Okay, thanks everyone for coming and welcome. Rachel, it's a pleasure to have you here at OIST as a theoretical sciences visitor. Let me just very briefly introduce Rachel, which is a fellow in biology at the University of Oxford, starting her lab and Queens University in Belfast early next year. She's an expert on ecology evolution of microorganisms or evolutionary microbiology, especially microorganisms associated with some other organisms, plants, animals, bacteria such as pseudomonas, rhizobia, many other organisms, and the ways how they compete or live together, such as chrysporacas, antibiotic resistance and so on. She's a rising star, I would say, in the field of evolutionary microbiology and forward to that. Also, thank you very much everyone for coming to my talk, and thank you for the lovely introduction. So I'm going to be talking to you today about how does antibiotic resistance evolve in pathogenic bacteria and what can we do about it. It works a second, okay. So my talk is going to be split into three parts today. So starting off, I'm going to give quite a general introduction to antibiotic resistance, what are antibiotics, what's their history, and how can we learn and understand resistance. I'm going to give an example from my research. So I'm going to talk about, well, so how can we understand how resistance evolves in a patient with a bacterial infection. So I'm going to wrap things up by talking about some perspective across the field and thinking about kind of what are some leading ideas on how can we combat antibiotic resistance moving forwards. So starting off, if we think about antibiotics, they're super useful for bacterial infections and bacterial infections have been a major killer throughout time in history. I'm going to highlight a couple of examples. So if we look back in the Middle Ages, we've got the bubonic plague, or the Black Death, which spread throughout Europe, and all the rest of the world and it's estimated to have killed around a third of the total world population during its spread in the 1300s. And we now know that the bubonic plague is caused by this bacteria eucinia pestis. Moving forwards, we've got tuberculosis, which has been a big problem throughout history, and antibiotics are still today really useful for treating tuberculosis which is still present. And this is showing an image here, so this is London in the 1930s, where the standard treatment for tuberculosis prior to antibiotics was fresh air. And tuberculosis again has a bacterial agent, so we now know it's caused by this bacterium called myco bacterium tuberculosis. So we've seen bacterial infections as a major cause of disease and death throughout history. And if we look at some major milestones in public health over the last century, one that really stands out to me as this first use of the antibiotic penicillin. But it's in kind of collaboration with a lot of other changes that have happened. So this is looking at the crude annual death rate from data in the United States, and it's highlighting some kind of key points over the last 100 years. So we've got the introduction of fluorine disinfectants into public water supplies. And we've got, so linking back to the first slide, the last recorded human to human transmission of plague in the US. Then over here in the 1940s we've got the first use of the antibiotic penicillin, which was really widely used after this. And then we've got some introduction of nationwide vaccine programs after that. So there's this famous story about the discovery of the antibiotic penicillin by Alexander Fleming in 1928. And the story behind this is it was actually an accidental discovery. What happened is Alexander Fleming was growing some pathogenic bacteria, Staphylococcus aureus on these agar plates. So this image just shows a plate filled with nutrients the bacteria like to grow on so it's how we can culture bacteria in the lab. And he was growing Staphylococcus on these plates and he went away for holiday left these plates out and came back and noticed something really interesting. So he noticed while he'd been away, his plates have got contaminated with mold. But what was really interesting about this if we look at this image here, so we've got the mold in this top corner here which we now know is the fungus called penicillium. We've got these little white dots are the colonies of the bacteria so the colonies of Staphylococcus growing. What he noticed was this zone of inhibition around the penicillium colony. So he saw where the mold was, there weren't any bacteria growing. And we can repeat this in a modern experiment where you can perhaps it a little bit more clearly. So this big white splodge is our fungal colony. The bacteria is streaked on the top of this plate and this is this white smear, and you can really clearly see the zone of inhibition where the bacteria are no longer growing in the proximity of this fungi. So this is really interesting he noticed okay this mold this fungi is producing some kind of substance that is killing back pathogenic bacteria, which is of course very important. And so moving forward, a lot of people started working on this, and then we see in 1942, the purification and then the effective use of this penicillin antibiotic in injection. I think this is kind of an interesting statistic in parallel. So in 1941 the worldwide stock of penicillin is estimated to have been probably around a few milligrams. So we move forward to 1945 this is absolutely skyrocketed. By 1945 just four years later it was estimated that around 4,000 kilograms of penicillin were being produced per month. And a lot of this was driven by use in World War Two. So this is a lot of production. And then this kind of really caught on and we've moved forward obviously using a lot of antibiotics. And what I think is really interesting is so the Nobel Prize in 1945 was awarded to Fleming Fleming and two others chain and flurry for their work with the antibiotic penicillin. In the Nobel Prize lecture that Fleming gave he predicted that antibiotic resistance could become a problem. So he said basically in the lab, it's not very difficult to make bugs resistant to palicillin. We've already noticed that this can occasionally happen in people. So depending on how this drug is used moving forward this could become a really big problem. And I think this is really a really interesting microbiological observation as well when we think about. So we know about evolution but actually kind of the Nobel Prize for the structure of DNA, the kind of molecule of evolution wasn't actually till later than 1945. So it is a really interesting observation. And this is of course as everyone in here probably knows this is exactly what we've seen. In this penicillin there's been a bunch of different classes of antibiotics that have been discovered. So we've got different classes and their data discovery along here. Then up in this panel is date of antibiotic resistance identified and effectively what you can see is where antibiotics go resistance will follow. We're currently in what is referred to as a bit of a discovery void with antibiotics where we haven't really identified very many new classes but we've been making modifications to the classes. We already have where there's already widespread and kind of easily evolveable resistance. And so if you look at what how is this actually happening so how do antibiotics work and how does resistance evolve. So it's broadly work by killing or inhibiting the growth of bacteria, and they can achieve this by a number of different mechanisms but generally the idea is they target something that's pretty essential for cell function. So for example, we've got the beta-lactam penicillin is an example of a beta-lactam antibiotic that inhibits cell wall synthesis. We've got antibiotics that target protein synthesis, nucleic acid synthesis, and the cell membrane. And then kind of in parallel there's a variety of different mechanisms by which resistance can evolve. I've highlighted a couple on this slide here. So for example, something we can quite often see is the up regulation of efflux pumps in bacteria. So efflux pumps are basically things that sit on the bacterial cell membrane that can pump out antibiotics and other things. And a common mechanism resistance we can observe is the up regulation of these so basically antibiotic comes into the cell but then it's quickly pumped out. So bacteria can produce enzymes that inactivate the antibiotics themselves. They can also evolve resistance via target alterations. So basically changing something about the sequence and structure of the target of the antibiotic. So the antibiotics can no longer kind of bind as effectively. The final one I've highlighted is decreased uptake. So a bunch of these antibiotics, they need to of course travel inside the cell. They do this by forens that already exist on the bacterial cell membrane and the bacteria can mutate these, stop these working so the cells no longer able to take up as much antibiotics. So there's a couple of mechanisms of action and mechanisms of resistance. But how does this actually work from an evolution perspective. So here I've just highlighted kind of two major mechanisms that we can think of. So we can think of we see the NOVO mutation. So this is a key mechanism of resistance evolution. This is basically spontaneous mutations. So just kind of random mutations that arise as an artifact of replication that just by chance provide enhanced resistance to an antibiotic. So this means is that if this mutation just by chance is present in a population of bacteria. If this mutation is treated with antibiotics, it's going to be really strong selective pressure for those individuals that carry this mutation.  And all the cells that have this resistant mutant mutation will be able to replicate and thrive. And this is kind of a method as well we can think of as mother cell to daughter cell transmission. On the other hand, an interesting one is horizontal gene transfer. So by this I mean basically existing resistance genes can be transferred between bacteria in a population and this can happen between neighboring cells. So for example, an antibiotic resistance gene might be carried up carried on a plasmid, and this can move by a conjugation to another bacterial cell. So these those are kind of two key mechanisms you can think of. And just as Fleming predicted back in the 1940s antibiotic resistance is indeed on the rise. And there's been a number of attempts, a lot of interest in trying to quantify the scope of this problem. I think a really nice paper came out that did this last year where they looked at global death data in 2019 and tried to categorize deaths that were either directly attributable to antibiotic resistance or associated with resistance. And from this they saw that already at least a million deaths a year are directly attributable to antibiotic resistance. And this is calculated on data from 2019 and a further four million associated with resistance. And at current rates this number is only really predicted to rise so again there's been some modeling and some estimates to efforts to estimate kind of what is this looking like in the future. And if we look back actually at this first image to the left, we can see so this is deaths associated with different infectious syndromes. And if we look further to the left here so kind of responsible for the largest budget burden of deaths. We're seeing so LIR means lower respiratory infections, so infections in the lungs. So we're seeing kind of causing a really significant burden of death is respiratory infections in the lungs. So things like acute short term infections like pneumonia as an example. So I think this makes trying to understand so well how does antibiotic resistance evolve during the spiritual infections a good question. And this is something we're really interested in during my postdoc and the research story I'm going to present today is a project from my postdoc which I did in the lab of Craig McLean in Oxford. In this room involved as part of a large scale clinical trial called compactor, which basically stands for combating antibiotic resistance in Europe. And this is kind of a large scale collaboration and involve hospitals, kind of all over Europe and lots of different countries and lots of different locations. And the overarching kind of aim of this project was to understand learn more about antibiotic resistance and we were working on a very very small part of that. And we were interested specifically in how is antibiotic resistance evolving in a specific pathogen. And the pathogen we were working on is an opportunistic bacterial pathogen called pseudomonas originosa. And this for a couple of reasons so pseudomonas is a major cause of hospital acquired infections. So it's an opportunistic pathogen which means if you're quite well and you encounter it, you'll probably be fine you won't really notice. But it's a really big problem for people who are already sick or immunocompromised which means it's a really big problem in hospitals and causing secondary infections in hospitals. So the World Health Organization critical priority list of pathogens that show very worrying levels of antibiotic resistance already and we're in need of new treatments for so high levels of resistance. And individuals that do get infections the infections themselves are associated with significant mortality. So for pseudomonas pneumonia infections, it's estimated around kind of 30% mortality out of people who acquire those. And I'm just showing some pictures of pseudomonas on a plate here. So you can see it's a very just looking at it growing it's a very diverse pathogen it can produce lots of interesting colored pit pigments that help it with virulence. And the type of infections we were specifically interested in is these acute respiratory infections so by this I mean short term infections are rather than kind of chronic long term infections an example of this being ventilator associated pneumonia. And what we're doing is so patients were coming into the ICU intensive care unit they were on ventilators. And they were enrolled in this study and basically their lungs were sampled every couple of days for a period up to 30 days because these are short term kind of intense infections. And then we were looking at the pseudomonas population in their lungs. And we were kind of looking at a collection of six to 12 pseudomonas isolates per patient per time point, which differs from the kind of standard thing done with this sort of clinical microbiology where the standard thing is you look at one isolate per patient per time point coming out of some of these lungs or another sort of infection. So really interested in the population biology of resistance evolution. And the story I'm going to tell you about is what happened when we looked across this whole patient cohort and so I'm going to break down what we did here. So we ended up with a total of 35 patients from ICUs across Europe. And we were looking what's going on in their lungs using endotracheal aspirate. So this is when patients are on mechanical ventilation, a kind of extra tube can go down there and get out this aspirate so it's really representative of what's going on in the lower respiratory tract. And we were looking at, as I said, so six to 12 pseudomonas isolates per patient per time point. And this is what I mean by this. So it's a quick exclamation of what I mean by isolates in microbiology. So basically what happens is the sample from the lungs is plated out onto an agar plate. And a single one of these circles or colonies is an isolate. So that's picked and that said, okay, that is one pseudomonas isolate. So this is an illustrative example where you can see if you've got a mixed sample of lots of different things in there, you want to get this solution down to a concentration where single cells are sticking across the surface. And so a colony the idea is it's growing up from a single cell population so you can kind of think of it as like one similar very similar genetic entity. So in this picture here, this is a mixed culture that's been plated out, where the different bacteria, the different species that have been placed out, make different colors on these plates. And so you can see when they're in these colonies, each colony is a different single color, rather than a smudge or a mix of colors. So that with a total of 441 isolates in total. And what we're doing with these are a bunch of different things but probably we're interested in so how resistant are they to antibiotics, and which antibiotics. So we're doing things called minimum inhibitory concentration assays, where we basically have a plate that has lots of different tiny tiny wells in, and you create an increasing gradient of antibiotics, you put your cells in all these wells. And then you see what concentration of antibiotics that they stop growing. So this is a way that you can characterize antibiotic resistance from a phenotypic perspective. Then we were also sequencing their genomes and looking at what's going on there. So we're doing whole genome sequencing of each isolate, and I'm going to highlight two things from this that we are particularly interested in. So we wanted to know, kind of what strains or sequence types of pseudomonas do we have in this population. So this was basically characterizing strain identity, and this is done by something called multi locus sequence typing, so that looks at the sequence variations in a set of seven housekeeping genes. And this is the way you can characterize strains within a species. And so these strains will be really quite different to each other because they've got variations in these seven quite core genes. And so then you call these like sequence type, then a number ST and a number and this is a method to use kind of across microbiology to characterize strains across bacterial species using kind of this core system. So when I say sequence type or strain, this is what I'm referring to I might use them interchangeably. So basically strain within a species, these things are really similar. And then of course we were also interested in so what's going on during the course of an infection. So analyzing mutations, so for example looking for any known antibiotic resistance mutations arising in this population. And we're also looking at gene gain or loss during infection so looking at, as I mentioned at start horizontal gene transfer of these acquired resistance genes. So what did we expect going into this. So this is kind of outlined the methods of what we were doing, but what were expectations about what we might see. So the kind of classical view and standing knowledge, particularly for these type of short term spiritual infections. So the two infections are clonal. So by this I mean the assumption is that infection will generally be started by a kind of single clonal identity entity that gets into the lungs and then replicates and proliferates over the course of the infection. And this is due to kind of extreme bottlenecks that happen during transmission it's quite difficult to get into the lungs. So our assumption is that each patient would have a single sequence type or strain of pseudomonas. And kind of as a result of that, we're expecting and what you often see is the antibody resistance emerges by a selection but did only for mutation. So the kind of. So single entity starts an infection growth growth growth replicates mutations randomly occur in this population and just by chance, some of these mutations can provide enhanced resistance to an antibiotic. And this is known by this little lightning over here. So when a patient is treated with antibiotics, so really strong selective pressure for those bacteria that just by chance have those resistance mutations. And so then you're ending up with okay, much increased antibiotic resistance by these bacteria that are now in a patient's lungs, and this could be kind of an antibiotic resistance infection. So these were assumptions going in and kind of your textbook view about how these source of infections happen. And indeed we've seen some good examples of this in our single patient case studies so far so when you dig kind of deep into the dynamics of a single patient by doing lots and lots of sequencing and lots and lots of sampling to get trying to get a really high resolution. So for example, we're able to see in a particular patient. They had one sequence type of pseudomonas. And the interesting things we saw were mutations to some kind of key antibiotic resistance genes. And we saw it again so again you've got another patient we sampled them over the course of the month. And we're seeing resistance is driven by mutations in these antibiotic resistance genes again, and this is something you'll see a lot of examples of it across the field. But so kind of that's the method that's what we expected what did we see. So if we look across this whole patient cohort. So what I'm showing you here is, I guess, quite a complicated bar charts so we've got along here we've got patients. And these bars show the number of pseudomonas isolates that we analyzed and the color of the bar tells you what sequence type or strain of pseudomonas that is. But all you really need to think about is the actually this graph kind of splits into two. So, on the left hand side you can see, all these patients have a single colored bar, I a single sequence type of strain of pseudomonas in their lungs. So this is what we're calling single strain populations, which is kind of a classical view, and indeed to the majority about two thirds of our patients were colonized by a single strain of pseudomonas. But quite surprisingly we saw actually there are a third patients which weren't so third patients we saw were colonized by multiple strains of pseudomonas at the same time. So we've caused called these are mixed strain populations and you can see in their lungs. They have two sometimes three different strains of pseudomonas at the same time. So this is pretty interesting. And so this allowed us to ask the question so what is the impact of within patients pseudomonas diversity on antibiotic resistance evolution. And to look at this we looked at a subset of patients. So we looked at a subset of 13 patients where kind of two criteria, they've been sampled on multiple days, so we could compare between time points, and they've been treated with antibiotics that we predict to be active against pseudomonas. And then we looked at the pseudomonas isolates that came out of their lungs and basically characterised them as multi drug resistant MDR or non multi drug resistant so resistant or non resistant isolates is the basic characterisation. And quite conveniently this population of 13 patients nicely split split into six patients who had these mixed strain infections and seven patients who had these single strain infections. And our hypothesis going into this. And so these mixed strain populations, purely as a kind of aspect of having multiple strains in there at the same time, are going to have an increased source of standing genetic variation compared to these single strains that just have a single strain. And we know from evolutionary biology and through theory and evolutionary biology that obviously standing genetic variation is really important for evolution. The hypothesis is that these mixed strain populations by having this increased source of standing genetic variation resistance may be able to emerge more rapidly in these population than the single strain counterparts. And so what we did to look at that is we could characterise each individual as so we've got single strain in blue, mixed strain in orange, and we could look at the initial prevalence of resistant isolates versus the change in prevalence of resistance isolates. And something you can see from this is this kind of line here, which quite, yeah kind of as you'd expect so when initial resistance is low we're seeing larger changes in resistance, larger increases. And then when you correct for this effect of initial resistance, and this is kind of our key finding here if we look comparatively at how does resistance change in single strain, compared to mixed strain populations. We indeed kind of saw agreeing with our hypothesis that mixed strain populations were indeed associated with larger increases in resistance. And we're seeing kind of 20% larger increases in resistance. And this is really our key finding here so mixed strain populations are indeed associated with the accelerated emergence of antibiotic resistance in patients, and this is significant. So our next question of course is so after we've observed this difference and this is a fact. But what are then the drive what the drivers of resistance in these mixed strain populations what is behind these larger changes in antibiotic resistance. And I'm just going to take you through an example of how we analyze this. So what I'm showing you here is a clinical timeline summary of an individual patient. So on the y axis here we've got percentage in MDR resistant isolates. And on the x axis we've got time between sampling so you can see this patient was sampled here and here. The percentage of resistant isolates in their lungs goes from around 60% to 100%. This colored bar here represents the different classes of antibiotics that they were treated with. So you can see this patient was only in for about two weeks and they were treated with a lot of antibiotics is a lot of different antibiotics that are going to be in front of them while they're in hospital. So if we look at these inset pies, this tells us what's going on with the pseudomonas. So this inner ring tells you which strain or sequence type of pseudomonas was there. And the outer ring shows you the percentage of these isolates that had this multi drug resistant or non multi drug resistance classification. So what we can see is we can see at our first time point here this patient has a mixture of this light blue ST235 in their lungs which is 100% multi drug resistant and this purple ST2211 which is 0% resistant. This is a mixture of loads of antibiotics and indeed at this last time point we can see now 100% of the population that we're sequencing is this multi drug resistant body ST235 and indeed 100% of the isolates and now multi drug resistant. And so this is showing an example of where these changes in resistance are being driven by changes in strain composition. So we can kind of partition these differences into differences that were driven indeed as this example shows changes in strain composition or changes due to within strain acquisition. So this is a classical view of de novo resistance mute mutations so when is resistance being driven by changes in who's there versus at the within strain level ie a strain acquiring new resistance mutations over the course of the infection. And when we did this. So what's the contribution to the change in multi drug resistance prevalence, we can see within strain changes, this is like our de novo resistance mutation here at zero or in one case 25% or changes in strain composition like the example I just showed you. What's really quite strongly is that resistance is emerging in these mixed strain populations due to selection for pre existing resistant strains. And so I'm going to wrap that story up there and just summarize kind of some of the take homes from that. So we saw in the study that mixed strain infections of pseudomonas was surprisingly common in ICU patients who had these acute respiratory infections. And importantly this within strain within host strain diversity is something that impacts antibiotic resistance evolution. And what we see is that resistance emerges much more rapidly in patients colonized by mixed strain populations, rather than single strain populations. And this is due to selection for pre existing resistance strains. So I think a kind of cool idea that you could think of staring off this. And so I think it raises the question. For example, as an application is so well could you measure within patient pseudomonas population diversity and use this to help you predict the likelihood of treatment failure. So high diversity populations. Okay resistance might emerge more rapidly. And this is something that's already done and very well developed with cancer. So with chemotherapy, you can predict the likelihood of treatment failure based on the kind of diversity in the cancer cells that you have. And this is an example of where you can go from basic to application science. And we still have a lot of questions about this project and stemming off this for example so I think a big one is well how are people getting mixed strain infections. So what is the location of these different strains in the lungs. We take one sample of endotracheal aspirate. How representative and what does this tell you about where the strains are given the lungs have a very large surface area. And so we don't actually know kind of the proximity of these different strains to each other. Okay well when you've got lots of different strains in there how are they interacting with each other and what's the significance of this.  We're thinking back again a bit more big picture so trying to think about okay some perspective of the field. So we've kind of talked you through antibiotics, antibiotic resistance on the rise, an example of how we can look at this. But what are some ideas about how we can combat antibiotic resistance. So this is kind of the area that I'm kind of most linked to is this question of well, if we understand how antibiotic resistance evolves during infections and how patients are getting antibiotic resistant infections can we stop it. And I think kind of cool example of this is a paper we published last year. So big question is so when someone has an antibiotic resistant infection, where is it come from, especially in these very severe and fast up acting lung infections. And what we're able to see is an example of where a patient's lungs were getting repeatedly colonized by the translocation of Pseudomonas from their gut. They're being treated with an antibiotic for an unrelated thing they're being treated with an antibiotic for urinary tract infection, and Pseudomonas was just chilling in their gut. It evolved really, really quite severely increased antibiotic resistance while just chilling in their gut where I didn't think it was causing too many problems, but then translated up to their lungs where it causes an infection. So the idea kind of an example of what you can use from that is you can say okay well if we reduce the intestinal colonization of Pseudomonas, could this be an effective way to reduce lung infections in critically ill patients. I think another example of this kind of thinking kind of linking understanding to okay what can we do. So this is an example of identifying a drug so actually already an already approved drug that in this paper they were able to what they kind of called it an evolution slowing drug. So this drug they saw. These anti-coli encounters, the antibiotic Cip prophylaxis in a stress induced mutagenesis pathway is upregulated and they identified this drug inhibits this specific one specific stress induced mutagenesis pathway. And the idea there being that well if you get fewer new mutations. There's a lot of new mutations that provide enhanced antibiotic resistance. There's lots of work going on and looking at kind of well what effects mutation rates, what effects horizontal gene transfer in bacteria and if you can identify things that can inhibit kind of upregulated mutation rates or conjugation between bacteria is this one way that you could reduce the kind of emergence or spread of resistance in populations that's kind of an example of the thinking behind there. A very cool new therapy, phage therapy, so useful for me to know put your hand up if you've already heard of phage therapy. Okay, so maybe 5050. So bacteria phage, so just like we have viruses that can infect us, so COVID being a really good example, bacterial cells have viruses that can infect them too. These viruses are called bacteria phage, abbreviated to phage, and kind of just as what happens with us. So these phage or bacterial viruses can infect the cell get inside replicate replicate and burst. So the idea here is well could we use these like natural predators of bacteria to target bacterial infections and could this be a really good idea for example when we've got chronic antibiotic resistance infections where the antibiotics are no longer working. And there's a lot of work going on in this space and trying to develop this. And this I'm just highlighting here so this is a paper where they've looked across a bunch of well 12 cases at the moment it's really at the kind of customized level so at the moment it's working with people who have long term infections and developing what's called a customized phage cocktail so phage are understood to be quite specific. So they'll kind of get a sample of the bacteria and test or even evolve phage that can effectively effectively infect the bacterial cells burst them open. And then this was just kind of a review of these trial cases. And they said yes to actually yielded favorable clinical or microbiological outcomes in two thirds of the cases here. So that's pretty good. And then the other idea is so and this is something I'm also interested in is microbiome manipulation. So effectively using bugs to fight other bugs. So put your hand up if you've heard of microbiome manipulation. What about people microbiome transfer. So the idea here again said bugs bacteria can do lots of different nasty things to each other so actually our penicillin was isolated from a fungi but we have lots of antibiotics are actually isolated or modifications of bacterial products that are used like in their natural setting as toxins to kill competitors. So the idea here is that we can manipulate the microbiome with strains that are particularly effective at killing or inhibiting our pathogen of choice. And the really famous example of this is fecal microbiota transplantation. So this is very famously been used to treat chronic rostridium difficile infections. So these are basically chronic bacteria infections in the gut that we, yeah, they get to a point they get really resistant antibiotics are no longer working. And what's done is so basically healthy stool samples. So kind of a sample of somebody's healthy microbiome and transplant that into the intestine of a patient with one of these costridium difficile infections. So we can restore the healthy gut microbiome and indeed this has been successful in getting rid of the costridium in there. And so again just showing an example of paper where they've done that and have a pretty cool name. So again showing success in these proof of principle studies. And then kind of last but not least, I think something important to be aware of is so it's, yeah, there's lots of cool ideas, but a really good idea is well antibiotic stewardship and infection control. So the kind of aim of antibiotic stewardship is just to overall reduce the consumption of unnecessary antibiotics. So we see a really strong correlation between the uses of usage of antibiotics and the emergence of resistance so anything you can do to reduce the use of antibiotics, particularly if necessarily is good. And by this I mean so kind of well controlling the source of infection. So just like good hygiene and sanitation processes, lots of hand washing and hospitals trying to make sure there's too much not too much like into a hospital spread. Yeah, trying to use the appropriate antibiotics so using cultural results when available. And yeah kind of what only prescribing antibiotics when they're needed so not prescribing antibiotics for viral infections but using them for bacterial infections. And I'm going to kind of wrap that up with what I think is a pretty promising study and a bit of good news and links to antibiotic stewardship and infection control. So this paper came out a couple of months ago, and it's a Spanish national wide study, where they've looked at antibiotic susceptibility and resistance in pseudomonas so the bug I've just spoken about on a nationwide scale. And what we can see here in 2017. So basically the darker the color that higher the percentage of extremely drug resistant pseudomonas isolates that have come from that region. So we can see in 2017 it's not looking great there's some kind of extremely drug resistance this is when they're resistant to almost all classes of antibiotics we have available. It's I'd say pretty widespread. And then across Europe there were lots of kind of national action plans for antibiotics including I think a really good one in Spain, where they implemented a lot of these ideas of improving infection control and antibiotic stewardship. And this hasn't been like mechanistically linked, but I think this is kind of nice results, regardless, so actually when they looked at the picture in 2022 five years later, they saw a kind of generalized and widespread decrease in resistance to antibiotics, particularly these kind of extremely drug resistant isolates that are really concerning. So I'm going to wrap that up with a bit of I think a nice story there. And finally, I've done a bit of a deep dive into antibiotic resistance evolution, but I've got a bunch of other interests that are kind of moving forward and thinking about this in my new position and also while I'm here. I've been kind of understanding the interface between antibiotic resistance and the microbiome so for example how do interactions in the microbiome shape the emergence of resistance and vice versa how does a pathogen, having enhanced levels of antibiotic resistance shape that it's interactions and ability to invade a microbiome. And I'm also very interested in so CRISPR-Cas systems, kind of famous for their use in genetic engineering, but I originally identified as bacterial defense systems. I'm very interested in how they work as bacterial defense systems and using comparative genomics to understand more about that. So please get in touch if you're interested in any of these topics that I've presented and would like to chat about them more.  The names highlighted there, but especially Craig McClain and Julio Diaz Caballero and Natalia Capell, acknowledgements to my funders and also a big thank you to the TSVP for inviting me on this program. Yes, thank you very much for listening and I'm happy to take questions. Thank you questions please use the microphone. Thanks for the very clear presentation. That was great. I had a bunch of questions I'll try to limit them. When you were doing the species analysis you were using seven poor housekeeping genes is that right. So, a couple questions about that one is how did you choose those seven because I think usually there's more housekeeping genes is that right. So it's a system called hub MLS T. So it's, it's, yeah pretty is very well developed as a method in microbial genomics. So they weren't chosen by me but this is quite an old and established pipeline for identifying and classifying bacterial species. Yeah, so I'm not sure exactly how they were chosen, but it's used as kind of the common genetic approach that's used. And then, if you had like, I'm just trying to figure out how you define like a different species so if you had like one of those seven that was a different amino acid sequence then it would be considered a separate species is that right. I mean that's a great question isn't it how do I how do we define species in bacteria. There's a lot of debates on it. So they went through a couple of different pipelines. So first of all, so the stuff that came out of the patient's lungs would play to doubt on what we call pseudomonas selective a girl. So it contains basically compounds that are supposed to be selective for pseudomonas originals specifically. The isolates were then randomly picked off that and they went through moldy toff. So moldy toff was used to characterize. Okay, are these pseudomonas originosa. And then we got sent the isolates and we extracted their DNA and we sequenced them. For the malady top. Are you looking at the secondary metabolite weights or like the weight of the isolates. But then we hold genome sequenced them. Yeah. And we could put them through, yeah, this M LST pipelines that said yes, pseudomonas and these are the sequence types. But we also had the whole genome so we could plot them out on a flat phylogeny and say yes okay this looks like pseudomonas originosa. Yeah. And then for your, like, when you had the patients and you had like the number of isolates per sample, like obviously a patient sample. Yeah, obviously that was non uniform. And is that because they're from different hospitals or like different clinics each with their own procedures or. Yeah, so it's from we wanted six to 12 per patient per time point. Sometimes they couldn't get 12. So we had patients where we're only sent three. So that's some of the variation, but we tried to sequence between six and 12 per patient so it's kind of stemming from like, yeah I guess the samples we got sent from the hospitals that was a variation. Questions here. Hello. That was a great talk. Very understandable even for a non biologist like me. I was wondering if you could go back to the evolution slowing slide. Yeah. I was just curious if there were any downsides to this drug. Yeah, so in this study, I think, for my understanding what they've done is they've tried to go okay well long approval processes for new drugs let's see if there's anything that's already out there that has a side effect that is beneficial. So at the moment they've just tested it on E coli and with one antibiotic resistance I guess I mean there's like this general stress response is pretty useful from the bacteria's perspective in that like this is a useful process for adaptation like generating mutations and is that thing so there's definitely downsides for the E coli. So we tested, at least not in this study. This is all done in the lab. So we don't know whether there's other effects if you put it into an animal or human system. But from like an evolutionary microbiology perspective. It's a pretty neat story in the study system. Yeah, cool. Thanks. Any other questions. I have a question about strain level diversity if so if in one third of the patient diversity is already there at the beginning. What would be the ideal therapy in that case if it's sequencing or the other way you see that the patients have multiple strains of pseudomonas. For me, like, the evolutionary solution would be like, as an evolutionary biologist would be to hit the bacteria with as many antibiotics as possible right from the beginning. Yeah, that's thing one by one. So what's now done in hospitals. Is that what is my interpretation. Yeah, so I think that's an interesting question I think there's a couple of things that I think I feel like the ideal or the ideal thing is it so why do these patients get mixed strain infections and can we target this is this kind of just an artifact of being in a high infection rate setting. Are there some strains that kind of promote or enhance the colonization with other strains. And I also think an interesting idea to agree as you want to hit them with loads of antibiotics at once, or kind of a cool idea could be so that example I showed there was quite a common pairing we saw so we saw this like multi drug resistant ST235 with the comparatively quite wimpy other strain. And actually if you compete these strains and the absence of antibiotics, you see the, the soup the more resistant one is comparatively much less fit. It's out compete competed by this wimpy ST. So I think that makes you think well, could you think about kind of how the dynamics of how you're using drugs. And could it be okay, you wait for it. I'm not sure whether this would be morally okay to do people, but you wait for kind of the wimpy strain to do better. And then you could hit with antibiotics but it's all the wimpy one there, and then the wimpy one will crash, crash, but ideally, kind of make it so the wimpy one out competes, the really resistant one. And could you use something like that, I don't know. And a related question is, did you see any cases of plasma and acquisition horizontal gene transfer in resistance acquisition this way. We were expecting to say we looked for that we looked at during the course of infections are we identifying any horizontal gene transfer. And we didn't non resistance friends were just simple out competed. Yeah, they were getting out competed. I think an interesting point here is as well the time scales were quite often quite short. I think quite often in people when we look at horizontal gene transfer. We're looking at longer time scales and maybe populations in the microbiome that coexisting for a long time, whereas the time scales here in some cases just a couple of days. And you'd see, yeah one of the strains would get completely wiped out just from a wet lab perspective, I think it's going to be harder to see the horizontal gene transfer. And if it's a plasmid, it's highly dependent on the DNA purification and sequencing protocols. So that's something that's easy to miss if you have like low coverage or you're doing like some kind of non DNA plasma purification method. So we did like a hybrid sequencing approach so we used a luminous short read and nano for long read. So we're able to complete the genome for at least one well for at least one isolate for each ST and use that to help us inform what was going on with the mobile genetic elements. So we were able to identify pseudomonas isn't a super plasmid species, maybe about 5% as an estimate have plasmids, but we were able to find plasmids and kind of look at what's going on using this long read sequencing as well. But I'm sure yeah I think I'm sure we missed some things and I think also methods for looking for horizontal gene transfer as well can be a bit tricky. Is there one more question. Hi. Are there estimations of the overall mutation rates of the of the bacteria that are resistant or not based on the whole genome sequence. Um, there's yeah there's general estimates of mutation rates for pseudomonas we didn't do specific and estimates of mutation rates for these strains. Do you know if the resistant ones are overall mutating more often. So we looked at. Yeah we looked at the accumulation of mutations both in resistance genes and then across the whole genome. We looked at the mixed strain and also the single strain and also by resistance phenotype and we didn't see any differences. Okay, thank you let's thank Rachel again for. Thank you guys for a few more months. So if you're interested, please find her and talk to her projects. Thanks.


But that is not all about gunmen in Zangun, Qatar. Another village in the local government has been attacked and two persons killed. Soldiers reported the incident in Onguantaila Village and the deceased have been identified as two women. The Katuna State Commissioner for Internal Security and Home Affairs, Samoa Arunwa, says Governor Nassu Airefai has received the report of the attack and expresses deep regret.


All right, today we are going to talk about fractions. It seems like no matter what math class I teach, algebra, trigonometry, calculus, all the students struggle with fractions. All right, so first rule is simplifying fractions. If you have a fraction like, let's say, 3 over 43, now just because they both have a 3 in them doesn't mean you can magically cancel those 3s, okay? Just like for example, if we had, I don't know, like x minus 2 over x plus 4, because these both have x's in them, you can't magically cancel those. You need to build a factor of things and then you can cancel stuff. So better examples then would be like 3 over 15, okay? That one you can actually reduce because you can factor a 3 out of that denominator. So this would be like 3 over 3 times 5, cancel those 3, so you'd end up with 1 5th, okay? In a similar way then, if you had x's in there, if you had like x minus 2 over x squared, minus 4, so similar to what I had up here, but I changed it just a little bit, you can factor that denominator, right? So you could factor that denominator as x minus 2 and x plus 2 and then we can cancel those factors out, so we're going to end up with 1 over x plus 2, okay? So that's simplifying fractions. So just because they have something in common does not mean you can magically cancel it. You can only cancel factors. All right, so then adding fractions, how do we do that? Well, remember you've got to have a common denominator. So let's say we had, I don't know, how about 1 5th plus 2 3rds, for example, okay? So fractions sometimes end a common denominator, sometimes they don't. So adding and subtracting they do, we're going to do an example with multiplying where they don't, okay? So here you need to find the common denominator between these two. That would be 15 because obviously these are both prime numbers, so nothing else will go into them. So we can change this into, let's see, multiply this one by 3 over 3, multiply this one by 5 over 5, so we end up with 3 15ths plus 10 15ths, which now that we've got the common denominator we can now combine like terms basically, okay? So combine those numerators together, we end up with a grand total of 13 15ths, okay? So first thing we did was simplifying, second thing we did was adding, third thing we're going to do here then is multiplying, okay? So let's say we're going to multiply these same two fractions. Multiplying is actually a lot easier, believe it or not. Multiplying you can just multiply straight across, okay? So that's going to end up giving us 2 15ths, and then maybe we can look at that and see if we can reduce it, but obviously 2 won't go into 15, so that's going to be our final answer. So we've got final answer here, final answer here, okay? Last thing we want to look at then is dividing. So dividing is very similar to this, but there's one more step. So that's going to be if we wanted to divide these two fractions, okay? Well dividing you've got to do the multiplying and then you've got to change it to a reciprocal or you've got to invert it, you've got to flip it, whatever word you want to use there. So that's going to give us 1 5th times 3 halves, and then again you can multiply straight across, so that's going to give us a grand total of 3 10ths. Again, 3 will not go into 10, so we are done with that fraction too. All right, this is a crash course on fractions, but watch this video whenever you're doing something more complicated, because then you can always go back to the simple ideas. Thank you for watching.


What's up guys? Welcome back to Espemba's. My name is Shiko Gitov-Costley. We are coming to you from Mombasa and we are right here with the president, Mr. Eric Omondi, mum of it. Asante kalibu sana Mombasa ni monangu. Ira 2 po sarama jototu. Jamani jotola kini, but tuta survive? A tuta, ita bidi sa, tofana bidi. Tia doing good? I'm doing good. How you doing? I'm doing good too. Thank you so much. It's been a while.  Mbidi, you know, a few hours ago you've seen you and CS Murkomen. Samo ya. Najiwa Kenyawengi wata takaku jua labda, mekwa na mazungumza sababu Kenyans have been waiting to hear from him, especially with the things that are happening, especially on roads. Bata kuna wana funzi, wana puteza maisha accidenti ni. Jam mekwa na ha mazungumza, mekwa kidogo, sautia monangu. Mbidi siyesi ongele, Murkomen tumesalamuena, nindugu yangu, nim Kenyamunzangu, Anafanya Kaziakevenya Anafanya. Ila atujaongia, tumiwa manenu yote. Mbidi siyesi ongele siya sirikali, peke hangu. Siyesi ongele siya any cabinet secretary, any official of the government, any person that is part of the Kenyakwanza government. Sina bieshara nao, sina usiyano nao, nasingependa kuwanaio, kibinafsi. Unless we organize a meeting that involves young people, involves border-border riders, involves Mamamboga, involves the stakeholders of this nation who are the citizens, then I can be there. But me kibinafsi siyesi. With that, you may be planning on having such a meeting. No, I'm not, I'm planning to help Kenyans who are meeting here in Mombasa next month with youths who are looking for employment to shakutana na vidyana na Nairobi, but not after employment, so Mr. Kikutana na sirikali. Takutana na Kenyawunzangu, tutafutesu luhisha, kwa sababu sirikali imetu anguisha. It has failed the people, so unless and until they do their work, miswenetu na bieshara nao. Eric, in the future you'll probably be part of a government. Takuwaji? If I ever become part of a government, first of all, I must... I don't know what I'll do. Tizi kama tiaenda ni umbewe. In fact, na takakuwaji shah, Fandreza, Kenyans in the diaspora, I want to save money and look for money. If I ever find myself in the government, tutabomoa hii paliament. We will... Tutabomoa lafutu jengempia. I don't know whether it's the physical building. Atami na ugopa kwinga kwa sirikali. Tizi kama ni mashetani. Tizi kama ni urogi ama witchcraft. Because people get in there and forget everything. Ono na tutusakaji na fanyasasa na pigawa mamu. I don't know what happens when you get in there. So atami na ugopa. Because president Ali Tuambia atasapotu mamamboga, atasapotu boda boda, ali wasawu. We have a contract signed by next week na skiafununu kutakwana C.S.S. 50 of them. So if I ever find myself in the government, we need to have an agreement, a contract signed by people getting into leadership. Constitutionally. That anything you say on this mic, but then the SPMA mania cities yana manini, holds you accountable. Otherwise, our leaders keep saying siawa boda boda, awa mamamboga. It's just a vicious act. Akuna tufotiai regime na zile zingine. Ni promises that are not kept. So we need to find a way that we keep leaders accountable. If you don't do what you said you'll do. We kick you out. Nani ligi nilo, iko apu. Kama winiwa some countries in Europe. So natsukenga president amerezaen, minister amerezaen, batatuna accountability, akuna kituna zafanya, atatukedanganiwa. So moving forward, we want to come up with a legal framework that nonesia, ukisema kitu tunae record. Nga get. Utena makitua kisha wamefanya. Sipu efanya enu wania. Una toka. Utsikadu utu alisema ata punguza aunga. Alika kuwa, kuwa ni ni kuwa leadership wania. Aku punguza. Nga get. The big question Eric, a lot of Kenyans are asking, you have used the term if I ever find myself in government. With everything that you're doing, a lot of people actually out there think you're aing assets in the government. Leo beli kamera Eric, 2027 is in 3 years or even less. We are aing every seat in parliament and every seat in the government. We, we are a new generation of young people who are going to do things differently because the people who have been in leadership are going to change. President Ruto is going to change. Mudavadi is going to change. Ali kuwadipiti is going to change. Ruto is going to change. Government is going to change. Kalonzo is going to change. I'm going to change. We are going to change. We are going to change. We are aing generation of Kenyans but we are going to work for the people of Leo to free. After that we are going to have corruption, tribalism, nepotism, thagari theft. Nothing will change. So, we are going to change. Ruto Amalize President Ruto Amalize Niniake We are planning a takeover. We are planning to, we will takeover because you know, to me discover that there are only 2,000 leaders from Ruto to MCA while we have 63 million Kenyans and out of those 63 million Kenyans 70% are youths. So over 45 million Kenyans are youths. So we are going to gather them, we are going to rally them, we are going to wake them up, we are going to write songs about those MPs that passed the finance act. We are going to uproot them by all means necessary. I promise you she could keep this video by 2027, wale MPs wote wale pigia finance bill kura, awata kua as long as God and Aishi we are going to uproot them, we are going to remove them by every means, awata iba kura, watatoka. Abda Eric, nijagani yutatumi alabda kusa fisha, kusa fisha, we call it a system, this whole system, nijagani yutatumi. Kichunafani kakwamba onona, kisha pata warumojiya kwa guniaime oza, ita ozeysha zilezote. It is very simple, we are going to go around this country, mombasa kisumu nyeri, eldoretu, we are going to go around, 2kuna time, we have 3 years, we are going to raise up leaders, new leaders, yu palimet next, kutakwana new leaders, a new way of thinking, Gen Z, millenials, watu winiwana think kwen ambele, watu winiwana, awana madeni zawazungu, kama our current president, awana madeni zawazungu, tatu onona lasimi mawachuku wema loans, wakuna contracts wali sign, datukingia utafanya ii na ii. So we are going to raise, na hapen already in West Africa, we have all those countries, they have young people, and they are going to change this continent. This is not a Kenyan thing, this is not a Kenyan thing, it's an African thing. Apos, nisenagola mawapi, we are like president Juzi, he is young, he is almost as young as me. It is not an recommended thing. Even a chance would you be the president, why for the seat of the president, the Republic of China? You know, at this point, mimi sijali, whether I will why or I won't why. Sijali kamaanda kwa women rep, kamaanda kwa MCA, I am a president. Kitu na jali ni, na kukaki kisha, there is a revolution that is coming, and it cannot be stopped. Ni stopped, where is the stop, where is the stop, wushu onona, mada tuome fika nine months, you can't stop, so I don't know what form it will take, but I know it will come. Yes. Kiji angaliya sasa heivi, probability, a jina, ya erikomondi kwa kwenye deba in 2027, kamaangapi. Kiji egzami in 2027?  We can't change things from sitting out here, na kuwa na, oh, tuta ingi apondani tuta wa toa, tunanda apondani kupika, dasta kuwoshi, kufagia, so chances are getting very high by the day. Na itika muito? Ya, the voice of the people is the voice of God. Yes, so mi naskiwa, watu wa na ni ambiya na mi naskiwa, yes. All right, now we go back to Tuesday this week.  Elisha poa tulikuwa na around 3,500 youths from Nairobi who are graduates, who are not employed, wakafanya elections, manda ndakuelika, tunafungu ofisi apotaun, iofisi nataka watua elewe. It is the central place, erikomundia kisha ndakua macopret, nika leta job na wa letter. Awa wana distribute. Awa ndu wali chaguana. Awa ndu wali chaguana. Ya, tunafanya elei kazi, sirikali meshindo kufana, kupatia vijana kazi. So asa tutaka tu, tu goji ama tu ombe sirikali, tupatia kazi. Tutaku wa creative, tutakonect employers to employees. Mimimimifanya na kampuni gapi. Safarikom, bitko, unileva, zote ka in general, zote, faras, spotpesa. So awa kuna vacancies. So we are going to provide employment for the 3,500 first, then to takuja apa mombasa. We do the same, 20 nyeri, we do the same. In the next one here. So this means on Tuesday, iliku election speke, there was no match of distribution. We collected, no, we see me, I went and got jobs, around 67 jobs. 67? Yes, I got jobs. But now the people who came in 1500, tukachukuwa nambazau, majinazau, e-mailzau, anabet na kutana every Tuesday, na kutana wato na peo job. Kutana wato na tukosirias, wisi yadatu kukama ii government ii Kenyakwanza. So that meeting was important to Salamiani. Oh, when in us? Ah, wumasomia doctorio. Wumasomia malimu, tujiwa natsalamone rikumondi wandike majinazau, wadjelect, nusasa safari ansa. Yulengene, tukwa Instagram kwa namba kwa WhatsApp niakina naniwa. So we met and we talked. Kwa po the whole day? Tukwa skizana was the way forward. Tata futa kazi, tukwa pata kazi, ata kawene doctorio, na we pata kazi, ago kwa mukubwa supermarket, ansa nai. So we needed that contact, that conversation, that meeting, in the opia to set agenda. The first time you told Kenyans that you are going to look for jobs for young youths in this country, you said you had over 3,000 messages. You met 3,500 youths this week who are jobless. Looking at this whole numbers, in opportunity as a country? Ok Google says it, uta pata 81% of Kenyans are unemployed. 81%. That means only 19. I replied. Generally. So they are graduates, it's even higher. So we are in a crisis. Wato hana ma job, nama suma. Parents wali tumia pesa kwa invest kwa tohiko shule, wana jobs. So in the next few years, uta kwa na, uta kwa na, it's a time bomb. Wato handa kukula, uta kwa li parent, uta kwa nda usi, wana pesa, wata fanya ni, uta kwa na wazi, uta kwa na crime. The country will be ungovernable. You must provide employment and job opportunities to especially young people if you want to be safe. Now what would you tell the youth concerning this? Because at the site, admissions are going on in universities, colleges and stuff like that. What would you tell the Kenyan youth right now? Don't register for university yet. You discouraging people from going to higher education? In Kenya. Don't go to any Kenyan university. It is useless from what I saw.  It is thagari. I would encourage any young person who has finished form 4. Don't register for university in Kenya unless you are in Canada or America or Tanzania or Uganda. It is useless. It is useless. I saw it in my two eyes. Let us empty these universities because they are government institutions that are used to pick and take money from Kenyans without results. It is just another way of collecting your taxes. I would encourage young people and parents if you have a form 4 or if you have English or if you can do one plus one subtraction and if you come at your literate your money please to me is a waste of time. It is a scam. You better have that paper and a chance may come. There are no chances. There are no jobs. There are no jobs. How much does it cost to go from first year to fourth year?  We are going to boycott Kenyan universities because they do not have or empower results. Moving forward Eric Komondi you will be having such sessions in other counties. You had one in Nairobi. You said next is Mombasa. Where are we going after Mombasa? After Mombasa we are going to Kisumu. After Kisumu we go to Nyeri. Are these gatherings happening weekly? No. We will be there in Government. There is no promise. We will be there in the next month. We are doing 2 weeks in Nairobi. 3 weeks. At least on Shikoh 200 people are working to own a post. We will be there in Nairobi. How much are you doing? Adding We are giving 21 days for every county. 247 counties. The next time we will be there 250 to 300 jobs Tuna chayu kiki tukenda letna in the next count Kwevo you plan and schedule kwa zina eko palivo via your Instagram page via my Instagram page and my Facebook page All right, kido go to kwa palivo kuna mona dada, ameta tu Eri kumundi familiar ya kumuna umekutuna niyo Pa doi kwa pili kiki? I wish I had my phone right now But it will be a little hard to access it Lemit try Tuone kama tizakwe pata But I don't know what you would say about that kwa nada I kwa piku ume pata Kwa pa netinat nasumbua Aha, yes Pa le SPM bars on Instagram Yes I kido bonet Teimepote ya Uwata ya mga himai himai himai himai But I don't know general I know you will come across that SPM mma me eko? Yes yes Mwa e kaleo?  Anetuna ni?  But you have posted. the reason, why we have started to share Right, to Kimalizia najuwa mambu ya meko mengi, of course, last week shubling zima mambu mengi ilkwangakusiana na mazishia, brand chira, it happened, a lot of people had to say different things concerning the whole burial, you saw it? Yes, I saw it. I don't know what you have to say. I just have to repeat once again, let's support people when they are alive. Nasi me kana kwa mba the Genzis who attended the burial misbehaved and as it stands right now, looks like there will be some cleansing ceremony kulek. Wale ni Genzis ni tiktokas wana expect, they were celebrating their colleague. So kisha ya kwa young Genzis in place tiktokas wana celebrate na kuna pombi, wana expect ni. Ya, so mi mi I expected that before. Bwaisubu ni kwa najuwa pale wakuta doka, apa kuta ribika. That's the way of celebrating their friend and I expected it personally due to their young people. So mi kudu kwa na goma, kudu kwa na gengetu pale noma zana, yu kwa na pombi. Lafona shere kia bestia wana. Ni, ni, ni that's their culture. Tiktokas Genzis ni watuwa shere. Na... Ni ni, brand chira li kwa mutuwa? Brand chira li kwa kwa shere. Ali kwa kwa kwa shere. Ali kwa matuka shere. Ali kwa me lewa. Ali kwa that was his life. So mi mi yu aiku na surprise, na getu. No, a lot of people think that was quite disrespectful, especially to the family that was mourning. Respectful to who? To the family that was mourning the loss of their... Who's funeral was it? Brand chira. So Ericumundi, you support... I don't support, I was not surprised. I'm okay. Who's funeral was it? Brand chira. Ya, not the family's funeral. I understand what they mean by saying it is respectful. But brand chira lived his life the way he lived his life, had his friends. It was the biggest funeral of this year with his fans. And they celebrated him the best way they knew how. Do you think they were mourning without... Okay. All right, Eric, thank you so much. To Natarajia kuna labda hi shubuli sana sana ya vijana ppata kazi. Because I know it's quite a headache in our country, in different parts of the country. And thank you so much for coming to our show today. Thank you. So thank you so much, guys. Until next time, I've been a whole Shiko Gita on all platforms. You can find us at SPMBASKE. You can find me too at i underscore. I'm Shiko Gita. Bye bye.


Friends, so those who are online, what we are doing right now is, now we are in middle of the chapter. So, this is a class that is going on, so those who are online are actually seeing a live class. We are in between a chapter, this chapter name is Ray Optics. And till now what we have done is, we have talked about reflection, we have discussed about refraction. When it comes to reflection, we have discussed about plane mirrors, spherical mirrors. And why we are discussing all this? Because these things will deflect the ray that is coming towards the observer. And if rays get deflected, then you may not be able to see the object where it is. You will be able to see only the image, you will feel as if rays are coming from somewhere else, if rays gets deflected. So, we learned about the laws of reflection. We applied laws of reflection in plane mirror to identify the location of image. Then we also discussed the spherical mirror, how it creates the image. So, after that we had discussed about refraction. In refraction, we first discussed about interfaces, how interface affects the deflection and how it can create the image. So, not only how much ray will deflect depends on the refractive index that is mu 1 and mu 2. So, light if it changes the medium, it will be always in some, already will be in some medium, isn't it? And then it will change the medium, it will go to next medium, fine. So, what happens is that this deflection not only gets affected because of the refractive index, but also it get affected because of the geometry of the interface itself, fine. So, interface could be horizontal, could be flat, right. So, we discussed about how image gets formed from the flat surface and this flat interface is very common, like water in a bucket is a flat surface, water in a swimming pool is again a flat surface, right. So, we discussed that and then we also talked about how spherical surface will create the image, are you getting it? So, we had in fact a formula for a spherical surface, what is that formula? We had mu 2 by V minus mu 1 by R, this is the formula which can be used for every image formation in any interface. And what is the interface? It is a boundary between two refractive indexes, getting it. In fact, this is what we call mother of formulae's because even for planar surface, you can use it, R for the planar surface will be infinite. So, you can use this formula and what is mu 1? So, you can use this formula and what is mu 1? So, you can use this formula and what is mu 1? So, you can use this formula and what is mu 1? Refractive index, there is no first or second medium. You will not be able to identify based on the question, what is first medium? What is the second medium? But then you can say that medium of the object, fine. So, mu 1 is medium of the object and mu 2 is the other medium, fine. So, like that we will be using, we had actually used this formula and solved many numericals on it, fine. So, after this what we did? We started talking about lens, right. So, this is convex lens, fine. So, we discussed about convex lens, right. And any lens, our first assumption was what? That it is a thin lens, okay. Thickness of the lens is negligible, fine. And another assumption is both sides of the lens have the same refractive index, okay. Once you assume these two things, then you can derive some formulas which will be called as lens maker formula or lens formula. And how you derive this formula? Using this interface formula itself, okay. So, we had done this. So, we had this interface, sorry, you have this first interface which has this refractive index and that refractive index. Then you had that interface which separates this one and that one, okay. So, first formula which we have derived for lens was lens maker formula, okay. What are the lens maker formula? 1 by F is equal to mu 2 minus mu 1 divided by mu 1 multiplied by 1 by R1 minus 1 by R2, right. What is mu 2 and mu 1? What is mu 1? Reflective index of? Reflective index of the surrounding, okay. Mu 2 is refractive index of the lens, fine. Now, if you see lens maker formula for fixed R1 and R2 and for fixed refractive index of the lens, even if you change mu 1, the focal length can change. So, if you change the refractive index of the medium also, then also focal length will change, okay. In fact, you can change the sign of the focal length also by changing the mediums, sorry, the surroundings refractive index, fine. So, we had discussed this also last class. What else we discussed? We discussed about the lens formula, right. What are the lens formula? 1 by V minus 1 by U equals to 1 by F. This is true for thin lenses and for the scenario where both sides have the same refractive index, fine. Now, using this formula, you can directly get the location of the image. But if you use this formula, even this formula is valid here, but you have to use it twice. You have this interface, first interface and then second interface, okay. And if you already know that both sides have the same refractive index, you can directly use this formula, all right. So, we discussed all this and then after that what we did? We combined lens with mirrors and saw a few numericals on it, fine. So, it need not be that only one lens will be present all the time. There can be multiple lenses together, which all of them together forming some sort of image, okay. So, this is what, you know, is the brief summary of what we did till now. So, you know, I just wanted you to recall all that, recollect all that, okay. Fine. Next topic, which we are going to take up in this class is prism, fine. Write down prism in some sort of experiment or something. 10th grade, right. There you have used prism to do some minimum deviation experiment. So, no. So, what we did in that experiment, what was the purpose of that? The purpose was to find the refractive index of the medium, okay. So, prism offers a very simple experiment using which you can find the refractive index of the material. That is why we are studying prism, fine. So, experimentally, it becomes very difficult to find out what is the angle of incidence and what is the angle of reflection. Because you will not be able to see a ray going like this and then you draw normal and find the angle. You will not be able to do that, okay. So, you should, I think you are not able to find the angle of incidence or refraction directly, okay. But the Snell's law relates refractive index with angle of incidence and angle of refraction, okay. But you cannot measure it directly, experimentally. But if you somehow relate angle of incidence and angle of refraction with the angles which you can measure easily, then you will be able to find a refractive index. You can write I in terms of angles which you can measure directly. Are you getting it? And similarly, angle of refraction also, if you can somehow write in terms of angles which you can directly measure, then you will be able to find refractive index, okay. So, prism offers a very simple experiment to do all that, okay. Let us see what is that experiment. Do you know how prism looks by the way? Prism is, suppose I take a book like this and this is prism, okay. So, from front, it looks like a triangle. Are you getting it? So, I'll just draw the front view because everything is symmetrical on the lateral side. So, I don't need to show what is happening. There is no variation on this inclined face, fine. So, draw this prism. All of you who are live also, please take a notebook and draw it on your notebook. Suppose this is the instant ray that is coming. Can you draw its path? How it will travel and come out from this side? You have to show the normal and everything. Only 5 people. So, total we have 5 plus you guys. Anyways, so first step is what? To see where it goes. Draw the normal, right? So, this is the normal suppose. Now, lightly bend away or towards the normal? Why? Because you are assuming that, suppose this is refractive index mu1. Mu2 is more than mu1. That is fine. I mean, it's a reasonable assumption. So, you should know what you are doing. So, mu2 is greater than mu1, you are assuming. So, what happens to this light? Then what will happen? It will bend away from the normal. But first step is to draw the normal itself, right? So, that is normal. So, bending away from the normal means that angle of refraction will be more than this angle. So, it will bend away. So, this ray of light, this one. This is the emergent ray. Right now, nomenclature. This is incident one, which is coming from this side, left hand side. Incident ray. This is angle of incidence. Right this as I. Okay. Let's name this as R1. This angle as R2. And that angle as E. Fine. Okay. Now, what we discussed initially, we wanted to find out the relation between angle of incidence refraction and the angles which I can easily measure. Okay. So, first tell me this. If I rather than taking like this, if I take prism like that, will that affect anything? So, it doesn't matter. So, prism's identity is not what is happening. The identity of this angle. Because when you do experiment, the refraction happens from this phase and that phase. So, you call this as prism angle. Let's call it as angle A. There is another angle which you can track. That angle is, can you show me where is the angle of deviation? What is deviation? This is the original path. What is the path now? This is a path. So, how much is a change? This angle is a change. Right. Let us say this angle is delta. Fine. Experimentally, it is seen that delta is in those two pins. Okay. When you track delta, you'll see that delta will keep on, you know, keep on decreasing. But after some point, it starts to increase if you change the angle of incidence. Fine. So, you can actually pin point. Where is the location or what is, what, where is the situation? What is the situation in which deviation angle is minimum? Because initially we will keep on decreasing. And then after which it will start to rise. So, the point where it just starts to rise, that is the point where minimum deviation happens. Are you getting it? Fine. So, we will assume here is that we can measure A and delta. The relation between refraction angle, incident angle, this angle with respect to A and delta. Relation between R1, R2 and A. There is a relation. Geometrically, you can find out. Do it. What is the relation? Is it equal to R1 plus R2? Are you getting it? You can see here that there is a quadrilateral here. This, this angle is 90 degree. This one. And this is also 90 degree. So, these two sum is 180 degree. So, these two sum should be also.   So, write down 180 minus R1 plus R2 plus A is equal to 180. Get R1 plus R2 equals to A. So, this is our first relation. We got a relation which connects angle of refraction. Are you getting it? Now, can you find out angle of deviation delta in terms of I, R1, R2 and E? All four angles will feature now. This is what you are getting? How you got that? Exactly. So, this angle delta is an exterior angle. These two. Fine. So, this angle is what? This one is I minus R1.  So, delta is this angle plus that angle. So, fine. Now, this will become I plus E minus R1 plus R2. Right? R1 plus R2 is what? A. So, I can write this I plus E minus A. Okay. This is delta. Right? So, we have a second. Fine. Now, let us try to rearrange the terms in delta. So, delta will be equal to minus of 2I into E plus 2 times I into E minus A. So, delta will become this constant. But if you see this bracket term will be minimum. This is a square term. The minimum value of a square term can be 0. It cannot be negative. Right? And it will become 0 when? When I is equal to E. Fine. So, I can say that delta direct derivation that this is what this necessary condition. But this is just to show that, you know, when angle of incidence becomes angle of emergence, then delta will, experimentally, this is true also. I is equal to E 1 and R2. Now, you can hear. Are you able to hear? Hello. Check your net speed, internet speed. For that internet speed. Now, what we have found? Okay. So, you get 2R1 is equal to A. So, R1 will be equal to A by 2. Okay. Now, I must be audible. Fine. Refractive index is more for higher frequency. All right? But then in our numericals, it will be written that for this medium refractive index is 1.5. So, till now, we have always used refractive index as a fixed number. We never thought about that. What is the wavelength of the ray that is hitting the interface? Right? So, we will continue doing that only. This is just for your information. There are not many numericals on it. Unless you write J advance and probably some paragraph question may come. But that is like far-petched.


I always say food is food like if you can make a great taco you can probably put your mind to it and make a great doughnut.  District started in 2013 here in the Lower Garden District in New Orleans. We wanted to kind of reach every person at any time of the day, breakfast, lunch, dinner. And doughnuts was one of those things that came to us just as a form of comfort and a form of something that we could really take a culinary approach to. We were in here every day. The amount of creativity we could bring to the table on a daily basis, the amount of feedback we could receive from our team and from the people who come in as guests, that teaches you a ton. Everything in here is scratch kitchen. Everything from the cookie toppings to the sprinkles to the dough obviously, it's just all scratch. So if we love something we grew up on, if Twinkies are your thing, whatever. We can look at that and say, well what does that look like in a doughnut? Something that makes you go, oh wow. And this is something people should feel good and warm and happy when they have it. The one I like the least, I think that we've done is the maple sriracha glaze. Come on, man. With the candy time. Come on, man. This is highly personal. When you create jobs in a neighborhood and then you realize the neighborhood is impacted by that job creation environment, that changes how you view a neighborhood. And so our hope is to tailor our gift to serve the community and change it for the better. We started the Roaster on Coffee. Basically for every bag of coffee goes a dollar to specified non-profit and we branded it Cool Kids Coffee. Cool Kids Coffee Roasters focuses on the cool kids of children's hospital or the cool kids of a foster care non-profit. We think if businesses can take what they do, their products, and figure out how to turn that into a way to serve people outside of that immediate relationship of buyer and seller, that creates better communities. I see what we do is a truth to the city, which is say, how else would we be? We're from New Orleans and that's just kind of how we think down here. What's next for us is to continue to spread the love and figure out how to bring donut sliders and coffee to new neighborhoods and bring cool kids coffee roasters and this as we go. So we're hopeful to continue to build the brand of district.


And here at CES 2020, and hi, hey there. So, who are you? So, my name is Derek Manuel, I work with Colgate Pomalov, and I lead our Colgate Directed Consumer and our Colgate Connect Group. So, you're launching here a new toothbrush. This is a very special, little smart toothbrush, right? Yes, it is. This is our award-winning Colgate Placless Pro toothbrush. We've actually been recognized as best of innovation in the health and wellness category. And what's amazing about this toothbrush is that it actually can detect biofilm as you're brushing, and more importantly, give you meaningful feedback to let you know whether you've done a good job removing that biofilm. Biofilm means like food? No, biofilm is a scientific name for the bacteria that starts to form on your teeth and can end up being the root cause of most of the dental conditions we have, like gingivitis, perionontitis, et cetera. So, there's a little sensor here, is it IR, or what's happening there? No, so you have optical sensors that are here in the head. And what's amazing about these is that they actually emit blue lights, light in the blue light spectrum, that when it comes in contact with biofilm, there's a substance known as porphyrin, that porphyrin fluoresces back red light. Those optical sensors are able to see that red light, and that's an indication that biofilm is there.  It's gonna be the new trend to actually stare at your smartphone while you brush your teeth because it's gonna be even more information right there, right?  Yeah, so let me tell you first and foremost, one of the great things about this brush is you don't need your smartphone with you for it to give you all of its benefits. Again, that feedback that you get from this blue light ring enables you to know whether you've removed the brushes brushed away all of that plaque or not, which is a terrific thing. So you can actually see the blue light. That's right, there's nothing. There's a brushing either in the mirror and your peripheral vision. Ah, yeah, you'll see it in the mirror. That's right. There is an app that goes along with it which can provide supplemental information. But as I said, the great thing about this one is you don't actually need to have the app with you to get the most benefit out of this brush. What is the supplemental information in the app? Thanks for asking. So you can actually, on the Kloge Connect app, which is free to download, either a Google Play or from iTunes, you get brushing frequency, duration and location. And then with this particular brush, we have what's called a clean score, which can actually give you an assessment of how you're doing. We've also built in a number of things in the app, including ways to incentivize and encourage, even make competitive against your friends so that people are more engaged with the overall experience. How do you connect with the friends? Like, who's brushing better? Well, you can potentially reach out to them through the app.  Only if they give you access to their account, but yeah, you could do that. Yeah. So does it also maybe help in brushing not too much because some people just brush way too much and it's actually damaging the mouth? I'm glad you asked. Actually, it actually has a feature in it. That blue light that I was mentioning will turn white after 10 seconds and that's precisely to stop people from overbrushing. One thing is it will stay blue if you have, for example, tartar or sometimes known as calculus. That can't be removed by any commercially available toothbrush. There you need to go see the dentist. All right. And is it sonic vibrations? Sonic vibrations, 30,000. We've actually designed the brush itself to be lightweight, slim, sleek design and relatively quiet. So you have a pleasant brushing experience as well. Is there any way to teach it to not go too strong in a place where it might hurt more? Some people have some areas want to go lower in frequency. So you can build in features like speed control so you can go to a lower speed if you want. As of right now, what you're talking about isn't on the brush necessarily, but those are things that we can actually sink through the app and build into the app experience. Is it pretty much the best toothbrush in the world right now? Is that what you're going to say? I certainly have a biased opinion, but there's nothing else like it. I would say so. Nothing similar. Nobody has this optical sensor. Yeah, a lot of companies make great toothbrushes that help people remove plaque. This one is unique. Nothing else in the world like it. Do you show also the historically what you've done before here at The Booth or are you only talking about this? So I'm happy to take you on the tour of The Booth. Come around. So let me show you here. Come this way. Yeah. So I don't want to get the awards we've won. Yeah. We've been recognized by a number of organizations at CES, Best of Innovation, Health and Wellness, Reviewed Editors' Choice, Best of Gadget Watch, Good Housekeeping, Tech Advisor, Best in Show, a lot of recognition. We're actually featuring this amazing toothbrush. If you have children, you know how hard it is to get your kids to brush. This is a terrific product, very clever. Takes an average Colgate manual toothbrush, three to four dollar brush. Puts this thing on the bottom, what we call a dongle or the shoe. If you notice it has colorful dots on the bottom. What's amazing about that one is any smartphone camera can pick up those dots and the child will know where in their mouth they're brushing. And this creates a gamified brushing experience that teaches them how to brush properly, rewards them with masks like a snapchat or whatever. And then also there's a great feature in it that parents can check up on their kids whether they've been brushing. Nice, and they can get like an extra Lego or something if they brush their teeth correctly the whole week. That's right, but their parents will have to give them that. Yeah, it's not that good. And then it's important to note that in 2018 we launched in Apple our first connected toothbrush called the Colgate E1. How on? It's not in this cabinet, but these are successors to that. We came out with connected tooth brushing, as I said in 2018, what's great about our system is that it actually has 16 zone detection capabilities built into it. And what's great about it is it can store up to 10 days worth of brushing. So again, to the question you asked before, you don't need to be staring at your phone while you're brushing. That said, one great thing about our products we know is that when you have a connected experience, you actually can remove up to 50% more plaque than using the same brush without the connected experience. So giving people that feedback and information, we know can actually go a long way in terms of improving their brushing. Nice. And if you will. We're also featuring one other... Is this how it was originally? Yeah, these are some of the interesting things that Colgate has done through its history. Colgate was the first company to put toothpaste in an aluminum tube. First one to put toothpaste in a... When was that? Oh, it's got to be closer, yeah, 100 years ago or so. In the U.S.? What's that? U.S. And then what I'm especially proud of is... Colgate is the parent company of the Tomsa main brand. What you're looking at here is the world's first recyclable toothpaste tube. It's actually made out of materials similar to what you already have in your house. They can go into your municipality recycling stream. But what makes me especially proud here is that Colgate is treating this as open source. So while we develop this, it's proprietary. We're letting any company that wants to use this technology use it so we can get more people to recycle their toothpaste tubes. All right, so you don't do preparatory design for that? Yep, it is proprietary, but we're sharing it license-free to anyone who wants to use it. Nice. And then there's another collection of the stuff we have. Let me show you the demo. Why don't you do the recyclable on every toothpaste? I mean, they're starting with the Tomsa main brand and we want to bring it to... Of course, the Colgate brand, which reaches billions of people a year. Are you the leader? That's the intention space, no, by far. By far you're the leader. Yeah. Is there... Two to three times higher market share than anyone else. The fluoride is a requirement to have good hygiene. So again, step chain? Sorry? No, to have strong, healthy teeth, fluoride is a critical component of good brushing. And everybody just uses that all the time. Every day. Yeah, that's the best way to make it effective. Let me show you this technology demo. So you might want to change it around, but here's a visual demonstration of how the brush is working.  They're flashing as you're brushing. And effectively what the optical sensors are seeing is what you see on that model, the tooth model there on the left. You see the red? That's typically where plaque builds up along the gum line or between the teeth. That's what the optical sensors are seeing. And then giving the user feedback. White light means you've cleaned that plaque right. Blue light means you still need to do more brushing in that area. Nice. And this is accurate. What's that? This is accurate. Yes, yeah, of course. All right. So how much is the price for this toothbrush? Yeah, so we haven't finalized our pricing, but if you look at comparable products in the market or at least other advanced products in the market, I would say nothing is comparable. They're in the $200 to $300 range. Our intention is to be somewhere around there as well. And it should be available later this year. And is there some kind of warranty for like 10 years or something? We haven't, not 10 years necessarily, but we'll definitely stand behind our products and make sure people are satisfied with them. One thing that I noticed with my Philips is the battery has run out after a couple years. And people have to swap the batteries themselves, I guess. Well, in a Philips, you probably can't swap the battery because they're, I believe, lithium ion. But like any rechargeable battery, it tends to erode over time. But the charge here should last you two weeks so that you can go two weeks between charging. At least that's what we're targeting from the get go. All right. So thanks a lot. So the CES has been an important launch. Very important for us. It's our first one ever. Actually, I have to say we've had quite a successful one. We're quite proud of the effort that the entire group has put together to get us here. So thank you. And there's a lot of science behind. There's also collaborations with experts in the industry to develop this, right? Many experts, technology partners, Colgate researchers. It's been a collaborative effort across a great number of groups.


Welcome to Combined Wing Chun. I'm Sifu David. Today we're going to show you Wing Chun vs. Boxing Punching. We're going to show you the difference between Boxing Punching and Wing Chun Punching, and it's not what you think. So let's get started. Let's start with Boxing Punching. Now, most people are familiar with Boxing Punching. Very popular is what? 1, 2, right? Jab Cross, right? Okay, so What's the main difference between this and Wing Chun? Well, number one is the stance. Most of the time, if you go to Boxing Class, this is the stance they're going to teach you. All right, you have your weight slightly forward. All right, you have your hands up, you know, in the guard position. All right, you have your chin tucked in. You have the back foot. If you can see, my back foot is on the toe or on the ball of the foot so that I can rotate. Okay, so Boxing Punch will go straight like this. And another characteristic to the Boxing Punch, most people are punching with a Horizontal Fist, all right? Horizontal Fist. Horizontal Fist, all right? So where a jab is going to be straight out like this. Okay, or sometimes with a step, like that. That's a jab. Okay, so notice what I'm doing. I'm stepping into the punch, and then when I land my foot on the ground, that's where I want to land the punch. All right, and what you also see is that most of the time I hide my chin behind my shoulders so that it blocks an attack when I'm punching a jab. Okay, very effective. Jab is very useful, okay? Okay, across. Let's hold it all here for a second. Across. Get it like that. So same thing. I'm using the rotation of my body on my hips, on my shoulders to generate power. Okay? All right, it is a longer reach. I'm using the full extension of my arm and the full extension of my arm, okay? And there's also a slight rotation, a little bit more advanced for you guys who've done a lot of boxing, probably know about the rotation. So when I'm punching, at the end, I snap it as a rotation. Okay, so that has a little more power. Like that, okay? Add that little bit of rotation at the end. Okay, so that's boxing punching. You're very familiar with it. You see it all the time, all right? So now we know what it is, the characteristics of it, that's as we want to wingtune punching. All right, wingtune punching is often misunderstood because a lot of people just don't know how to apply any character. Because if you've been doing a lot of boxing punching, if you're using a rotational force, all right, you probably won't be able to use rotational force in a wingtune punch. At least if you want to do it the traditional way, okay? So in wingtune, what we want to use is what you use spring force. I showed you in the other video how to increase punching power part two, the difference between rotational force and spring force. So you want to learn about that with that video, but here I'm just going to show you very quickly. This is rotational force, rotating your body and your shoulders.  So with spring force, wingtune punches, number one, the main difference is made in a shorter distance because your elbow is down, all right, versus this way, horizontal, your elbow is down. So it's meant for a shorter distance, all right? And also, you're using spring force going in the upper direction, all right? So that's more of a springtune punch. So I'm not really putting rotational power. As you can see, I'm using spring force, okay? Another main difference is in the stance. You'll notice that my stance is weighted on a back leg instead of leaning forward. I'm kind of leaning backward a bit, maybe a little bit straight up, okay? The reason I'm doing that is because I want to use the spring of my back leg to generate that force, okay? And I want to be able to thrust my hip forward in that. If your hip is already forward, you can't thrust it forward more, okay? So that's why in wingtune, one of the reasons you put the weight on the back leg is so that we can spring off from it and then use this hip check power like in hockey, you do hip checks like that, right? So that's what you want to do. You want to use that hip power, okay? So once again, the characteristic is weight on the back leg and you're using a spring power, your elbows are down, and the third thing is that your punch is a vertical fist instead of horizontal fist, vertical fist and horizontal fist. And it's used in a shorter range, okay? Okay, why shorter range? Because the person doesn't have enough time to react to shorter range punches from here, okay? Boxing, the guy can see it, they can slip, they can duck it, they can parry it. And once you get to here, the eyes do not, and the brain does not have enough time to react to it. It was the time we seen boxing, people punching this range, what did they do? They just clinch, they just clinched, right? Because they don't, they can't react to it, okay? So that's when Wing Chun, we do a lot of Cheesaw, do a lot of sensitivity, so we don't need the eyes. I just feel something and then I go punch, right? I feel a punch, feel something and then I go punch, boom, boom, okay? So that's where Wing Chun punches are better if you can train the sensitivity into them, okay? So because without my eyes, I can punch, I can punch, and I know where he is because I've got his hands, so I know where his head is, okay? For example, right?  So I don't need to use my eyes to know where my target is, right? Because I can feel where the target is, right? So that's one advantage you can train, Wing Chun, not to use your eyes, basically just touch. And I know that's the outside of his arm, here's his elbow, so his head is there, I don't need to think, okay? If he's trying to hit me with this one, I know that the energy is coming, I can feel it, I don't need to see it, right? And I know his head is there, okay?  Okay? So I don't need to look. And you're using the advantage of being in a close range to use your tactile sensitivity to take advantage of them. So you don't need to use your eyes. You know what? It takes a lot of training, it takes a lot of sensitivity, training. There's stuff that I can show you, you can do at home, even without a partner to do this. A lot of people don't know how to do it, but I can show you how to do it. So just stay tuned to this channel. If you're interested in learning more, you want to learn Wing Chun, then go ahead and grab my free DVD. Do you just pay shipping? Just click the link on the bottom, a lot of the comments here, and a lot of people like it. So make sure you get that and grab that before we run out of copies. So we'll see you soon, next video.