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Molecular Mechanism of alcoholic liver disease
Christian Trautwein, University Medical Center, RTWH Aachen, Germany
Thursday, Sept. 7, 2017 · 6 p.m. · 35m 45s
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i think are much for a minute to be here i'm just discuss the
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last time was yourself as well which is now around fifteen years
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this was the time maybe we're still together that's easily we're working hard for use like this is
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a time um better small so i think it was is more round i think even happier
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and f. i. very happy to be here today and i really enjoy the city it's very nice because
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uh you have nice you mountains and i'm hopeless also try me and they
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also some you that some mountains but not so high is here
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so um i would like to first start to some slides which um you may know which very easy
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and um you see that i could do the seasons with the puppy cults parading around the world
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and you see that um especially in russia there's a lot of a colour but also
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in europe of ago so it's a major problem and besides maybe nash and
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um everybody sees is the name of the common diseases we have to lift
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this and we have to do our work or and also control investigations
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is a nice uh sort of correlation which amino and um you see
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very clearly that alcohol and liver diseases is a direct correlation
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i think it's very important to know that and this means that when you
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think first i'll call this chapter action of how much you drink
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i have to tell you that the awesome mechanisms which are important and if i
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would like to show you the again delve today what would cover i will
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start this risk factors because i respect i think it's very important especially they
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are mechanisms which are essential uh for the molecular mechanisms unlikely the seas
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i will then go to the intestine discloses level
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disease will then discuss signals involved in progression
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of to caesar the s. and the and i would go to have that injury
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so if you look about potential genetic factors um i would like to cover what we
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know up to now they obviously right now five factors which are relevant for gene
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mutations in specific genes which are relevant for disease progression the first and the much
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well known is p. o. p. three i think it's a child with patients
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uh which changes to the function of the pro team they put metal isn't
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and this was first discovered in first described around seven years ago
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and since then more different genes where involved
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not a kind a as a team s. f. as as if to uh interval i fell forward also relevant
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first for our hepatitis but then obviously also relevant for other little diseases
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and the last which was published around two years ago uh the statistical which was involved
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is in the o. a. t. seven which also involved all these factors at the end
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increase information so this mean inspecting relation and the direct correlation
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which is you about are correlated to see this
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is not only this also fifty percent around of progression is
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fibrosis so obviously besides the chat i couldn't take
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it's very important to state but they also mechanisms which increase the mechanisms which me
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to toxic situations liver and and it's just easy to do things right
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so of course um when you discover boston activities you also would like to show them oh data never would like
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to point you to a may potentially the fixed new genetic factors which are right we are working on
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and i just would like to um emphasise that other one hundred scene is a
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very important brodie that of course we know that it's important fallen diseases
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but we shouldn't forget that this protein is produces a liver
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and why is produced liver up i'm wondering is important to tried last
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days and if you don't have i've and it says scene which
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is important for the line then we have a chronic informations a lime
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and because important to protect a line for my last days
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and therefore we have here a lot of functions situation if you don't have a hundred zoom would you trigger emphysema
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this is the common thing everybody things about this if they think the advantage of sin but you shouldn't forget
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on the other hand if you have a miss for the pro team you have a kind of
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functions situation this means i miss for the protein of a hundred scene which leads to like
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off secretions a plot leaned leads to miss folded protein in the liver and this also triggers
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chronic hepatitis fibrosis zeros is and h. c. c. softens the if the
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thing about two different fat function above about uh what on trips
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and um if you think the channel important thing all think about this you
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and uh it's very important to tell you that around to ferret
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off the dioceses normally when you are smoker is related to line
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and this is why we are so prominently thinking about
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uh around had situation about uh the liver
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but i mean well i think often switzerland eunice awesome smoking have different situation
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we have people now which are less prominent in smoking
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and therefore uh if you have no smokers
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then you only forty five percent of these is a trigger pollen and around nearly one
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third thirty percent if the disease so this means if we now have around eighty percent of
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non smokers in favour of smokers impact off
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about interesting is increasing concerning liver disease
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and effort without some time ago it's not support the also by by the
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easel that you look for patients is about obscene uh uh with patients
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and you see here the typical set set mutation this
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means bows audience have um would take the
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protein which pizza truncation and i miss folding in the liver and up to now we have
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uh these countries in both we have right now like yesterday we have a new corporate hundred patients off
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of puerto go and therefore we have mean but i think about one fifty five for patients
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segmentation is constantly increasing so i think in the future maybe we will have a very big corps critical to
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make sure that everything could understand what is important for progression of to see um this act was that
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we now looked on these first trend twenty patients it's interesting to see that average
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these patients compared is normal situation without invitation haven't increased in fibrous kind
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and you see that around twenty four percent of these patients have a vipers can above seven point
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one run ten percent about over ten and obviously
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males are more permanent compared to one
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so obviously this leads to a liver disease equality policies in these patients and the sink and say
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i want one quarter of these patients have increase a a liver um a little fibrosis difference
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so if you know what specifically in these patients you see a pleasure mechanisms by this happens
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and obviously patients visits at segmentation haven't increased in fact acknowledge
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this means that uh the miss for the protein also triggers
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a compilation of fed any significant compared to the controls
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so this indicates that obviously one of the mechanism very likely how we have a have
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a trigger or whatever disease is more fat in the level of these patients
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they can hear a show for the fibres can you see that the uh that
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the uh male have a higher i'm fat accumulation compared to the field
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so this is something which is seldom right i mean twenty twenty patients and all this court's however we know
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that at least in germany we have around two to
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four percent this this mutation is ahead of cycles
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and if you look for all the good patients which off out of others in need ten percent in all public
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for this new visitors are the quality is quite high prevalence inauguration the the that
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with patience is promised one as the prevalence around two to four percent
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and therefore we now looked huge study look on the headers i was a population
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and the the every found that s. found all sons that that set set all the end set
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of course avenues for the protein in the liver and also they haven't increased levels difference
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so indicating that the hypothetical situation maybe it quite a high amount of
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of of persons everybody increase in people fibrosis indicated by the vast difference
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so this means around twenty percent of these patients have increased in levels distance
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so what that means so what i mean if you have this situation that they're the sort
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of prevalence made this more fat in the liver run twenty one of the population
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and everything looked in future corps understand if this mutations that
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had aside what is important for icon people disease
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and these results i think are quite interesting we had uh it
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it totally need to some five hundred i don't miss us
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and this is the first court which is the german swiss and the british this
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total these these patients and you see very interesting the if you have this set variant is
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ahead of that situation you have over or alteration of more than five indicates that patients
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with this with patients have the highest risk factor of disease progression all the other potential before
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uh lessee here so this means bend your head aside as motivation in the steadily though
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uh um uh the adviser that's really it's the highest price to increase trigger all five boroughs
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and oh this is the edges of page also you see it
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in the six it's a nice explode indicating that this
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header cycle set fire and is obviously important uh for progression of disease i call you disease
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and as discussed before of course there's more fat in the liver and there are
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also looked on subject this novelty and in this a little bit smaller court
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around six hundred uh subjects began had the same situation around five to six fold cost
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ratio whatever it out one look at it again you see that an increase
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fibrosis indicating that obviously uh the and set situation is is it your one
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and you have to really be cautious because two percent to four percent
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off the question situation to has had a good motivation and they what we
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think that our our budget is a very important mechanism of disease progression
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and a lot because only two to four percent but relevant if it comes ostrich
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this means that i would like to indicate that besides the five known
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genetic markers are like t. v.s tuna fish spawn and i think this market should be
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looked at in the future like a little season messing would be nice for example
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uh this is really to do this in the record that is very
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interesting to see if these mechanisms are in the future quite import
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the the first part that would like now to go to the second car and
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i would like to show you ashamed i think your very well aware of
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and we know that there's a very close interaction between the got and the liver
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and it's normal that in a normal situation your son microbial home and of
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course the market was very essential to take nutrition up to the liver
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and of course you have trays of micro components and we know that the
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cup for sellers very important situation for the torrent and liberals this means
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the call for cells isn't even normal thirty state towards mechanism that means
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that burned out talk scenes coming to the liver the uh
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the the the the couple cells don't regulate the moon response in
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order to have this nice interaction between got into that
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however we know that in patients which have an increase in chronic i call consumption
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we have an increase also in our call into powerful plot does indicate in these patients obviously be
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of changes whichever development and these changes go to
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the cup mike repeal it therefore it's obvious
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that is the way she but you have to change in current icon
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contention if also change the greek it beep room between the gap
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and also the liver and you have changes in the microbial much leads to hire
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a trance location of butter the name however the creation of l. p. s.
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and this then trigger this corpus else region activated to different state activate
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state which made case activation of the moon mechanisms in the liver
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so obviously this equilibrium is there in in essential to understand
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the molecular mechanisms of icons used to that is
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and a half i would like to stop the second topic internist little discloses according to disease which i think is a
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very prominent feature in the future i think we'll have important mechanisms which had looked at it in this regard
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best of all at first i think good study was published
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around one half years ago uh by um lopez at
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all and they found a very interesting he that when you look on the different method in the different
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diseases either either mom i click appetite this muncie be i
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go like appetite is also the icon at that
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is that you have to change the microbial indicating that
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specific bacteria i changed compared to the non disease
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uh the non deceased a liver indicating that obviously this change
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in in the c. v. s. i. e. and activity is linked to a change in the microbe
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and there's also a linked to changes in correlations concerning
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interest like room changes is a putting parameters just see that the
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bacteria i linked to the severity of alcoholic appetite is
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some visibility rabin and they have office with these changes may play important rule i quickly but it's
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and now the uh some months ago there was a publication of a habit ticks group
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and they showed very nicely that in patients with chronic i call conceptions
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you have reduction in feed to a common symbols you part
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is and this is shown here that unhealthy compared to
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see via alcoholic a disease patients if just don't you have
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a strong decrease in this uh of this bacterium
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and he again you have the the the no cramp from a program in features of our commands yeah
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and you see again that there's a direct correlation between the severity of disease compared
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um to the l. c. controls so indicating that this could be one
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of the mechanisms how uh uh discloses leads to an increase
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um security i quickly but it's the amount the human patients but
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they went then into the animal models and they uh
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looked on animals which have that this chronic i got conception
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and they found that in this situation they love changes
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in the different uh um rebuttal speeches and multiple tracks are different rich
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the to come of control and also as that animals and uh they uh they
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showed also in the animal model but obviously in these animals feature fat
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those are cool again you have reduction uh you have a
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reduction in the commons you're suggesting that in humans
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but also in animals fed this chronic arco consumption you have says change the come expires
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and f. are they now trees animals with zach amanda understand this mechanism our commander
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might be relevant for disease progression the shown here so they now use
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um i call for animals we have first as a phase but you adopt the animals to the alcohol
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and then the pet animal and then they every third day they gave these animals i command you
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and if you now look on the mechanisms to see first of all that also i
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love animals by giving by got lash these i commands a bacteria increase in um
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in the at command see a a speech yes so indicating that
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by additionally feeding them of the commons yeah rest user phenotype
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and if we now look on the disease progression again see that in
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these animals bit which retreated now sacraments yeah you have a reduction
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uh entranced amazes indicating the function relevance of a command the
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reduction in animal models and thinking back to you
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with situation that i commands and these animals is in this in the human situation is for you
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so then the question of course is when you see a change
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in for example a command yeah uh is it important
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for only i caught diseases also metabolic diseases and i would like to show
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one of few slides of uh um what animal will be used
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uh this was a very similar direction company that may be a command as important channel metabolic diseases
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and uh i just would like to show you hear a little bit how the layers are built
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uh you see that you have a physical layer which is the most in later and the type function and
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then give us a lot a barrier which is below that in the test in which also leads to
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in in a a protection that you don't have much but you're going into the body this means
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these two layers i essential to have sick lean body protected from the dirty got newman
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and here we have macrophages to whichever developments for the
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interaction of this uh intestinal fellow layer and
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the fact that factor kind respect receptor sixty of
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one is their essential to mediate this interact
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left unused uh a model baby used effect we can look out mice and checked
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uh if uh if you have died in use didn't hide is this also relevant for disease progression
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yeah but you see very nicely is but also in the metabolic situation if you have affected kinda cover sceptre
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where the intestinal barrier is changed but you have increased
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in fat accumulation as shown here or here
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and this increases the regulation lead somehow mess score and and higher increase in trenton aces
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and this indicate that the fact that kind of separate the macrophages in
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the intestine of every essential for protection does in two ways
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if you now look in these animals but changes here very soon laces it's the most innovation s.
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in point i call you to see to see again the commands yeah is to create decreased
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uh compared uh to the situation um uh in the controls
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so in a kinda again that commands yet place of relevant will here and we know that commands yeah
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is important bacteria because it promotes the moose in layer
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and therefore in test nobody here uh integrity
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we should now look on the moose elated used in these animals and again you see that in the talks is increased
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due to the reduction of the movie seem they are in correlation is the commands of activism indicating
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that a great actually these but also depend limited by the policies if it change necromancer
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if you're not really the animals this a bacteria shown here uh this uh with
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the antibiotics and high fat diet you see that the filter this reversible
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you see that when you treat a locally in the got uh
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the high fat animals that uh animals deferred action uh
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in fact accommodation and your production to next like indicating that
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you would change the back to flora if an increase
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uh in in s. w. f. function and if you have decreased techniques
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so this indicates that potentially commands yeah isabella bacteria in the
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body was these alcoholic but of princely also in niche
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so besides bacteria in the matter broom what else could be important i think the very interesting uh uh um
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paper published just some time ago of the group of
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dungeon robbins and you go and they looked
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in an hour models uh but also in humans if
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you have changes uh in the situation concerning funky
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and you see here the the genius level but changes in patients if
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you have controls all progressive different levels of like a little disease
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and you see that in these patients jeffrey strongly increase uh in canada and um
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if you look more specifically you see that different from the i would use
00:21:05
but kind of has increased again indicating that the um
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this joe says it'll we only rated the bacteria
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well last or related to fully suggesting that decide this also from the are relevant to situation
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and they for the look in these patients about this change
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and they showed that the um that the um antibodies
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i should she against fully is increased in patients is i can only the seas compared
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to h. b. nice roses indicating that potentially accuracies um uh from the unimportant
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and interestingly they also showed that supports a viable of patients i collect uh roses
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it's linked also 'cause antibody against fully suggesting that um
00:21:52
for me but also very important role in the microbial concerning
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i probably have height is a progression of disease
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i would like to summarise the second part i quit consumption
00:22:03
trickles intestinal best shows it's changes of to think bacteria
00:22:08
have been found and obviously i commence image part is could be a very interesting bacteria which is relevant
00:22:16
one impaired interest about yeah function and increased and the papers location of part your product
00:22:22
and s. degree segment is also found other seizes it might be in channel important
00:22:27
formidable liver diseases in the got intestine and first was such a test
00:22:33
but also fully could be a new player in the game the
00:22:36
microbial couple question of academic literacy so if you're now look
00:22:43
from the back repeal them it's of course important but other signals
00:22:47
which mitigate these changes in the liver and have the next part will go on signals involved and
00:22:55
i quickly the distance and uh if you look on the thing of it might be relevant
00:23:00
see that pens and ends are activated and trigger different factors in different
00:23:07
cells for example the call for cell still are so important
00:23:10
and also in a um in a product islet cells and therefore it's interesting to see
00:23:16
that you love force that seems to be important mediator icon ability
00:23:21
and the first link to to the four in signalling came some time ago already fifteen years
00:23:28
betty where the first application showing that then you have to have fought deficient mice
00:23:34
that competitive outage situation they have a decreased a liver enzymes
00:23:40
so indicating that to a four is important to make it is effect concerning activate of the moon system into the room
00:23:46
but you see also that i eternal uh levels are similar so obviously
00:23:51
distiller for a sceptre seems to be quite relevant in this situation
00:23:56
and if you're now looking quite model as shown here for example is
00:24:00
easier for model a call to see it also in this model
00:24:09
to love for and and the products are very important this is the first slide showing up in you treat
00:24:15
animals uh this low climate products in the uh in the intestine introduction
00:24:21
in uh h. c. c. progression reduction in the two more number
00:24:25
but also in into it laughs just two more and you but at a ratio in the meeting to my trip home uh important
00:24:34
reduced to mow grows the same has been shown by the uh by uh the credit by the uh try to group
00:24:41
when you use now to the phone knockout mice in this situation you also for action into will grows as
00:24:48
shown here for the two or three t. love for isn't important mitigate affordable jesus in the situation
00:24:56
what could be a second signal i think they're very interesting
00:24:59
you a recent results concerning like three infamous inactivation
00:25:04
if you think about my three there too important signal the first
00:25:08
signal activates a uh for example and after about b.
00:25:13
and this leads to increase in uh the different components of
00:25:18
the infamous omen then you have a second signal
00:25:20
it's leads to the accumulation of sunlight streamed from us on it then mainly activates cast space one
00:25:26
and the two mediators out on data in our one and our eighteen saw
00:25:31
for the these two things are important again he lucidity love was involved
00:25:35
so this means that the infamous all would be the second important signal to make it specific
00:25:42
and here are very interesting results concerning the relevance
00:25:46
often extreme from a song you see here that in animals you have an increase
00:25:51
uh in transom analysis and if you're now look on the protein
00:25:55
level just rolling treason i want pattern i call fat animals
00:25:59
suggesting that doesn't activation of the night three infamous on
00:26:04
your falsify activation of class pays one activity
00:26:08
and if you now use denied three knockout animals as shown
00:26:12
here you haven't i'm ration of liver disease suggesting
00:26:16
that the first signal is still up for and then you've activation of the infamous all night three
00:26:21
and you then reduction transom amazing as a second potential mechanism
00:26:26
indicating that besides the law for obviously also the infamous on is involved in getting
00:26:32
to in effect uh in liver injury uh in human but also in mice
00:26:38
so if you're now look again back on the mechanism of the funky and i think it's very
00:26:45
interesting to share in this paper it's x. by activating income false else i want data
00:26:56
so obviously well some mechanism also besides bacteria which might be relevant
00:27:01
for the activation so i can fully because in this paper has been nice
00:27:05
to shown that also could process of activated backward by a fungal
00:27:10
products and this leads to activation of i've on that and therefore it's
00:27:15
got in it it's interesting to see if you're not treat
00:27:19
but these animals this and before goats that for somebody and put us in b.
00:27:24
they can you have a reduction in transom races again suggesting that besides bacteria
00:27:30
for me seem to be relevant role in the molecular mechanisms of psychology but is it
00:27:36
so the last point in this third part is how can be
00:27:42
officially change this and f. i think it's obvious that's it fickle mike what a manipulation
00:27:48
could be a promising paraplegic target you see here paper reason to punch a hat
00:27:54
and here they again use this uh protocol where they started this lower doses
00:28:00
off alcohol and then the increased up to fact and i call
00:28:04
and they treated the animals either this fickle michael contents fair
00:28:08
or with a um with a a pack team which is which is um supplemental
00:28:14
a diet to um to increase the and to the the uh the microbial
00:28:21
and if you use now these two different uh uh regimens you see that when you
00:28:26
use a either the f. m. t. or
00:28:30
the uh the um the appropriate expecting
00:28:34
you see that you have to you have a diversity of the cup microbial is again
00:28:39
step allies indicating that when you treat the animals with alcohol your production
00:28:45
uh in this time the back to read is if you're then again treat them
00:28:49
this f. m. t. or was a pure projects you can reverses effect
00:28:54
and this effect nicely uh correlates uh with the injury in the liver you
00:28:59
see here that you have an increase in fat accumulation which is reduce
00:29:03
when you either make or from f. m. t. or you treat animals respecting
00:29:07
and this also reflected on the trends unless levels different action transom races
00:29:13
and you also for reduction look to just write indicating that when you
00:29:17
have a menu have a continues f. m. t. that this
00:29:20
may also be effect on reducing i quickly with disease in this
00:29:25
situation so therefore i would like to summarise the first part
00:29:29
so i showed you that obviously actual products trigger tearful activation i call able injury
00:29:37
we found that to love was also involved in prevailing h.'s he grows
00:29:42
besides still of for the infamous home seems to be it seems to be
00:29:46
a prominent role the ah i want activation in according to label these
00:29:52
and obviously anti fungal and out when activation come together because here
00:29:57
uh the uh uh we showed very nicely in the group of puncture novel that
00:30:01
andy from good treatment arrays i could be in intuitive a a disease
00:30:06
and of course the correction of interest discloses is another prominent
00:30:10
uh situation to choose i couldn't just leave it
00:30:15
so in the third in the in the last in force part we're now going from the microbial home it
00:30:20
was just take notes to that at itself so other mechanisms for and they have at the first
00:30:32
indications also long time ago but obviously apple toasters
00:30:36
my play a very prominent role for a year in a
00:30:40
study by keep iowa published in two thousand four
00:30:44
so that he found that and i can get the disease
00:30:46
if inc is internal positive internal positive uh cells
00:30:51
and also increase in cleave 'cause space activation suggesting that
00:30:56
opposes but an important role and i quickly ballistics
00:31:01
and if you're now look in patients tonight he see that also in
00:31:05
patients jeff activation off three class days eight as shown here
00:31:10
and also you have a correlation off please cast base activation uh in the patients visit visit
00:31:17
theses so obviously close to the punch it potentially cast pays eight place probably grow
00:31:24
if you not use in mouse models these mechanisms
00:31:28
to understand how have space eight is activated
00:31:31
it's obvious venue feet animals this article but
00:31:36
also here increase in cost space activation
00:31:40
as shown he or shown here so obviously has space eight and adopt hoses
00:31:45
it's triggered in animals this i yeah but it is it's also found in patients
00:31:51
however if you now look on animals which don't have cats pays eight activation as shown here
00:31:59
this effect is not function relevant so besides just some cafes activation apart of light
00:32:06
you seen those animals that just eleven increasing transom mazes and i call feeling still have an increase
00:32:13
in in fact relations suggesting that even cast bayes is activated you don't have just from effect
00:32:20
and and therefore if you know check in the animals you still see cast pastry activation
00:32:26
indicating that despite cafes a is the way just to have the activation oppose
00:32:33
therefore we checked for other mechanisms inside the direct have space inactivation to understand
00:32:41
what's going on and we all know that we have in accuracies
00:32:45
sit sit twenty one activation basically which leads to racks to
00:32:50
ross activation and two activation of so many channels
00:32:54
and this should also may need to tighten side uh come see release and cast based not activation up poses
00:33:01
them is we we thought that the size class based eight maybe
00:33:05
the internal our product possibly might be relevant to understand
00:33:10
and then we checked for telecom screenplays and also cast baseline activation is you nice
00:33:15
this nicely see that in the animal siege don't have class based eight
00:33:20
just have a very strong and an over shootings had to come
00:33:23
see release indicating that this past they might be relevant
00:33:27
and you also see when you look for class basin eight nine
00:33:31
that lead cast baseline activation is strongly activities invited controls
00:33:36
but also in a in i call fact animals which don't have class pays eight
00:33:40
suggesting that income space a knockout animals this possibly is is activated
00:33:46
and it's very interesting that besides having discussed it's nine
00:33:51
you have no impact on past ways which are which are which
00:33:55
are related to make proposes should don't have inactivation offered three
00:33:59
and you don't have an activation of force for mikhail indicating that have space activation important
00:34:06
but it appeared have space eight or b. r. ross and cast based mind relevant in this model
00:34:13
therefore we think that our whole acts in a puddle side
00:34:17
we had two different possibly the extrinsic pass way which is
00:34:24
relevant in the situation of information been cast pastry
00:34:30
i mean you don't have class pays eight just let this second pass
00:34:32
fate has space really the testing that up in akron activity
00:34:45
or like to summarise the fourth part i cast the eight and nine so
00:35:00
vision of what poses could pick isn't into a promising a target
00:35:05
and the situation because they need to be further it's so summarise i showed you today first of all
00:35:12
static factors here scene was it the main features very yeah commands yeah
00:35:23
and also full streams of important to think does that involved
00:35:27
the to discuss to love for ends infamous on at the end
00:35:32
terror injury rate is cast up close is yet to
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