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And Eugene the telling us. And that and
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I would like to talk about a novel
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hypothesis that would be somewhat
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controversial and probably take real
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credibility if I had any major interest
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might talk. Um but I I feel strongly
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strongly enough about the new
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hypothesis quickly the underwater
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presented. And that should be some fun.
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So I just quickly go with this that we
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already have heard much about what
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alzheimer's is most come from an
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dimensionless epidemic dogs a lifespan
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is already videos all eighty five forty
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fifty percent people showing symptoms
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of this disease that the mind how many
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have apology on the way. And the
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current trends are really just a better
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than nothing modestly temporary benefit
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from now if we look at the the the high
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quality of the disease we have plaques
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we have tangles we know that class come
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from the M like data peptide which
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system cleavage PPP by beating domestic
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suitcase tangles come from top protein
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especially has hyper fast probably
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state that was George glider back in
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the early eighties really first mid
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eighties prefers formulated the beta
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and what it purposes yes always get
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credit face but he called alzheimer's
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disease the commonest form of Emily
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doses. So you his English was a little
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off comments most common. But basically
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he he said that you know I'll send this
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is Emily doses of the brain and that
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the rest of topology including tangles
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just out of by am avoiding also
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addicted then is it already this cried
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the Emily data laptop. Um that that you
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two are so that techniques that that
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the the time I promise twenty one
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because of down syndrome patients under
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so much medium white. And agree by
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middle age and of course use right when
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we know there's plenty feedback
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abilities it was I promise twenty one
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we know of four different genes that
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cause also Simon says use in the
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eighties and nineties three of them
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yeah what because the protein recent
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one is known to have mutations that
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guarantee with book and it turns the
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onset of what a somewhat dominant early
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onset of it. And the majority of these
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mutations almost all of them
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increasingly she'll eat a forty two D
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data for they don't increase totally
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beta okay only one rotation dismiss
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mediation which was used in the most
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famous transedit most TG two thousand
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six increases will probably be the
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production by making. PPP more
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vulnerable to be the secretary which
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but the majority piece that ratio forty
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two to forty W important later in some
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iterations affect accommodations the
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people using its data down roses is
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here for the about those tangerine at
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me when I tell you that in like causes
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this disease. Um you for increases risk
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anywhere from three point seven to ten
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all depending on what you have one two
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copies and and one hypothesis however
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we ought works is that is about
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Clarence E bay to from the plan
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although main we so do other things. So
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this is easy to really that me propose
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apology for half time is is you having
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like data deposition do we now do
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begins decades before symptoms tangles
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on the brain of this right to the brain
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that's quite an apology. Um and or
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inflammation which probably is killing
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the majority of neurons and a full
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blown off time is a patient but one of
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the biggest questions over the last
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several decades since glider is not
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that you describe waiting on what is
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made of is does pay to like the
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position actually need to check
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formation and for a long time. And
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start to some extent today we have the
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people believing in with their protein
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those of believing tingles also
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oblivion either what is the
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relationship and the problem is when
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harm others I miss monies from a when
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the early onset FAD jeans imitations
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put to mines. They basically got clocks
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because some very informational the
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time was like to some memory
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impairment. But they didn't that
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angles. So this let's fuel to the fire
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to say family doesn't cost at angles
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and and and maybe in raging debate is a
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camel entertainers that matter. Um and
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so this this became a big question so
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we can add all that developed a system
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using human neurons make "'em" stem
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cells this is a paper from the end of
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last year in nature too much to Managua
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in my post office a controller with me
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people who do the work. And that's not
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good wasn't me my computer stuff okay
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alright so so basically this is
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basically three D cultures approach
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human arrives into back to in attempt
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to re capitulate house some is apology
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and await this more physiologically
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relevant in an mouse especially since
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we can simple apology some display what
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we did. So many different studies we
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taken stem cells whether they like yes
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cells or human embryonic stem cells
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expressing our Simon jeans improvement
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we culture. And uniquely peter in a
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float around intellect wait and you
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know see any technology. So my my
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colleagues and R unit you I can say
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well you know really their brains that
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made of what would you know the brain
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is gel brings better job it is just
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floating around the so what we did
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instead was pro the same human Erasmus
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themselves in jail. This is making
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channel and lo and behold we need of
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someone the float away into the liquid
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but the majority of it isn't a jealous
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tossed advocate into a bigger grammars
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and the plastic around the rocks and
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this was a big a step forward. So what
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we will be able to do is take human
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embryonic stem cells that you can buy
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commercially these original lines that
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would be needed and sold commercially
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misstates respective viral vectors to
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express EPP and a these no limitations
00:05:44
definitely magicians this is for the
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purpose of getting results to make a
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big so we want to have a situation
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where we have no runs growing in a dish
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in gel mimicking the brain radiators
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accumulating around these neurons in a
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job at least media. And then we have
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what we call a the the the the for
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speech in it it does drastically so so
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the encounter that then cost is where
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you have a little bit of gel and it's
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the another point one two point three
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millimetres where you can then recited
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chemistry in actually looks a plaques
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and tangles. And then you just model
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where you have a four millimetres of
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jail allows you to take that like a
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chunk of brain and biochemical process
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it into alliances fate data content top
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content itself. So we show you what we
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fall first of all this is just showing
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up like get this to go. Um a really
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image these neurons that are drawing in
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jail and then making connections
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therefore forming so kind of a limited
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number of neurons in and the jail let
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these neurons grow. And somewhere about
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six weeks of what we see is that this
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is confocal imaging and would you seen
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here partner to go listening here's a
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couple imaging with that are a lot the
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middle which is applied. So in this
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dish we're thrilled when do guys think
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came into my office we actually have to
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go up by in dish and you can see it
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here constantly image enthusiast is
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right through the the really culture.
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So the next question okay you know can
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we somehow block yeah what can we show
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proof of concept for drug hits and
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white in this is that if it is purpose
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we used yeah the taste modulators. So
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he's an academic secret ace inhibitors
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like really use the problem I have a
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secret ace inhibitors blocked the game
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is you could basically which of many
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other proteins and the member. And when
00:07:43
you think about how many proteins and a
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membrane get the domain shed even
00:07:48
behind the stuff. That's stuff has to
00:07:50
be removed you can look like you a
00:07:52
secret ace whip reasonableness reactive
00:07:54
protein in it as a starter so it's
00:07:56
hyperbole stops and so you can have a
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cell there for the protein stops at not
00:08:01
be removed and that's quite a lonely
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drive gamma sigma case inhibitor failed
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yeah basically takes modulators don't
00:08:08
pick that campus if we taste like it's
00:08:09
analogous in other subsidies like notch
00:08:12
is Alistair modulators it only hit
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eight PP then affect the length of the
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lady you make I told you earlier longer
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to social forms of a beta. And so these
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these compounds which we were fifteen
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years we published in first two
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thousand K and the size of a data may
00:08:29
have to get me sick days cleavage and
00:08:31
this is that the rumours we just
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published last year is a aside
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quantities modulators the original ones
00:08:36
work very excitable celebrate greater
00:08:39
candidates. So we did a quite a bit of
00:08:41
work we get and IH generic therapeutics
00:08:43
blueprint ranch really an age helps you
00:08:46
like a Farmer company would with CR
00:08:48
also developed a drug. And to get into
00:08:51
clinical trials and so I description
00:08:53
our GS sense is probably what that was
00:08:55
about and machine be thousand to what
00:08:58
we thought about this is just of the
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compound it's about to go into court
00:09:01
trials early next year is that in rats
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and mice related to that huge
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reductions yes that yeah plastic beta
00:09:09
even at a five or twenty twenty five
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but it's it's it's a very very
00:09:14
effective and lowering it forty to with
00:09:17
some that's only data forty but as
00:09:20
actually we hear no that's whatsoever
00:09:22
unlocked. So yeah I see this is that
00:09:25
again basically taste inhibitor we can
00:09:27
see you're blocking the pony analysis
00:09:29
not and that's probably one of the
00:09:30
things that led to really that trial or
00:09:34
whatever that they're spending these
00:09:36
cleavage events whereas the STSM what
00:09:38
working with here looking not even out
00:09:41
twenty five micron bowler we're really
00:09:43
doing nothing at all to not to just not
00:09:45
exactly decided all that if that the
00:09:48
really shouldn't covered epsilon sigma
00:09:50
taste some heavy because they B fifty
00:09:53
is you have one side you have to cut
00:09:54
that first and then you should back to
00:09:56
forty two or down to thirty seven and
00:09:58
discover these constant fifty the only
00:10:01
affect how much related should back by
00:10:04
if you see the start by tacking how
00:10:06
well the PP fit into the dark side
00:10:09
mostly security have Tennessee because
00:10:12
so we tried this and our cultures is
00:10:14
the MS so it's not a for like six weeks
00:10:17
into the culture basically case
00:10:19
inhibitors which also and files lower
00:10:21
class yeah basically conservatives
00:10:23
black slacks and you also see pretty
00:10:26
good blocking apply not quite as their
00:10:28
eyes these but the game secret case
00:10:29
modulator shown down here. I mean it's
00:10:33
just shows possible that now we also
00:10:35
saw now we sell that so we can really
00:10:37
see tangles right away problem we
00:10:39
waited about two more weeks this is not
00:10:41
eight or nine weeks into the cultures
00:10:43
sure enough we would be able to see
00:10:45
modified class I told us what you see
00:10:47
here appeal performance by by yeah and
00:10:50
I don't think anyone I've shown
00:10:52
including you know dynamo tolerance
00:10:55
that other people have said these these
00:10:56
appeal performance and a lot of other
00:10:59
data in the paper showed silver
00:11:00
staining in show the evidence of angles
00:11:02
and the neurons is really what what
00:11:04
what major really wanted was to show to
00:11:08
the limits of this just shows a variety
00:11:09
of them that one too so we can Inglis
00:11:11
but we get a two weeks after you start
00:11:14
to see plaques. So that was occluded
00:11:16
details of following the parts that
00:11:18
maybe the fax a leading to details. So
00:11:21
so was that okay well we could do that
00:11:28
too So so that that was everything what
00:11:32
you know why don't my get tangles when
00:11:34
you put in jeans Paul savages a close
00:11:36
family. And one of the reasons is for
00:11:38
repeat all in the brain human praying
00:11:41
this this is the ratio for repeat I'll
00:11:44
repeat any need for repeat are to make
00:11:46
candles another mountain range is very
00:11:48
little probably a turns out new
00:11:51
approach human runs into flip a touch
00:11:54
it is also very very little for repeat
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are but for some reason when you
00:11:58
program it really culture the ratio for
00:12:01
repeat all matches that of the bright
00:12:04
if you look at these other remark of
00:12:06
this is to D here three D culture here
00:12:09
in you can see from any number the
00:12:11
tomorrow's is an exponential increase
00:12:13
in expression. SLC seventeen S seven
00:12:15
into a even tile this much more highly
00:12:19
buy C D.'s never answered expressing
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normal markers a exponentially higher
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levels in three D culture change gel
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with that forming networks versus
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probably around it to D you know like
00:12:30
with culture. So we believe that this
00:12:32
is one of the reasons why receding
00:12:34
tables. So the big question was if we
00:12:36
block heavily production again using it
00:12:40
basically case again basically case
00:12:41
some papers can we also block candles
00:12:43
and sure enough to do this just shows
00:12:45
democracy comes to hear DMSL showing
00:12:48
PHF one as a plastic antiviral for
00:12:51
tables if you use basic because if you
00:12:53
lose or gamma steeplechase here is you
00:12:55
dramatically lower the amount of things
00:12:57
you see you can also see this sponge
00:12:59
possible tile it's a DMSL and now it's
00:13:03
was gone with PH one using those using
00:13:06
the babysitters and matter what use
00:13:09
again sigma over here you see a a
00:13:11
dramatic reduction of possible purses
00:13:13
DMSO so what that says then is that if
00:13:16
you block yeah way and way you also
00:13:19
block contains. So this we took as
00:13:21
proof of concept the tables follow yeah
00:13:24
away. And all censuses. So then the
00:13:27
attitudes of major who started running
00:13:29
my wow. Um say well time but if you're
00:13:34
saying like directly closest echoes
00:13:36
natural cascading was was really not a
00:13:38
cascade is remember that so called
00:13:40
party sadistic aspect of this does not
00:13:42
as dangerous as neurons in addition if
00:13:44
you ask the size of the market wheels
00:13:46
once and you getting tables directly
00:13:48
they say you should be able to do
00:13:49
something that allows additional before
00:13:52
family can still get no tanks. So
00:13:55
obviously we tried at kind is or we
00:13:57
could get responses what we participate
00:14:00
but that's not that's a good all that's
00:14:08
that's everytime industry or the other
00:14:10
way I recommend directories there okay
00:14:14
that's the okay but recap. okay which
00:14:29
is all work what a anyway So we use the
00:14:35
GSATVO had a call has camped while was
00:14:38
another when called that thirty one and
00:14:40
O is is disallowed massive amounts of
00:14:42
family yeah plaque situate in the dish
00:14:45
yeah we would read so no passport are
00:14:48
we so no change. So this says that in
00:14:51
also I was using the dish model that
00:14:55
tangles are induced by a lake in this
00:14:58
GSTV beta depending basically only just
00:15:00
be beta but at least this was one
00:15:02
example where you could block single
00:15:05
kind is have lots of family and that
00:15:07
translate that into tables and addition
00:15:10
by nature to get if you just one in
00:15:13
every I'm what happy with the paper.
00:15:15
Now another question that they didn't
00:15:17
ask this luckily but we've done since
00:15:19
then is okay forty five a getting
00:15:21
tangled validation runs. I've this this
00:15:23
function in their rhymes. And is very
00:15:25
wanna show you what we did so we're
00:15:27
able to look at calcium imaging this is
00:15:29
using GG can't sixes calcium indicator
00:15:33
what you see here in the first panel
00:15:35
it's how these neurons fire working
00:15:38
calcium imaging user control neurons
00:15:40
queries into the addition to see in the
00:15:42
fiery if only connections going to just
00:15:44
by when you look into the a timer sells
00:15:48
this is to be bits into the ditch you
00:15:49
can see the firing but a watch not
00:15:52
quite as much firing also seen
00:15:54
somebody's larceny about costumes
00:15:56
accumulating a ninety seven weeks
00:15:58
sounded just want to have class and of
00:16:01
some candles and passport are climbing
00:16:03
is seen very little five thirty this
00:16:05
demonstrates these neurons as the going
00:16:07
in the dash William white intent was
00:16:09
not very happy here to control airlines
00:16:12
which are far away. So this would say
00:16:16
that that is go is that in the idea you
00:16:21
know what processes we modified beyond
00:16:23
cascaded in this case it shows that
00:16:26
yes. I am waiting human neurons and the
00:16:29
directly that angels again the more
00:16:31
dysfunction based on calcium imaging.
00:16:33
But the table formation nineteen what
00:16:36
requires to use can it. So I think to
00:16:39
the my eyes in the menu my Collins eyes
00:16:41
are rubber all this kind of dress this
00:16:43
debate that there's family details and
00:16:46
human neurons as opposed to a mouse
00:16:49
family does lead details but of course
00:16:51
there are other ways to get tingles of
00:16:52
many like independent rules to get the
00:16:55
changes concussion dramatic brain
00:16:57
injury egos daemon I showed in a simple
00:17:01
question directly go to tangles don't
00:17:03
medium like actually stress models you
00:17:05
can directly get tangles Fonda temporal
00:17:07
about dimension mutations directly the
00:17:09
tendency don't have to have yeah away
00:17:12
but also and this is it looks like a
00:17:14
sim family induced talk this however
00:17:17
how about we can classify it definitely
00:17:20
dish basically. So sense not I mean it
00:17:23
was just a formal tangles that would do
00:17:25
the dramatic brain injury you can get
00:17:27
mixed apology so I think the questions
00:17:29
good dead you know you're from eating
00:17:30
person you have enough apology and you
00:17:32
also wrap around that class later on
00:17:34
some mimic psychology is a prototype
00:17:36
about dimension which support. So if I
00:17:40
hated that scores tangles and there
00:17:42
were dysfunction why do so many
00:17:44
clinical trials targeting the data fail
00:17:46
miserably and you know and we military
00:17:48
trials they were trying to block into
00:17:50
the production training sky spigot
00:17:52
other trials they were trying to clear
00:17:54
it data from the brain but I mean
00:17:56
apparently yeah right out and that all
00:17:58
these styles yeah so this is where I
00:18:00
need to turn into famous American
00:18:02
baseball player which some of you may
00:18:04
know Yogi bear sorry record of your
00:18:06
devour. That's good so so that's about
00:18:09
so you know you not only was a
00:18:10
legendary player manager may need to
00:18:12
say the word yeah he's from Boston but
00:18:16
he was it you just passed away just
00:18:17
this past year not thought but nobody
00:18:19
explains the whole family journey of
00:18:21
all fantasies better than you do their
00:18:23
use attracted source of very high that
00:18:25
often profound thoughts. And after the
00:18:28
filters I just showed you just product
00:18:30
but was appropriate nobody goes there
00:18:31
anymore product. So right away from
00:18:36
family and and in many companies you
00:18:38
know right away from our sinuses
00:18:40
altogether. But had another famous
00:18:42
quote which was you can observe a lot I
00:18:44
watch I so I know what that people
00:18:49
began to watch was when the sample like
00:18:51
acid and perform and that's where we
00:18:52
can look at data like this will you see
00:18:54
there's a fifteen year yeah between
00:18:56
when you start to see plaques and any
00:18:59
avoiding the brain versus when you
00:19:00
start to see dimension if you look at
00:19:02
the line basically you see that that
00:19:06
yeah family is is permanently here this
00:19:09
is when name's slackers is is someone's
00:19:11
already be basically you can we can
00:19:13
apply to what we do we will treat
00:19:15
patients here. We have Y drugs. That's
00:19:19
like having somebody we can justify
00:19:21
create here we just had an am I going
00:19:23
to a cardiologist justice system or
00:19:25
just take a look at or what you had to
00:19:27
do that fifteen twenty years before I
00:19:29
think that's what we'll learning now is
00:19:31
that yeah why does its job very early
00:19:33
on that's when you need okay so another
00:19:37
brit oh we make too many more mistakes
00:19:40
so you you know it was following in
00:19:43
this career the whole family story. so
00:19:47
I think batteries eighty So now what
00:19:51
we're seeing is that is that basically
00:19:53
you might hear more this from from from
00:19:55
from a line stock item are maybe a
00:20:00
couple trials that now where we're
00:20:02
going more toward using imaging
00:20:03
modalities family your imaging
00:20:06
protocols by rockers including looking
00:20:09
passport quartile in spite of who your
00:20:12
like this that's going to see early on
00:20:13
real somebody's on the way to D and
00:20:16
then treating it trying to treat it as
00:20:18
real estate is once we have to do
00:20:19
something with drug. But this data
00:20:21
secret ace inhibitor the game
00:20:23
executives modulator and into body like
00:20:26
by regions are doing the very early.
00:20:30
And I would add that you know just take
00:20:32
a like that when when someone has a
00:20:33
tumour filming even smallest level we
00:20:36
say they have cancer. We treat the case
00:20:39
if there are no symptoms with somebody
00:20:41
has some classification five and
00:20:45
therefore we say you have heart disease
00:20:46
research research really exercised I
00:20:48
stand if necessary do is you discuss
00:20:51
that photographs you say of purposes.
00:20:54
But it also I was diseases finding we
00:20:56
wait until somebody already has to
00:20:57
mention but in actuality if you look at
00:21:01
this is perhaps I mean they have a
00:21:03
sinus disease three dimension this is
00:21:05
just the silence age of a sinus
00:21:07
disease. We talk about preventing
00:21:09
alzheimer's is pretending that it's
00:21:11
only there when this dimension really
00:21:13
dimensions the final stage of this
00:21:15
disease and I think we need a paradigm
00:21:17
shift or secondary cancer and heart
00:21:19
disease even diabetes that this is a
00:21:21
disease before this dimension and we
00:21:24
that not just preventing the trillions
00:21:26
before this dimension. So we obviously
00:21:29
trials okay the secret ace inhibitors
00:21:31
we're working like them a secret is
00:21:33
smartly doesn't devices also doing
00:21:34
that. Um will is working as soon as a
00:21:37
map of taking about from biology and
00:21:39
another target whatever connectivity to
00:21:41
write about that. But all these trials
00:21:43
not targeting a data really so treating
00:21:45
at this pretty symptomatic one very
00:21:47
Miles usually stages of the disease
00:21:49
that and to a family yeah would argue
00:21:52
maybe even temples. So Yogi better the
00:21:54
future think what it used to be so I
00:21:57
hope a single story and I also have
00:22:01
much on that is what I wanted turned
00:22:04
out to a genetics not trying to hurry
00:22:07
along a little bit you know just sort
00:22:08
of we have enough time for for pretty.
00:22:11
Um could basically in one of the rescue
00:22:13
watson's a republic no we we found jean
00:22:15
Paul CD thirty three ideas or some
00:22:18
other genes a k-mart of case controlled
00:22:20
you want since I was yeah based. And
00:22:22
then many other genes schema so now we
00:22:25
have a whole slew of different genes
00:22:27
that come up come up or forced to
00:22:29
studies we we're we don't know what's
00:22:32
going on these genes I mean his life
00:22:35
back alley caused you ask don ward
00:22:38
awful science it was a dentist. really
00:22:42
I just ahead of and and yes once said
00:22:44
to me well you guys to at least too I
00:22:46
suspect you collecting baseball cards
00:22:47
just steps we gonna do with these jeans
00:22:49
you don't even know what they do. And
00:22:51
and you know like they're right because
00:22:53
GY simply disability points a finger to
00:22:56
a region in the genome it says
00:22:58
somewhere in there is something going
00:22:59
on. There might be that gene Vegas that
00:23:02
is closest to what like Eugene next or
00:23:04
you don't really know for certainly in
00:23:07
most cases almost nine yeah so you
00:23:09
don't have to mediation you don't have
00:23:11
to pathogenic there in the causes the
00:23:13
disease you just have knowledge that
00:23:15
that she batteries because you have
00:23:17
some comments that just been about four
00:23:19
hundred thousand years that showed us
00:23:21
association about what you need to do
00:23:24
then this whole genome sequencing what
00:23:26
some people to collect so so this will
00:23:28
be engaged in read the whole genome
00:23:29
sequencing. And fourteen hundred
00:23:31
eighteen members from four hundred
00:23:33
thirty seven families from the and then
00:23:35
each family simple. And the baby was
00:23:37
much more work time and money. She
00:23:39
seeing a processing that data in
00:23:41
general the data which is the real
00:23:43
bottleneck compatible of data exactly
00:23:46
you also did sixteen brains with you
00:23:49
levels of flat screen in so many cases
00:23:51
tangles but they had no dimension. I
00:23:54
that I did use also what made them
00:23:56
resilient. Um and I'll tell you the
00:23:59
answer according to talk to recycle
00:24:01
missus actually people later is that
00:24:03
they had no information at all these
00:24:05
sixteen brains back something was no
00:24:06
dimension there is no information. So
00:24:08
that it was a generated the data and
00:24:12
the goal was we find actual functional
00:24:14
various imitations that influence with
00:24:17
in these genes to came up and she wants
00:24:19
to be all be on by reputation. So this
00:24:22
is this is a is it a summary statistics
00:24:24
about phone genome sequencing this is
00:24:26
unpublished data in the NH families we
00:24:29
about forty six million cents forty six
00:24:33
me I I was involved with ritual
00:24:35
Huntington sweeper Jim this a lot with
00:24:37
back in the early eighties what we
00:24:39
found the first twelve sniffs in the
00:24:41
genome first what are we doing the same
00:24:44
thing you know really use thirty five
00:24:46
years later oh but that we get forty
00:24:48
six million we used to say only with
00:24:50
thirteen million variance across all of
00:24:51
humankind well no just and this
00:24:54
wonderful mister forty six million
00:24:56
years to be file. And one million
00:24:58
insertions deletions that remind other
00:25:01
copy number variance that we compare
00:25:03
this you can see so we did thirty six X
00:25:07
coverage you it you know T code
00:25:09
probably something you know sequencing
00:25:10
down alzheimer's data tenets coverage.
00:25:13
They are twenty million hits we part
00:25:15
forty six mail two possibilities one is
00:25:18
a nice when there are fewer variants.
00:25:21
Um yeah the possibilities that you
00:25:23
gotta to thirty six that covers the
00:25:24
text coverage is enough interestingly
00:25:26
in the ad dataset to we also processed
00:25:29
eight hundred samples we've got three
00:25:31
million periods. So then it could just
00:25:34
be a bit better coverage recognise
00:25:36
under if few insane here with a four
00:25:38
million so insertions deletions in
00:25:41
Iceland decode a file one point one
00:25:43
million so much fewer. So that the
00:25:45
question what to do with this data. So
00:25:47
the first thing we did you perform the
00:25:48
burden analysis. And so we were using
00:25:51
this this shows it a list of known
00:25:53
Angie last confronted teachings in the
00:25:55
are we're not really but the question
00:25:57
was do eighty genes contain more ED
00:26:02
associated mutations compared to a set
00:26:05
of control it's so the car control
00:26:07
jeans you have to fine ten genes the
00:26:11
same size as your it EG with the seeing
00:26:14
the combination. So you give them the
00:26:16
same chance to have limitations same
00:26:18
size in college. So actually these
00:26:20
these ideas of the control jeans used
00:26:22
issue the jeans matched to the east and
00:26:25
then the question was do multiple
00:26:27
rehabilitation cluster in single PD
00:26:30
patients and families as it jean burden
00:26:32
of red it it might be the cause. And we
00:26:35
did in our says I served there we this
00:26:39
is a little cumbersome but basically we
00:26:40
look at the XL we look that only
00:26:43
deleterious mutations predicted to
00:26:45
impact to function and then we'll but
00:26:47
that is not also function mutations
00:26:49
here. So so these two a subset of the
00:26:52
total Exxon very insecure. And fig
00:26:55
established what they do change we can
00:26:56
really see much in terms of association
00:26:58
usually D of bird right but that kinda
00:27:01
makes sense you know we have for the
00:27:02
energy mutations PPPS one I believe
00:27:05
boards almost possible dependent maybe
00:27:07
I'll say this for the energy in if you
00:27:09
live long enough right. Um but we could
00:27:11
see was it in the G must confront jeans
00:27:13
these are bad things. We see a
00:27:15
significant burden amounted you asking
00:27:17
to take some steps anymore you look at
00:27:20
the deleterious once we see in excess
00:27:23
burden of of of a family base
00:27:25
associated you got mediation in G last
00:27:28
and even just missing to give his point
00:27:30
O seven here lots of function mutations
00:27:32
that completely chill the G is a frame
00:27:34
shift subdivisions of the G so if you
00:27:38
don't ask by categories these regions
00:27:41
here of the teachings easily D jesus me
00:27:44
need Rolls that are so if you ask which
00:27:46
genes carry the most we're mutations
00:27:49
clusters in patients that were driving
00:27:52
those those those people values results
00:27:54
this is the lesson then right you can
00:27:57
see the jews in a profit in the
00:27:58
community in the community information
00:28:01
that category it's those jeans about
00:28:04
innate immunity information into the
00:28:06
most to burden somehow sentences. So
00:28:10
this gives importance of information.
00:28:12
So you to be up they did you say eighty
00:28:14
from previous slightly into those those
00:28:17
you suspect about a half hour G process
00:28:19
can angles you can see that is a
00:28:21
growing number of genes in the innate
00:28:23
immunity information box that one of
00:28:28
these is trying to this was that a
00:28:30
sliding down a couple years ago. And it
00:28:33
was founded this mutation are forty
00:28:34
seven each time to which one homicide
00:28:37
responses that's not so local disease
00:28:39
which is dimensionally pulses that head
00:28:42
was I guess the distant tuition confers
00:28:44
with the late onset ED that was usually
00:28:48
too original papers and wondering what
00:28:50
madison. And then the question is you
00:28:52
know is this replicated what is not
00:28:54
issue individual papers they claim that
00:28:56
trying to that mutation had the same
00:28:58
effect and risk as having in April
00:29:00
we've probably which is of course you
00:29:03
know very high to some physical thing
00:29:05
about almost four as an odds she'll. Um
00:29:08
and we also asked as trying to
00:29:09
associate with other religions agenda
00:29:11
sources that L the a less parkinson's
00:29:14
and experiences first of all by better
00:29:16
analysis is no doubt trying to
00:29:18
disassociate the this is just really
00:29:20
matter analysis system recently did
00:29:22
about right right. But you can also see
00:29:25
the final right ratios two point seven
00:29:26
so still pretty high enough for like
00:29:29
the original papers that but two point
00:29:31
seven would still places the second
00:29:32
highest a ratio among the answer this
00:29:35
product is after when we looked in
00:29:37
front of temporal about mentioned it
00:29:38
was one positive study. And that was
00:29:42
possible enough to work for you value
00:29:44
looks positive but the no all the
00:29:46
subsequent studies an negative. So you
00:29:48
have five mega studies one positive.
00:29:51
But analysis shows a somewhat
00:29:52
significantly so but really mild
00:29:54
evidence for slow something really
00:29:56
given it only wanna stick studies was
00:29:58
positive you know I mean not know as
00:30:00
strong association as with the the
00:30:03
environment for about a consensus in a
00:30:05
less no association and all the matter
00:30:07
analysis an egg. So there's a lot of
00:30:09
speculation trying to which a lot as a
00:30:11
as a as a less important since was back
00:30:14
to because men analysis quite big data
00:30:16
sets come up not so what is trying to
00:30:21
do in the disease. Most of us believe
00:30:23
that tram to keep Michael yourselves
00:30:25
clear why in stops them from becoming a
00:30:28
flame users think about microbial
00:30:30
oxidation state you get the more
00:30:32
beneficial back acidic side thing up
00:30:34
debris in retrofit you get the other
00:30:37
side of my quickly or the doctor or
00:30:39
mister Hyde where they should a few
00:30:41
articles and sighted persons that
00:30:44
that's for resident my probably but
00:30:46
other studies like people like ran
00:30:47
stuff off and and even re society by
00:30:50
Diego suggest that when you look at
00:30:52
infiltrating macrophages to come into
00:30:54
the brain and become a clear here looks
00:30:57
like trying to pass directly that the
00:31:00
they should later about class I don't
00:31:01
think so is it looks like the big
00:31:04
difference estimated travel choose
00:31:05
protective when you look at the man was
00:31:08
a like yourselves which use the
00:31:09
majority of what the the brain purses
00:31:12
multiply that come from infiltrating
00:31:13
macrophages so that's why it is a bit
00:31:16
of a debate about trying to this last
00:31:18
debate about CD really we see thirty
00:31:20
need to we describe you know away and
00:31:22
then in two thousand nine two thousand
00:31:24
eleven other write scripts which shown
00:31:27
in this G one at least not show to be
00:31:30
protective we had a paper in your on
00:31:33
last year or year and a half ago
00:31:35
showing that that protected step
00:31:37
insecurity we actually but less CD
00:31:41
thirty three in markedly also surface
00:31:43
in because that might yourselves
00:31:45
cleared eight data more better. So this
00:31:47
was the model that you have a markedly
00:31:49
also and and and normally it's clearing
00:31:52
X amount of emily. But when you have
00:31:55
this protective very like to
00:31:57
dramatically reduce the minus utility
00:31:59
in the self service. And you got much
00:32:01
better clearance a family so we should
00:32:04
culture systems clearance that season
00:32:05
also that was in that paper so not
00:32:08
gonna show those data again. But but
00:32:11
basically the idea was and it is it's
00:32:13
easy to read about what is fact acidic
00:32:16
state of like yeah versus the something
00:32:18
immaturity state. So the question was
00:32:20
you know can we should yeah so no
00:32:22
obvious data we ask how to
00:32:24
significantly affect information state
00:32:26
you know to show you want slide. And
00:32:28
that is that if I look at the
00:32:29
inflammatory my quickly on Mars we see
00:32:32
that that did not go to CD thirty three
00:32:36
that you see the the microbial
00:32:38
inflammatory markers and now going down
00:32:42
very subtracted Marcus go up to that
00:32:44
says that CD thirty three not only
00:32:46
regulates the clear activating and what
00:32:48
about the sectors says but it promote
00:32:51
the the expression of is Michael clear
00:32:54
markers associate with actors actresses
00:32:56
in protective rules about the and and
00:32:58
brings down significantly marketing
00:33:01
virus and I don't want beta signifies
00:33:03
more quickly exhausted and interrupt
00:33:05
limit or at least. And that makes sense
00:33:08
given this diagram but but when if I
00:33:10
was sitting in on the this state
00:33:11
security we basically takes them and
00:33:14
the fact acidic state. And make them
00:33:16
inflammatory so if you wanna keep
00:33:18
Michael real selves chilled out in the
00:33:20
brain to protect children see the brain
00:33:22
doesn't see a lot a tingling free dial
00:33:25
in but we ourselves and our meeting fee
00:33:28
radicals and cited tries not to be Nasa
00:33:30
sites you wanna not on CD ready three
00:33:32
Michael yourselves based on his down.
00:33:34
So and and again this is just the paper
00:33:38
I mentioned I highly recommend it by go
00:33:40
trees are comedies the showing that in
00:33:44
these brains very resilient assignments
00:33:46
is which is lots apartment angle but
00:33:48
these people dynasties no disease it's
00:33:50
lack of information that's the key. So
00:33:53
I just I use a preview probably data in
00:33:56
a halting sequencing is brains the
00:33:58
protective mutations that if I didn't
00:34:01
look yeah we started their fine about
00:34:03
you know that database systems. But you
00:34:05
can be so protective now limitations a
00:34:07
showed up and trying to so we think
00:34:10
that maybe strange looking CD thirty
00:34:12
three as well. But sometimes genes are
00:34:14
protected from information despite lots
00:34:16
of so that blacks contains. So this
00:34:19
would be like yeah then we're doing
00:34:21
drug screens now to try to block thirty
00:34:23
three as a way to keep what clear one
00:34:26
state despite apology. And then it was
00:34:29
you were working with David clothesline
00:34:30
about a cologne started trying to
00:34:32
define small molecules that er non tram
00:34:35
to so we you turn on them to what
00:34:38
turned out to be thirty three we should
00:34:41
keep quickly also some month back to
00:34:42
select and just a question is can you
00:34:45
do that so we got a recipe in the
00:34:47
immune system produces something or
00:34:48
doing whatever okay. So now I wanna and
00:34:52
with yeah where the hypothesis but like
00:34:56
I said if if if I think any credibility
00:34:59
and so far my talk all lost in the next
00:35:01
ten minutes. But but I wanna say recent
00:35:04
data it's in it I think it's intriguing
00:35:06
it's it's a french hypothesis but just
00:35:10
recently you might have heard that's
00:35:11
about a study power fungus. And also I
00:35:14
miss planes versus control brains. So
00:35:16
different factions so that's call this
00:35:19
yeah to make for the defence hypothesis
00:35:21
or just simply because the infection
00:35:23
hypothesis it consider question is it
00:35:25
possible that data and what is not just
00:35:28
john. But plays a role in the right
00:35:30
okay so I'm just first of all tell you
00:35:33
about entire microbial peptides in uni
00:35:36
immune system when you have an effect
00:35:39
before your adaptive immune system gets
00:35:40
its act together it makes him into body
00:35:42
to me members that you saw this before
00:35:45
or that you have to be ready by that
00:35:47
takes days properties yeah you would
00:35:49
die if you don't have any immune system
00:35:51
which is your first line of defence for
00:35:53
example about thirty seven is a in the
00:35:56
immune intimate probably have time this
00:35:59
thirty seven year S as long as I gets
00:36:02
the lot of about thirty seven don't
00:36:03
list has three is all you need any
00:36:06
who's recent world of difference
00:36:07
different it to my problem peptides
00:36:09
used by any new system your first line
00:36:11
of defence against infection. They like
00:36:14
bacteria envelope viruses like herpes
00:36:16
virus or simplex virus one different
00:36:19
fungus they can even affect transform
00:36:22
cancer cells typically get a mac
00:36:24
problem peptides twelve to fifteen
00:36:26
amino acids more maybe is about forty
00:36:29
minutes the right yeah that's it take
00:36:31
kind of popular so I maybe she
00:36:34
combination the data. And then you yeah
00:36:37
derived yeah but once a fountain of
00:36:39
history and like those sees that the
00:36:41
fairy and and some of best going away
00:36:43
and I million like in all cases these
00:36:45
into my program appetite by bacteria
00:36:48
like I mean I'm worried about. So it's
00:36:50
not too big a stretch to think about
00:36:52
another animal in the body beta Emily
00:36:55
as possible intellectual the repair. So
00:36:58
that in two thousand ten we had a grad
00:37:00
student did this work we publish this
00:37:02
impossible one we didn't think we get a
00:37:05
lot of attention but then you look a
00:37:07
lot of four hundred times story size
00:37:10
times about it that how that's writing
00:37:13
me sane rewire you pick up the paper
00:37:16
plus one and I said I didn't do it with
00:37:18
you know they they pick up on this one
00:37:20
but not longer possible but basically
00:37:23
what we found was that we tested data
00:37:26
forty to a data for up against L thirty
00:37:29
seven as control antenna so against a
00:37:32
hosted different other pathogens the
00:37:34
small the number here the more
00:37:36
effective the peptide is some fighting
00:37:38
that package. So you can see that it is
00:37:41
very very true for the most only desk
00:37:44
and the napkins east of pointers pretty
00:37:47
protective definitely co are against
00:37:49
Africa dramas and this just shows you
00:37:51
do you about that that's a penicillin
00:37:52
for those last here. So all this says
00:37:55
it compared to L thirty seven in this
00:37:57
paper using just straight microbiology
00:37:59
essays a beta is a pretty probably
00:38:02
endemic problem. Then what we did was
00:38:04
we took in Ukraine temporal cortex what
00:38:07
is lost a family versus cerebellum this
00:38:10
is not a D oops this is not a being
00:38:13
brain is is a union pink camper point X
00:38:16
and we could see that bring to market
00:38:18
is probably avoid actively kill see a
00:38:21
candid applications you just with the
00:38:24
cerebellum weather was not we avoid you
00:38:26
got no beneficial effect that if we
00:38:29
took an antibody in immediately to take
00:38:31
data from the I mean sample we sort of
00:38:33
lost a protective again suggesting. And
00:38:38
what I don't like time is the special
00:38:42
but then you it. So I am a very
00:38:46
wonderful development. Um so it that
00:38:50
combined with this almost done but a
00:38:52
combined with this paper that that
00:38:55
brain regions are affected from the
00:38:57
south sounds these from the party hi-fi
00:38:59
various Candice pieces I mean it it
00:39:01
brings suggest that perhaps this is
00:39:03
what they did is well this is beta is
00:39:05
to fight induction in the brain. So
00:39:08
wanna call this the effects of
00:39:09
hypothesis this is the summary of what
00:39:11
different studies that one paper press
00:39:14
revenues in their arms see elegance
00:39:17
just awful well might as well which
00:39:20
were infected with various focal
00:39:22
pathogens either used but salmonella in
00:39:25
each case when use organisms expressed
00:39:28
yeah like they're protected against
00:39:29
infection like that. But the way it
00:39:33
works is very simple a beta first
00:39:35
prevents decision to the sell then you
00:39:38
need to use and then it won't ever like
00:39:41
fibre track around at least this is not
00:39:44
new intimate probably peptides it might
00:39:47
estimate would have ties of already
00:39:48
known from you know nets like the fan
00:39:50
since around box this is one I let's
00:39:53
doing. So can we see direct reference
00:39:55
to this no I that so that's why I have
00:40:01
to show decide because just slide. I
00:40:03
have had my wife. I don't I don't I
00:40:06
don't have the slide a butterfly don't
00:40:09
want. I don't know it's almost almost
00:40:11
like this there very few slices work
00:40:13
two slides. But you gotta see this
00:40:15
because it's CD and I'm not sure what
00:40:18
is I will try and that's oh you so
00:40:28
cause that just shows quickly okay this
00:40:34
just shows that for a lot of different
00:40:35
project yeah what I was going to be
00:40:37
superstars once an hour et cetera that
00:40:40
this is how fast my probably five
00:40:42
works. But this is the coastline okay
00:40:44
so what we do here we took and half
00:40:46
time is most it's probably told by XF
00:40:49
eighty most probably so is mice have no
00:40:51
family. They don't get yeah but like to
00:40:53
about eight months old okay what you
00:40:56
see here this is a control models those
00:40:58
red dots Simon no we have read for
00:41:01
assisting salmonella rejecting starter
00:41:03
tactically internet campus is nice
00:41:05
Simon I would one a brain that most
00:41:07
eyes and about one day. But in what
00:41:09
present they last longer that special
00:41:11
last slide. Now takes out but I wanted
00:41:13
teach injected into now simon's mouse
00:41:18
you see nothing is no we have a wide we
00:41:20
is not some analysis he kills bacteria
00:41:22
as a control. But not take that for
00:41:24
people now so is no Emily at that age
00:41:27
again not to I want so we have we have
00:41:29
really enjoyed some allow you to read
00:41:32
we forty eight hours not somebody
00:41:34
whiplash. So I want to get a like the
00:41:39
mouse now not reject bacteria overnight
00:41:42
just about in a you look here. So it
00:41:45
was really that was once that green is
00:41:48
the plaque in happy that has one single
00:41:51
talk we just having to make probably
00:41:54
peptides were they for socks around
00:41:57
about so if your money away really fast
00:42:00
have just a little bit of bacteria or
00:42:01
yeast in your brain you don't need a
00:42:03
lot you don't need to have meningitis
00:42:06
encephalitis plus symptomatic infection
00:42:08
it's enough to have one but to get a
00:42:10
back and this that so this is a new
00:42:13
hypothesis this just shows that another
00:42:15
sort of this is a three D thing so the
00:42:17
upon some you know what this is the the
00:42:19
mechanism inside vision nation
00:42:22
entrapment that once the talk. And so
00:42:25
this would say then adjusted to have a
00:42:27
process that family can be seated but
00:42:30
pathogens rapidly and perhaps
00:42:32
sandwiches playing a role in meeting
00:42:34
new system using coincidental the
00:42:36
current information like a real cells
00:42:39
also stop family like build up
00:42:42
benefactor said okay. So that's the
00:42:44
status and with this slide me with age
00:42:48
as we have silent infection of clothing
00:42:50
the brain this computer how retarded
00:42:51
disease nasal bacteria but this bios
00:42:54
the speed even the UTI impure community
00:42:57
with a compromise but being barrier to
00:42:59
have something to a symptomatic we
00:43:02
actions that it I noticed this concert
00:43:04
rapidly babysitting inflammation
00:43:07
Michael Leo that was that was a is dire
00:43:10
if you believe also sense the days
00:43:12
access family this detailed information
00:43:13
is writing about this function why no
00:43:16
information is some other package
00:43:17
insert a can is based on the literature
00:43:19
the minimum only I could be superstars
00:43:22
one HHP six to implement. So and just
00:43:27
to show what they can do was a siamese
00:43:29
teens we found using insertions
00:43:30
deletions well adaptive immunity G so
00:43:33
maybe you can adaptive immunity. But
00:43:35
being compromised idea levels contrary
00:43:37
to this as all these conclusions. And
00:43:41
we'll give her sitting over till it's

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Conference Program

Introduction to the 12th Nestlé International Nutrition Symposium
Thomas Beck, NRC Director
22 Oct. 2015 · 8:57 a.m.
418 views
Introduction to Session I - Cognitive & Brain Development
Susan Gasser, Friedrich Miescher Institute, Basel, Switzerland
22 Oct. 2015 · 9:04 a.m.
The development of a healthy brain
Michael Gazzaniga, University of California, Santa Barbara, USA
22 Oct. 2015 · 9:16 a.m.
221 views
Q&A - The development of a healthy brain
Michael Gazzaniga, University of California, Santa Barbara, USA
22 Oct. 2015 · 9:56 a.m.
Early influences on brain development and epigenetics
Stephen G. Matthews, University of Toronto, Canada
22 Oct. 2015 · 10:49 a.m.
Q&A - Early influences on brain development and epigenetics
Stephen G. Matthews, University of Toronto, Canada
22 Oct. 2015 · 11:29 a.m.
Building the physiology of thought
Rebecca Saxe, Massachusetts Institute of Technology, Cambridge, USA
22 Oct. 2015 · 11:38 a.m.
154 views
Q&A - Building the physiology of thought
Rebecca Saxe, Massachusetts Institute of Technology, Cambridge, USA
22 Oct. 2015 · 12:10 p.m.
Introduction to Session II - Cognitive Decline
Kathinka Evers
22 Oct. 2015 · 2:02 p.m.
Brain health & brain diseases - future perspectives
Richard Frackowiak, CHUV University Hospital, Lausanne, Switzerland
22 Oct. 2015 · 2:11 p.m.
Alzheimer's disease: genome-wide clues for novel therapies
Rudolph E. Tanzi, Massachusetts General Hospital, Charlestown, USA
22 Oct. 2015 · 3:15 p.m.
Q&A - Alzheimer's disease: genome-wide clues for novel therapies
Rudolph E. Tanzi, Massachusetts General Hospital, Charlestown, USA
22 Oct. 2015 · 3:59 p.m.
Immunometabolic regulators of age-related inflammation
Vishwa D. Dixit, Yale School of Medicine, New Haven, USA
22 Oct. 2015 · 4:21 p.m.
Q&A - Immunometabolic regulators of age-related inflammation
Vishwa D. Dixit, Yale School of Medicine, New Haven, USA
22 Oct. 2015 · 4:59 p.m.
Introduction to Session III - Nutrition & Cognitive Development
Pierre Magistretti, KAUST, Thuwal, Saudi Arabia and EPFL, Lausanne, Switzerland
23 Oct. 2015 · 9 a.m.
Energy metabolism in long-term memory formation and enhancement
Cristina M. Alberini, The Center for Neural Science, New York University, USA
23 Oct. 2015 · 9:16 a.m.
129 views
Q&A - Energy metabolism in long-term memory formation and enhancement
Cristina M. Alberini, The Center for Neural Science, New York University, USA
23 Oct. 2015 · 9:53 a.m.
Building the costly human brain: implications for the evolution of slow childhood growth and the origins of diabetes
Christopher Kuzawa, Northwestern University, Evanston, USA
23 Oct. 2015 · 10:29 a.m.
Q&A - Building the costly human brain: implications for the evolution of slow childhood growth and the origins of diabetes
Christopher Kuzawa, Northwestern University, Evanston, USA
23 Oct. 2015 · 10:57 a.m.
Nutrition, growth and the developing brain
Prof. Maureen Black, University of Maryland, School of Medicine, Baltimore, USA
23 Oct. 2015 · 11:09 a.m.
Q&A - Nutrition, growth and the developing brain
Prof. Maureen Black, University of Maryland, School of Medicine, Baltimore, USA
23 Oct. 2015 · 11:49 a.m.
Introduction to Session IV - Decline & Nutritional Intervention
Tamas Bartfai, The Scripps Research Institute, La Jolla, USA
23 Oct. 2015 · 12:48 p.m.
On multi-domain approaches for prevention trials
Miia Kivipelto, Karolinska Institutet, Stockholm, Sweden
23 Oct. 2015 · 1:04 p.m.
Q&A - On multi-domain approaches for prevention trials
Miia Kivipelto, MD, PhD, Karolinska Institutet
23 Oct. 2015 · 1:39 p.m.
Methodological challenges in Alzheimer clinical development
Lon S. Schneider, Keck School of Medicine of USC, Los Angeles, USA
23 Oct. 2015 · 1:49 p.m.
Q&A - Methodological challenges in Alzheimer clinical development
Lon S. Schneider, Keck School of Medicine of USC, Los Angeles, USA
23 Oct. 2015 · 2:32 p.m.
We are what we remember: memory and age related memory disorders
Eric R. Kandel, Columbia University, New York, USA
23 Oct. 2015 · 3:03 p.m.
138 views
Concluding Remarks
Stefan Catsicas, Chief Technology Officer, Nestlé SA
23 Oct. 2015 · 3:50 p.m.

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