draca world live That came to draca world live cry all of the soros. That was it. Um, not too long ago But they've extended this out so much. So if you do get the season pass I don't think you can make a level 40. I think you get about six or seven Even if you get lucky with like these feisty flock packs Um, a bit interesting. Okay, let's have a look. So one Possibly two three Okay possibly four plus five six uh So six so far if you got lucky Seven so you're one off you have to open all of these packs Get super lucky and unlock it like sorry like managed to pull it from the pack even then Paying for the season pass. You don't get a level 40, which is so weird to me. At least I have that as an incentive Yes, you go all these extra missions who honestly cares. So crowbow spino I'm assuming it's going to be on the other island, but I'll use this to quickly find it Where are you? Should be a meat eater Is it going to be near the bottom? Yes, there it is level 36 So we can get that to level 40 and that was like 20 freaking million Whoa, that's a lot of food. It's a big boy likes to eat or big girl uh 11,000 health and 3488 attack and uh, yeah, oh and you can take care of that. That's only 30 pet Um, so we do have this as well the dodo and now we have the dodo already unlocked Um, but this is a tournament. I don't know if we unlock it with the pack though that you get from it It's a twin dodo pack says it's guaranteed doesn't say it's unlocked though. Um, I'll have a quick check to see If now quickly go to noob law Is dodo a carnival? I feel like it might be a carnival Let's have a look dodo dodo Right, so Apparently I haven't unlocked over apta even though I just did a tournament and got it. I'm pretty sure Um, I still don't have I still see comments of people asking could you get to run an office or is please I don't have an unlock I think there's been two events for the officer gen two Apart from you know the first original one, which I didn't get it and then another one which I missed I think I started it though, but I got busy with some other stuff Um Yeah, didn't well it's saying that I haven't unlocked the big one Which is interesting because I do have it. Let's have a look. So what do we have here? Ah, that's right. I did have that Uh Jillicus which I'm not really too fussed about again. I just put these in because they took ages I'm happy them more than happy to sell these guys If I really need them I'll buy them But if I'm honest I very rarely use any aquatics, but they oh They have a treasure trove of food in them. So I'll quickly claim this anything interesting more food. Sorry not food DNA Um, there you go 500 of that. What's the next one? It's an over raptor Yeah, sure. Why not? Yeah, there you go. I'll claim some of this claim a little bit more Uh, they have switched up the missions somewhat sometimes It's complete five battles which you see here. Sometimes it's not Um, there's more annoying to complete five battles Uh, I mean to be fair We could just do like do this battle Go quit give up and that counts for one of the fives Uh 15 at half as well. So last time. So yeah, there you go. That's counted as completing one of five battles You can get lucky with some of the events that are just entering for coin Which is very nice because then you can easy route through these Especially when it comes to use 55 carnivores like this one you can just um Find a battle like this that literally costs Nothing to enter and just I think you can use any common So we could use I don't know those guys start Give it up And I mean if you've got lots of carnivores that are easy like majungasaurus for instance They're instantly like refilled whereas The ground long level level 11 won't be and that way you can go into this already We're on 4 out of 55 and that's a good way to cheese 885 because if you've got 885 straight away, you've got a feisty flock Um But I wanted to have a look because there's some things I have not used a lot of power ups Um like four instant hatches the speed ups other things. I can't remember of the top of my head Um Let's have a look. What what have I gotten recently? I know the over after was one of the things Let's have a look because I do want to see a new creature and no 800 000 DNA Is there anything in particular that we could get that might be worth our while so we do have the big one So I'll instant hatch that for 250 so at least we do get to see Um now what I'm very curious about. I love this is just my reject corner for things that I'm like I don't know where they go So the big one Its model looks slightly different It's interesting because the drastic part raptors have a very specific model like if you're a drastic part fan Or you know, you're very you know acquainted with the raptors from drastic park the first movie You can take one look and go. Yes. That is a hundred percent drastic part raptor The colors are great. However, the head is a drastic world raptor. It's too elongated. I don't know what Oh, no, actually, you know there it looks like it, but here does not look like it I wonder if it's to do with the way it's posed Get my headphones across my arms to judge and then I got them stuck in headphone wise Um, yeah, like there kind of looks like it But to me it's like it pops into the drastic part raptor and then goes back into normal And I'm sure that's to do with the rig Um, so, you know, actually, yeah, there you go. So I got a level 10 752 health and 235 attack damage. There you go. We have the big one But that's not all I wanted to check out nicknamed by robin mull dune The big one is the alpha female Velociraptor of drastic park this creature is also known as clever girl for capacity To lethally outsmart a human prey the big one rules over two velociraptor subordinates And using a bit an ambush maneuver. The big one is the predator of both robin mull dune and ray arnold Can we not just say like murderer The predate predator sounds a bit weird when you call it, but anyway This celebrity dinosaurs that have been in the game for a while For me They don't really do anything and I don't think I'm alone echoing this sentiment like You've got blue you've got beta and they're they're all just kind of Regular dinosaurs. They're like legendaries or maybe like rexie for instance They're maybe a little bit better than regular dinosaurs at level 40 like we've got a couple here. We've got three rexies I don't know how I got three rexies because I don't know if they have a hybrid or not But so cool to actually see rexie and the big one in drastic world the game Like almost 10 years after the game launched in fact I think it is 10 years because it came out in 2014 if I remember correctly or Very early in 2015 So that is interesting Um But they don't really serve any other purpose because you can't fuse them because they're like celebrity dinosaurs because to do that It's like well, they're no longer, you know what they were meant for So it is very interesting Because for the longest time we were getting hybrids it was like a new hybrid a new hybrid new hybrid And then I think it that's kind of still happening But not to the extent that we did used to see it now. We got bumpy. We got rexie. We got blue. We got beta Um, is there any other ones like any there should be another category for like those kinds of dinosaurs um Let's have a look they do have a different look on their icon. So maybe yeah, so bumpy beta Ghost the big one blue panthera rexie um But the thing is A lot of the times they're not unlockable You only get them in the past or some other way that you know, you can't actually just get loads of them Um, so you can't get them to level 40 You got a load of other dinosaurs like the pejadosaurus, which I didn't get Struthiumimus Yeah, there's loads that I missed this guy the um nyctosaurus This was another one that came out not too long ago, and I missed it because it was super quick um Now the these sorts of tournament dinosaurs like the lovus or gen 2 serodactylis Make sense to put in the game because eventually they will get hybrids like the terra terra quetza And the torano lovusaurus, which I don't have Um, or I don't even have do I have this guy? Oh, I do have this guy I have little fatty toes Oh Hold on This could be one that's worth it actually because it's an amphibian and really the only good amphibian I have at the moment Is osteoporosaurus And osteoporosaurus ain't that good Oh Evolve instant fuse. Let's go Okay, now actually can I get another one is the question I will get you to level 20. So what does room in 10 out of 409 attack? looks so odd Anyway, tea break guys grab your cup of tea Oh, look my tea's pink Because it's ube tea That's right. I'm a weirdo. I'm a weeb. Woohoo. So I have been ill recently Um, like I had a lovely time the philippines, but for the for half of it. I was like dead Um and still recovering from it now. I don't know what it was. This doesn't really matter I can't even uh, I can't even level it up. Ah, yeah, how do I get two of them? See, this is the thing Okay, I've unlocked blue apparently I've unlocked the dip lip sip sip sip But I haven't unlocked any of these. I do have panthera haven't unlocked it I do have trait notice. I'm pretty sure haven't unlocked it It's just so annoying that like rex I got three rexies haven't unlocked it Ah, it's just like meh. Why are you like this? Actually hold on. What's the what's the most expensive one now? Okay, it's the Orphasepsis. That's the most expensive hybrid in the game How many do I have? I have a level one Oh, no, I have one and it's 20. It's level 20. So that means that I need six more Oh Oh god, that's But again, it's one of these creatures that's more health than attack and they always seem like terrible choices That we do have a level 40 chromo spinos um The oh the cryo luffa burgey in it or whatever it's called. Hold on. Let's have a look at these two So Yeah, it's got a thousand less health Oh, but it has It has like 500 less attack as well For like 4,000 less DNA Really not worth it. All matter. I have a level 40 chromo spinos. I have a level 40 iguana sutures. I don't but again Oh saying that it's got 3,000 attack Scorpius rex We have level four. I was gonna say surely I've got level 40 scorpius rex. Okay Uh pakigalosaurus. I do have that much photon. Yes second daunter one though No, not really. Do I have zelmox? I have zelmoxies Oh, did something just happen? Something clocked over? I think something clocked over. Is it new events? Oh, no, it's not. Okay. Well something just happened. I heard that weird noise there Uh, so we're going to market like there's gotta be something that I need There has to be like or something I can make so go out on the market Just really doesn't feel like there is they have however started to add new events into the game that have good prizes, but you need So many of the same creature. So it's like only t-rex can can participate and only t-rex And that's it. So you need like Three level 40 t-rexes and then three level level 30 tier basically you need eight level 40 t-rexes or 12 level 40 T-rexes in order to do the event Uh, and the prize is really good Um, because it gives you bucks. It gives you so much. However, let's see if there's one in the cards coming up Only herbivores. No, it's not one of those Uh, not one of those. No, not any of that Any creature Huh, as if just to tell me like no, there's nothing there. They're not showing it. Okay. That's interesting Right. Well battle stage infinite has the Obserpses and the other thing that I can't even freaking get brilliant. Okay. Let's have a look at flyers Okay I'm gonna put some monodon in and then Let's put in Because they'll switch to Alangosaurus We'll switch to that And then when they do that I need something kill Alangosaurus I don't really have anything too crazy Except for Indoraptor. I think I'll put an Indoraptor and then we'll switch to metro. Okay. Here we go. Here we go Can we do it? It all depends on what they do because he can't kill me in two hits It'll be very close to do like seven to eight thousand damage, but he won't I think he'll switch Mmm Did not factor in how much damage that thing did so Salmonadon is doing what it needs to do.  Oh, okay.  So that's about 10,000 12,000. Yeah, I mean I had a feeling that was pretty easy Look at that thing weird-looking His eyes are looking in different directions.  So we kill it in the three Now I need to make sure even if I reduce the attack by half I was damaged you six thousand. Okay, one two three that'll do I think I don't think it's gonna have more than 22,000 I should have checked that too Yeah, 9,000. Okay Wow That thing's got that like so much. Oh it freaking tried it though What? Oh you cheeky bugger you okay, okay But guys leave in the comments down below What I should aim for because I feel like there's nothing else to To really get at the moment. I've got like all the dinosaurs I could possibly want and okay Let's check this card pack. So we get times two limited time subscriber bonus and then Another times two bonus. So really we want to open up some packs right now Let's have a look solid gold. They're platybing genius or whatever it's called It's not owned and I don't have it. However, I'm not spending 50,000 for it. Um, I don't know of the Melionia Uh overaptor Hold on hold on let's have a look Right. What's the best thing I have that's ready to hatch We'll just screw past all of the things that I don't have And don't care about So the things that I do have that I want to hatch. Oh, maybe maybe I should have went the other way Yeah, yeah, probably should have went the other way. Wow. Okay. There is a lot. I don't have anymore Oh my god. Finally. Okay. So overaptor is new. I I mean, it's a VIP creature. So we can't really get any more of those In Montessor Montessor I'm really at a loss. I'm still trying to get through all of my super res. Look at that 11 poster sutures 19 entered on 22 raptors Uh, what's the most I've got 50 over codons and that's because I was just rattling through the ball stage infinite Uh load so it's getting so many dinosaurs. I've I've so much dna saved up I wish I could just go sell all 40 none of such as all 36 depleted because Because I would just get thousands of dna, but I can't it's all stuck behind a freaking incubation period Um, let's have a look. What do we have inosaurus gastonis? Ah Pro serratosaurus. I mean these things aren't really worth Instant hatching because the VIPs hatched super quick Um, I might as well just put you in actually it's saying it's 250 right, but it's five hours So why hold on why would I spend 250 bucks to instant hatch it?  Are you you're not you're not listening You're not paying attention to your game Oh, that was a cheeky shenanigans there. Good job. I knew that the VIP was quick. All right pro serratosaurus I mean because this is a dinosaur that's came from drasa world alive That the quality of the model is beautiful It just shows that they can put really good and well detailed things into this game that came out 10 years ago They can do it and we can evolve it Um, I mean I might as well just waste an instant fuse because you know who cares the golden bros serratosaurus Glorious and let's feed you up to level 21,243 health and 999 attack Oh the devil Let's go say the devils the devs really had fun with you. They're like, well, this is almost a thousand Put one off it you cheeky git Oh Serratosaurus. I'm so sorry, buddy. 3.5 meters long. Ooh Okay, so that's good. That's something isn't it? Um, also another thing that I barely pay any attention to are the omegas Um, because they do get power up moves depending on what if you prestige them Okay, not exactly too sure how you do that Uh, let's have a look Right. I think yeah, omega 09 it made more sense to just do one dinosaur up to like super max level so I think I've got all the moves So deal damage equal to 250 percent I don't know what this one roar of champions increase team hp by 30 percent and increase team attack by 30 percent Of course, these are moves that you can keep on doing. Um, and I think If you just have him out first Keep on doing keep it like spam that ability and then when it dies The next thing comes in and just has so much health Uh, what do you do wound all opposing creatures by 100 percent of attack power Wounded creatures take an additional 33 percent of attack power as damage at the end of it All opposing creatures like the whole team And stop it remove two action points from opponent each turn for two turns Oh, that's cool. I didn't even notice that little animation there but attacking the floor. Okay. Okay. You're looking good. What about you? Uh, gain one block point immediately next turn and gain one attack point Feel like I've definitely seen that one before increase max hp by 25 percent and heal to full As opposed to gain one attack points and increase attack by 25 percent so Increase max hp by 25 percent or increase attack I mean if if what you're doing is basically just healing Every time you do it and increasing your hp by 25 percent and I think that stacks So next time you do it is 25 percent extra of what you got and that previous 25 percent So it just keeps getting like exponentially more And that way you just won't die But the thing is The the folly how fun that sounds it really does the folly of it is that you can only use them in boss events And the rewards for boss events seem good Like oh you could get all of these creatures But you ain't getting it you ain't you I mean you're probably not you've got to defeat 19 foes Oh wait, hold on defeat 19 foes And what can I use I can use any of them Wait, how do I prestige? Unlocks at rank two Wait, what okay, okay eight nine 40 Oh does it cost anything to prestige? 5 000 amber Unlock a new prestige rank for your creature. Oh Oh, I just I gained these Oh Oh And I've even noticed this Okay, so it's prestige to level two is it and I get five. Oh, okay New level maximum wait Oh, okay Right out for a second. I'm thinking hold on hold on hold on Are you talking everything in the park? Can all be level 50? No, just these terrible scream Right, so I haven't unlocked that last one. That's why you're level 54 Because I I had to get you up to that next level. Okay. Okay So I'm kind of cute. I kind of want to give this a shot because Oh, I could only use one Wait, wait, wait, wait, wait. Do I got to choose? Gain one action point to be used immediately gain revive ability when coyote revive with 25 health increase team hp by 30% increase team attack does that count is I mean you're part of the team Part of the crew part of the ship I'll level you up a little bit more because why not you're an omega Right. Okay. Let's let's give this a shot 30 books 30 books. Let's see how far we can get Do I get a choose or do I just have a random one? I forget how this works I'm very curious now again doing a battle a cool battle with the boss and everything However, it's not a new battle arena. It's the same visitor center that we've seen so many times I really wish they would do something different All right, so you went for three Uh So where's Where the heck Is my What do we call it? Where's my ability? Oh, is it is it not? Oh god. It's not a miss arena I leveled up juggernaut being like, oh, yeah, we'll use that can't even use its ability Right, I haven't even checked how many attacks it had Okay, okay, but level 55 We can do this so The max level you can get these bosses must be level 60 then Probably if I wasted all that DNA On that juggernaut could I could have got this guy up to level 60? Damn it And it's been months since I've used all of that like boss DNA Months so it's going to take me months again to get that much. I mean, I haven't been doing the the missions To be fair. So if I probably Knuckle down look to the missions I'd be able to do it 45 damage How dare I suppose if you had the abilities this would be way too easy Let's go for that Ha ha ha yes Okay 15 left doing good doing good Seems fairly easy at the moment I mean If we just look at this statistically I've entered 30 bucks For this battle 30 bucks. It's not much If I manage to get through and defeat every creature It'll be interesting to see what 30 bucks can get me now again. It's a spin wheel sort of prize. We don't know what I'm really gonna get But 30 bucks, let's see It would be interesting however To just do a hundred battles of this And see What prices we got average it out how many times we won coin? How many times we won food? I'd like to do that. However, I don't have time for that. Unfortunately. I would I would like to do that. It'd be quite interesting Because is it really worth it if I did a hundred battles? That's That's three thousand bucks Because there there will be ways that to make Your your books go far there used to be a system where you could buy mystery packs for books And it worked out way better to do that than anything else Anything else you could spend your books on would not give you the amount of resources and dinosaurs and everything else That just buying the mystery packs would However, once I made a video Showcasing that they got rid of them and it's the same with the battle stage infinite, right? Or you could refresh it, right? Like you still have to use your same dinosaurs You had to buy them back if you wanted to use them the battles were just as difficult But you could refresh to get a good pack um But it's it's just a shame that all these You know unique ways in the yes, it wasn't intended but It was it was something cool. You know, it made people want to play the game More time in the game is better, right? No, no It was stopping people from buying the latest card pack at a ridiculous price. So we got rid of it Oh, I'd like you know, I'd like to make a dinosaur game in a way because I see all of the the sort of Little nuances that either game devs miss in these ones and fun aspects Like I would leave a glitch in to see if people can find it Not a game breaking glitch just something that's fun because it's I mean, that's what games were, right? Like you could you were exploring you were seeing a new world and all that jazz And now I'm starting to get a bit worried. We're getting towards dinosaurs that are uh, are doing a fair bit of damage to us Gonna go for that Yeah, gonna go for that. I see righteous. They get coming up next and I don't lack it Thankfully, we still have our carnivore advantage going for us um So I don't know what para has and I don't think I can oh I can check 400 okay, so one one two one and then one two. Hopefully yes So that through an 84 attack. It's turned into 200 attack Now better mind it has six you could still do a whopping amount of damage to us Okay, there it is. So it's got two block.  I oh it didn't even go for an all out block Okay went for some reserve interesting interesting once we get two more defeats We've got gold Not the best But we'll see Let's try that Ah, I don't I should I should have held off Got two to 72 attack gets to oh no. It's actually not too much So right. I saw you're kind of pathetic in this game. I've completely forgot even though you're the same size as a god zeta rex Okay, so three yep a little bit of damage. I'll take a little ditty bit of damage Uh, I'm gonna go for that. I know I know yep three was not worth it, but Four reserve saving it. You got five. Okay. Okay You go for two Right, I'll take that. So you've got three possible blocks Let's go Okay, okay, okay now. They never seem to go for an all out attack. They always like divvy up their at their points So if he went for five, I might be dead, but I don't think he will I was hoping I was really hoping that okay, okay So one Two three Two I'm gonna go for that. I think he might have had three block. He didn't okay One more kill and then we're through and then I think we need to make two more after this. He's got five It's pretty tricky now Okay, but it's a parasol up next but it is level 97 that 97 parasol. Okay, so one one two three and then just two block Okay, unfortunate unfortunate. It's gonna have a lot of attack. Okay. We're on to level five We need to kill two more. This is it.  Yes. Okay. This is close. This is close Come on go for four, please Okay, I'm gonna have to play this cool Because as long as I just have enough to go for an all-out attack on the thornax. I'm good I think this might kill me if he goes for oh, he doesn't okay looking good Uh, I'll go for three here because I think that's the most it can do and I'll go for three block No, it was the most it could do, but I didn't expect it to do it Oh my god Okay. Okay. This could be it. The thornax is killed in one hit. That's it. We won We did it.  He did he could have went for four and this is it. Let's finish it with a bang I think it's a bite Yum There we go. So the best reward you can get in this arena. We just got Right, let's see now there's a chance. We could get a really good card pack But I think it's way higher. Let's have a look What are our chances? 40% chance of amber Basically, we're gonna have way more chance of getting those resources One percent chance of getting the platinum reward. Let's see. Let's spin most chance of getting amber, but let's say for 30 bucks I got Imagine imagine for 30 bucks. We got the pipe with 750 DNA now. What does that get you? How does that translate? Let's have a look. So we're going to the amber market Uh, we'll do the other way. Oh, there's a lot of dinosaurs that I already have that are in here. So um guys guys tajongasaurus You heard that right tajongasaurus I I just did and won the best amber dna or pro sorry amber you could get And it was 750 It's not even half It's not even a quarter Of what a tajongasaur costs. What's what's the most expensive that I got 56,000 for a scab I let's say I won amber every time 10 battles takes me to 7,000 I would have to win like 50 battles or something like that in order to afford one scapigannathas, so that is 1500 bucks 1,500 bucks gets me now might get me other prizes. Let's be honest. You spin the prize wheel. You might win something good It just doesn't seem worth it and that's the problem. I I honestly feel like Was it um, not ludia jam city? Maybe it's both Are putting things in the game and not testing them. They're not really thinking things through They go, oh, let's lock some dinosaurs in the amber market That sounds good, right? It'll get people to maybe play different battles or or you know that they have to level up different things but when you're putting a tajongasaurus at that higher price and I'm you know, someone who's played this game for god knows how long and to have an omega level 55 in order to do this which is already like ridiculous in itself and That's it. Actually that event is done. I can't keep doing it Uh, only wait only one creature so 50 bucks and what I win for this I have a chance of winning a domination rewards. Okay. Well, let's just do this because why not am I as well? I've got you uh A revive I suppose sure Two omegas going at it.  I'll just keep putting them all into that and then do it Um, yeah, it just doesn't seem like they thought that through You know Right there we go that I think that takes us to 100 we should have that ready Yep, are you gonna are you gonna do anything?  Okay. Well Not that it really makes much of a difference. I guess I could use this Just take it rub salt in the wound as opposed And then just I don't know go for like all attack I got an extra action point, but you're definitely dead He is Actually defeated an omega Who would have thought we'd see the day Right, and we got gold rewards. So for 50 bucks. I got a tyrannodon Uh, I got all this is what I wanted it for boom and then boom again 600 That's so good that like okay that makes that that's worth. That's good. That's fun Right, but I don't even know Why I'm getting the extra times too. There's nothing on the game that's telling me oh extra rewards Oh, yeah, also it's clocked over now. Uh, that must be more clocked over. What did I win? 5,000 bucks, uh, which I guess isn't so bad, but when you spend 1,500 vip points You know I mean what we can do actually Let's have a look. So I could get pterodactylus for 20,000, but if we spend 10,000 on this pack We get 2,500 dna. Anyway, we get a cool creature that we can sell for 5,000 Uh dna and not only that We get all of this so really This pack only cost me 7400 vip points And I got dna. I got a vip creature It's really it's like really good I don't know what else to say that that that's like awesome. I love working out these little things like oh my god You know if I had okay, that's terrible All coin and a tani callagras. We'll do one more Oh We're still getting We're still okay, uh 500 bucks. Okay, pterodactylus is a very good creature Uh, keep going. Okay, and then I just want to get 100,000. That's 100,000 vip points. Let's let's go to that And that is 5,000 dna right there all the old and catfish or whatever it is And then of course 2,600 of that So I'll do one more because Oh, it's all food and coins. We've got concavenator, but we also get another 2,600 of this Takes us very close to 100,000 awesome And did we get anything for this open 17 card packs? Is there anything here that could give us anything good any creature, but That's not so bad actually Hell yeah What I mean, what do we win from this? Oh, this could be good. Okay guys quickly. We'll do this.  It's absolutely Chacking his pants at this point It goes for two hits does a decent amount of damage dies in one We go for what this is gonna be the quickest sort of battles as long as the next two battles are just as easy I Do I like this game? I do I genuinely do and that's why I get annoyed when they add certain things to it It's like no stop ruining it And like I said if if I could change one one thing about this game Arenas Mix them up add more. I don't care like the budget that you're putting towards Um like new dinosaurs and stuff just have one update where you you you fix the arenas And you make some new ones just Just one update Just put the brakes on whatever you're working on for one update and make it fun for the battle arenas um Ooh Oh, yeah, this is tough Very very tough Again though I really don't see Why I shouldn't just go for all indoraptors if I'm honest I mean, yes, I don't I'm not really getting any of the advantages of types but You know he's gonna do 3 000. I'm maybe 4 000. Okay. Cool. Cool. Cool. And at this point I can go for one attack Oh, sorry two attacks on one reserve and kill them.  It has nothing I can go for that one reserve and kill it Okay, now I'd love to see that this gig on a source gen 2 In a nice environment where I can actually appreciate its colors because it's so dark You can't see it with the shadow. So this goes for one attack Weirdly enough And it can only go for like two blocks. So yeah, definitely dead Boom. Okay. One more come on. We got like 20 minutes now 20 minutes Some extra dna Right and the last one again No real reason why we shouldn't just keep on going for carnivores Right. Oh my god, 503 attack. No, he does Oh, I'm so sorry, buddy. Oh, bless it. It tried it tried now. Can I kill it in two? No, I can't you know what? We'll keep it alive Because I can farm I can farm action points from it but in farm action points That's what we want to do. Yeah, you could go keep going for it. Go for it, buddy We'll go for one reserve for three And then I think it's just that's it. We've done I could probably go Three attacks Depends what he does here. He could kill me if he goes for three. Oh, he does Oh Would you look at that? All right So one two three still kills you and then four reserves.  What's it called? Arambosiana Okay. Yep. You killed it Demetrikanis one of the super hybrids And then rajas staker. Well, we might as well see the eight animation. How much damage level 40 maxed? No type of advantage does rajas staker do 34 000 damage Wow Well done. Well done. Well done round of applause. He did just great there Gold award and I got lots of gold another to run it on but The important thing there it is another 2006 Hondo Oh, it's so good No, bad. Oh, I don't care All right, so we've also got this which is complete some battles. Like I said, I mean I could do this pet the dinosaur one two three four five Also, we haven't been to the trade hub or I've completely forgot. I'm so sorry guys We've just got to quickly pet some things There we go. No, leave me alone So it's 18 of that This ends in two days. So if I wanted to I guess I could keep up with this right. Okay. Let's have a look at this trade However, what are we trading? So for an acanthos staker, which is a tournament creature um, we could trade a level 10 of all the basics Now If you don't have acanthos staker Could be worth it Let's have a look at this one Welcome to Jurassic world a triceratops Alangua lima lima lima lima and i'm a junglesaw Two of each basically because it's a level 20 and you need to feed it a little bit for a super rare again Maybe not so bad actually those two and then this one boninosaurus of easy galamime is easy and kalasaur easy level 30 dimetrodon Oh, but you unlock this Wait, hold on Wait a minute. It wants me to What what? Unlock drako rex Is drako rex not I've unlocked drako rex What what's going on game?  I thought maybe it was like oh showing you you'll get a level 10 drako rex, but no It's legit asking For a drako rex a level 10 For me to unlock drako rex so How do I have a drako rex to start with? Not only is it a bad trade, but how do I even get that trade if I don't have it? Interesting it could be a good way In order to unlock certain dinosaurs because Like we've said in the past and people have brought it to my attention the dinosaurs that are in here Are only amber dinosaurs that you can't unlock some of these dinosaurs in regular battle stages for some reason They took that out of the game again. I don't know why they just want they didn't think so If we go into the harbor and one of these dinosaurs is unlockable here now parasol again was in that amber I don't think you can lock it normally, but here. Yes, you trade all those dinosaurs, but you still don't unlock it So it's like why why did you do this? I don't know man. I really don't know. Anyway, anyway I'm gonna leave it here This is almost been an hour, but my god I thought it was gonna be a quick one. I thought it was gonna be a quick one then just Thing after thing start coming again. Like I said, I still do really enjoy this I'll put you in because why not? Yeah, let's get you sort and if you enjoyed this video guys Leave a like and until next time I'll see you guys later. Oh buh-bye


Hello and welcome to the session. In this session we will discuss one area theorem. According to this theorem we have the area is equal to a triangle on the same base in altitude. To prove this theorem, consider this figure in which we are given and the rectangle has the same altitude qt. The theorem we have that the area of the parallelogram is equal to the area of the rectangle on the same base and of same altitude. So, as both the parallelogram pqrs and rectangle pqs pq and also they have the same altitude qt, we are supposed to prove is equal to the area. Let us now start with the proof rectangle. So, all the angles at this rectangle would be of measure 90 degrees and so t is of measure 90 degrees and also angle qtx is of measure 90 degrees. And we also know that qt is the altitude of both the parallelogram and the rectangle. Now, consider the right triangle rpq. In these two right triangles is equal to qt. The opposite side triangle opposite sides are equal so px is equal to qt. Then the hypotenuse ps of triangle is equal to the hypotenuse of the right triangle rpq which is qr. So, the opposite sides know that opposite sides of the parallelogram are equal. Also is equal to angle qtr as each is equal to 90 degrees. Therefore, using this result, we can say that the triangle pq by the rh is Iteria. The congruence is equal to the area of the triangle rtq figure qts of triangle lateral qts is equal to area of triangle rtq plus the quadrilateral pqts. And now, when I am adding the quadrilateral pqxs, we get the quadrilateral pqts to the triangle rpq. We get to be equal to area of the parallelogram. This is what we were supposed to give altitude are equal. In this session, hope you understood the area theorem discussed.


A key human capacity is our ability to experience emotions and to talk about them to express them a subjectivity. As a psychiatrist, this is one of the core capacities that I rely on every single day. In fact, the very definitions we use for psychiatric disorders are based on the subjective. So my job then to try to heal people and help ameliorate their distress, people with emotional disorders like depression or anxiety, is to try to understand and help them understand their emotions and work with that. The problem has been, however, as I'll show you in a minute, that psychiatry is at a standstill. Our ability to do anything about that, the suffering that we recognize, is very limited. So I'm going to invite you in the next little bit to rethink psychiatry with me, but hold on to that thread of subjectivity because we'll need that later. This story is going to start almost 30 years ago in 1987. So before we start the story, let me give you context. 1987 was an interesting year. Stock market crash. Black Monday happened. Madonna started reaching the peak of her career. And we saw movies like Fatal Attraction. In fact, it was actually a very good year for Michael Douglas. He had another movie that echoed events of the day. But another very interesting thing happened in 1987 in the biomedical space. AZT was introduced. It was the first drug approved for HIV as well as Prozac. Prozac's not the first drug for depression, but it was the first in a new series or new class of drugs called SSRIs or Selective Serotonin Reuptake Inhibitors. So where are we now in these two conditions? Well, HIV can actually be managed successfully and people live pretty normal lives now. Depression, it's a different story. But morbidity and the mortality associated with any mental illness, depression just being one example, has not changed over all of these decades. So let's start to think about why and what that means. Well, the first of which is what does it mean that it doesn't change? What are the effects of depression, anxiety, schizophrenia, bipolar, what have you, not changing? This graph shows, this is from the World Economic Forum. It shows by 2030, a mere 15 years from now, the economic toll the non-communicable diseases are going to take. And as you can see, here we have cancer, cardiovascular disease, all things we think a lot about, diabetes. The cost is dwarfed by the cost associated with mental illness. And this bar right here, COPD, that's due in large part to smoking and pollution. If you decrease those, the bar goes way down. So mental illness overwhelms in terms of economic impact and personal impact, any other chronic disease, and yet we've not moved the bar. How do we diagnose mental illness? I mentioned any psychiatric disorder is defined by subjective report of that person, and we define it based on a checklist. And not just any checklist, a checklist you can meet any number of ways. So depression, you have to have five out of nine criteria. Post-traumatic stress disorder can be diagnosed in 600,000 different ways, all with that same disorder. That to me doesn't sound like biology, that's very descriptive and distant. So what if we start using biology, let's say brain imaging scans that we would be doing a lot of in the lab, to try to ask questions about the brain basis of mental illness? Well, we did that recently, we found something very interesting. There are 300 plus psychiatric disorders in the diagnostic manual in the United States. And then we said, well, maybe simply having a psychiatric disorder is in being distressed, not being able to understand and experience your emotion, not being able to deal with, put labels, words to your emotion, not being able to regulate your emotions, as well as all the other things that come with psychiatric disorders. Maybe they take a toll on the brain that underlies or belies this diagnostic criteria that might suggest different disorders, but in fact there may be at least a common thread, not necessarily the only thread. And that's what we found. What I'm showing you here is a brain section with little blobs on it that show where across all psychiatric disorders, there is decrease in gray matter or brain tissue. I'll come back to what this means in a second. Then we said, you know, maybe that's just one way to kind of look at the data. Let's look at how people engage their brains in tasks and do the exact same thing, all psychiatric disorders. And you might think I'm actually showing you the same picture. It's not slightly different, but it tells the same story, which is when you start looking at the brain you get very surprising answers. In this case, it's three regions here and three regions there that are the same three regions that are abnormal across all psychiatric disorders. And guess what? They're not three random regions. They actually form a circuit, an interconnected circuit that we understand quite well.  The brain is made of many circuits. This isn't a picture here of wires interconnecting different parts of the brain in different colors. What you see here is brain activity unfolding over those circuits. And however you want to look at these things, well, it's sort of a map, right? You can start thinking about where in the brain you might go and where it might be connected to. But what kind of tool would you want to use to start to address questions related to circuits? Let me introduce you to one called transcranial magnetic stimulation or TMS. It is an electromagnet placed outside the head that noninvasively turns on or off little bits of brain underneath. Our brain is an excitable organ, and so we're using an electromagnet to talk to an excitable organ. There are wires there that I just showed you. And so you take a TMS coil like this, you stimulate a part of the brain that's interconnected to some other parts of the brain, and you can see activity evolve in the brain. And I'll show you examples in a second over time. So it's a way of interrogating circuits. It's also a way of manipulating circuits. So this image that I've shown you here is not just a pretty cool-looking brain that you might want to put on a wall just as a piece of art. These are different networks in the brain that you can see in every single person, and they're very much the same or at least highly similar between people. So looking at this, that's a nice picture, but what does it tell us? Fortunately, with brain imaging, it's a story that we tell when we take pictures. When you start to intervene with circuits, you get what I call the causal connectome. You get information about cause and effect in brain circuits. So for example, you stimulate one part of the brain, and you see activity evolve in yellow here over time, stimulate another part of the brain, and this goes on. We're going to stimulate all these regions at the same time, and look at the patterns. These patterns, this is a loop playing, is 120 millisecond, a fraction of a second, in brain time that's playing out when I stimulate a bit of the brain. What should become readily apparent to you in looking at this is the patterns aren't all the same. The pattern depends on where you stimulate. So if you want to reach one part of the brain or another, you want to know where to go. So now we have a map. We have tools to start to manipulate this, and you can start thinking, like, this is great. You can now think of modulating these circuits. The trick is finding the right circuit to modulate to get you the effects you want. So I'm going to argue that this is not pie in the sky. This is actually happening right now. I'll give you an example in a second. So if the brain then is a bunch of circuits, our job on the one hand is to build tools and know how to use them to manipulate those circuits better, but then appreciate the brains are really complicated, interconnected place, and so we have to really start to untangle this, even as we build tools that allow us to go much deeper and more precisely in the brain than we ever could before. The reason I'm saying it's not pie in the sky is I'm going to give you a very concrete example coming into the lab right now that speaks to this issue of understanding, labeling, and regulating your emotion. The amygdala, this is a monkey brain, the amygdala is a region deep in the brain that cannot currently be reached by TMS. But it's a region that's very important for a lot of our emotional experiences, whether they be fear, happy, sad, all these sorts of emotions that are critical to psychiatric disorders. And so we looked at this study in monkeys and noticed that there's this little area labeled L12, this colored area, that actually sends projections down to the monkey amygdala. This area has never been stimulated in humans before and we don't know what it does. So we said let's use our TMS tools while we do brain imaging, turn on this area which you can see on somebody's head right there so we stimulate and then see what happens. Well, it turns out when you stimulate this region in healthy people, you inhibit or turn down activity in the amygdala and that's what you can see in the cool colors up there is the amygdala turning down. We then took patients, in this case with post-traumatic stress disorder who are unable to regulate their emotions, did the same thing and nothing happened. So we identified a causal pathway to the amygdala that's never been targeted before, that's abnormal in these patients and then when you disrupt this pathway in healthy people, guess what happens? They're unable to label and put words on emotions. So it starts to give us a completely new perspective on how to use the circuit approach to interact with the subjective component. So what does psychiatry look like in the future? Well, psychiatry, I don't think it's going to be one thing. It's going to look something like this. We interact with patients and we do maybe psychotherapy or maybe we talk to them, we engage that subjective sense. So now we're taking that thread and we're going to try to weave it back into this tapestry.  And you know what, let's just throw something else in. Let's throw medication in. Maybe that medication is targeted towards making the brain changes that we're inducing by stimulating last longer. It's a very different psychiatry than what we have now. This is psychiatry meeting the patient, honoring their subjective experience, leveraging tools to understand their brain and modulate their brain at the same time so it's no longer stuck, hopefully, in the way that it's been stuck before and hopefully be better for all of us going forward. Thank you very much.


It's a cool idea, especially with foes that have such a small community compared to everyone else's games like we're kind of the closest, I actually know what I'm going to say, I was going to sound really arrogant then, I don't want to say that. I forgot that was a lot sharper than I thought it was. If I get this, I gotta stay off the road with strips, we're good, we're good, got it, saved it. We're turning a little bit deeper there. Or a really, really long handbrake drag. Why did I try a 360 angle? Apparently he's trying to follow us, whoever this frosted Baron is. I made it! Random lobby hoppers, see who knows us.  It was like, you know, as far as like foes and public lobbies go, there is kind of a negative stigma around it. This is something that should be added into the video, because there's a lot of bad people, not bad people, bad foes or drivers that tend to stick around in these lobbies. Obviously I'm Frederick Arsenal, but at the same time I can link a few corners and do a satisfying looking skim. So when somebody is in a public lobby like this, sometimes you don't get the best driver, sometimes you don't get the... Right, I don't know who this guy is, but he wants to follow us. That sort of stuff does happen sometimes. Kind of take it or leave it with public lobbies. I was too early. I feel like it's much worse. And I feel like with racing it kind of tends to be a little bit more grim, because there's people that are just going to crash. That sort of stuff. Drifting, you kind of don't get that, because everyone's trying to crash, because that's part of drifting. Right. A lot of time.  I feel like if we can showcase some of the positive stuff from public lobbies, people might do it more often. Especially if your videos do well, which they have been doing recently. Yup. Go ahead, Mason. I was going to chuck it. Back of it in there? Nope. I entered too early last time, and then I entered too late this time. Four to seven players. What's your nose? Maybe you get famous and actually become an excellent driver. I mean, there is that possibility.  So if I start looking away, it's that I promise. I'm surprised I held that. That's what's happening right now. Come on. Come on. This track's not over. He's like jumping around for me. He's just turned into a wall. Start on purpose. Doesn't see it that way. Start crashing into him. Why?  Matty brother was over. It's in the floor. It's so annoying. All right. Let's find another track. Let's do it. That's cool. Random thrasher lobby. Where are we going? Ooh. I like this track. Oh my God. I like Rio. Do you like Rio? Rio Mountain Reversed. I like it. There's a volvo! There's a volvo at v60. I dare you to judge him. Yeah, I dare you to judge him on a volvo. I'm not judging him for a new volvo at all. I promise. I nearly bought one of it. I'm joining. Message from Skye. You've done the biggest lag spike ever when we're joining. Yeah, we're about to. I'm already on the track. Skye just hopping off my name. I'm about to be on the track. I'm so happy there's another volvo. That's my other goal, is to find as many volvos as possible. Speaking of volvo, I think that Chris Sasaki loves me not. Because I bought him a sub 2 arrow. No, what's funny is that someone didn't get the melody that we got in some GTRs. GTRs? I haven't driven this track in so long. Oh my God. I haven't done a reverse in forever. It's been a while since I've been behind a wheel. Oh my goodness. I like this part reversed. Oh my God. I've literally never driven this track. Oh, I forgot. GTR does not let you go over those curbs. Was it a curve or something? Oh my God. He slowed down a lot. Dude, that must have slowed down so much. Look at this. What happened? Oh, my staying slows down so much. I'm going to give him some room. So we're going to hold up. Volvo neck breaking. Just a tap. That's a wall. Oh my goodness. Frasher lobbies. Much bigger than that safety. We got like a six man train going on right now though. And a random lobby. I'm trying to maintain your... I'm trying to fill these guys but they're running some weird lines but it worked. Goodness. Mate, this is actually fun. Oh, no. Saved it? No, I didn't. No. I tried almost. Oh, we just wrecked Ryan's turn. Just drive, just drive. We're good? No fault. It's funny that a big pile of cars but the three TUS members make it out. Continue to scrape it. Then I'll scrape down. Yes, but I like scraping. Wall scrapes. Exactly, especially that wall. We got Ryan Cerk behind us though. Somebody's in Racy Boys. Oh, sorry LP. The focus lost it and he scared me. No. Oh, we got another GTR boy. We got another focus right here. You got to be careful. We got another GTR boy that wants to drift with us. I'm passing him. Let's go. Blaming all of you. Let's sandwich this. Oh, GTR, drive straight, bro. Never mind, I'll just pass you.


At our feet is the amazing Brian who you sponsored as a result of the campaign that we ran in 2017. Can you tell me a little bit about the history of why you named Brian Brian? Brian is called Brian because he's named after my father who was Brian Gorman. Oh dad was a great guy. He's up in the heavens now but he was a man with four daughters no sons so yes he was quite a tolerant one. He did have to wait for the shower right? Yeah he did have to wait for the shower. Yeah he was incredibly supportive of what I've done my business and you know everything that his children have done.