We just click here again. I don't know why it's doing that. Let's let's let's test this before. Yeah, yeah things work. All right, um, amidst my night's dream, lovers going into the woods, a strange country, the rude as a area where stings things happen, and they meet someone who is a bit nasty. I don't know who it is in this analogy called Puck. Puck is a fiend.   And he's appropriately named Botund, but luckily for him, the lovely Ticciana is still interested in him, and it all ends well in the end. But then who among us is Botund?  And I when I read the the paper or the introduction to this session, I have to confess Pete, especially I sort of saw your phrasing in it, and I was a bit miffed because it almost seemed that if the only people there losing things would be UK archaeologists. Well, at the same time, I'm very much thinking that I would lose things as well. And that also tells you about the emotional value of that. But there are some warnings in the text I'm thinking, is this all about the UK? And I have to say that I would be moaned the day that I would not be allowed to go in the UK or any other part of the European Union, for whatever reasons, because I'm very much aware that as an archaeologist, I'm made by my experience outside of my borders, the borders of the Netherlands. I'm a European archaeologist, that's the way I perceive myself, and I have matured thanks to, well, talking to lots of poor people, not only the people in this room, but also outside. So there is something to gain there and therefore something to lose. There is anger, there is emotion, and if you talk to archaeologists in general in, well, almost everywhere, we tend to be on the side of the remainers, or remoters, if you like that way. It's an interesting travel, it learns new words. Till two weeks ago, I never even heard about this word. Perhaps I should have paid more attention to the constitutional ways of the British parliament, but a discontinuing of a session, in the sense of discontinuing of a relation as well between us, emotional bunch archaeologists, and therefore you get these mean things, and archaeologists against the Boris. Well, but then you have to ask you, what would it help if we sort of all tremble on Boris? Well, we have a Boris less, but in the end, this whole drive for Brexit is not Boris related, and this whole idea of depicting someone else as a Nazi or calling me a fascist or whatever, is also not very helpful for your personal narrative. Whatever Boris does, I want to have a relation with other archaeologists across those borders, how stentent these are, and is this something in European archaeology, in the history of European archaeology? Let's go back to the year 1936, a year which some historians say started World War II. Well, we can agree on it being a prologue or an intro.  There are these tensions and extractions during the Berlin Olympics and, straightly enough, I put it in the film Amidst the Malayans doing World Oscar, and you would say, oh, that's great news, there was a big brawl about it, so even that was not helped. 1936 is not a nice point in time. But at the same time, 1936 hosts one of the most successful archaeological conferences with the international flavour ever. The Congress Internationale des Sciences Tristurique, a proto-historic, sorry, my French is atrocious, and also by chance it was an organisation that was meant to bridge gaps and in Bern, 90 years ago, perhaps this place, but somewhere around here, the Réglement, the rules were put up, and the first successful session was done in London, 1932, with 639 participants, and in Oslo, during the same year when the words seemed to start to burn, it was well attendant. I couldn't find the numbers, I know there were less people there, but still it was more than 400 at least. I have to thank these gentlemen from Romania who wrote this in our article, so I found it, so I have heard about it, but then if you want to have the sources, then it's pretty difficult to get this materialized. And if you see the sentiment, I wish to point out that everyone, I just found quotes on speaking French at this stage. The French was Dilligné Franca of European Ideology, and here we have Charles Riet, who is the President of the First Congress, and he tells us that he assures that the London Congress has resulted in a close ties of friendship among scholars of all countries, and in the removal of it remained of any divisions between us. So there was war there, there was hardship, but the Archaeologists have found each other. It's even a bit stronger, for years later in Oslo, Yes, we are going to take advantage of the possibility and the importance of international collaboration in our sciences, if, first of all, international science of prehistory and of the proto-history, sort of, okay? That's an answer to Kocina. And he translates in that sense that, yes, the end of the conference is there, but he's totally convinced that there is an importance of international collaboration in Oslo, international sciences, the science of prehistory and proto-history. There was, at this stage, a very strong belief that the archaeologists of Europe would have a sort of a counterculture, and they would be able to reach all these things, all these divides, all these borders, which were then strengthening itself and making international work, these are nice words, but then if you look at, for instance, Graham Clark, I have to say at this stage, my whole presentation collapsed thanks to E.T. work, so you have to look at Berger for the rest of the presentation. Clark is a prime example of someone working across these borders. From 1931 to 1937, he visits all over northwestern Europe, from Sweden, Denmark, he visits Germany twice, he goes to Poland, he talks to Polish archaeologists, and the effects of his visits are so big that, to my amazement, I discovered that in 2014, there was a special congress on the influence of Clark on Polish archaeologists with a bundle of his material, so there was something there, and I have been very lucky that the father of Dutch archaeology, Van Giffen, to just use the short version of his name, was in correspondence with Germans, Italians, French, English, Irish, archaeologists in more than one language, so there was literally the work people connecting with other people and working together on research across all these borders. So, difficult situation going on through these borders, but now we move to the blessed time when there are no borders. I want to introduce you to the idea of a Euratio, Euratio's EU, a radio is a system where across a national border you make connections with each other and you sort of make differences between them all systems, very small it has to do with the European program of Interrecht, and one of the most famous ones is the area where three countries have decided to do this, Germany, the Netherlands and Belgium, it's the Maas-Rein area, it is a large area with a historic continuity as well, and if you think about the prehistory or the Roman period or the high medieval period, there are great connections in that area, so in 1976 it is decided to go with that kind of area of protected and promoted working together, and you would say that's wonderful, but if you look at the literature for instance for the Roman period and you look at the study of Roman land use you will see that the modern borders are in high influence, the Belgian studies although they speak about the land use in northwestern Europe only go to the national border, while the systems of the land measurement and the regular forms cross into the Netherlands, the same can be said that the German articles on this thing also speak about the north-eastern Europe but only talk about the German forms of Roman land use, there is no German form of land use, but those areas, and there is no connection from both sides to the part in the middle where the excessive big villas or furandale etc are which are connected to all these other Roman stuff, so amazingly till this day even with all the removal of borders there's hardly any connection between the researchers of these things, so if there is a total freedom to move you cannot find the borders, these people meet each other on receptions for the new year or shake hands or like each other but there is no collaboration, this is a bit of a negative, the same thing EAA has been very busy in committees about the connection between transnational working working across borders, so you think what happened in the time when we needed people from other places in the world to come work for instance in Dutch archaeology, in the end I looked at it again and in the late 90s early 2000s we had three very big projects and in the end approximately 22 to my count British archaeologists came over and then you sort of think how many of them stayed in the Netherlands and the answer is three and two in archaeology, there is hardly any movement in that direction nowadays there is a very large project in the UK known as high speed two and they're desperate for people and you sort of ask around how many Dutch archaeologists are there and the answer to so far I can say is three so the amount you are able to move but are you willing to move and the strange thing is that the border in itself seems to play a part in hardly any roles you can move these things around you can have this idea you can like British archaeology and almost every Dutch archaeologist will say oh it's great British archaeology is much better than Dutch archaeology and all kinds of sentences come around but then you would say well what's keeping you to go into heaven and cross the pond work on the other side or academically speaking the idea of the North Sea culture the North Sea culture is this idea that modern civilization comes up on both sides of the North Sea so academics should be working on it from well British and English sides and work together there's no research being done on this page this is not so much as a negative but also a a strange outcome to my mind from the success story of the British and the Dutch universities strangely enough the British and the Dutch have had the highest success rate of getting money from the EU so therefore partnerships in European context has to be done with groups outside of the leading countries so the Dutch are leading in most things organizing projects and the British are and you cannot both be at the same time leading so therefore you sort of avoid each other and you go in coalitions which don't work together so you can be very successful but then even sort of cling to your order what to do about it a future perspective I personally whatever happens in the strange world of brexit politics and it makes good television there will be great films about it in five years time or so but regardless of what is happening regardless how hard the border will I will try to stay involved in British archaeologists yes it's on the periphery yes I want to work there that's probably very difficult at this stage but I will be there and the big question is not so much what borders do for us but how much do you want to invest in each other do we want to become part of each other's story and you see in the example of the 1936 is that you could all once become hopeful from it that if the problems and the borders and the divides between you are very strong as perhaps also a willingness to engage more with the other side in that sense you could be hopeful and say well maybe this gives us a chance to sort of rethink our relations and rethink the possibilities to work each other in general British and Dutch archaeology like each other in general we want to work with each other but now's perhaps the time to have this dream or this idea become actual fact in a sense there is nothing which stops us apart from our lack of interest to film make true what we already have been preaching for the last 30 to 40 years thank you


Can I still get the skills and experience I need through a screen? Can online learning actually be fun? Is attempting to teach in your PJs? I'm not going to stand up now.


So, I'd like to go ahead and get started with our first speaker, who's Mike Snyder. Mike Snyder is a mod-encode researcher. He is the Stanford Asherman Professor and Chair of Genetics at Stanford, and one of his specialties is personalized medicine. Thanks, Mike. Great. Well, thanks very much for having me here and giving a chance to tell us what we're up to on trying to look at regulatory information across different organisms. And I think the mod-encode consortia along with ENCODE has really provided some nice opportunities here. Let's see. So why would you want to compare regulatory information across organisms? Well, first, if you do see conserved elements, you know they're functional. And if they're functional, that can be quite useful to you. It implies something you might want to study or understand if it gets mutated. I think the other reason you want to look at comparison of regulatory information across organisms is that you would like to try and understand basic principles of design, what kinds of circuits lead to what kinds of outcomes, and then, of course, ultimately how you modulate those circuits and change outcomes is of high interest. And lastly, I would argue that, and probably many more than us, but the third possibility is that we'd like to get a general understanding of how we're similar and different from one another, both within a species and between species. I think many of you may be aware of this general question, is just how much are we identical to one another? How much of that is due to differences in, say, amino acids or the genes we have? Or how much is it due to the fact that we have the same genes but how the regulator makes us different from one another? And along the lines of this last point, there is some controversy in the field about how much is binding site transcription factor binding site conserved or differing amongst different individuals. And so we had a paper out along with Tonka and Odom in about 2007 suggesting, in fact, there's extensive divergence of binding sites amongst different organisms. And the pilot phase of the ENCODE consortia had similar conclusions, but there have been other papers out there suggesting that, in fact, binding site information is incredibly conserved between different organisms or within the same species. And so there is this unresolved issue that's there as well. So what I'm going to talk today is about general characteristics. So I should back up and say, so my ENCODE, along with ENCODE, does provide a really nice opportunity because there's a huge amount of data to really get at this question, although I have to admit there's still many more questions to get answered as you'll see at the end. Okay, anyway, here's what I'm going to talk about in today's talk. So first I'm going to tell you a little bit about general transcription factor binding data. And this talk will really just focus on transcription factor binding information. Jason will talk more about the chromatin information, which is obviously another aspect of regulatory information. And then I'm going to give you a few vignettes, if you will, of some of the comparisons we've done. This is a work in progress. And some of those questions are just how much are the features of binding site of different transcription factors in their binding sites similar or different to one another? How much are the partners of transcription factors differing between different organisms? And even a fundamental question of do transcription factors like to bind the same types of genes between different organisms? And most of what I'm going to talk about is worm, fly, and human comparisons. But for reference, I'm going to sprinkle in some mouse ENCODE data as well. Okay, let's start with the data sets. As I say, there's really a lot of data sets out there now with transcription factor binding. And since humans have been studied the most with the most groups and the most amount of time, they have the most, there's 700 different data sets. For worm, there's 236 flies, there's 102, but there's a lot of chromatin data sets here. Again, we'll talk about that. And for mouse, there's quite a few as well. These represent a number of different transcription factors, generally 50 to 168. This just shows that in general, there'll be a lot of transcription factor binding on one or two cell lines. Although for a number of factors, we can get them across different developmental stages or different conditions. So for example, here's human, you can see that there's a lot of effort put on a few limited lines. But you will find a decent number of data sets, tens of data sets across multiple lines, and the same is true for worms. Okay, and a little bit less for flies and mouse. Okay, so all of the data was processed using a very common pipeline for mapping for calling peaks. And then for running through various quality control measures to make sure the data sets are of high quality. And at the end, we do come up with these data sets. There are some additional data sets that are put aside that don't make this analysis, I'll tell you about. If we look within these data sets, how many so-called orthologous data sets are there? That is to say where you have orthologous transcription factors. How many are in common? And there's zero between all four organisms, so there's not huge amounts. There's the most between human and mouse, not surprisingly, because they're the most closely related. There's a decent number between, say, human and worm, and human and fly, and so on and so forth. And again, that's what you would expect because these things, it's reflecting how close the organisms are relative to one another. And if you look at the transcription factors involved, in fact, they are quite similar based on expectations. So red means you're 80% or more identical in amino acid sequence. And so you can see most of the human mouse orthologs are quite similar. And if you start picking the worm, human, or the fly human, these are really quite divergent with only one of them really being super close in terms of its amino acid sequence. So within this, first thing we did was analyze all of these. And sure enough, there are these hot regions, which Mark told you about. I won't say a whole lot about them other than there are thousands of these things in the various organisms. And you can identify them by statistical overrepresentation of regions. And they do change across development. So that is one of the conclusions that does come up. And so, for example, there's only 212 of the hot regions and worms that are similar between the various stages that were looked at. Embryo, first larval, second, third, fourth. So there's only a small number that are conserved, most are stage specific. And they do change quickly. So for example, the embryonic ones are very specific to embryos. They will shift down. Many of them are lost as soon as you move to L1. And likewise, when you move from L3 to L4, you get a lot of stage specific hot regions, okay? First question is, how conserved are the binding sites? Now, worms, flies, and humans are quite far apart. So you can't really get synthetic relationships there. But you can ask some general principles about this. Are they binding the same motifs? Are they binding in the same locations? So step one is to look, are they binding at the same motifs? And this is the work of Playa Kay from Manolis's lab, who's done this very systematically across all of the different motifs. And just looking at his data set, it's over 80% of them seem to be identical or very similar between the different organisms, that is between flies, worms, and humans. This is just one example here of blimp one. You can see it looks pretty similar between flies and humans. But there are some interesting differences there. And here's one case here that Alan Boyle from Alan Boyle's slide in our lab. So this is C. elegans ag one, and it's homologous ag one. And actually quite different binding sites, okay? And it's not simply a matter why we only happen to look at one stage. If you look at different stages, you'll see that you get the same binding site for worm across different stages. And so it's not really changing. But the bottom line then is that this factor does have different targets in the two different organisms, okay? All right, so binding sites are usually conserved, but not always. What about binding locations? Well, we thought we'd start with the simplest case. And if you compare orthologous factors between human and mouse, you can see are they binding your promoters or enhancers or what have you. So if you look at transcription factors, they fall into three classes, I would say. There are those that love to be around promoters. There are those that love to be around enhancers, which tend to be fairly distant in humans and mouse. And then there are those that like to be at both. Now the way we have the relationship set up here, this is the TSS and that's a 20KB away. You can plot in an accumulative fashion whether something likes to be closer further away. If it's red in this region, it means it likes to be around the promoter. And if it's green, it means it likes to be distal, typically at an enhancer. So the bottom line is if you start comparing human and mouse, you'll discover that in fact, in general, they're clustered obviously by, these are more proximal, and in general, there's some trend towards us, but there was surprisingly a lot of variation in this. When one digs into this, you realize it's actually because we're comparing different cell types, and this is interesting in its own right. So if you look within orthologous cell types, so for example, K562 and MEL cells, which are semi-orthologous, if you will, they're cell culture cells, you can see there's actually quite a bit of conservation in terms of location of these orthologous factors. So these factors, again, are near the promoter, and they're near the promoter and mouse, both mouse and human. Okay, so what that implies then is that these factors do vary a bit amongst different cell types. And in fact, we do know that, this is some work from Carlos Araya in their lab, and he's actually looked at the binding relationship of the different factors across different development and different, well, just different developmental stages in this case. And the bottom line is sometimes they're together, and sometimes very often, in fact, they're not together. We had seen that from other studies from Wei Zong as well. I should point out all this has done in collaboration with the team that I'll mention at the end. So the bottom line is for certain kinds of factors, you can see that they'll cluster based on, like these blue factors. These are different stages that like to be clustered together, but there'll be times when they're further apart, meaning they'll actually be binding at different locations and with different partners. Something I'll get to, in fact, in a minute. So just for completeness, we did in fact compare humans and worms. And again, the promoter loving factors for humans, sometimes they're promoter loving for worms, sometimes not so. And we varied this whether it's 20kb or 2kb, you get pretty much the same result. Okay, so the conclusion then is that these orthologous factors, they're often binding the same motifs, but they're not necessarily in the same general locations across different organisms. What about partners? Well, initially, so we want to see whether the different factors work together in different organisms, excuse me. And so first we'd set up a general clustering scheme. And in fact, we didn't see any relationship. That is, the co-associations in one organism did not match up with another. So then we said, well, let's make this, let's define the context of this. So we decided to just look around promoter regions. So you look around a 2kb of promoter region, you ask our factors working together in these regions and are they conserved across different organisms. So again, we first set up a co-association relationship in a 2kb region around promoters. And it's somewhat of a standard clustering, if you will, not quite standard. And we looked for within species comparison defined relationships. And then from that, we then looked for those that are conserved across species. What I'm gonna show you is this slide here, which is the most complicated slide, I think, of the presentation. So just focus on the right for the moment. So we're gonna compare co-association of these different factors, if you will, with these different factors within an organism. And the only comparisons I'm making are the cases where we have orthologs between, in this case, worms and humans. Okay, so we're gonna compare relationships within an organism and then we're gonna ask which ones are the same between. Is that clear? Okay, so let's look here. If you take this factor, EGLE38, and you say who does it like to be associated with? Around promoters, you'll see it has, it turns out, three partners. Faw4, there's a Faw4 data set here and here, and it likes to be at both of those. Also this one, EFL1 and MDL1, okay? So those are its partners, if you were. It's co-association partners. You can then say which of these are conserved in humans, and here's the orthologue of EGLE38. Unfortunately, it doesn't have the same name, so we should rename all these things, mind you. And PAX5 is the same as EGLE38. And what you notice is that when you look at its orthologs here, you don't see co-association, all right? So we do it again and get the same result. Zag1, which I mentioned before, co-associates with blimp1. It's homolog Zag1, does not associate with that fellow there. And we do it again and get the same result. So we still didn't get any co-associations. So that didn't sound so good. So then DanChi and Alan Boyle said, well, wait a minute. Maybe we're asking too hard a question. We're asking these things to co-associate across all of the genome initially, then across all of the promoter regions. What if we start just asking in specific segments of the genome? And this makes a lot of sense, because it turns out different transcription factors work together with one another at different gene targets or different specific locations. And so when you do this across a genome or across a broad range of segments, you'll have a hard time finding these relationships. So they came up with an idea to use the self-organizing maps, and this kind of approach was first started by Allium when he was in Barbara Wald's lab analysis at UC Irvine. And so the idea is the following. You'll take one kb stretches, and within these one kb stretches, you look for enrichments of partners of factors, and they need to be multiple partners across essentially the whole genome. You're looking for enrichments. And you then basically generate these neurons, which are, show that big one there, which are statistically significant enrichments of these transcription factor co-associations. That's the general principle. Clear? OK. So first you do this with humans. And you say, let's look at all the one kb segments of humans and see which ones like to be co-associated. And here's the answer. Crystal clear, I know. But you look into these at the neurons, and you see things that make sense. So for example, in this neuron, all the Paul III, nearly all Paul III, there's a few other things that belong there. They're all together, binding near one another, as you might expect for Paul III components. Same is true for some of these other things. Here's an enhancer type area, which has all of these factors that like to be together. So you can start finding relationships that come up. This is the regulatory code within an organism. Again, makes a lot of sense. Now can we find similar relationships between organisms? And first we were thinking, well, this is going to be complicated. You've got to find all of these and compare it to all of another organisms. But then actually Alan and Dan came up with a clever idea. Let's just mix them all together. We'll take all of the worm 1KB segments, all of the human 1KB segments, all of the factor binding information, put it all in the same pot, and let itself organize. And if they're the same relationships, they should show up on the same neurons. That's the general scheme here. You take all the binding information here, all the binding information here, again, mouse, human, funny looking human, throw them together, let themselves organize, and see who belongs together. And then see, now if they're human specific ones, you only get human specific relationships in one of the neurons. If they're mouse ones, they'll be mouse neurons. And if they're mixed neurons, you'll get a mixture of both.  We mix them together, and this is what we get. We get a lot of species-specific information, which there can be technical reasons for some of this. But the idea, this is a neuron with a lot of co-associations that are primarily mouse. The red ones are primarily human, but you do get plenty of these yellow and orange ones, which mean they're conserved across. These relationships are conserved across organisms. These are the ones that are conserved. You can see things here. And I don't know what a lot of these factors are, but I know this one makes a lot of sense. CTCF, one of its good partners, is RAD21 and SMC3. In this relationship, you can see it's shared in both humans and mouse because it's orange, yellowish orange. So in fact, that makes sense. And you can find others as well. And then there are these species-specific ones, so the green ones and the red ones, presumably are species-specific, although there can be technical reasons for this. And so we have to look at that harder. So then we say, all right, we can find relationships between mouse and human. That's good. We should be able to do that. What about humans and worms? And lo and behold, it actually does work. So on humans and worms, you can find, again, you'll find these species-specific green is worm in this case, so species-specific relationships for humans. There are red ones, but you find the yellow and orange ones again, and these would be shared relationships that you can see between humans and worms. So these kinds of relationships are shared across organisms. So this is one way you can tease this out. And what makes it special is it's not across the genome. It's at very specific locations. And now we need to do the go analysis to see exactly where those locations are. We have done general go analysis to see where the different orthologous factors bind at various gene locations. And what we've discovered is the same general message I'm giving you, which is sometimes information is conserved, and sometimes it's not. Let's see. So this is a case where these are the different worm transcription factors. These are the different go categories. And the bottom line is you can see that some factors and clusters of factors, if you will, have certain functional relationships. You can do the same for fly and get the same result only the color has changed. And then you can compare the two between worms and flies. So here's a factor in worm. You compare it with what factors it has in common based on its go categories of its targets. So are they binding the same kinds of genes? And the answer is what I told you, sometimes yes and sometimes no. So this factor here, onc 52, has a very similar go relationship with these four factors here, two of which are in fact orthologs and two of which are not. So sometimes it shares with its ortholog and sometimes with other things. And the same is true for this relationship. And this is a complicated slide, but the general point is the one I just said. So in conclusion, we've compiled a massive set of ChIP-seq data sets, which are out there for everyone to use, and we're glad lots of people are using them. We can use this to look at regulatory variation within a species, and Mark talked about some of that yesterday, and there's actually quite a bit of analysis of this, and I think it's quite interesting, because regulatory information does change across developmental stages, which is something you can tease out from having worm and fly data. And then lastly, I can tell you across species that binding locations, co-associations in particular, and even go analysis can be different. The types of genes they're binding can be very different across different organisms between the various homologous orthologs. So regulatory information can be quite divergent. So for future directions, we need to understand what these rules are. We are seeing some conservation and we're seeing some that's not, and we want to understand what those basic principles are. And there's a lot of ways to attack this particular problem, even with the data sets we have. You can look at different kinds of relationships. One area that we're particularly interested is this idea of looking at things in terms of networks. How much can these principles be deciphered based on regulatory networks? And Mark mentioned this yesterday, how you can organize regulatory information into hierarchical networks. And then you can start looking at various principles of what regions are most interacting, what regions have certain properties. And one very interesting property related to conservation, either within an organism or between organisms, is that when you have these various layers, so this is the top, the middle manager, if you will, and the lower level peons, if you will, in a regulatory network, basically it turns out that there's much more conservations at the top. That is, these are, I should say, these are under negative selection at the top of the network, which is something that came out of the Human End Code Project. And of course, this is what we'd now like to look at in terms of worms and flies and see if that same general principle is true. And then you can map the conservation information I just mentioned previously about partners and other things based in the context of where you are in these networks. So there's really lots of interesting ways to attack this problem. Okay, so I gave you the conclusions already. Here, in fact, the people who did all the work, none of it was done by me. These are the people in my lab who did the work. Let's see. Well, I'll zip through a bunch of these. Yong Chen, Dan Chi, Alan Boyle, Manoj, Pirahan and Carlos Aroya, and Philip Tating. These are the analysis folks. These are the people who did a lot of the chip seek and Valerie, where are you? There you are. She's over here. We've had merged people. Wei is a double, double dipping here. Okay, we work a lot with Mark Erstein's lab. There's folks who did the analysis partner over here, at least some of them. Anshul Kenjali, of course, is the hero in all of this. He processes lots of data sets and is up here. I mentioned Poya on the motif stuff and, of course, they work with Manolis Kellis right now. And then, for fly work, we have various people including Li Ja Ma. We work a lot with Bob's lab, with Misha Saroff and Tony Hyman, Lincoln Stein's group, of course, is essential, and we work a lot with Stuart Kim's lab. So I think I have time for some questions. Thanks. So, Mike, when you look at the hot spots that are constitutive, that are not developmentally different, do you find a DNA configuration that's inimicable to a nucleosome formation? Is there a binding characteristic? Sorry, do I find what? A DNA sequence that doesn't bend very well would be disinclined to form nucleosomes. Well, we haven't looked at the structural aspects. That's a great question. We should look at that. I don't know if Mark or anyone else has looked at that. We certainly have not. Yeah, to see whether it's got bent DNA or poly-A runs and that sort of thing. Yeah. It would be a great thing to do. Great suggestion. Yep. Thanks. Very interesting analyses. This isn't my real area of expertise, so this may be a naive question, but in the self-organizing map that you showed initially for humans, that huge cluster of neurons that was very dense with multiple factors and things, I mean, what was all that? I mean, the two you called out were, looked to have quite fewer members. I was just wondering, what that huge, dense? Yeah, so you can find, you mean that one region up above that was, well, we're on the Jason's talk. I'm thinking of the very first picture you showed, it was black and white, and you caught it out with two. Yeah, then there were these regions with lots of edges, basically. That whole cluster of many, many neurons with. Yeah, this can look at all possible relationships, so it can look at pairwise relationships. I can't remember if we put a filter of three or more for this one. We've done this several ways. So it can look at all three more possible relationships, if you will, as well as former, as well as five more, all the way up to 168 for the case of humans. Does that make sense? So some of them will have lots of partners that could be working, and the goal is to look for them being enriched in a one KB region over the genome as a whole, and I'm sure we didn't do any of the fancy genome structure correction stuff that Ben Brown does, but hopefully we're still very healthy here. I don't know, did that answer your question, though? So you're looking at all possible combination, combinatorial relationships. That was great, Mike. I haven't been on the Joint AWG Coles in a little while, so it's great to see. That's right, all this is done in the last week anyway, you won't see. Oh, okay, good. I'm a little concerned about one part, which is when you were showing the clusters of co-binding, in one of the groups that you called the enhancer group, there was RAD 21, which is a cohesin subunit, and that's something that is associated with insulator elements, but it should be very broadly distributed across all sites that have. So I'm wondering about whether the list should be culled for things like that, or more importantly, why is that showing up? Why is something that should be more in Jason's area? But just more broadly distributed across all regions that are probably gonna be active in the genome. What's nice about this is that this is unbiased, this pulls these things out, and it is what it is, and it may not be what you wanna see. But having said that, we've looked a lot at actually RAD 21 and CTCF, and there's clearly the guys that are near insulators, and others can comment on this as well. We've looked at this a lot in humans, and there are clearly about a third of them are sitting right on enhancers and another third are around promoters and such. So they're not just insulators, they're really at different locations. The CTCF and RAD 21 and CTCF, they're pretty together nearly all the time. So in fact, they're different classes of CTCF slash RAD 21 sites, and I think that's what that data set's telling you. Can I comment on that as well? So when we're looking at the chromatin state annotations and how transcription factors associate with that, we actually find RAD 21 clustering with CTCF in a specific insulator state, and very rarely do we see sort of enriched in binding in promoters and enhancers. It's found there, but it's actually not enriched there. So most of the enrichment is actually found in insulator regions, as you would expect. Yeah, that might differ a little with some of our results. We might wanna talk about that later. But I think the point is that you can't use that data to make the conclusion that RAD 21 is specifically associated with those sites. Oh, I hope I didn't say it was specific. All I'm saying is this is a cluster of things that are enriched together over the genome as a whole. So yeah, there's plenty of other RAD 21 buddies out there too, okay. So my question, I don't know much about self-organizing maps, but my question is, so a 2KB region is very different on a worm than human, right, because of the size of the energetic sequence. So have you varied that across the different types of organisms and had them re-utilized? Yeah, so we've done a lot of that for the promoter proximal part I showed you, and we've done a limited amount of that for the self-organizing map. So we can do it more extensively, and we will do it more extensively for the worm human self-organizing map. We've done 500 bases and 1KB for a number of the relationships. We haven't gone from 100, which we will do to much higher numbers, and see what relationships do hold and such. And our experience for some of this, when we varied the windows, it didn't make a whole lot of difference, but it's something good to do. Yeah, Ross. Hi, my question is, so you made certain predictions, for example, from human to fly, which I care about. And there have been many examples where we've put, where the communities put human transcription factors into flies and shown that they drive, at some level, transcription in reasonable tissues and so on. Have you compared that data to your predictions? So in some cases you have predictions that it shouldn't bind the same transcription factors, or that they use different cofactors and so on. Have you actually compared them to the data that sits there? And I guess, of course, in the future, you could actually make direct tests of those by throwing those back in and seeing if they can drive transcription in a reasonable place. Right, now great comment and question, or comment, I guess, question. So we can, I think we would do it, first, it suggests some obvious follow ups. We should see those that have different motifs, the prediction is they probably wouldn't rescue, or maybe we're not looking at the right cell types or conditions, that's a possibility. Unfortunately, those may not be published. What's that? The negatives may not have been published, unfortunately. Yeah, well, we should do that. You put it in a case where you get lots of positive results and you can publish it. And you can do, what was the other comment? Oh, so you can do obvious follow ups like that. Yeah, you would say from the co-association none of this stuff should work. I think it comes back to the point that was raised yesterday. We don't know which of these sites are functional or not. We just know these are binding relationships. So it's conceivable that some of the more functional ones are primarily driven by one or a limited number of conserved things. Jason, I'm flipping through your talk here. Anyway, so it's conceivable, two stories, all right. Anyway, it's, I'm not touching anything. I'm moving away from this. So it's conceivable, it would be nice to figure out which ones are really truly functional as far as driving genes, because that might help explain that relationship. And the other thing I think I could say is that small amounts of activity can rescue phenotypes, and you point out they're almost always partial rescue. I'm very familiar with the yeast experiment. And yes, they rescue, but they're always, they're various grades of rescue. And I think that might be what you're seeing, because the partner relationships aren't perfectly established. So that would be my prediction. Yes, I agree. But you make hard predictions, or fairly hard predictions, about ones that will work better or worse. Yeah, no, I think this, like any good experiment, it suggests more things to do. Okay.


The study examined the relationship between ego defense mechanisms, medication adherence and self-management in patients with type 2 diabetes. It was found that mature defense mechanisms such as sublimation and suppression are associated with better self-management and medication adherence. Additionally, females had higher levels of neurotic defense mechanisms such as pseudo altruism when compared to males. This article was authored by Fatima Akram and Mahwesh Arojnaz.


The idea is to take the pressure off of the doctor's surgery because they will have people coming quite frequently who may not need medical input but actually want a longer appointments so the social navigator can see these people that she can spend a lot longer with them, perhaps visit them in their own homes a help them to access all those very many voluntary things which are going on in our villages. Patients will see doctors and nurses initially, they will refer them to me if they think it's appropriate if the patient has identified that they're socially isolated or could do with some more holistic help is how we're looking at it. Then I will approach the patients either book an appointment or visit me at the practice or visit them in their home if they're house bound. When I see the patient then we then have a conversation about what they're interested in, what barriers they think might be stopping them from making those connections and I would help them to find solutions so they can make those connections. I'm a local funeral director and I lost my wife two years ago and my mother within five months of each other and this scheme is absolutely wonderful because there's so many lonely people, not just youngsters, the youngsters in the elderly and some people don't see anybody from one week to another. I'm lucky, I've got a good family and friends so I'm one of the lucky ones but this scheme is ideal.


Hi, and welcome to How to Manifest the Man of Your Dreams. I'm Matthew Coest and today with me is Marcy Newman from marcynewman.com and Newman spelled N-E-U-M-A-N-N. Marcy is not only a mentor of mine but she's also a law of attraction expert as well as a manifestation coach and I've actually known Marcy for a number of years now and we've gone through a lot of different things together. She's helped me with a whole bunch of different projects of mine and she's a great friend, a great mentor and an amazing person who's always helped me out with just about anything that I've asked her to and I'm really, I feel blessed and honored to have her here to get here today. So thanks a lot for joining us Marcy.  It's fantastic. Awesome, so there's a, you have a number of different products available that help women, that can help women manifest and find and attract Mr. Wright, the man of their dreams and love. So how did you get started in helping women and helping people in general do this? Why is it important to you? Hmm, great question. First of all, I've been in this people helping business for over 40 years and in that 40 some years, you can only imagine the progression of my work as well as the focus. Life is a journey and I think that that's something that's really expressed in everything that I do and it's an important aspect of life for people to both accept and to embrace. Life is a journey and so in my journey, I've experienced many different things and throughout all of those personal experiences, I of course became sort of hyper aware of what was happening within me as well as the things that helped me to get through those times in my life where I needed something more than just an everyday support system and so one of the first things that I did and I really credit the, I credit my whole evolution seriously on this one thing and that was when I needed the help, when I needed the mentoring, I reached out and I got it. What that did was it catapulted me forwards. There's something amazing that happens when we reach out for the help that we need. It's like the universe just suddenly pays attention says, whoa, we have a live one here who's asking for some help and it's as if the universe just laid itself at my feet and when that happened, Matt, incredible things started to happen. I started to get these processes, these programs that were more or less downloading through me and each one of them, I recognized as being connected to something that I also needed in my life at these particular times that I was referring to and so in combination with the information that was coming through me, I also had the benefit of that 2020 hindsight where I could take the wisdom and the experience that I had and really connect the dots and when I did that, I was able to create these programs, these products that I speak of and thousands of people have benefited from them but it's all about creating the awareness about what's happening within us, getting exactly what we need at the time that we need it and letting the universe do the rest and it's always there for us. That's how it happened for me and I've now been blessed to bear witness to it happening to like I said, thousands of other people and I think it's how we're meant to live. Yeah, I agree and I definitely, one of the things I just wanted to kind of touch on that you said was this whole idea of reaching out and having mentors and finding people and one of the things that has been just monumental in my life is going out there and really connecting and getting people who are in the place that I want to go to. That's right.  All the attempting to figure it out, all that kind of stuff is always secondary if not tertiary to really finding people who have already gone on that journey and figured some things out. So can you tell us a little bit about what this process is? How do you begin manifesting and attracting the things that you want in your life and specifically we're talking about men here and if a woman is, she's single and she wants to get started, what should she do? Oh, it's a great question also. So I'm going to say something that may be considered blasphemous to others, but I just have to share this. There is a school of thought that our manifestation happens from a place of thought and it's untrue. It's absolutely untrue. That's only part of the picture and in fact it's a small part. What actually happens is that those thoughts are never random. They come from someplace and where they come from is a sequence actually that is created originally from a feeling, a sensation that we have about a certain circumstance or a situation. What happens is this sensation creates a response within us and based upon our past experience we either have a positive response or a negative response. From that response is a whole perspective of the world that instantaneously comes forward in our mind. The moment that that perspective starts to roll itself out, our emotions keep feeding it and then thoughts follow it and from those thoughts come our choices, the actions that we take and of course then the life that we live. So what I think is the most important thing for people to understand that part of their frustration and not being able to manifest what it is that they want in their lives and particularly a relationship or a soulmate, really exceptional, deep, intimate relationship is because they're relying on misinformation to get them there. The information that they need is already within them and it starts as I said this feeling. Now here's the issue. So many of us have been taught to ignore those feelings and rather than following what our heart is essentially saying to us we start to logically try to maneuver and contort and make things happen based on what we want and ignoring the message really that's coming from inside that's saying this might not be right for you. This is maybe not for your highest good. So part of what I'd like people to understand and particularly I think women is that we have this programming inside of us. This programming that started when we were little girls that told us that our job was to make ourselves into someone that somebody's going to love, is going to save, and is going to marry. And what this has done is that it has created this huge gap between who we really are and who we think we need to be in order to be that person. And as you can imagine it creates a lot of confusion. But in that confusion and chaos we can't manifest what it is that we really want. When a woman in particular is looking for a very deep and intimate relationship there's only one way to get there and that is to create that deep and intimate relationship within herself. To know herself and most importantly to start from this place of self-acceptance. Because if you're already in this place believing that you're not enough that you have to be someone else or something else or meet someone else's standards and by the way the media has done a great job at really distorting what that's all about. Then the path of energy that is being sent out cannot bring anything back but chaos and confusion. So this intimate relationship that a woman develops with herself is one really based on creating clarity, creating that self-acceptance, creating this connection so that she can once again sort of reclaim all of those lost parts that she's left in these other relationships where she was left feeling incomplete, feeling like there's something wrong with her, feeling like she just wasn't enough to get to that finish line. And unfortunately it creates this whole domino effect. So in wanting to create these relationships of deep abiding intimate love it really requires this place of coming back to self, really knowing yourself and being bold enough, courageous enough to put aside those programs and to say here I am ready to be loved. Great, so that makes a lot of sense to me and I know that a lot of the women that are listening to this right now have at least some of the feedback that I've gotten from them is that they've experienced that before, they've experienced those kind of knowing or those feelings that maybe they're in a relationship where something's wrong or maybe they're doing something that they know they should be going in another direction except they have maybe all these different expectations and standards for what they should be doing and how their life should look and they need to be in a relationship because there's a lot of shaming on people that aren't in a relationship. So one of the issues and this might have be kind of connected in a way is a lot of the women in our community tend to attract, they complain about attracting the wrong types of guys, guys that are emotionally or just completely unavailable or guys who come to them and they promise them the world and then they disappear one day. So how could a woman stop attracting those types of guys and start attracting the types of guys that she wants to attract? Awesome, it's really very simple. Not so simple an application if you're not willing to do the do, but if you are, what needs to take place is number one, a commitment to do so. So what that means is that you need to be aware when you're going off track, when you're ignoring those inner messages and when you start to take in the not enoughness, the feeling that you need to contort yourself or change yourself to meet somebody else's expectations. The moment that those start to come forward, you need to know that you're in the wrong direction and you need to come back to center. The issue really is in attracting someone who's emotionally unavailable is that that is the energy that's being projected. A lot of people may be sort of reeling from that statement, but that is the energy that's being projected. There's only one law about energy, whatever you put out is coming back to you. Energy works in a boomerang effect. So if that's what you're experiencing, it requires your commitment to yourself and to what you want to really experience and examine where is that coming from in me. If I'm not willing to look at myself and accept myself on a very intimate level, including all those parts of me that I deem unacceptable or a part of me that I think is unlovable or just can never be allowed to come to the surface, all of that are parts of me that are unavailable. And those are the parts that I need to embrace. Those are the parts that I need to create a path so they can come to the surface. And I can see that all of my parts are what makes me so unique, so wonderful, so beautiful and ready for all of me to be loved. I can't tell you how many times I've heard someone say, I just want to be loved for who I am. And yet there's this whole pile of things that they don't love about themselves. How can they be loved for who they are when this pile is already seen to be unlovable? So it's constantly being squished down, constantly being shoved down, hidden and loaded on top of all of the distortions, like I said, that are created in the media, that are created from other people's expectations that have nothing to do with you. So you want to attract someone who is emotionally available. You need to be emotionally available for yourself. You want to attract someone who is capable of taking you to that finish line and creating a relationship that is sustainable and that is filled with all of the wonderful things that you want to experience in love and in relationship. There's only one place that that can start, but it creates confusion, like I said, when the programming is allowed to be in control rather than the heart. Our hearts tell us everything that we need to know and it's in listening to those hearts and listening from a very keen point of awareness where we begin to understand how all of this works. Unavailability is unavailability. So yeah, and you're right. And I just want to make sure that there's a little bit of clarity here. What we're talking about right now, what Marcy's talking about is this process of healing. It's a process of creating wholeness within yourself. And really when I first heard stuff like this, it kind of seemed like this kind of like hokey, almost like weird, silly, like Stuart Smalley type thing where I'm looking in a mirror telling myself I love myself. And after I started going through this process of finding out what it really meant and exposing these parts of myself that I was hiding because I thought that's what I was supposed to be doing. I thought that it comes from this, I started from this place and if you're at all familiar with my background, you know that I used to be a men's dating coach. And when I first got involved in that, it was like, it was all about how to get. How do I make or how do I get? And it's like, how do I make this happen or how do I get her to do this or how do I make her do that? And really the shift became, how do I work on myself so that when I meet this woman, these quality people in my life, it's not me attempting to force them into this little box or making them push these different buttons and outcomes this result that I want. Instead it's, they meet me and when you kind of develop that wholeness and you go through that healing process and you start meeting people who have done the same thing. When you start meeting emotionally mature men, when you start a meeting other emotionally and spiritually mature people who have gone through these different types of processes, you'll find that they're attracted to you. And they want to do those things. Those people are relationship oriented. You think that a lot, I get a lot of complaints that all men are commitment phobic and it's simply not true. It's just this space where a man becomes, when he becomes emotionally mature, he sees things in a different way. So can you talk a little bit about your manifestation process? I can. Do you mind if I just touch on something for a moment? In terms of that commitment, again, commitment can only be brought in if it's being projected out. And I used that word before in this process. It requires commitment. It requires that you are committed to, as you described, self love. But there's a lot of confusion there. People have this idea that self love is either selfish or that they are narcissistic or that it is consuming yourself with self care. It's none of those things. Self love is the taking of action that is in alignment with your goal. That's what self love is. And it requires a commitment to do that. It requires, as you described, a willingness to be vulnerable, a willingness to let those cats out of the bag and say, I'm lovable just the way I am. But it's also requiring a willingness to let go of this whole misperception that we need to go out there and find someone who'll finally love us. Uh-uh, it's all about attracting the person that you're going to love being with. And that's what you were describing. It's when you become that person, that emotionally mature and available person, that committed person, that person who intimately knows themselves and is living authentically and saying, here I am. That is the only thing that you can attract is someone else who's in that same space, that same vibrational frequency. So here's my manifestation process. Number one, you must begin to create this awareness about how you're feeling at any given moment. That is essential to everything because from there, as I described earlier, there's a whole domino effect of what's going on. If I can feel myself ill at ease, I need to stop right there and say, wait a second, where's it coming from? Is this something from that programming? Is it something because I'm stretching myself out of my comfort zone, which is essential? Or is it something that is calling to me to pay attention to? The moment you ask yourself those questions, you'll get the answer. The committed you will take the action that that answer requires.  Any of those things you need to be admitted and say, I have to pay attention to what's happening inside of me. All of that information that you need is right there. So you need to believe, number one, that this is happening for you right now. You're already in your process. And the more that you are attuned to yourself, you can accelerate that process. So what we know about manifestation is that it requires that every step along the way, that there is something that we are going to need to let go of. What is that? It's the past programming. It's the immature idealism. It is the lack of commitment that we've had to ourselves in the past. But here's what I have found, more than anything else. It requires that we begin to let go of the false beliefs about ourselves that we have accumulated from all of these past experiences and past relationships. There is nothing that is more diminishing to our authentic being than those false beliefs of being not enough, unlovable, unworthy, undeserving, or in some way, just not good enough. And it's those false beliefs and the energy connected to them that this acute awareness begins to point out to us.  You know, and really preventing us from having everything that not only that we want but we deserve to have. We're meant to be in these wonderful, joyful relationships that are freeing to our spirits. That's how we get to deliver what we are meant to deliver in this world. You cannot deliver who you are and the special and unique gifts that you have come to deliver if you are constantly making yourself smaller and separate from your true self cannot happen. And so part of this whole relationship thing is to understand that its purpose is to also bring your purpose forward. There is something incredible that happens when the energy of that truly abiding love comes together and the joy and the freedom that it's created unleashes you into the world. And it's incredible, not just to witness but to experience takes you to a whole nother round of existence and that's, I believe, the birthright of every person here. Cool, so real quick, so let's take a second out real quick, Marci. I'm getting some feedback from your side. Do you have any idea what that might become? It's like that echo of me talking and it keeps- Okay, because I wasn't hearing it on my side. Here, try this again. Okay. Why don't you try this again? Okay. Why don't you speak and see if you hear anything or if you hear anything from me? Yeah, I can still hear it a little bit. It keeps switching our screen because it'll go on to your side but it sounds a lot better now. It does, okay. It did before. Let me just unplug something over here, let me see that. Okay, try this. Okay, let's- I'm literally in a room with nothing else in it. Never really. So, there was a little heating, you know, space heater. I unplugged it. I don't know if that was creating interference or not. It could have been. You never know with technology these days. I still hear it a very little bit but it's not kind of in your face and switching the screens as much as it was before. Let me see if I can move the computer or- It may just be with the computer itself. You never know with technology these days. So, did you want to- Was there something else that you were about to say? No, I think that was a good spot for you to interrupt. Fine. Okay, okay. Okay, so we'll just start now. So, one of the things that I found to be really, really useful in my life is I have this practice, right? And it's kind of this practice of creating the things that I want and kind of focusing myself and focusing my energy and kind of reprogramming my mind for what it is that I want is do you have any specific things that a woman could do that she could practice on a daily basis that would help her start attracting the guy that she wants in her life? Yeah, and I think that this is one of those great accelerators that I was talking about that changes everything. It'll change your whole game. And that is ultimately what you are doing here is that you're changing your energy vibrational frequency, right? You want to keep erasing that frequency so that you are attracting from a higher frequency as well. So here's the accelerator. With all of my clients, one of the first things that I do is that I suggest to them that they become a love detective. And in becoming a love detective, their assignment is to start a love journal. And their job is to go out throughout their whole day and to start paying attention to all the things that make them feel good. It can be hearing a bird sing. It can be hearing a little conversation between two people that just sort of make a smile. It can be a smile that you exchange with stranger. It can be a song that you heard that takes you to a time where you were footloose and fancy free and just feeling right. It can be anything. Anything that makes you feel good. And you start to keep a log of these things. At the end of the day, you read through that log and just for a quick second to recapture those moments. As you're going to sleep at night, it's important to know that the energy that we go to sleep in is the energy that will sort of be condensed during our sleep. And it actually feeds all of the dimensions of our being. The next day, you accumulate more information and more information and more information. And then in this new awareness that you begin to create as you are that love detective and looking for only the things that feel good you begin to notice very quickly then when you're not feeling good. And rather than just ignoring it, pushing it down, it actually speaks to you in a different way. And the more that you're focusing on the love aspect, the things that feel really good, the louder that the discomfort is that the discomfort is when you're not feeling good. The beauty is the moment that you have that discomfort, you have a whole log of things that you can now refer to that you read through, you recapture for just that moment. And it immediately brings your vibrational frequency back to that place of feeling good because that's the place that you want to attract someone from. When you're feeling at your best, when you're feeling happy and joyful and free and when you know all of these things about yourself that are so valuable because you know what's gonna make you feel happy. It's incredible how quickly this happens, but I suggest that someone does it for a minimum of seven days, 21 days, and it becomes a habit and your whole life will change. It changes because your entire vibrational frequency has been elevated. So not only are you seeing things through a different lens, you are attracting other things into your life that are only going to support this happiness because energy has a boomerang effect. Whatever you put your focus on will come back to you. It is miraculous and I would love to hear the results of just that of every single one of our listeners. Yeah, you know, and it's kind of cool that you said that because I think that's the first time I've heard you talk about that specific exercise before. It sounds very similar to some of the things that I've done previously and some of the things that have really impacted my life and if, I don't know if you can believe it or not, but at one time I was one of the most stubborn, kind of angry, like, just, you know, like always down in the dumps. Yeah. What I ended up doing was an exercise of gratitude and just creating a log of what I was grateful for every single day. And it did an amazing thing because I actually still do it, but after a couple months of doing it, it was like my entire reality had changed because I went from this guy who was so full, it was like I was so caught up in what I was mad about and what was wrong and who's to blame and all the things that are negative in my life and around the world and just in society in general that I never really stopped to appreciate and experience the great things that I had in my life. And what I started to find from it was that I just naturally started and, you know, part of it was probably me attracting it, part of it was just me seeing it more often in my life and kind of feeling those emotions and moving towards the things that I was grateful for. You know, and so the more I started doing that, I started finding very specific things to be grateful for and what that ended up doing was it kind of narrowed my focus down. So when I started saying, okay, I'm going to be grateful for the relationships, which is actually one of the things that I did that I have in my life, I started noticing that it directly impacted my relationships. And one of the things that you know, you can speak more on this too Marcy is just this, an idea about looking at men and you know, I know there's a lot of anger out there about men and about how men act and it's not just on, you know, that kind of viewpoint isn't just kind of set up around women. You know, when I was a men's dating coach, it was the exact same way. You know, the men that were there were, it was, you know, how can I blame women? How can I make women better? How can I improve women? You know, and it really destroyed their ability because if you think about it, you know, you meet a guy, you meet a great guy who's put together and he's looking for a great woman to share his life with and you walk up and you've got all these thoughts and beliefs and all these and you're just stuck in this kind of thought process about how bad your life is, about who's to blame, about how men are to blame. You know, a guy's not going to want to be around that and so if you want to start pulling these guys in, you know, good thing to do would just to be, to start finding things that you appreciate in men, find things that you're grateful for about men. Do you have anything specific you'd like to add to that, Maxie? Yeah, I would like to just take it back just a step further and say that before you can have that level of appreciation for others, it has to start within you. You have to start that same appreciation process about you and again, I have to come back to the commitment. This is, you know, not for the, it's not for the weak of heart. This is about strengthening the heart and so this commitment that I'm talking about has to include the willingness to look at yourself.  You know what, Matt, it may require that you lead that circle of friends.  You may have to leave that circle. It requires commitment. It requires taking everything that you're learning and putting it into action and it goes the same thing for a man. You know, all of the women bashing, how can they possibly expect to find a woman who, you know, is going to be what they want to have a relationship with from that energy?  So it's about the awareness of what you're feeling at any given moment and it gives you all the information that you need. You know, another thing that I think is really important is for us to begin to be willing to see how so often we are betraying ourselves. The entire time that someone is in that circle of men bashing, they're betraying themselves. They're saying they want one thing but all their actions are pointing to another. They're talking the talk that they think that everybody wants to hear and in their hearts, they're crying because they don't want to be alone anymore. They want to be with that man who is going to create that relationship that they so yearn for. That is such a great form of self-betrayal and it has to be transformed. It has to be 100% commitment to what it is that you want and you will have it. You will have it, you'll have it all. So going back to the idea that you were talking about earlier with the whole clarity thing and we're talking a lot about what a woman wants. What should she start out doing? Should she put together a list of the characteristics of the type of man that she wants? Should she, like how should she get this process started? Yeah, a list is a wonderful place to start and the list does two things. First of all, it's putting your focus on what you want rather than what you don't want and in the law of attraction, in manifestation, we only want to stay focused on what we want. So that's something that's really good that comes out of that list-making. But those characteristics need to go someplace. They need to begin to explore how these characteristics play out in the relationship. So if they can describe first the relationship, how they want to feel, sometimes it's easier then to think about the characteristics that a person might need to have that will help you to actually create that relationship or be able to partner with you to create that relationship. As an example, let's say for instance, in this vision that you have of this perfect relationship, it's one where trust is really important, that you want to be in that place where you can trust not only that person but trust in the viability of the relationship. Trust that each of you is going to show up and be emotionally available to continue to feed the relationship what it needs to be fed. That trust needs to be an essential part of who you are. So that characteristic cannot just be something that you're writing on a piece of paper. It needs to be something that you then look at yourself and say, how can I become more trustworthy? How can I create more of a trusting relationship with my heart? How can I create more trust in how I relate to the whole world? I can tell you this, if fear plays a huge part in your life, trust is absent. So it's not just what we write on paper, it's understanding how this plays out in life. What do we need to look for? And the other thing is, go on a trust quest. Ask the universe that it shows you trust in every aspect that it can because it might be something that you haven't experienced before or haven't trusted enough to see, to allow it in. And so sometimes we need a little remedial help in experiencing what it is that we want more of. And that's when you start to really put yourself in the position of trusting then after you've made that request, what the universe brings back to you and says, okay, this is what it looks like here, this is what it looks like there, this is what it feels like, this is what it sounds like, this is what it tastes like, this is what it sounds like. So it's not just writing it on a piece of paper, it's starting to understand, as I said, how it plays out in life and knowing what to look for. Okay, so one of the things that a lot of the women in our community- We're going much deeper here than we have in the past. But this is really important information because you can go through steps, one, two, three, four, five, six, and say, okay, I'm done, and go out and then be shocked when you're right back in the same situation.  It's because writing it down is not enough. It's time, like I said earlier, to start gathering all this information and taking the actions that it demands of us. We want to raise this to a whole nother notch. We want something more, right? It's why we're here, it's why our audience is watching and listening so intently to what we're speaking about. So it's all about now applying. It's experiential time to take everything that you've taught that your other experts have shared that I'm sharing and put it to work.  No, that was actually really, really great, and I think you brought up a very, very important point. And it's just in this, you know, one of the things that a lot of people talk about and they talk about in the law of attraction is this idea of affirmations. And we talk about visualizing what you want and writing down what you want and all these different things. And one of the things that I think a lot of people kind of miss all together and it was what you're kind of talking about at the beginning of this call was this idea of, it's more than just the words. You know, it's more than just writing down. It's more than thought. You know, it's more than just having these thoughts because the thought is only one, it's only one small part of the whole equation. And there's all these other aspects of it. And one of the big ones for me that's really kind of transformed the way that I've experienced my, not only attracting and bringing in the things that I want in my life, but also just the way that I experience my life in general. And it's this idea of emotionalizing all the things that I want and that I think.  You can write it down a whole bunch of times, but it's when you start associating those positive feelings with it and start putting yourself into these states of feeling it that the process really starts actually happening. And until you do that, it doesn't happen. And then there's another aspect to it that's really, really important. And it's one of the things that I know that you've, Marcy, have emphasized a lot in the past.   It's all up in the door.  You're just doing one aspect of it and one aspect that's important. It's an important part. It's just not, it's not the whole picture, you know, and there's no way to expect or even really, you know, plan on having anything come into your life unless you fulfill all of these different aspects of it. And there's another one that I'd like you to talk a little bit more about, Marcy, and it's this idea of receiving, right, and being open to receiving, you know, how can a, you know, one of the things that I kind of differentiate in some of my materials is the idea of, a lot of times, people and women will get into a situation with a guy and she'll, you know, try to force things to happen, you know, I wanna make a, you know, have this commitment or, you know, like, he'll try to give her something and she'll be like, oh, no, no, no, no, I don't want that. You know, can you talk a little bit about receiving and how important it is and kind of what that looks like? Sure. And it's such an important focus when we're talking about manifestation and it's the difference between having, it's the difference between having the superficial relationship that you were describing just a moment ago with yourself and the deeper relationship with yourself that, of course, will then create a deeper relationship with another and here's how it works. As I said earlier, the most important information that you can gather is this ability to tune in and to see how you're feeling at any given moment and I said it contains all this information that you need for manifestation and here's how it plays out. So, in basic manifestation work, and we're gonna talk about the differences now, basic manifestation work, there's six steps. First, you have to believe that whatever it is that you want is there waiting for you. Second, you have to ask for what it is that you want. Third, you have to be able to visualize it, right? You have to be able to get ready, right? You have to be able then to be willing to receive it in every single step along the way. If you're not paying attention to how you're feeling, it is creating nothing but inaction. It cannot go anywhere and this is why.   In that moment, you need to stop right there in your tracks and say, where did that come from? You need to go back to the first step and say, what do I have to do to believe? I have to let go of the disbelief in some way. What's it connected to? My unworthiness, connected to past experiences, connected to this, connected to that. You're trying to visualize, right? And you have this great vision of your love, the relationship, all of that. And you come out of this wonderful visualization, you feel it, it feels great, but the moment you open your eyes, something pops up and it says, wonder how long I have to wait for that? That's for other people, it will never happen for me.  It can't happen. Because every step along the way of that manifestation process, you haven't paid attention to what has really come forward. You've only been trying to control your mind when in fact your heart is trying to speak to you and saying, there's something here that needs to be fixed. There's something here that needs to be healed. The energy needs to be shifted in order for you to be in alignment with us. And so it's that alignment process that is so essential. It's a very important aspect of the manifestation and most people don't really understand what that means. It's not just showing up at the bar at seven o'clock. That's not it at all. It is every step along the way, what do I need to do to be in alignment with my own success here? So it is always about creating self-awareness. And as I said earlier, coming back to that self-acceptance and loving yourself wherever you find yourself. Remembering, we're all on a journey. It's all a process. But your awareness is what will catapult you forward. Absolutely, and that was well said, Marcy, well said. So just to take it even more into the specific things, I've gotten a lot of feedback that a lot of people have really enjoyed and liked all the how-to stuff that I've given them and are looking for some more. And I was wondering if you have any specific affirmations that could help a woman on this journey or any visualizations or what are some other specific things that you could give a woman that's on this journey looking to attract the man of her dreams? Again, in terms of affirmation, it has to be something that touches their heart, that speaks to their heart, that speaks to their authentic self. This is not a cookie-cutter program. It cannot be because each and every one of us has a different need. We have our own past history, our own past experience, and this is why very often we need to connect with someone who can help to lead us on this journey, who can mentor us, who can be our eyes and our ears in a way that we don't necessarily hear or see ourselves. So affirmations need to be constructed to speak to that, to that part of ourselves that is in the gap between where we are and where we want to be, okay? So they need to be personalized. Secondly, it is in making certain that each person gets what they need in terms of the programs, the structures, the processes that also speak to them, but give them the path to their authentic selves. Authenticity is the key to being loved for who you are. So that's the search. And don't be afraid to try out many different things, okay? Find what speaks to your heart. Don't try to follow the crowd. Follow your heart and get what you need and you'll have many others who wish that they followed you. Yeah, absolutely. And that's definitely echoing a lot of the things that I talk about in my programs and the message that I'm sending. So I really appreciate that and that was really beautiful. And so if somebody wants to find out more about you, Marcy, they wanna find out what you're up to, what kind of programs you offer. I know you do coaching and different things like that. What, where should they go? What should they do? How can they connect with you? Two places. One is marcynuman.com, M-A-R-C-Y-N-E-U M-A-N-N, and the other is heart shift coach. H-E-A-R-T-S-H-I-F-T coach.com. The processes that I use are all about heart shifting to really create those frequency shifts that will start bringing new life in. Yeah. Awesome. Well, it's always a pleasure to have you on any of the projects that I'm doing and you're such a great inspiration. You're so wise and you have so many great things to share and it's just an honor to have you here. So thank you so much for being with us, Marcy. And so everybody else that's out there that's listening, thanks for tuning in and I hope you got a lot out of this and I will speak with you again soon. Great. Thank you so much, Matt. It's been such a pleasure, really, as always.


What's happening guys? It's Shane. So basically this was a requested video. It's going to be a real quick one. Somebody sent me an email asking me if I can go over this study by gobankingrates.com and basically they had a study where they polled a bunch of different people who graduated college and asked them if they thought it was worth it as well as a bunch of other really interesting and related questions. And overall about 42% of them said that college was not worth the student debt that they accumulated, which is insane. And of course that number has been steadily going up over the years as college has gotten more expensive and in this video I'm going to go over why that is and I'm going to go over the study and just talk about some of the most important nuggets that you can get from this study. So at the time of this study the total amount of student debt here in the United States was a little over 1.5 trillion. I believe since then it's gone to around 2 trillion or so. So it's growing at an extremely fast pace. And like I said in this study they basically asked a bunch of people if their student debt was worth they're getting the degree. And as you can see here in this table about 41.6% of them said no. Now the results of the survey also showed that although Americans don't necessarily regret going to college, they definitely regret the cost of going to college. So they liked their college experience. They probably had a great time. They made tons of friends and all that good stuff. But unfortunately they had to accumulate a ton of debt in order to have that experience. Now there are several really interesting things about this study and nuggets that you can take away from it. So what they did here was very clever. They actually broke down the respondents by age group and they found as you know the ages got higher and higher more and more people thought that college was worth it. I'm 30 years old. None of us are enrolled in the college. So for instance 25 to 34 year olds only about 65% of them thought it was worth it. Whereas if you get up to the 65 and older group about 90% of them thought it was worth it. And this makes sense because back in the day not only was college a lot cheaper but there were a lot more opportunities that were opened up to you. You could basically get any degree and it meant that you were going to have a really good stable job for the rest of your life. Now as we all know that's not necessarily true anymore. So I think if they polled people who have graduated say within the last 10 years or so maybe 15, 20 years at the most that 42% of people that thought college wasn't worth it would probably be a lot higher. Now another really interesting thing about this study is a significant amount of people about one fourth of the total respondents indicated that they would have chosen a different major. And considering that 60% of them who are asked this question shows none of the above as an answer it's probably a lot higher than 25% in reality. They just didn't quite give enough details and the answer choices. And so a lot of people didn't really have a really good response. Now unfortunately they didn't exactly break it down into further details in this study but I've talked about it in other videos and I've seen a lot of other studies on this where they actually break down the amount of regret by the person's major. So you know if somebody got a computer science major how many of them regretted it versus if somebody got an arts or a fine arts major how many of them regretted it. And as you can imagine many more of the people who got these liberal arts degrees these fine arts majors had huge regrets later on because they simply could not find a job and the few jobs that were out there had crazy amounts of competition without being paid very well. That's all I got a request for this so I just wanted to quickly go over the video make sure to check out my other videos right here go ahead smash the like button hit the subscribe button and ring the notification bell and then comment down below any ideas you have or thoughts or comments on this video thank you so much and bye for now