do you know what the words island aisle and aisle have in common it's the silent
s this is Susan Brodar from SPEAK Languages & TRAVEL the World here to
help you improve your English with minimum effort a maximum benefit and
today I'd like to talk to you about the silent s because a lot of my students
when they were read the word is la nd they pronounce the S but there are a
couple of words in English where the S isn't pronounced and so Island is one of
them the island where Robinson Crusoe used to live then there is also Isle as
in the British Isles which is a group are usually of islands and then there is
Isle a I SL II which is a narrow corridor between two rows of seats or a
series of rows of seats such as in a church or in a in an airplane that's the
aisle in all three of these words Island Isle and Isle the S is not pronounced so
that's something very important you mustn't pronounce the S also any words
of French origin such as boudoir which ends in an S or a prop or which also
ends in an S none of these words should have the s pronounced so that's very
important please don't pronounce this and remember it's a silent s there
aren't many words but the S should not be pronounced in any of these words you
might have noticed that I've tried to change the video quality and I'm trying
to improve therefore I'd really appreciate it if in the comments box
below you could leave your opinion on it and tell me if you find it's better than
it was before that's all then I hope you found this information useful and please
remember to subscribe I
For more infomation >> Can You Pronounce "Island"? The Silent S - Duration: 2:10.-------------------------------------------
Can Demarcus Cousins Boogie With Anthony Davis And Make An Underdog Title Run - Duration: 7:21.
Little moonlight don't
Land on the baby hey
Anyway anyway, so
Alright so Anthony Davis Marcos cousins two best bigs in the league
Man if Wallace messes this up right if they don't find a way to make this work
Wow what an opportunity to be squandered all right you have
two superstars on your team right if you let what cuz different rumors about letting one of them walk if
You let one of them walk, and you don't get a superstar in return
this this
It's a tragedy. It's a tragedy, but any was against this video really quick. I heard boogie went off. I wanna see the game and
Ha
Boogie be working boogie stuff, bro
Boogie stuff he got a little attitude problem, but he's tough man, and they could both pass they're very versatile pigs
It's not like fair the you know traditional
low post
Only bigs they can stress the floor they could dribble both of them can dribble they can shoot threes
They're great rebounders. They're both physical. It's almost like
They should be able to win more game. They should be better than what they are
In my opinion, I know having two bigs isn't necessary
For this brand of basketball is not necessarily the zeitgeist of this error you
Got you got to figure it out
Because this is that's just so much talent
That's like having Tim Duncan and Shaq on the same team in the early 2000s and not being able to win basketball games
You guys gotta figure it out. See what you have to or if not
Shoot, I don't even know cuz I would argue that boogie and Anthony Davis there. There are two top-10 players in my opinion
Didn't you figure it out man? Yeah? I'm saying lately see that like boogie could play the point okay. He could play the point
Are you working like he's working broke his eyes up, bro
Up
man oh
You know David I mean Davis be hurt, that's one thing it just be hurt that
boy fragile
We'll get it on I was crazy. Yeah. It was nuts they just need it well. Julie's a straight point guard
He's just not like that dynamic. He doesn't shoot that well
But shoot, man, I don't know I
I
Understand we have a weak bench. They have outside of boogie
And Anthony Davis injure Allah late they pretty much trash
They pretty much trash. He's gone all the points but
Sheesh, man. I don't know
You're gonna have to figure this out if not, I I would trade I don't know I
Feel like boogie won't want to leave again I
Feel like if anybody leaves, or would walk I feel like it'll be anything at Dave's even though
Boogie has a more erratic personality. I do think antique dealers to be the first one to walk I
feel like boogies loyal
well anyway
That's just a knockdown jump right there. He could do it all mid post low post take you off with Jewish crew three step back
Dishing and timing everything bro. Well. You could do all 8002 could do it all could do it all
Turnaround fader yes sir off on foot dirt. What's good, bro. That's really good
That's really good would it broke?
Dad and one bro stop hacking
I'm right here. Yes, I hustle I hustle
All your shot yes, I do this oh
Yeah in the lane razzle-dazzle pittypat pittypat
Bookie really be working
He working
blue collar
blue collar and he's seen the oh
Look he's dicey up
Boogie's nice
Boogies nice bro ad is nice too. I
like boogies game better
Ad was proud Ricky we could probably say a DS better, but I just like boogies game
I just like everything about believe for some reason hey
You be working bro he be working
With this Dutta come here
Yes, sir, oh
my god
Yo this team is a nightmare
Imagine a
picture of Steve Nash being born ten years later and him being in the middle of this and then just put D'Antoni in there a
Championship team nobody's beating them nobody put Nash in the middle of this
You put Dan Tony as the coach nobody's meeting this team ever they were winning. I don't know how many championships
Man sheesh, man, New Orleans man they got to do better than this
Man, but um I mean, what do you guys think what what?
What's the what's the prognosis for the pelicans at this point I mean you got 80 you got cousins
Where do they go from here because I don't know I don't have the answer
You know then maybe one of you guys could figure it out for me, but anyway
This is a quick little video that I wanted to do just want to see this game really quick
And yeah i'ma not just you guys next time. It's your boy JD. I'm checking out peace
That was gay. Whoa that was pause my foot boss John Paul is stuck my tongue out like
You
-------------------------------------------
Alcohol in the sky - when and how much can we drink? And where for free? AeroVlog [ENG+SUBS] - Duration: 3:26.
Many of us, in order to relax a bit before flight, like to have a sip or two of our favourite
spirit.
But before we decide to drink alcohol during our journey, it is good to know some facts
about availability and consumption of alcoholic beverages on board of aeroplanes.
That will be the topic of today's episode.
Enjoy :)
Majority of airlines do permit to bring own alcohol on board and consume it.
However, sometimes, some restrictions apply.
For instance, companies like Air New Zealand or Lufthansa do not allow their passengers
to take more than 5 litres of alcohol per person and it can never be more than 70% volume.
So pure spirit will always be rejected.
Also, there exist some carriers that do allow to drink alcohol during the flight, but under
the condition that it was bought via on-board sale.
Here a good examples are well-known European low-cost airlines like Ryanair or Wizz Air.
Good news is that still multiple airlines offer alcohol free of charge to its passengers
on all flights.
For instance, if we travel with Air France, even on shorter routes, then we can enjoy
free bottle of true French wine, or maybe more if we wink a bit to stewardesses.
And when we are on board Ethiopian Airlines' plane,
then we can choose from wide selection of local beers.
And if it comes to Emirates or Etihad Airways, passengers can enjoy free whisky, wines or
even cognacs from on-board menu.
Unfortunately, we need to be prepared also that some airlines do not allow
to drink even a single drop of alcohol.
Officially, the national carrier of the Islamic Republic of Iran, Iran Air prohibits both
consumption and sale of alcohol on board its planes.
It is similar with some Aeroflot flights.
Wait, it's Russia...
but including those from Moscow to Havana, Bangkok
or Shanghai.
Russian Airlines introduced a ban on drinking due to some acts of violence that were occurring
on mentioned flights and were provoked by passengers that were intoxicated with alcohol.
Finally, some air carriers permit to drink spirits, but just in specific time.
For example, when we are flying on Aeromexico, we would legally drink after 11 am.
Of course all questions concerning sale, consumption or even carriage of alcohol are regulated
by airlines themselves.
If then we are not sure how much we can drink, simply visit airlines' website and consult
conditions of carriage or our tariff rules.
Because why resign from a small dose of pleasure that is our favourite beverage?
Cheers :)
Thank you for watching today's episode.
I hope that I've presented you in a simple and interesting way some facts about drinking alcohol in a plane.
If you liked a video, please leave a like down below, a comment
and subscribe to our channel for more aviation-related content.
Take care and fly high!
-------------------------------------------
How can you illustrate the expansion of space from the absolute beginning of the universe? - Duration: 4:19.
Ankerberg: And you've got an illustration in terms of using a balloon that describes
this.
Craig: It's very important not to misunderstand this model.
It's much more radical than the layman normally thinks.
The model does not describe the expansion of our material universe into a preexisting
empty space.
The model is much more radical than that.
Rather, what the model describes is the expansion of space itself.
And to get an idea of this, we can think of a balloon with buttons glued on the surface
of the balloon.
Now, the buttons are stationary with respect to the surface of the balloon.
They're stuck in place.
But as the balloon blows up, the buttons get further and further and further apart because
the balloon itself is expanding.
Now, the surface of the balloon is just like our three-dimensional space.
The galaxies are actually at rest in space, but they move away from each other because
space itself is expanding.
And the radical implication of this is that, as you trace the expansion back in time, the
galaxies get closer and closer and closer together until finally everything is contracted
down to a single point before which the universe literally did not exist.
So this is an absolute origin of space, time, matter and energy in the big bang event.
This prediction of an absolute beginning of the universe has now stood for almost 100
years through the most tumultuous and incredible period of advance in both theoretical and
experimental physics.
In fact, in the year 2003, three leading cosmologists, Arvind Borde, Alexander Vilenkin and Alan
Guth, showed that any universe which is on average in a state of cosmic expansion cannot
be eternal in the past but must have an absolute beginning at some time in the finite past.
According to the Borde-Guth-Vilenkin theorem, classical space-time cannot be extended to
past infinity but must terminate in a boundary.
If that boundary was the beginning of the universe, then the universe began to exist.
If there was something on the other side of that boundary described by a yet to be discovered
theory of everything, then, Vilenkin says, that is the beginning of the universe.
What you cannot have is a universe that exists for infinite past time.
So Vilenkin is very forthright about the implications.
This is what he says: "It is said that an argument is what convinces a reasonable man,
and a proof is what it takes to convince even an unreasonable man.
With the proof now in place, cosmologists can no longer hide behind the possibility
of a past eternal universe.
There is no escape; they have to face the problem of a comic beginning."
Ankerberg: Yes.
What you're saying is, the layperson hears all of the different theories that are proposed
to defeat what they're saying.
But for a hundred years it's stood, and the very defeat of all of these proposals
show that the universe had a beginning.
Craig: That's exactly right the history of 20th century cosmology can in a way be
seen as a parade of failed theories trying to avoid the absolute beginning of the universe.
Steady State Models, Vacuum Fluctuation Models, Oscillating Models, String Models.
Over and over again theorists have tried to avoid the absolute beginning, and none of
these attempts has proved itself more plausible in the minds of the scientific community than
models with a beginning.
-------------------------------------------
Great News - You Can't Fool Portia (Episode Highlight) - Duration: 2:40.
For more infomation >> Great News - You Can't Fool Portia (Episode Highlight) - Duration: 2:40. -------------------------------------------
Systemic immunity protects the mind: Can immune checkpoint blockade combat Alzheimer's disease? - Duration: 1:00:13.
>> GOOD AFTERNOON
I'M DANIEL REICH
IT'S MY HONOR TO INTRODUCE
TODAY'S WALS SPEAKER.
THIS TALK IS JOINTLY ORGANIZED
WITH THE INFLAMMATORY DISEASES
INTEREST GROUP SO IF YOU WILL
INDULGE ME FOR A MOMENT I WANT
TO TELL BUT THAT.
THIS GROUP WAS ESTABLISHED IN
2015 FOLLOWING THE INTRAMURAL
PROGRAM'S LONG TERM PLANNING
PROCESS TO TRY TO BRING TOGETHER
THE LARGE NUMBER OF LABOS CAMP
US THAT STUDY INFLAMMATION AS A
UNIFYING THEME IN DISEASE.
IT CURRENTLY HAS SUPPORT FROM
SEVEN ICs AS WELL AS THE
DEPUTY DIRECTOR FOR INTRAMURAL
RESEARCH.
MOSTLY IT'S A SPEAKER SERIES BUT
HAS A STEERING COMMITTEE FROM
MULTIPLE ICs AND THERE IS A
LIST SERVE.
SO IF ANY OF YOU WANT
INFORMATION ABOUT THE TALKS THAT
ARE BEING ORGANIZED, PLEASE SIGN
UP ON THE LIST.NIH.GOV WEBSITE.
THIS IS OUR LINE UP FOR THE REST
OF THE 2017-2018 SEASON.
WE HAVE A LOT OF GREAT SPEAKERS
AS YOU CAN SEE, BOTH FROM NIH
AND FROM AROUND THE COUNTRY AND
AS YOU'LL SEE TODAY, FROM AROUND
THE WORLD AS WELL AND WE HAVE
ALREADY STARTED PLANNING NEXT
YEAR'S SEASON AS WELL.
JUST A REMINDER THAT THIS IS THE
MIDDLE TALK OF THREE SOMEWHAT
RELATED FORETUE TUS TALKS TODAY.
THERE WILL BE AN IIG SEMINAR AT
4:15 IN LIPSETT.
DAN IS SPEAKING THERE.
AND AS WELL RIGHT AFTER THIS
TALK, THERE WILL BE A RECEPTION
IN THE LIBRARY.
SO, ON TO PROFESSOR SCHWARTZ WHO
STUDIED CHEMISTRY AT THE HEBREW
UNIVERSITY OF JERUSALEM AND WENT
ON TO DO HER GRADUATE STUDIES
UNDER MICHAEL SELAH AND MOSES AT
THE INSTITUTE.
AFTER A POSTDOC AT THE
UNIVERSITY OF MICHIGAN, SHE
RETURNED WHERE SHE HAS BEEN
SINCE 1987.
A PROFESSOR OF IN OR ABOUTO
IMMUNOLOGY.
OVER THE YEARS, SHE HAS WON
NUMEROUS AWARDS FOR HER WORK IN
OPTHALMOLOGY, SPINAL CORD
INJURY, NEUROSCIENCE,
NEUROIMMUNOLOGY, INCLUDING 2015
LUMBERING PRIZE FOR EXCELLENCE
IN MEDICAL RESEARCH IN THE 2017
RAPOPORT PRIZE FOR EXCELLENCE IN
BIOMEDICAL RESEARCH.
SHE IS IS THE PRESIDENT OF THE
INTERNATIONAL SOCIETY OF
NEUROIMMUNOLOGY AND HER OWN
SCIENTIFIC JOURNEY AND IDEAS ARE
SUMMARIZED IN HER 2016 BOOK,
NEUROIMMUNITY.
PROFESSOR SCHWARTZ IS ONE OF
THOSE PEOPLE WHO LOOKS AT THINGS
DIFFERENTLY FROM THE WAY OTHER
PEOPLE DO AND OF COURSE THAT IS
THE BEST WAY TO DO SCIENCE.
HER WORK HAS LONG BEEN FOCUSED
ON THE INTERFACE BETWEEN THE
BRAIN AND THE IMMUNE SYSTEM AS
WELL AS NORMAL AGING.
AND THAT WORK HAS REALLY SHIFTED
THE PARADIGM IN THIS SPACE.
IN A SERIES OF GROUNDBREAKING
STUDIES, SHE AND HER TEAM SHOWED
THAT BOTH THE ADAPTIVE AND THE
INNATE ARMS OF THE IMMUNE SYSTEM
CAN CONTRIBUTE NOT ONLY TO
DISEASE PATHOGENESIS, BUT ALSO
CRUCIALLY TO REPAIR PLASTICITY,
A CONCEPT SHE CALLED PROTECTIVE
AUTO IMMUNITY I.
AS PART OF THIS WORK, SHE
RECENTLY DEMONSTRATED THAT THE
GATEWAY FOR THE IMMUNE SYSTEM TO
INTERACT WITH THE BRAIN IS NOT
THE MEN IN GEES AS COMMONLY
THOUGHT BUT RATHER THE HIS PEE
PLEXUS DEEP WITHIN THE
VENTRICULAR SYSTEM OF THE BRAIN
AND THAT DYSFUNCTION OF THIS
GATEWAY PLAYS A MAJOR ROLE IN
ALZHEIMER'S AND IT'S THIS WORK
THAT IS THE TOPIC OF HER TALK
TODAY SISS STEMMATIC IMMUNITY
PROTECTS THE MIND.
SO WELCOME PROFESSOR SCHWARTZ.
[ APPLAUSE ]
>> THANK YOU FOR THE
INTRODUCTION.
--
[ LOW AUDIO ]
WHAT I'M GOING TO DOE FOR YOU IS
SUMMARIZE BRIEFLY 20 YEARS OF
WORKING WHICH WE CALL PARADIGM
SHIFT AND DEVOTE BIG PART OF MY
TALK TO ISSUE OF IMMUNE SYSTEM
BY IMMUNE CHECKPOINT BLOCKADE
CAN COMBAT ALZHEIMER'S DISEASE.
SO FOR THE LAST 20 YEARS HAD
RELATIONSHIP BETWEEN THE BRAIN
AND THE IMMUNE SYSTEM AND THIS
WAS SUMMARIZED -- WHERE IS THE
POINTER?
SO THIS WAS SUMMARIZED LATELY IN
AN ARTICLE, WHICH WE ASKED, CAN
IMMUNE THERAPY TREATMENT OR
DEGENERATIVE DISEASES SUPPORT
THE TRANSIENT BOOSTING ADAPTIVE
IMMUNITY CAN FIGHT ADVANCD
ALZHEIMER'S?
SO WE KNOW THAT ALMOST ALL
NEURODEGENERATED CONDITIONS,
WHETHER THERE IS ACUTE INJURY,
BRAIN OR SPINAL CORD OR MORE
DEGENERATED DISEASES,
ALZHEIMER'S, PARKINSON, ALS, ANY
DEPRESSION OR JUST AGING
DEMENTIA, THERE IS LOCAL
INFLAMMATION.
FOR DECADES IT WAS BELIEVED THAT
IT IS VERY MUCH SIMILAR TO THE
INFLAMMATION THAT WE SEE IN
MULTIPLE SCLEROSIS AND THEREFORE
ATTEMPTS HAVE BEEN MADE TO FIGHT
AGAINST THIS LOCAL NEW
INFLAMMATION WITH
ANTI-INFLAMMATORY DRUGS.
IN 20008 THERE WAS A HUGE
CLINICAL TRIAL USING NON
STEROIDAL ANTI-INFLAMMATORY DRUG
IN ALZHEIMER'S WHICH FAILED AND
THE QUESTION WAS, WHAT HAVE WE
MISSED?
ACCORDING TO OUR UNDERSTANDING,
THE BRAIN IS NOT --
[ LOW AUDIO ]
WE HAND IT NEURODEGENERATED
DISEASE INVOLVES NOT ONLY THE
BRAIN BUT ALSO DYSFUNCTION OF
SYSTEMIC IMMUNE SYSTEM AND WE
HAVE TO BE CAPER TO DISTINGUISH
BETWEEN THIS NEURODEGENERATED
DISEASE AND NEW INFLAMMATION
ASSOCIATED WITH AUTOIMMUNE
DISEASE.
SO WE KNOW THE --
[ INAUDIBLE ]
MAJOR ROLE IS TO RECOGNIZE AND
DESTROY MICROORGANISM AND
MALIGNANCY.
IT WAS BELIEVED FOR DECADES THAT
THEY KNEW THE BRAIN ESCAPE
IMMUNE SURVEILLANCE.
THIS WAS BASED MAINLY -- BLOOD
BRAIN BARRIER -- COVERED BY
BLOOD BRAIN BARRIER BASICALLY --
[ LOW AUDIO ]
DEFINITELY BLOOD BRAIN BARRIER
SHOULD BE SEEN UNDER ALL
CIRCUMSTANCES.
--
[ LOW AUDIO ]
NOW WE KNOW ALSO WITHIN THE
BRAIN THERE ARE RESIDENT CELLS,
THE MICROGLIA.
FOR YEARS IF YOU OPEN ANY TEXT
BOOK OF ANY PAPER FOR 10 OR EVEN
5 YEARS AGO, YOU WOULD SEE THERE
IS INFLAMMATION MICROGLIAL FLESH
INFILTRATING MICROPHAGES.
WE KNOW THE MICROGLIA HAVE NOT
IDENTIFIED TO MACROPHAGES,
MICROGLIA, THE ONLY RESIDENT IS
IN THE BRAIN.
-- SLOW PROLIFERATION AND
MACROPHAGES DON'T REPLACE
MICROGLIA.
BUT IT IS VERY IMPORTANT TO NOTE
MICROGLIA, THE BRAIN CELLS
NEVERTHELESS THEY ARE UNDER
TIGHT CONTROL TO ENSURE THAT
THEY -- ACTIVITY WITHOUT
ENDANGERING ANY NEIGHBORING
CELLS AND THEREFORE THEY ARE
CONTROLLED BY THE MILIEU OF THE
CNS, WHICH IS ENRICHED WITH
TGF-BETA AND THERE IS ALSO VERY
TIGHT CELL SETTING INTRODUCTION,
THE MICROGLIAL EXPRESS RECEPTORS
AND WHICH VERY MUCH SUPPRESSED
BY THE LIGAND WHICH IS EXPRESSED
BY NEURON AND THERE IS ALSO --
SO OVER ALL MICROGLIA HAVE TIGHT
CONTROL WHICH ENSURE TIGHT
ACTIVITY BUT UNDER VERY STRICT
REGULATION.
SO SPECIFICALLY, WHAT WAS
BELIEVED FOR MANY YEARS THAT THE
BRAIN DOES NOT REQUIRE
CIRCULATING IMMUNE CELLS.
IT RELIES ONLY ON THE MYELOID
CELLS.
IT WAS BELIEVED THAT MICROGLIA
AND INFILTRATING CELLS ARE
REDUNDANT CELLS.
WE KNOW NOW THEY ARE NOT.
IMMUNE CELLS ENTRY THE CNS WAS
BELIEVED FOR DEC DECADES THAT IT
IS ONLY PATHOLOGY AND IT IS BAD.
WE WILL DISCUSS THAT'S NOT THE
SITUATION.
AND WE KNOW NOW THAT ENTRIFUL
IMMUNE CELLS FROM THE
CIRCULATION REQUIRE BREAKDOWN OF
THE BLOOD BRAIN BARRIER WHICH
WAS COMMONLY BELIEVED.
SO WHAT I'M GOING TO SHOW YOU
TODAY, VERY BRIEFLY THE PAST AND
MAINLY TO THE PRESENT.
SO IN 1998-1999, WE SHOWED FOR
THE FIRST TIME T-CELL AND
MACROPHAGES SUPPORT REPAIR.
WE FOUND THAT T-CELLS SUPPORT
NORMAL BRAIN PLASTICITY AND
EXCLUDED FROM THE BRAIN AND
SINCE 2017 WHERE WE DISCOVERED
THE PLEXUS SUPPORT ENTRY OF
IMMUNE CELLS TO CNS WITHOUT THE
NEED FOR BREACHING OF THE BLOOD
BRAIN BARRIER AND THEN WE FOUND
IN AGING AND IN ALL NEW
DEGENERATED CONDITION, THIS
BARRIER DYSFUNCTION AND WE CAN
OVERCOME DYSFUNCTION BY IMMUNE
CHECKPOINT BLOCKADE.
SO BRIEFLY, AS I SAID, WE FOUND
IN 1998 THAT MACROPHAGES SUPPORT
REPAIR.
THAT THE TIME IT WAS ACCEPTED
WITH A LOT OF SKEPTICISM AND IT
WAS CITED ONLY IN THE NEGATIVE
WAY.
HOW COME MACROPHAGES SUPPORT
REPAIR IF THE BRAIN IS FULL OF
RESIDENT MICROGLIA?
WE CLAIM THAT THEY ARE NOT
REDUNDANT CELLS.
SUBSEQUENTLY, MANY OTHER WORK
INCLUDING ALZHEIMER'S,
DEMONSTRATED RECRUITMENT OF
BLOOD-BORN MACROPHAGES OR
MONOCYTES DERIVED MACROPHAGES AS
WE CALL THEM, ARE NEEDED TO
FIGHT AGAINST MANY OTHER
PATHOLOGIES.
WE BELIEVE THAT BLOOD BORN
MACROPHAGES ARE NEEDED TO BE
RECORDED IN PATHOLOGICAL
CONDITIONS.
WE KNOW NOW THAT BLOOD BORN
MACROPHAGES CAN DISPLAY INSIDE
THE BRAIN MANY ACTIVITIES.
INFLAMMATORY TO INFLAMMATORY.
THEY CAN BE SOURCE OF DEGRADING
ENZYME.
THEY CAN BE ACTING INFLAMMATORY
TO DISPLAY ACTIVITY.
SUBSEQUENT TO THE MACROPHAGES,
WE DEMONSTRATED AN INDEPENDENT
PAPER THE T-CELL ALSO SUPPORT
BRAIN REPAIR AND SPECIFICALLY
T-CELLS THAT RECOGNIZE CNS
ANTIGEN AND WE COINED THE IDEA
OF PROTECTIVE AUTOIMMUNITY.
AT THAT TIME WE DIDN'T KNOW WHAT
THE RELATIONSHIP BETWEEN THE
T-CELL, THE MICROGLIA AND
MACROPHAGES.
THESE WERE TWO INDEPENDENT
OBSERVATIONS.
SUBSEQUENTLY, WE OBSERVED IN
MODEL OF SPINAL CORD AND I JUST
TOUCH IT VERY BRIEFLY.
WE FOUND T-CELLS SUPPORT
RECRUITMENT OF MONOCYTES DERIVED
MACROPHAGES STILL.
AND THE MAJOR ROLE OF MONOCYTES
DERIVED MACROPHAGES, AT SITE OF
THE INJURY IS TO SUPPRESS THE
MICROGLIAL RESPONSE AND
MONOCYTES DERIVED FROM IL10
DEFICIENT MICE FAIL TO SUPPORT
REPAIR.
SO OVER ALL WE HAD AN IDEA THAT
T-CELL CAN SUPPORT RECRUITMENT
OF MACROPHAGES AND THE LOCAL
MACROPHAGES ARE NEEDED TO
RESOLVE THE INFLAMMATION
SUBSEQUENTLY WE FOUND NEEDED TO
RESOLVE THIS TISSUE.
INDEPENDENT WORK AT THAT TIME,
GRADUATE STUDENTS WERE IN MY
LAB.
ONE IS A PROFESSOR NOW AND ONE
AT THE WEIZMANN INSTITUTE, THEY
WERE SPENDING WITH ME HOURS AND
ASKING ME IF T-CELL ARE NEEDED
TO SUPPORT REPAIR WHY WE NEVER
HAVE FULL REPAIR?
AND MAYBE T-CELL MUCH MORE
FUNDAMENTAL FLOW BRAIN
PLASTICITY.
AND WE THOUGHT IF THERE IS THE
CASE, IT IS VERY EASY TO CHECK.
WE TOOK ANIMAL AND PLACED THEM
IN RICH ENVIRONMENT, A CAGE THAT
WAS DEVELOPED BY ANOTHER LAB,
AND WE PLACED THE ANIMAL AND
UNDER THIS CONDITION YOU CAN SEE
INCREASING IN OR ABOUTOGENESIS.
WHEN PLACED IMMUNE COMPROMISED
ANIMAL IN THE SAME CAGE LIKE
SKID MICE OR MICE THAT ARE
DEFICIENT IN CNS T-CELL, WE
FOUND THERE IS DRAMATIC
REDUCTION IN NEUROGENESIS.
IN OTHER WORDS, WE FOUND THAT
ONE OF THE MECHANISM BY WHICH
NEUROGENESIS IS BOOSTED IN THE
RICH ENVIRONMENT INVOLVE T-CELL.
YOU CAN SEE VERY NICELY HERE ARE
NEWLY-FORMED IN THE HIPPOCAMPUS
OF THE WILDTYPE ANIMAL AND VERY
FEW IN IMMUNE COMPROMISED
ANIMAL.
WE CHECK COGNITION OF THESE MICE
AND FOUND THE SAME THAT
COGNITIVE ABILITY IS DOWN
REGULATED IN IMMUNE COMPROMISED
ANIMAL AND THIS WAS THE DEPLETED
BY NUMEROUS WORKS THEREAFTER.
SO WE SUGGESTED THAT T-CELLS
SUPPORT BRAIN PLASTICITY,
INCLUDING NEUROGENESIS.
HIPPOCAMPAL ACTIVITY AND LATELY
IT WAS SHOWN ALSO SOCIAL
BEHAVIOR.
SO OVER ALL WE ARE LEFT WITH KEY
ISSUE.
HOW CAN LEUCOCYTE ENTER TRAFFIC
TO CNS WITHOUT BREACHING THE
BLOOD-BRAIN BARRIER?
BASICALLY OUR MACROPHAGES
CONNECTED TO CNS AND MORE
IMPORTANTLY, HOW CAN T-CELL
SUPPORT BRAIN PLASTICITY IF THEY
ARE EXCLUDED?
WE KNOW THERE ARE NO T-CELL IN
BRAIN PARENCHYMA.
STRUGGLING WITH THIS QUESTION
FOR A WHILE, ONE OF MY GRADUATE
STUDENTS, OUTSTANDING GRADUATE
STUDENT, SHE WAS STRUGGLING WITH
IT FOR FOUR YEARS.
AND FINALLY, SHE DISCOVERED IN
THE MODEL OF SPINAL CORD INJURY
THAT MACROPHAGES SUPPORT REPAIR
AND CAN ENTER INTO THE LEFT --
BUT THE ONES DISPLAYING LOCALLY
AND INFLAMMATORY ROLE ARE COMING
BLOOD BARRIER WHICH IS IN THE
FRONT VENTRICLES.
THIS WAS A BIG SURPRISE BECAUSE
THE SPINAL CORD INJURIES
INFLICTED HERE, SHE FOUND THAT
MONOCYTES IS DERIVED MACROPHAGE
THAT IS LOCALLY DISPLAY
ANTI-INFLAMMATORY ROLE ARE
CRAWLING THROUGH THE BLOOD
BARRIER.
SO THE QUESTION WAS, WHAT
REVEALED ACTIVATION OF THE BLOOD
BARRIER?
WE WENT FURTHER AND ISOLATED THE
BLOOD BARRIER.
THIS IS THE COREY PLEXUS
EPITHELIUM AND WE FOUND THIS
TISSUE, EVEN IF WE EXPENSIVELY
PRO FUSED THE ANIMALS, WE FOUND
T-CELL OUTSIDE THE BLOOD VESSEL
IN STROMA.
WE TOOK THIS T-CELL AND WILL WE
DECIDED TO EXPLORE FURTHER HOW
IT WORKS.
WE ENVISIONED THAT MAYBE UNDER
INJURIOUS CONDITION, WE KNOW
THERE IS RELEASE OF IL6, TNF AND
IL1 BETA.
SO ENVISION THAT MAYBE THEVILLE
I OF THE EPITHELIUM CELLS SENSES
THE CYTOKINE MAYBE THERE ARE
T-CELLS SITTING IN THE STROMA.
WE ISOLATED THIS T-CELL FOUND
THAT ALMOST 97% OF THESE T-CELL
ARE CD4 POSITIVE T-CELL WHICH
MEANS THEY ARE ENGAGED WITH THE
COGNITIVE ANTIGEN AND WE FOUND
IN THE STROMA T-CELL ENGAGED
WITH ANTIGEN PRESENTING CELLS.
WE FOUND THAT THIS T-CELL CAN
LOCALLY REPRODUCE INTERFERON
GAMMA AND IL4 AND IL10.
WE DIDN'T FIND ANY T-CELL IN
THIS STROMA.
TO TEST OUR WORKING HYPOTHESIS,
WE TESTED WHAT ARE THE T-CELL
RECOGNIZING?
AND TOGETHER WITH THE WEIZMANN
INSTITUTE, WE DECIDED TO
SEQUENCE THE T-CELL RECEPTOR OF
THE T-CELLS WE ISOLATED FROM THE
EPITHELIAL AND PLEX US AND WE
FOUND T-CELLS, 70% OF THEM ARE
RECOGNIZING CNS ANTIGEN.
IN OTHER WORDS, THE GATEKEEPER
OF THE BRAIN, THE COREY PLEXUS
EPITHELIUM IS ENRICHED WITH
T-CELL THAT RECOGNIZES TNF
ANTIGEN.
WE CREATED A MONOLAYER AND
TESTED WHETHER INDEED THERE IS A
CYTOKINE EPITHELIAL CELLS ARE
SENSING SUCH AS TNF ALPHA UP
REGULATED INTO IT AFFECTING
EXPRESSION OF TRAFFICKING
MOLECULES BY THE CHROID PLEXUS
AND CHEMOKINE AND INTEGRIN.
SO WE EXPOSED THE CELLS EITHER
TO TNF ALPHA, OI6 OR IL1 BETA
AND ALSO TO THE CYTOKINE THAT WE
FOUND AT THE T-CELL ARE
PRODUCING SUCH AS INTERFERON
GAMMA, IL4 OR IL10.
TO MAKE A LONG STORY SHORT, WE
FOUND THAT THE ORANGEY CYTOKINE
THAT COMES FROM THE T-CELL THAT
ACTIVATES THE COREY PLEXUS IS
INTERFERON GAMMA.
CHROID PLEXUS.
NONE OF THEM ARE ACTIVATING THE
CHROID PLEXUS EPITHELIUM.
THEY DIDN'T ACTIVATE ONLY
INTERFERON GAMMA.
AND THERE WAS ENERGY BETWEEN THE
TNF ALPHA AND INTERFERON GAMMA
TO ACTIVATE THE CHROID PLEXUS
FOR TRAFFICKING MOLECULES, WHICH
WAS VERY SATISFACTORY FOR US
BECAUSE THAT IS WHAT WE
ENVISIONED.
THERE IS A SINGLE GENE BETWEEN
WHAT EPITHELIAL CELLS SENSE WHEN
IS THERE INFLAMMATION IN THE
BRAIN AND CYTOKINE THAT PRODUCE
T-CELL.
WE FOUND THAT INTERFERON GAMMA
KNOCK-OUT MICE OR INTERFERON
GAMMA RECEPTOR KNOCK-OUT MICE,
THERE IS A DRAMATIC REDUCTION IN
THE NUMBER OF T-CELLS THAT WE
FOUND IN THE CSF AND THERE IS
DRAMATIC REDUCTION IN
TRAFFICKING MOLECULES.
WE TESTED WHETHER TNF ALPHA IS
ACTIVATION OF THE CHROID PLEXUS
EPITHELIUM AND WE FOUND YES, IT
IS INDEED VERY MUCH DEPENDENT ON
NF-kB/P65.
SO WE FOUND INTERFERON GAMMA IS
THE KEY CYTOKINE THAT IS NEAR
THE ACTIVATED CHROID PLEXUS
EPITHELIUM FOR TRAFFICKING.
OUR KEY QUESTION CAME OUT, WHAT
DOES THE FATE OF THE COMPARTMENT
EFFECT THE BRAIN
NEURODEGENERATED DISEASE?
AND IF SO, CAN WE MANIPULATE THE
CHROID PLEX US AND AFFECT THE
DISEASE?
WE STARTED IN AGING AND THEN WE
MOVED TO ALZHEIMER'S.
SO WE FIRST TESTED TOOK THE
CHROID PLEXUS WITH AGING AND WE
FOUND THAT THERE IS DRAMATIC
REDUCTION IN THE AVAILABILITY OF
INTERFERON GAMMA WITH AGING OF
THE MOUSE AROUND 18 MONTHS THERE
IS DRAMATIC DROP.
WE TESTED WHETHER THE CHROID
PLEXUS IN AGED MICE EXPRESS ANY
OF THE COGNITIVE IMPAIRING
MOLECULE THAT WE FOUND BY THE
CREW.
AND WE FOUND THERE IS A DRAMATIC
INCREASE.
WE FURTHER DECIDED TO GET MORE
INSIGHT WHETHER AGING OF THE
BRAIN REFLECTS AGING OF THIS
CHROID PLEXUS EPITHELIUM OR
AGING OF THE BLOOD OR AGING OF
THE TISSUE.
TO THIS END, WE COLLECTED 11
TISSUE FROM YOUNG ANIMAL AND 11
TISSUE FROM AGED ANIMAL AND DID
OTHER SEQUENCING.
TO OUR SURPRISE, WE FOUND IN
AGING OF THE CHROID PLEXUS AS A
VERY UNIQUE SIGNATURE THAT IS
ELEVATION OF INTERFERON BETA
WHICH WE DIDN'T FIND IN ANY
OTHER AGED TISSUE AND WE DIDN'T
FIND IN YOUNG TISSUE.
SO THERE IS VAST ELEVATION OF
INTERFERON BETA, TYPE I.
AND DOWNREGULATION OF INTERFERON
GAMMA WHICH WE FOUND BEFORE.
INTERESTINGLY, SEVERAL MONTHS
BEFORE OUR SCIENCE PAPER THERE
WAS ANOTHER SCIENCE PAPER
SHOWING THIS RELATIONSHIP
BETWEEN INTERFERON BETA AND
INTERFERON GAMMA.
WE GOT HUMAN SECTION FROM UK AND
WE ASKED EXPLICITLY TO GET
TISSUE FROM AGED POPULATION,
NEUROLOGICAL DISEASE AND WE
FOUND IT IN AGED POPULATION THE
SAME SIGNATURE OF THE CHROID
PLEXUS AND ELEVATION OF
SIGNATURE INTERFERON BETA.
TOGETHER WITH OTHERS, WE DECIDED
TO EXPLORE WHETHER THE ELEVATION
OF INTERFERON BETA AND THE
DOWNREGULATION OF INTERFERON
GAMMA IS CAUSED BY SIGNALING
FROM THE BRAIN OR FROM THE
CIRCULATION.
SO WE CREATED THESE MICE AND WE
FOUND THAT CONNECTING YOUNG
ANIMAL TO AGED ANIMAL, AGE TO
AGE, YOUNG TO YOUNG, IS
CONTROLLED.
TO MAKE A LONG STORY SHORT, WE
FOUND THAT THE DOWNREGULATION OF
INTERFERON GAMMA IS CONTROLLED
BY THE CIRCULATION WHEREAS THE
UP REGULATION OF INTERFERON BETA
IS CONTROLLED BY SIGNALING
COMING THROUGH THE CSF.
THE NEXT QUESTION WE ASKED
OURSELVES, CAN WE REJUVENATE THE
CHROID PLEXUS AND RESTORE
ABILITY?
TO REJUVENATE THE CHROID PLEXUS,
WE INJECTED INTO THE CS IS F
ANTIBODY DIRECTED TO TYPE I
INTERFERON BETA RECEPTOR.
WE ENVISIONED INTERFERON BETA
WHICH IS PRODUCED BY THE
EPITHELIAL CELLS CAN DO
REGULATION AND EFFECT EPITHELIAL
CELLS AND CAN EFFECT THE BRAIN.
SO TO NEUTRALIZE BOTH ACTIVITY,
WE INJECTED ANTIBODY DIRECTLY
INTO INTERFERON BETA RECEPTOR.
WE FOUND THAT WE HAVE STORED ALL
ACTIVITY OF THE CHROID PLEXUS BY
NEUTRALIZING INTERFERON BETA
RECEPTOR RELATIVE TO ISOTYPE IGG
CONTROL AND WE REDUCED GLIOSIS
IN THE AGED BRAIN.
TO FURTHER TEST WHETHER IT HAS
ANY EFFECT ON COGNITION, WE TOOK
AGED MICE AND SCORED THE MICE
FIRST TO FIND OUT THOSE AGED
MICE THAT HAVE IMPAIRED
COGNITION AS WAS REPORTED AND
THE SAME IN HUMAN, 30% OF THE
AGED MICE ARE STILL INTACT
MEMORY.
WE TOOK 70%, SPLIT INTO TWO
GROUP, ONE RECEIVED IGG CONTROL
AND THE OTHER RECEIVED THE
ANTIBODY TO INTERFERON BETA
RECEPTOR AND WE FOUND THAT THIS
GROUP SHOWED IMPROVED COGNITION
ALMOST TO THE LEVEL OF THE THOSE
WITH INTACT MEMORY.
SINCE WE PUBLISHED THIS PAPER,
WE DECIDED TOO CHECK WHETHER THE
SIGNALS OF THE INTERFERON BETA
WHICH IS PRODUCED BY THE CHROID
PLEXUS EFFECT THE MICROGLIA.
WE SAW THE MICROGLIA FROM AGED
BRAIN AND FROM YOUNG BRAIN AND
THEN WE FOUND THE MAJORITY OF
THE SIGNATURE OF THE MICROGLIA
AGED MICE IS TYPE I INTERFERON.
AND AMONG THE MOLECULE EXPRESSED
BY THE AGED MICROGLIA IN WHICH
EFFECTED THE NEUTRALIZING
INTERFERON BETA RECEPTOR WHICH
WAS PUBLISHED AS COGNITIVE
IMPAIRING.
AND ANOTHER PUBLISHED BY BETH
STEVENS AND OTHERS, IMPAIRING
COGNITION.
SO OVERALL, WHAT WE FOUND IS
THAT TYPE I IS A VERY PROMINENT
SIGNATURE OF THE MICROGLIA.
AND NEUTRALIZING TYPE I
SIGNATURE CAN ALLEVIATE SOME OF
THE SYMPTOMS OF AGING AND
RESTORE MICROGLIA ACTIVITY.
BASED ON THIS, WE DECIDED TO GO
TO ALZHEIMER'S WITH THE IDEA
THAT WE ALREADY KNEW IN
ALZHEIMER'S WE NEED MACROPHAGES
TO FIGHT AGAINST ALZHEIMER'S.
WE ALREADY KNEW ENTRY OF
MACROPHAGES TO THE CNS DEPEND ON
THE CHROID PLEXUS EPITHELIUM AND
WE ALREADY KNEW THAT WE NEEDED
INTERFERON GAMMA IN ORDER TO
SUBJECTIVATE THE CHROID PLEXUS
AND INTERFERON GAMMA IS GOING
DOWN WITH AGING.
WE DECIDED TO SEE WHAT IS THE
FATE OF THE CHROID PLEXUS IN
AGING AND WHETHER WE CAN REVERSE
IT.
SO, AS YOU'RE FAMILIAR, THERE
IDENTIFIED IN ALZHEIMER'S
INCLUDING AMYLOID PLAQUES AND
NEUROFIBERI LARRYITAGE ELSE AND
THERE ARE ALREADY SEVERAL ANIMAL
MODELS THAT MIMICS THE
NEUROFIBRILLARY TANGLES.
THERE IS A LOCAL
NEUROINFLAMMATION AS I SAID AT
THE BEGINNING OF MY TALK, TO
TREAT THE NEW INFLAMMATION WITH
SYSTEMIC ANTI-INFLAMMATORY DRUG.
NEEDLESS TO SAY THAT ANY THERAPY
THAT WAS DIRECTED TO A BETA PLUS
WASN'T TURNED OUT TO BE DISEASE
MODIFYING.
IT'S NOT BECAUSE A BETA PLUS ARE
NOT DESTRUCTIVE BUT BY THE TIME
THAT THEY ARE PROMINENT AND
THERE IS COGNITIVE DECLINE, IT
MAY BE EFFICIENT BUT
INSUFFICIENT.
SO WE DECIDED TO FOCUS ON THIS
IS JUST TO SUMMARIZE THE WORK
THAT WAS PUBLISHED ALTHOUGH THE
USE IS DEMONSTRATING THE
RECRUITMENT OF MACROPHAGES TO
THE SITE OF PATHOLOGY CAN
BENEFIT THE DISEASE NOT ONLY
FACILITATING REMOVAL OF BLOOD
BUT ALSO CHANGING THE MILL YOU
YOO OF THE CNS FROM ONE
INFLAMMATORY TO LES
INFLAMMATORY.
SO WE DECIDED TO FOCUS ON TWO
ANIMAL MODEL OF ALZHEIMER'S.
ONE WHICH IS A ASSOCIATED WITH A
BETA PATHOLOGY AND ONE IS
ASSOCIATED WITH TAU PATHOLOGY.
THE A BETA PATHOLOGY, THERE ARE
SEVERAL MODELS.
WE DECIDED TO FOCUS ON THE ONE
WHICH WE CALL THE FIVE X5.
THERE ARE FIVE HUMAN MUTATION
AND THIS WAS DEVELOPED IN
CHICAGO 2006.
THIS IS THE ONLY MODEL THAT
STIMULATE ALMOST ALL THE
SYMPTOMS THAT ARE IN HUMAN WITH
THE SENSE THERE IS A COGNITIVE
LOSS, THERE IS A BAIT PATHOLOGY
AND THERE IS ALSO NEURONAL LOSS
AND LOCAL INFLAMMATION.
SO WE STARTED WITH THIS MODEL
AND THE FIRST THING THAT WE
TESTED WHETHER THE CHROID PLEXUS
EPITHELIUM EXPRESSED TRAFFICKING
MOLECULES.
AND WE TESTED ALL OF THE
TRAFFICKING MOLECULES THAT WE
KNEW ALREADY THAT ARE NEEDED FOR
RECRUTMENT EVER MACROPHAGES.
WE TESTED BY -- AND THESE LINES
SHOW YOU THE EXPRESSION OF
TRAFFICKING MOLECULES BY AGED
CONTROL, YOU CAN SEE FROM TWO
MICE ONWARD, NOT ONLY THERE IS
NO ELEVATION THAT YOU NEED TO
FACILITATE MACROPHAGES BUT IT IS
GOING DOWN.
AND THE MOST STRIKING
DOWNREGULATION CYCLE WAS
INTERFERON GAMMA DEPENDENT.
BASED ON THIS, WE WENT TO SEE IS
WHETHER IN THIS MOUSE MODEL
THERE IS REDUCTION IN THE
AVAILABILITY OF INTERFERON
GAMMA.
AND WE FOUND BY FLOW CYTOMETRY
AND INTERCELLULAR STEMMING
INTERFERON GAMMA AND THERE IS A
STRIKING DROP IN INTERFERON
GAMMA IN THIS MOUSE MODEL.
WE TESTED EXPRESSION OF -- AND
FOUND IN AC YOUNG PEOPLE, THE
CHROID PLEXUS EXPRESS LEVEL OF
ICON GOING DOWN WITH AGING AND
FURTHER IN
[ INAUDIBLE ]
SO IN THIS MOUSE MODEL WE FOUND
THERE IS REDUCTION OF
TRAFFICKING MOLECULE AND
REDUCTION INTERFERON GAMMA.
SUBSEQUENT TO OUR WORK, THERE
WAS ANOTHER WORK USING ANOTHER
MOUSE MODEL OF ALD ALZHEIMER'S,
THE J20, AND THEY FOUND EXACTLY
THE SAME PHENOMENA THAT
INTERFERON GAMMA IS GOING DOWN
AND ICON IS GOING DOWN WITH THE
DISEASE PROGRESSION.
NOW IN PRINCIPLE, WE TESTED TO
SEE WHETHER THERE IS ANY
RELATIONSHIP BETWEEN EXPRESSION
OF TRAFFICKING MOLECULES AND
ENTRY OF IMMUNE CELLS TO THE CSF
AND IN THE MODEL OF STRESS WHICH
LEADS TO POST-TRAUMATIC STRESS
DISORDER SYMPTOMS, WE FOUND A
GREAT CORRELATION BETWEEN
EXPRESSION OF TRAFFICKING
MOLECULES AND OUR ABILITY TO
DETECT IMMUNE CELLS MAINLY
T-CELL INTO CSF.
SO IN PRINCIPLE THERE ARE
SEVERAL WAYS TO AUGMENT LEVEL OF
AVAILABILITY OF INTERFERON
GAMMA, WHICH I CALL THEM EITHER
PRESS THE GAS OR LOOSEN THE
BRAKES.
SO EITHER YOU CAN ACTIVATE THE
IMMUNE SYSTEM OR -- TO ACTIVATE
YOU NEED MOLECULES OR
ANTI-VACCINATION.
SO WE DECIDED TO TESTED WHETHER
AUGMENTING AVAILABILITY FOR
INTERFERON GAMMA COULD BE
ACHIEVED BY BLOCKING SUPPRESSIVE
MECHANISM.
NOW SUPPRESSIVE MECHANISM CAN BE
MYELOID SUPPRESSIVE CELLS OR
IMMUNE CHECKPOINT INHIBITORY
IMMUNE CHECKPOINT.
WE DECIDED BECAUSE WE KNOW THAT
WITH AGING THERE IS ELEVATION OF
REGULATORY --
[ INAUDIBLE ]
WE KNOW WITH EXHAUSTION OF THE
IMMUNE SYSTEM THERE IS ELEVATION
OF INHIBITORY IMMUNE CHECKPOINT.
22 DECIDED TO FOCUS ON APPROACH
OF LOOSENING THE BREAKS.
SO WHAT WE DID THE FIRST THING
WE DID IS BRED THE ALZHEIMER'S
MICE WITH FOX P3R WHICH WE GOT
FROM -- AND WE CAN DEPLETE
REGULATORY T-CELL.
WE DEPLETED THEM AFTER TWO WEEKS
THE LEVEL OF REGULATORY CELLS
REBOUND.
AND WE TESTED WHETHER A SINGLE
SESSION OF REDUCING REGULATORY
T-CELL WILL BE SUFFICIENT TO
ACTIVATE THE CHROID PLEXUS AS A
GATEWAY AND TO OVERCOME THE
DISEASE PATHEDDOLOGY.
SO WE FOUND THAT A WEEK AFTER
THE DEPLETION OF REGULATORY
T-CELL AT THE CHROID PLEXUS
EPITHELIUM WAS ACTIVATED BOTH MY
IMMUNOHISTOCHEMISTRY.
WE FURTHER FOUND THAT MONTHS
AFTER THE DEPLETION OF
REGULATORY T-CELL WE SEE MYELOID
CELLS AND REGULATORY T-CELL IN
THE BRAIN PARENCHYMA AROUND THE
PLEXUS.
WHEN WE CHECK COGNITIVE ABILITY
AND PATHOLOGY, WE WERE AMAZED TO
SEE, THIS IS THE PATHOLOGY IN
THIS MOUSE MODEL THE BETTER
PLAQUES ARE HUMAN PLAQUES.
SO VERY EASY TO DISTINGUISH.
WE USE ANTIBODY DIRECTED TO
HUMAN A BETA AND I'M NOT SURE
THAT YOU CAN SEE WITH THIS SLIDE
BUT YOU CAN SEE THE HIPPOCAMPUS
OF THE MICE WITHOUT DEPLETION
AND THIS IS THE DEPLETION ASSIST
STEMMATIC OF REGULATORY T-CELL.
THERE WAS A DRAMATIC REDUCTION
BOTH IN THE CORTEX AND THE
HIPPOCAMPUS.
YOU CAN SEE QUANTIFICATION HERE.
WE TESTED COGNITIVE ABILITY BY
MOUSE MAZE WHICH MEASURE MAINLY
SPECIAL LEARNING AND MEMORY.
SO THIS MAZE INVOLVES THREE
PHASES.
A PHASE OF LEARNING ACQUISITION
AND THE -- TWO PHASES OF MEMORY.
SO DURING FOUR DAYS OF MEMORY
LEARNING ACQUISITION, THE
ALZHEIMER'S MICE THAT WERE NOT
DEPLETED OF REGULATORY T-CELL,
DIDN'T LEARN THIS.
THE BLACK SHOW YOU WILDTYPE AND
BLUE SHOW MICE WITH DEPLETED
REGULATORY T-CELLS.
SO ALMOST BEHAVE AS NORMAL MICE.
WHEN WE REMOVED THE PLATFORM FOR
THE MAZE SO IN THE WATER POOL,
THERE IS A PLATFORM WHICH IS
VERY CLOSE TO THE SURFACE OF THE
WATER.
THE ANIMAL DON'T SEE THE
PLATFORM BUT THERE ARE PICTURE
AROUND THE WATER POOL.
SO THEY CAN REMEMBER TO NAVIGATE
THEMSELVES TO THE PLATFORM BASED
ON THE PICTURE AROUND THE POOL.
SO WHEN YOU REMOVE THE PLATFORM
WE MEASUREED THE TIME THAT
ANIMAL SPENT AROUND THE PLACE
THAT THEY REMEMBERED THE
PLATFORM.
SO THE ANIMAL DEPLETED THE
REGULATORY T-CELL REMEMBERED
VERY SIMILAR TO THE WILDTYPE
ANIMAL WHEREAS ANIMALS THAT WERE
NOT DEPLETED OF REGULATORY
T-CELL DIDN'T REMEMBER AND FOUND
ALSO DRAMATIC REDUCTION IN THE
GLIOSIS.
BASED ON THIS IDEA WE REALIZED
THAT WE NEED TO RECORD TOTALS
ALZHEIMER'S BRAIN REGULATORY
T-CELL AND IN ORDER TO ACHIEVE
THESE, WE INDIVIDUAL TO REDUCE
THE REGULATORY T-CELL TO ALLOW
AVAILABILITY OF INTERFERON GAMMA
PRODUCING CELLS AT THE CHROID
PLEXUS.
THIS WAS FOR US VERY MUCH
REMINISCENT OF WHAT WE KNOW IN
CANCER AND WE DECIDED TO CHECK
WHETHER BLOCKING THE IMMUNE
CHECKPOINT WE CAN ACHIEVE THE
SAME.
NOW WE DECIDED TO FOCUS ON
PD-1/PD-L1 FOR A REASON.
WE KNEW THE MEMORY WAS CD4 AND
CD8 EXPRESSING PERMANENT D1 AND
MORE IMPORTANTLY, THE LIGAND,
THE PD-L1 CAN BE EXPRESSED BY
EPITHELIAL CELLS REGULATORY
T-CELLS AND ANTIGEN PRESENTING
CELLS, ALL OF WHICH WE HAVE AT
THE CHROID PLEXUS EPITHELIUM.
SO WE ENVISION THAT SUPPRESSIVE
T-CELL CAN OUT SUPPRESS EITHER
BY REGULATORY T-CELL ANTIGEN
PRESENTING CELLS AND ALSO
DECIDES THE CHROID PLEXUS.
SO WE DECIDED TO GIVE THE ANIMAL
EITHER ANTI-PD-1 OR ANTI-PD-L1
AND THEREBY UNLEASH CD4 POSITIVE
T-CELL IN ADDITION TO THE CD8
WHICH WILL UNLEASH FOR CANCER
THERAPY.
WE STARTED WITH ANTI-PD-1 BUT
I'LL SHOW YOU UNPUBLISHED DATA
WITH ANTI-PD-L1.
SO, THE FIRST THING THAT WE DID,
WE GAVE THEM -- THIS WAS
PUBLISHED A YEAR AGO IN NATURE
MEDICINE.
SO WE GAVE THE ANIMAL ANTI-PD-1
AND CHECK WHETHER THE CHROID
PLEXUS WAS ACTIVATED INSIDE THE
INTERFERON GAMMA-TYPE SIGNALING
AND THIS WAS THE CASE.
AS CONTROL WE USE IGG CONTROL.
ANTIBODIESED TO -- WE CHECKED TO
SEE WHETHER THE CHROID PLEXUS
WAS ACTIVATED TO EXPRESS
TRAFFICKING MOLECULES AND SAW IT
ACTIVATED.
AND INTERESTINGLY, WHEN WE GAVE
THE ANIMAL PRIOR TO THE
ANTI-PERMANENT D1 A DAY BEFORE
THE ANTI-PD-1 INTERFERON GAMMA,
WE BLOCKED THE INDUCED ACTIVITY
OF THE ANTI-PD-1 WHICH WAS VERY
FINE FOR US BUT INDEED IT WAS
INTERFERON GAMMA DEPENDENT.
WE NEXT TESTED WHETHER AS A
RESULTED OF THE TREATMENT THERE
IS INCREASED RECRUITMENT OF
MONOCYTES DERIVED MACROPHAGES,
AND WE FOUNDED THAT TWO WEEKS
AFTER THE TREATMENT THERE WAS
ABOUT TWO FOLD INCREASE IN THE
NUMBER OF MONOCYTES DIVIDE
MACROPHAGES AND AGAIN, WHEN WE
GAVE THE ANIMAL ANTI-INTERFERON
GAMMA PRIOR TO THE ANTI-PD-1, WE
BLOCKED THIS ELEVATION.
BESIDES THIS, WE DECIDED TO MOVE
TO TEST COGNITIVE ABILITY AND IN
THIS CASE, WE INTENTIONALLY USED
VERY ADVANCED STAGE OF THE
DISEASE.
IN THIS ANIMAL, THERE IS A
COMPLETE LOSS OF COGNITION BASED
ON THE PEOPLE THAT DEVELOPED
THIS MODEL AND BASED ON OUR
EXPERIENCE AT SIX MONTHS OR
MORE.
SO WE STARTED AT 10 MONTHS OLD
AND TREATED THE ANIMAL 10 MONTHS
OLD WITH ANTI-PD-1 AND TESTED
THEM EIGHT MONTHS LATER.
THIS IS SAY SINGLE INJECTION IN
OUR RECORDINAL PAPER WE GAVE TWO
DOSAGE --
[ INAUDIBLE ]
SUBSEQUENTLY WE REPEATED AND
INJECTION WAS SUFFICIENT AND
MICE LATER TO SEE COGNITIVE
ABILITY.
NOW IT WAS RECOMMENDED IN THIS
MICE TO HUES THE TOOL MAZE SO
AGAIN WATER POOL BUT THEY ARE 6
ARM IN THE WATER POOL AND IN ONE
ARM THERE IS A PLATFORM AND WHAT
YOU MEASURE THE LEARNING CURVE,
THE ANIMAL BY THE NUMBER OF AIR
ERRORS THEY MADE BEFORE THEY
NAVIGATE THEMSELVES STRAIGHT TO
THE ARM WITH THE PLATFORM.
SO TO ADD SOME MICE SHOWN IN
THEY REMEMBERED.
THE BLACK SHOWS YOU WILDTYPE
ANIMAL.
GRAY SHOW YOU THE ONE SYSTEM
TREATED WITH THE IGG WHICH WE
CALL PLACEBO AND THE GREEN SHOW
YOU ANIMALS THAT WERE TREATED
WITH ANTI-PD-1 SO THERE WAS
REVERSE OF COGNITIVE LOSS IN
THIS MICE.
WE TESTED THE PLAQUE BURDEN AND
YOU CAN SEE HERE THIS ANIMAL
RECEIVED TWO SESSION OF
INJECTION AND ANALYZE TWO MONTHS
AFTER WE STARTED TREATMENT.
SO ANIMALS THAT RECEIVED 3
INJECTIONS WE TESTED TWO MICE
AFTER WE STARTED, THERE WAS A
VERY NICE PLAQUE REMOVAL AND THE
GREEN SHOW YOU GLIOSIS AND THE
RED SHOW YOU THE PLAQUE.
WHEREAS ANIMALS THAT WERE
TREATED WITH IGG YOU STILL SEE A
VERY HIGH BURDEN OF PLAQUE AND
GLIOSIS.
SO THE EFFECT ON HIS STOL GEE
WAS DRAMATIC.
SINCE WE PUBLISHED THIS PAPER,
WE DECIDED TO SEE WHETHER EVERY
TREATMENT IN THIS MICE MODEL
WILL PREVENT LOSS OF COGNITION
OR DELAY LOSS OF KIG NITION.
SO WE STARTED TO TREAT THE
ANIMAL AT THREE MONTHS, FOUR
MONTHS, AND FIVE MONTHS AND
TESTED THEM AT FIVE AND SIX
MONTHS.
AND WHAT CAN YOU SEE AT FIVE
MONTHS, THE ONES THAT -- THE
CONTROL MICE ARE STILL SHOWING
SOME COGNITIVE ABILITY AT THE
LAST TRIAL, THE LAST DAY.
AT SIX MONTHS THEY ALREADY -- SO
IN THE CAUSE OF THIS EXPERIMENT,
THE CONTROL ARM BECOMING WORSE
WHEREAS THE ONES THAT TREATED
WITH ANTI-PD-1 MAINTAINED 80 TO
LEARN AND REMEMBER.
SUBSEQUENTLY, WE TESTED TO SEE
WHETHER THE TREATMENT IS
ASSOCIATED WITH RESCUE OF
NEURONS WHICH WE MEASURE BECAUSE
THAT IS THE PLACE THAT WAS
RECOMMENDED IN THIS MOUSE MODEL
TO SEE NEURONAL SURVIVAL AND
CASPASE 3 IS A MEASURE OF
APOPTOSIS.
YOU CAN SEE HERE THAT THE
TREATMENT IS A VERY NICE NEW
PROTECTION AND THERE IS DRAMATIC
REDUCTION IN CASPASE 3 EXPRESSED
BY THE NEURONS.
WE DECIDED TO TEST WHETHER
ANTI-PD-L1 WILL HAVE SIMILAR
EFFECT AND YOU CAN SEE DOSE
DEPENDENT RESPONSE.
THE . 1 MILLIGRAM.
NO EFFECT .5 AND 1.5.
SO THE ANTI-PD-1 HAS SIMILAR
EFFECT AND SHOW VERY NICE DOSE
DEPENDENCY AND WE SHOW VERY NICE
EFFECT ON THE INFLAMMATORY
MILIEU IN FAVOR OF THE ELEVATION
OF IL10 AND REDUCTION OF IL20.
NOW IMPORTANTLY, BECAUSE THE
TREATMENT IS GIVEN SYSTEMIC AND
NOT TO THE BRAIN, WE ENVISIONED
THAT IT IS NOT DEPENDENT ON THE
TYPE OF PATHOLOGY OF THE BRAIN
BUT WE ARE ACTIVATING A CASCADE
OF IMMUNE EVENTS THAT STARTS AND
CULMINATES IN THE BRAIN.
SO WE DECIDED TO CHECK ANOTHER
MOUSE MODEL OF ALZHEIMER'S WHICH
IS NOT A BETA DRIVEN AND IT'S
TAU PATHOLOGY.
IN THIS MODEL, THE HUMAN
MUTATION OF MICROTUBULAR
REPORTING IS PHOSPHORYLATED.
IN THIS MOUSE MODEL YOU TEST --
RECOMMENDED TO TEST SHORT-TERM
MEMORY.
SO BASICALLY IT IS A ANIMALS
FIRST LEARN TWO YAM ONE ARM IS
CLOSED.
AND AFTER THAT THEY ARE
HABITUATED TO THE TWO ARM YOU
OPEN THE THIRD ARM AND MEASURE
THE TIME THE ANIMAL SPENT IN THE
NOVEL ARM.
IF THEY DON'T REMEMBER, YOU
SPEND EQUALLY TIME IN THE SHORT
ARM.
IF REMEMBER, THEY WILL SPEND
MORE TIME IN THE NOVEL THAN IN
THE TWO OTHER ARM.
SO, YOU CAN SEE IT VERY NICELY
HERE.
SO THE TAU PATHOLOGY TREATED
WITH IGG AND THESE ARE TREATED
WITH ANTI-PD-1 AND ANTI-PD-L1.
SO THE WILDTYPE SPENT 60% OF THE
TIME IN THE NOVEL ARM AND
SIMILARLY THE TREATED ONE, AND
WAS FOUND IN THIS MOUSE MODEL
AGAIN, THE TREATMENT IS
ASSOCIATED WITH RECRUITMENT OF
MONOCYTES DERIVED MACROPHAGE
SYSTEM INTO THE PARENCHYMA AND
THERE IS REDUCTION OF
PHOSPHORYLATION OF TAU.
SO THE EFFECT OF THE DISEASE IS
NOT DEPENDENT ON THE TYPE OF
ETIOLOGY BUT OF THE IMMUNE
SYSTEM AND THIS IS JUST TO SHOW
YOU THAT IT WILL CAUSE A
DRAMATIC REDUCTION IN THE
PHOSPHORYLATION OF TAU MUTATION.
NOW, WE REPEATED THIS EXPERIMENT
IN A DOSE DEPENDENT MANNER AND
THIS SHOWS YOU VERY NICELY THIS
IS WILDTYPE ANIMAL.
THE TIME INDIVIDUALS SPENT IN
THE NOVEL ARM.
THIS IS IGG CONTROL IN ALL ARM
AT THE SAME TIME.
THIS IS LOW DOSE IN ALL ARM THE
SAME TIME AND IF YOU GO IL, YOU
SEE ANIMALS SPENT MORE IN THE
NOVEL ARM BOTH IN.5 AND 1.5.
SO BASED ON ALL OF THIS, WE
ASKED OURSELVES WHY DO WE NEED
TO RECRUIT MACROPHAGES?
WHY MICROGLIA CANNOT DO THE JOB?
SO I FINISH WITH A VERY BRIEF
STORY ABOUT THE MICROGLIA.
WE DECIDED TO CHECK WHAT IS THE
FATE OF THE MICROGLIA IN THIS
DISEASE?
THEY WILL SUPPORT ON MICROGLIA
ALZHEIMER'S CLAIMING THEY ARE
NOT EFFECTIVE, SOME CLAIMS THEY
ARE INFLAMMATORY.
SO A LOT OF -- AND WE FOUND THAT
LACK OF CONSENSUS IS REFLECTION
OF NOT HAVING GOOD MARKERS FOR
MICROGLIA.
SO TOGETHER WITH THE WEIZMANN
INSTITUTE, WE DECIDED TO GO FOR
SINGLE-CELL RNA-SEQ OF THE
MICROGLIA.
I KNOW SOME OF YOU --
[ INAUDIBLE ]
MICROGLIA WE DID COLLABORATION
AND WE DECIDED TO COLLECT
SINGLE-CELL RNA AND SINGLE CELL
MICROGLIA INTO THE SEQUENCE.
WHAT WE FOUND IS THAT IN THE
ALZHEIMER'S THERE IS SAY SMALL
SUB POPULATION OF MICROGLIA THAT
BEHAVE DISTINCTIVELY FROM THE
REST, ABOUT 5-10%.
WE COULDN'T DETECT THEM IF YOU
DO YOUR BEST RNA SEQUENCING OF
MICROGLIA ONLY BY SINGLE CELL
COULD WE DETECT THEM.
WE FOUND THAT BASED ON THE
MARKERS THEY EXPRESSED, THEY ARE
LOSING SOME OF THE STRAINING
ACTIVITY OF MICROGLIA SUCH AS
CXCL1 AND THEY ARE UP REGULATED
MANY GENES THAT HAVE ALREADY
REPORTED BY GWAS THAT ARE
ASSOCIATED WITH THE DISEASE
PATHOLOGY SUCH AS
[ INAUDIBLE ]
SO BASED ON THE PROFILE, WE FELT
CONFIDENT THIS MICROGLIA
ASSOCIATED WITH ACTIVITY WHEN WE
FOUND THEY ARE ADJACENT TO THE
PLUS IN MICE AND IN HUMAN.
WE FOLLOWED THE DEVELOPMENT OF
THIS MICROGLIA AND WE FOUND THAT
THEY ARE DEVELOPING WITH THE
DISEASE PROGRESSION.
AND THEN WE COLLABORATED WITH
MARCO BECAUSE WE FOUND THAT THEY
ARE ELEVATEING TRENCHING 2 AND
IT'S -- TREMENDOUS 2.
WE FIRST SAW DOWNREGULATION OF
THE MANY GENES THAT ARE
ASSOCIATED WITH HOME STAYSIS AND
THEN WE FOUND FRESHMEN 2 AND
THEN FOUND MANY OTHER.
SO WE WANTED TO SEE WHETHER
TREM2 IS KEY REGULATED IN
DEVELOPMENT.
SO WE HAVE SINGLE CELL MICROGLIA
FOR WILDTYPE ANIMAL, 22 POSITIVE -- TREM2 POSITIVE AND
NEGATIVE MOUSE.
TO MAKE A LONG STORY SHORT, WHAT
WE FOUND THAT THE FIRST STAGE OF
MICROGLIA ACTIVATION IN THIS
MOUSE MODEL IS TREM2 INDEPENDENT
AND THE LAST STAGE IS TREM2
DEPENDENT.
THE DISEASE IS WORSE IN T.
RM2 KNOCK-OUT MICE AND WHAT WE
ARE SEEING IN TREM2 KNOCK OUT
ALZHEIMER'S MICE WE DON'T SEE
THE MICROGLIA.
ALL OF THEM ARE STUCK IN THE
INTERRING PHASE.
SO IT MEANS THEY ARE TREM2
NEGATIVE AND ELEVATION WITH
MICROGLIA ORCHESTRATE THE
DEVELOPMENT OF THIS DISEASE
ASSOCIATE MICROGLIA AND WE ARE
CURRENTLY FOCUSING TO SEE TO
WHAT EXTENT THEY ARE BENEFICIAL
AND WHETHER THE TREATMENT IS BY
RECRUITING MACROPHAGES OR CHANGE
PROFILE.
BUT WE HAVE ONLY PRELIMINARY
DATA.
SO OVERALL, IED LIKE TO
SUMMARIZE MY TAKE HOME MESSAGE
TODAY.
SO WHAT WE ARE SHOWING THIS WELL
CONTROLLED IMMUNE ACTIVATION
OUTSIDE OF THE CNS RATHER THAN
SUPPRESSION IS NEEDED TO COMBAT
NEURODEGENERATED DISEASE
REGARDLESS OF THE DISEASE
ETIOLOGY.
WE FOUND IN A BETA AND FOUND IT
IN THE TAU.
SINCE IMMUNE ACTIVATION IS NOT
DISEASE SPECIFIC, IT CAN
POTENTIALLY BE APPLICABLE TO A
WIDE SPECTRUM OF DISEASE.
THE CHOICES OF ACTIVATION MODE,
WHETHER STEPPING ON THE GAS
PEDAL OR RELEASING THE BREAKS IS
VERY MUCH DEPEND ENT ON THE
DISEASE STAGE AND THE TYPE OF
DEFICIENCY.
WE HAVE OTHER DISEASE MODELS
SUCH AS ALS WHEN WE FOUND THIS
CHROID PLEXUS DYSFUNCTION
NEVERTHELESS THE CHECKPOINT
INHIBITORY CHECK POINT ARE NOT
SUFFICIENT.
WE SEEING THAT ACTIVATION OF THE
SYSTEMIC IMMUNE SYSTEM
FACILITATES RECRUITMENT OF
MACROPHAGES TO PARENCHYMA BUT WE
DON'T KNOW WHETHER ACTIVITY SAID
TOTALLY DEPENDENT ON MACROPHAGES
OR THE MACROPHAGES INDUCE OTHER
CELLS TO BE MORE BENEFICIAL.
THE TREATMENT IS
MECHANISM-DRIVEN AND MICROGLIA
ARE POTENTIALLY BENEFICIAL BUT
THEIR ACTIVATION REQUIRES
RELEASE SOME OF THE MICROGLEIAL
OFF SIGNALING WE ARE FURTHERING
STUDY.
THIS IS A CARTOON PRODUCED FOR
ME --
>> WHEN YOUR ENTERTAIN UNDER
THREAT, IT SENDS A DISTRESS
SIGNAL TO THE IMMUNE SYSTEM TO
COME TO THE RESCUE.
BUT IMMUNE CELLS ARE TOO BIG TO
GET INTO THE BRAIN THE NORMAL
WAY.
SO THEY HAVE TO USE A BACKDOOR.
AS WE AGE, THAT BACKDOOR ENTRY
GETS HARDER.
BUT WHAT IF WE JUST GIVE THE
IMMUNE CELLS A BIT OF HELP?
A BOOSTER?
WELL, RESEARCHERS ARE FINDING
THAT CAN HAVE A POSITIVE EFFECT
ON ALZHEIMER'S MEMORY LOSS.
AT LEAST TO MICE ANYWAY.
COULD IT WORK IN HUMANS TOO?
>> SO I GOT THIS CARTOON FROM
THE EU FOR GETTING THE
ADVANCED -- ERC FOR THE SECOND
TIME AND I THOUGHT IS NICE
ILLUSTRATION.
SO BEFORE I FINALIZE BECAUSE I
TALKED A LOT ABOUT IMMUNE
CHECKPOINT BLOCKADE AND YOU KNOW
A LOTTED IN COUNSELING
CHECKPOINT, I WOULD LIKE TO
EMPHASIZE THAT BASED ON THE
MECHANISMS OF ACTION, WE DON'T
NEED TO KEEP EXPOSED ANIMAL OF
THE PATIENT FOR CONTINUOUSLY FOR
THE IMMUNE CHECKPOINT.
IT SHOULD BE TREATMENT.
WE FOUND THAT THE SINGLE
TREATMENT WE STILL SEE EFFECT.
AND THE INTERVAL IS NEEDED IN
ORDER TO ALLOW THE ENTIRE
ACTIVITY TO GET.
SO THE TREATMENT WILL BE
DISTINCTIVE FOR THE TREATMENT
FOR CANCER AND THAT IS WHY I
COMPETITIVE GRANTS BY THE EU,
WHICH IS CALLED THE -- ERC AND
MANY OTHER EU AND MANY OTHER
FOUNDATION, COMPETITIVE
FOUNDATION IN ISRAEL AND OUTSIDE
OF ISRAEL.
THIS GRADUATE STUDENT DID
CURRENTLY IN MY LAB THAT DID THE
WORK, QUITE INTERNATIONAL.
ALL THE SINGLE CELL WAS DONE IN
COLLABORATION WITH OUTSTANDING
YOUNG SCIENTISTS AT THE WEIZMANN
INSTITUTE AND SOME OF THE WORK
WAS DONE IN COLLABORATION WITH
STANFORD AND OTHERS FROM ISRAEL
AND FROM ITALY AND FROM SWEDEN.
AND THESE ARE FORMER GRADUATE
STUDENT MANY OF WHICH OR WHOM
ARE NOW INDEPENDENT PROFESSOR
EITHER IN THE STATES OR ISRAEL
OR EUROPE AND WITHOUT THEM I
COULDN'T BE ABLE TO DO THIS
WORK.
THANK YOU.
[ APPLAUSE ]
I AM HAPPY TO TAKE QUESTIONS.
>> HI.
SO, I'M USED TO SEEING LIKE A
TYPE I INTERFERON SIGNATURE
LEADING TO SOME SORT OF DAMAGE
OF SOME KIND.
I WAS WONDERING HOW YOU THINK
THIS CHROID PLEXUS IS PREVENTING
ANY SORT OF DAMAGE WHILE
MAINTAINING.
>> I THINK THERE IS MORE AND
MORE DATA ACCUMULATING THAT EVEN
IN MS AND TYPE I INTERFERON BY
ITSELF IS NOT DAMAGING.
IT MAY BE THAT OVERDOSEING CAN
BE BAD EVEN IN ANIMAL MODEL.
INTERFERON GAMMA BY ITSELF IS
NOT SUFFICIENT TO DRIVE THE
DISEASE.
>> THAT WAS TOUR DE FORCE.
THIS MIGHT BE A NAIVE QUESTION.
BUT PD-1 PATHWAY BLOCKADE HAS
NOW BEEN PERFORMED ON CANCER
PATIENTS.
IS THERE ANY EVIDENCE THAT THEY
EXPERIENCE COGNITIVE CHANGES?
>> YOU'RE ASKING A VERY GOOD
QUESTION.
WE CONTACT MANY CENTERS IN
ISRAEL AND IN EUROPE AND IN THE
STATES TREATING PATIENTS WITH
ANTI-PD-1.
OR ANTI-PD-L1.
FIRST OF ALL THEY ARE TREATING
IN A DIFFERENT REGIMEN.
SECONDLY IT WAS NEVER
RECOMMENDED BY THE FDA OF ANY
CLINICAL DRIVE TO TEST
COGNITIVE.
SO THERE IS NO REPORT ON THESE.
SO THE ANSWER IS ZERO.
THE ONLY THING THEY TOLD ME THAT
ELDERLY POPULATION RESPOND VERY
WELL TO ANTI-PD-1 AND ANTI-PD-L1
FOR CANCER.
SO IT MEANS A POTENTIAL.
BUT COGNITIVE ABILITY, NO
FURTHER.
>> SO THE QUESTION IS, IS THIS
SYSTEM OF IMMUNE PROTECTION
EFFECTING THE FETAL STAGE?
BECAUSE IT WAS SUGGESTED THAT
INFECTION OF THE MOTHER MIGHT
CAUSE -- SO I WAS THINKING IN
TERMS OF THE IMPLICATIONS OF
YOUR OBSERVATIONS IN THE MICE.
>> WE ARE CURRENTLY TESTING IT.
THAT IS A VERY GOOD POINT.
EXCELLENT POINT.
I DON'T HAVE AN ANSWER.
THE ONLY THING I HAVE CLEAR
ANSWER, WE TESTED MENTAL
DISABILITY AND WE FOUND THAT IN
ANIMAL MODEL, THE CONES ARE
DEPRESSION OR POST-TRAUMATIC
STRESS DISORDER.
THE GATE COMPLETELY SHUT OFF AND
IF WE -- SUPPRESSION, WE CAN
REDUCE SOME OF THE SYMPTOMS OF
DEPRESSION.
BUT WITH RESPECT TO PREGNANCY,
WE HAVE VERY PRELIMIARY DATA.
IT'S THE COMMUNITY HAS MODEL OF
BABIES DURING PREGNANCY -- WE
COULD NOT DETECT ANY EFFECT OF
THE CHROID PLEXUS.
>> THE CLINICAL TRIALS SOON?
>> IT IS BEYOND MY CONTROL.
BUT A START-UP COMPANY SIGNED
AGREEMENT WITH A COMPANY FOR
TRANSLATING INTO PATIENT.
>> SO DO YOU HAVE AN IDEA OF HOW
THIS IS GOING TO MOVE TO THE
CLINICAL TRIALS?
DO YOU THINK IT WILL STAY
SYSTEMIC OR DO YOU HAVE ANY
PLANS OF MAKING IT MORE SPECIFIC
TO THE CHROID PLEX US?
>> NO, WE CANNOT -- YOU CAN NOT
MONITOR INPATIENT, IN LIVING
INDIVIDUAL THE CHROID PLEXUS.
SO WE ARE USING BLOOD MARKERS TO
MONITOR THE ACTIVITY AS MEASURE
OF THE EFFECT ON THE CHROID.
THERE IS NO WAY TO DETECT THE
CHROID.
YOU CAN SEE THE SIGNATURE BUT
THE RESPONSE -- NO WAY TO
MEASURE CHEMOKINE.
>> HI.
FANTASTIC TALK.
>> THANK YOU.
>> I WAS WONDERING IF THE
T-CELLS THAT AFFORDED
PROTECTION, DID THEY GET TURNED
INTO TISSUE RESIDENT T-CELLS ORD
DID THEY STAY IN THE PERIPHERY?
>> THAT'S A GOOD POINT BUT I
DON'T HAVE ANSWER.
WE HAVE T-CELL THAT SIT ALL THE
TIME IN THE CHROID PLEXUS
WE KNOW THAT THEY ARE NATIVE FOR
ACTIVATION.
WE SEE IN SEVERAL PARADIGMS
ENTRY OF T-CELL INTO THE
PARENCHYMA.
BUT THERE IS NO WAY TO TELL YOU
THE -- IS THE ONE THAT IS IN THE
PARENCHYMA.
ALSO WE SEE WITH ALL THE
PATHOLOGY WE SEE FACTOR CELLS
AND THEN T-CELL AND WE DON'T
KNOW WHETHER IT IS LOCAL
CONVERSION OR SEPARATE
RECRUITMENT.
SO THERE ARE MANY THINGS THAT IS
WE STILL DON'T KNOW AND WE DON'T
HAVE THE TOOLS TO FOLLOW THE
SOURCE.
>> AND THEN JUST ONE MORE
FOLLOW-UP ISSUE.
I WAS GOING TO ASK IF THIS
PROTECTION IS TRANSPLANTABLE?
CAN YOU TAKE THE T-CELLS FROM A
PROTECTED MOUSE AND TRANSFER
THEM?
>> WE DID IT LONG AGO.
YOU CAN TAKE T-CELL AND TAKE ANY
EFFECT OF T-CELL -- THERE IS
NOTHING.
THEY SHOULD BE MEMORY T-CELL
THAT COGNITIVE ANTIGEN IS BEING
PRESENTED IN THE CHROID PLEXUS.
WE STILL DON'T KNOW WHETHER THE
T-CELL WE SEE IN THE PARENCHYMA
THE SAME.
THERE IS NO -- WE DON'T KNOW.
>> WHAT DO YOU THINK IS THE
MECHANISM BY WHICH CELLULAR
ENTRY IS RESTRICTED TO THE
CHROID PLEXUS AS DISTINGUISHED
FROM ALL THE OTHER TYPE
JUNCTIONS IN THE NERVOUS SYSTEM?
AND ASKED A FINNESTRA PLAY ANY
ROLE IN THIS PROCESS?
>> SO, THE DIFFERENCE BETWEEN
THE CHROID PLEXUS IS BECAUSE THE
ONLY PLACE WHERE IT IS NOT
ENDOTHELIAL
[ INAUDIBLE ]
IT'S EPITHELIAL CELLS CONNECTED.
WHERE IT IS NOT CONNECTED OF THE
CHROID PLEXUS WHERE MADE BY
EPITHELIAL CELLS AND EPITHELIAL
CELLS SAYS ONCE IT IS ACTIVATED,
CAN PASS THROUGH.
>> THANK YOU.
[ APPLAUSE ]
-------------------------------------------
'Europe in nuke danger' NATO chief warns North Korea missiles CAN strike continent - DAILY NEWS - Duration: 2:06.
'Europe in nuke danger' NATO chief warns North Korea missiles CAN strike continent
EUROPE is within the missile strike range of North Korea, NATO's chief has apocalyptically
warned.
Ahead of his visit to Japan and South Korea, Jens Stoltenberg said rockets from the rogue
state could be fired at NATO members.
He said: "We recognise that Europe has also entered the [North Korean] missile range,
and NATO member states are already in danger.
"NATO has protected its member countries from the threat of ballistic missiles through
deterrence.
"NATO has the capabilities and the resolve to respond to any threat and to any aggressor."
His comments confirm fears that Kim Jong-un's regime has developed intercontinental missiles
(ICBMs) that can travel thousands of miles.
But Secretary General Stoltenberg also said the alliance is desperate to prevent a war
from erupting.
He added: "No NATO allies and of course NATO do not want war… that would be a disaster."
His comments come as US Defence Secretary James "Mad Dog" Mattis warned on Saturday
the risk of a nuclear missile attack by the regime is peaking.
He said: "North Korea has accelerated the threat that it poses to its neighbours and
the world through its illegal and unnecessary missile and nuclear weapons programs."
North Korea has also been carrying out mass blackout drills in its east coast cities and
towns.
In a sign the regime fears a bombing campaign by the United States, citizens practised the
evacuation campaigns over the weekend.
-------------------------------------------
Batteries Made with Asphalt Can Charge in 5 Minutes - Duration: 2:49.
Batteries Made with Asphalt Can Charge in 5 Minutes
Lithium batteries made with asphalt could charge 10 to 20 times faster than the commercial
lithium-ion batteries currently available.
The researchers developed anodes comprising porous carbon made from asphalt that show
exceptional stability after more than 500 charge-discharge cycles.
A high-current density of 20 milliamps per square centimeter demonstrates the material's
promise for use in rapid charge and discharge devices that require high-power density.
"The capacity of these batteries is enormous, but what is equally remarkable is that we
can bring them from zero charge to full charge in five minutes, rather than the typical two
hours or more needed with other batteries," says James Tour, the chair in chemistry and
a professor of computer science and of materials science and nanoengineering at Rice University.
The Tour lab previously used a derivative of asphalt—specifically, untreated gilsonite,
the same type used for the battery—to capture greenhouse gases from natural gas.
This time, the researchers mixed asphalt with conductive graphene nanoribbons and coated
the composite with lithium metal through electrochemical deposition.
The lab combined the anode with a sulfurized-carbon cathode to make full batteries for testing.
The batteries showed a high-power density of 1,322 watts per kilogram and high-energy
density of 943 watt-hours per kilogram.
Testing revealed another significant benefit: The carbon mitigated the formation of lithium
dendrites.
These mossy deposits invade a battery's electrolyte.
If they extend far enough, they short-circuit the anode and cathode and can cause the battery
to fail, catch fire, or explode.
But the asphalt-derived carbon prevents any dendrite formation.
An earlier project by the lab found that an anode of graphene and carbon nanotubes also
prevented the formation of dendrites.
Tour says the new composite is simpler.
"While the capacity between the former and this new battery is similar, approaching the
theoretical limit of lithium metal, the new asphalt-derived carbon can take up more lithium
metal per unit area, and it is much simpler and cheaper to make," he says.
"There is no chemical vapor deposition step, no e-beam deposition step, and no need to
grow nanotubes from graphene, so manufacturing is greatly simplified."
The research appears in the journal ACS Nano.
Visit the website.
Click below
-------------------------------------------
Hyouka: You can't escape『Kimi ni Matsuwaru Mystery』ED / Ending (FULL HD - 1080p) - Duration: 1:32.
For more infomation >> Hyouka: You can't escape『Kimi ni Matsuwaru Mystery』ED / Ending (FULL HD - 1080p) - Duration: 1:32. -------------------------------------------
Can This Family Heal from the Damage of Addiction? - Duration: 1:36.
For more infomation >> Can This Family Heal from the Damage of Addiction? - Duration: 1:36. -------------------------------------------
Hyouka: You can't escape『Mikansei Stride』OP / Opening (FULL HD - 1080p) - Duration: 1:32.
For more infomation >> Hyouka: You can't escape『Mikansei Stride』OP / Opening (FULL HD - 1080p) - Duration: 1:32. -------------------------------------------
Can a Roblox noob get a girlfriend? - Duration: 8:41.
Today we will see if a roblox noob can get a girlfriend?
-------------------------------------------
O APOCALIPSE | Can you escape #1 - Duration: 15:36.
For more infomation >> O APOCALIPSE | Can you escape #1 - Duration: 15:36. -------------------------------------------
This video can change your life,with Hindi subtitles(Dont give up) - Duration: 12:52.
The major mistake that everybody makes is waiting.
Waiting for somebody to pick you.
Waiting for the right time.
Waiting for you to feel motivated.
It's not coming!
For the big stuff, for the hard stuff, it requires a push.
Always has. Always will.
Nobody it's coming to save your ass.
It is up to you!
And so, if you wanna change anything about your life, stop sitting around and wasting your god damn life.
And start pushing yourself.
Whether it's a fast or it is starting a business or it is changing how you talk to your spouse,
or it's changing the kind of parent that you are,
you got one life!
And all you need to do is turn on the freaking news and see the kind *** it's going on in this world.
It's both amazing and terrifying.
You never know when your time is up.
But I do know that you've got time right now to change things.
And so, the thing you should change is you should take 100% responsibility for your future.
You should decide what is it that you really want your life to look like.
Cause you only get one of them.
And it's not gonna start again.
But you could start building your future right now.
And that begins the moment that you realize that you're never gonna feel like doing things that are hard.
You're never gonna feel like stepping out of your comfort zone.
And the second that you do,
the second that you push through,
you win!
YOU WIN!
Because you see yourself becoming the kind of person who takes action.
You see yourself believing in your ideas.
You see yourself disregarding your own excuses.
That is the source of confidence.
It's the willingness to try.
It doesn't start with belief.
It starts with a push.
So do yourself a favor.
And stop thinking about all this stuff.
And stop commenting.
And push yourself.
Do something!
It is what it is.
You know, we talk about overcoming objections,
but a lot of times we don't know exactly what those objections will be.
And sometimes they can come up and it can become so overwhelming that we didn't anticipate that.
We didn't know.
We just...
You gotta still aim to do.
And still believe and recognize that they are things that are...
It's always worth it to do your best.
And to believe in something.
And to work towards the attainment of the goal.
And if it is...
but you have to expand your vision...
then you climb higher and you do that and you don't be afraid to do your best.
There are times in life when we feel like we're going in circles.
We're doing the right thing but not making much progress.
We don't see anything changing.
It's easy to lose our passion and get discouraged.
But one test we all have to pass it's being faithful when nothing new it's happening.
We're just going to work.
Raising children.
Coming home.
Doing the same thing again.
It's easy to be our best when we're getting good breaks.
Things are falling into place.
That doesn't take much faith.
But what about when you're working hard but not getting the credit?
You're being your best but your marriage isn't improving.
When you're faithful in the routine, something is happening that you can't see.
Your character is being developed.
The routine of this life is not exciting but it is necessary.
You won't become all you were created to be without being your best when it's mundane.
Being excellent,
having a good attitude,
when it's just another ordinary day.
Nothing exciting it's happening.
You're just singing in the choir another Sunday.
Going to work with a smile another week.
Doing the right thing with a good attitude another month.
You could see it as boring; "When is this going to change?"...
But if you understand this principle, you are being prepared.
When you're faithful in average days then you will see exceptional days.
But sometimes we're frustrated because we know we have more in us , but we are not seeing it happen.
We don't understand why we are not making progress.
Be faithful in the routine!
What's in your future it's going to be more rewarding, more exciting than anything you've imagined.
I'm challenging you to stay faithful in the routine!
As Michelangelo said:
And that's the thing about getting great.
That's the thing about being an artist of such caliber that you're remembered for hundreds of years after your death.
It is back breaking work.
It is a blinding amount of effort.
It isn't about natural talent.
That myth that some people are born with something that we celebrate so much, it's just that: a myth!
You're born a lump of flesh.
You can't hold your own head up.
You may have predispositions but that is a long way from actually crafting your ability and to the point where it looks like magic.
And that's the beauty of artistry, isn't it?
That is so unbelievable that you're more willing to believe that it was God-given.
That they were anointed with it.
Than that they just worked their ass off.
But the truth is every one of the great's, no matter how much natural talent they were born with,
they're remembered because they worked.
They're remembered because they did so much work.
Because in that work it's hardship.
In that work it's difficulty.
In that work, it's unbearable adversity.
But it's in that adversity that the magic happens.
And as Victor Hugo said:
So I know, right now you wish you'd been born with some talent.
You wish that all those dreams that you had they were yours for the taking.
That you didn't have to put blood, sweat, and tears into it.
That somebody would hand you at least something in the beginning.
That they would give you some starts.
Some spark.
That's where the monsters created.
If you really wanna get hard,
if you really wanna get tough,
if you wanna get great,
if you wanna be un****ing touchable,
because no one can bend or break your vision of yourself,
then you have to suffer.
That's the way of the world.
And as Florence Nightingale said:
And that's the secret.
At the end of the day, if you know what you want,
it's only a question of whether you're willing to pay the price to get there.
So ask yourself:
Are you willing to pay the price?
I wanna talk to you today about staying committed.
We all have opportunities to give up on what we're believing for.
Walk away from an uncomfortable situation.
Slack off. Not be our best.
But if you're going to reach your highest potential, you have to stay committed.
You can't be moved by what's not working out.
Give up on a child because he's not doing what he should.
Slack off at work cause you're not being treated right.
You have to have a made up mind that you are in it for the long haul.
It may be difficult,
you have a good reason to walk away.
Don't take the easy way out.
Stay committed to your marriage.
Stay committed to raising those children.
Stay committed to your friends.
They may make mistakes, give them some grace.
Don't be a fair weathered friend.
Be committed in the good times and the tough times.
Stay committed to your job.
Be a loyal person.
Somebody they can count on.
Day in and day out.
You're not always going to feel like it.
There will be good days and tough days.
Times when it's exciting.
Times when you feel like giving up.
That's when you have to dig your heels in and say:
"I'm going to do the right thing when it's hard!"
"I'm committed to this marriage!"
"I'm going to love you even though you don't deserve it!"
"I'm committed to this job!"
"I'm gonna be my best even though my supervisor isn't treating me right!"
"I'm committed to my dreams!"
But too many people are wishy-washy.
They'll love you as long as you perform perfectly.
If not, they're out of there.
They'll be their best if you keep them encouraged.
Keep them pumped up.
They'll pursue a dream as long as they're getting good breaks.
Their commitment is based on things going their way.
But when it's difficult, when it's taking longer than they thought,
they get discouraged.
Start to slack off.
"Well, they don't pay me enough!"
"I'm undervalued!"
"If they would pay me more, I would do more!"
But if you don't pass the test of being your best where you are,
showing up on time with a good attitude,
doing more than you have to...
"But Joel, it's difficult to stay committed to my job!"
"Committed to my marriage!"
"Commited to this dream!"
"Nothing is going my way!"
If it was easy, everyone would do it!
I've heard it said:
"On the road to your destiny, halfway through every person will be tempted to give up."
"Some turn around and go back."
"The others stay committed and keep moving forward."
What's interesting it's both people travel the same distance.
One goes halfway back to where they started.
The other goes halfway ahead and reach their goal.
Committed people outlast the difficulty.
Committed people stick with a relationship even though they have the right to walk away.
Committed people go the extra mile and do more than they have to.
1960 a young man opened a pizza place in Michigan.
He was an orphan that had been raised in a Catholic orphanage.
He borrowed 900$ and started this small pizza place.
He had all kinds of bad breaks.
A business partner got into his account and stole several thousand dollars.
His life savings.
1968 a fire burned his building down.
The insurance company paid him a penny on the dollar.
He could've gotten discouraged.
Thought this is not meant to be.
But this young man stayed committed to the dream.
He had an idea.
Instead of people having to come to get their pizza,
he decided to take the pizza to the people.
He came up with the first delivery service.
He called it Domino's.
He started with one restaurant, 900$.
Today there are over 6000 Domino's.
Two years ago, Tom Monaghan sold his company for a billion dollars.
He's incredibly generous.
He helps underprivileged children around the world.
Stay committed!
Keep doing the right thing!
You can't see it, put up in front of you it's a double portion.
-------------------------------------------
[ENGLISH] Writing in the air? This pen can draw in 3D! | Tipeye 3D Pen – Unboxing & Review - Duration: 1:36.
Hey guys and welcome to another video.
I got a cool 3D pen from the company "Tipeye" for free, which I am going to show you in
this video.
When you open the box, the first thing you will see is a little manual.
Then you can find the 3D pen there.
Moreover you can find a PLA filament, an USB cable, a power supply and a pen holder in
the package.
For using the pen, I am going to connect the USB cable with the power supply and connect
the cable to the pen, too.
Then I am going to insert the filament and connect the power supply to a socket.
At first, I will need to choose which type of filament it is.
In this case there's already written "PLA", so I only need to press this button.
Now, I have to wait, until the pen is hot enough.
When the LED is green, I can start using the pen.
If I press this button again, the filament will come out.
If I want to remove the filament, I only need to press the other button.
A very cool aspect is that you can really write in 3D with this pen.
So I can draw in the air a little bit.
It was not that easy to draw with is, but after trying it for a few times, it became
much easier.
After testing it a lot and creating many 3d models there's still much filament left.
So you can create a lot of things only with one filament.
Later you can also buy more filaments in the web for a few cents.
In can say in conclusion that this 3D pen is a very cool alternative to a 3D printer.
Using it is also very easy.
Now, it costs 36, 99 $ btw.
I think that's really ok.
That's all for this video, If you liked this video, you can subscribe to my channel.
Have fun with this pen, and see you in the next video.
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How Do We Know That God Can Sympathize with Our Weaknesses? - Duration: 4:25.
So how do we know that God Himself can sympathize with our weaknesses? One of
the most frustrating things for me in being in a friendship with God is that
whenever anything goes wrong, it's always my fault. God's perfect. Nothing goes
wrong for Him. He never makes any mistakes. He knows everything. He's got
all power. Everything is just right with Him. Anything goes south, it's always on
my shoulders. And that will give us sometimes the the tendency to think, well
God doesn't understand. I mean, He might know academically because He's
omniscient, but empathizing, sympathizing, being in it with us, knowing how we feel,
experiencing that with us, well, that's something that He is simply not capable
of doing. He's way out there. Okay, now the answer to that is actually quite
unique, in a way. Sympathy, like empathy I think, they're similar, is the ability to
feel for another person because you've been there yourself. Now, has God been
there before the incarnation? No. After the incarnation? Absolutely. In fact,
you can read in Hebrews chapter 2, I think it's 14 through 18 right in
there, that the Son took on flesh and blood to be like us, to endure what we
endure, to feel what we feel, to experience what we experience, so that
as the text says – and by the way, the experiences of temptation as well.
Temptation beyond what any of us would ever experience because remember, Jesus
had the power to do a whole lot of things we couldn't do. Turning stones
into bread - that's not a temptation for me. I don't know about you, but I can't do
that. Jesus could but said no. So He's got more temptation.
He's been tempted in all ways like as we are but without sin, so now He's able to
run to the cry, the writer of Hebrews says, of those who are tempted. Now we've
got a great High Priest in Jesus, the God Man who knows, who's experienced it, who
has been there in spades, so to speak, so that He can understand,
and this is why Jesus says come unto me all who are weary and heavy-laden and I
will give you rest. Do you think Jesus understood what it was like to be weary,
to be heavy laden, to in a certain sense, I don't know if overwhelmed is
quite the right word, but severely put upon? Every kind of distress that you
could possibly imagine in terms of the category. Whether it was physical
suffering, emotional suffering, friends leaving, friends dying, people turning
against you, living perfectly without ever doing anything wrong and people
leveling charges that were undeserved at you. Charges that were so severe they
called for the death penalty which He suffered. No, Jesus gets it. Jesus can
sympathize. Can God sympathize? Yes, the God Man, Jesus
of Nazareth, knows, understands, and can sympathize with us. Good thing. Good thing.
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How heavy a loss love can be | Dean + Cas (+13x03) - Duration: 1:30.
Sam: Maybe we can bring him back, like you said.
Dean: No, we can't.
Missouri: I'm sorry for your losses.
Sam: I mean, if we pray to him, or, or...
Dean: You don't think I've tried that?
Dean: Please.
Dean: Please help us.
Dean: God's not listening.
Sam: But we've been down before.
Sam: I mean rock bottom.
Sam: And we find a way.
Sam: We fix it, because that's what we do.
Dean: It got him dead! Now you might be able to forget about that, but I can't!
Dean: Cas, he is my best friend.
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When it Comes to Just Say No, There Can Be Only One - Duration: 38:34.
For more infomation >> When it Comes to Just Say No, There Can Be Only One - Duration: 38:34. -------------------------------------------
How the States Can Save America - Duration: 5:42.
The federal government has become a lumbering giant.
With each passing year, it gets bigger and scarier.
In 1965, Washington was 761 billion dollars big.
In 2016... it was 3.5 trillion – five times the size.
If the government spent only the money it collected in taxes, that would be one thing.
But it always spends more — which is why we're $20 trillion dollars in debt.
That's 13 zeroes.
Count 'em: Thirteen.
But the crazy spending isn't even the worst of it.
Washington is involved in every part of our lives.
Think about anything you do, from driving your car to buying your groceries
to mowing your lawn.
Whatever it is — your education, your job, your health — the government has its hands
on your shoulder, if not on your throat.
As a congressman and senator for 14 years, I know this only too well.
So, how do we cut this giant down to size?
Is it even possible?
Yes.
And the amazing thing is, the answer is right in front of us.
The Founding Fathers, in their wisdom, foresaw the situation we find ourselves in today.
They wrote into the Constitution a way to repair Washington...not from the inside,
because that will never happen but from the outside, where it might.
It's right there in Article 5.
Most people are familiar with the first part: "The Congress, whenever two thirds of both
houses shall deem it necessary, shall propose amendments to this Constitution..."
All 27 Amendments we have now started this way.
Congress proposed them and at least three-quarters of the states ratified them.
But is this the only way to amend the Constitution?
Well, let's read the next clause: It says that Congress, "…on the application of
the legislatures of two thirds of the several states, shall call a convention for proposing amendments..."
Did you catch that?
Congress must call a convention to amend the Constitution if two-thirds of the states
— that's 34 states — demand it.
The time has come to demand it.
The time has come to propose amendments that will restore
meaningful limits on federal power and authority.
The time has come for a convention of states.
Here's how it would work: Once the 34 states call a convention, all 50 states send a delegate
to represent their interests.
For any constitutional amendments proposed, each state gets one vote.
And an amendment only passes out of the convention and to the states for ratification if a majority
of the states' delegates vote in the affirmative.
In this scenario, Congress has no say.
It is completely in the hands of the states, which means it's a whole lot closer
to the hands of the people.
We've never once amended the Constitution this way — but that doesn't mean we can't.
But, you might ask, doesn't this open the door to rewriting the entire Constitution?
Antonin Scalia, the late Supreme Court justice, acknowledged this risk, but regarded it as
a "minimal" and "reasonable" one.
Why?
Because to be ratified, a proposed amendment would need the approval of 38 states.
That's a high bar.
Thirty-eight states would never agree to something radical like abolishing freedom of speech.
"The Founders," Scalia said, "knew the Congress would be unwilling to give attention
to many issues the people are concerned with, particularly those involving restrictions
on the federal government's own power... [so] they provided the convention [of states]
as a remedy."
This should not be a partisan, left/right, Democrat/Republican issue.
This should be a "who controls your life" issue: you or the government?
Today, politicians can turn your life upside down on a whim, kind of like King George in 1775.
Being at the mercy of distant, disconnected rulers was why the American Revolution was
fought in the first place!
But we don't need a revolution.
We have Article Five.
So, what amendments might a Convention of States propose to limit Washington's power?
Term limits, for one.
No one should be in Congress for 20 or 30 years.
The only people who disagree have been in Congress for 20 or 30 years.
And how about a limit on taxes, spending and borrowing?
Since you began this video, the national debt has gone up $8.4 million dollars.
Here's one more idea: A constitutional amendment that Congress can't exempt itself
from the laws it passes — something it's done dozens of times, from insider trading to Obamacare.
Now, I don't believe a Convention of States will solve all of America's problems.
But the Founders put it in the Constitution for a reason.
They knew a time would come when Washington would become so big, and so intrusive,
that only we the people could cut it down to size.
That time is now.
I'm Jim DeMint for Prager University.
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Why We Fear What We Can't Control: Airplanes, Hospital, Old Age | Tali Sharot - Duration: 6:56.
When we want to change people's behavior, we often say, "Do this.
Don't to do that."
Basically we are, a lot of times, giving orders—whether it is to our kids, people in our family, people
that we work with—we are exerting control over others or at least attempting to exert
control over others.
But what we find is that what the brain is trying to do... it's trying to control its
environment.
That's one of the major goals of what the brain is trying to do.
And it's trying to do that in order to get rewards and avoid losses.
And because of that, in the brain control has been associated with something good, with
a reward, and it's something that people seek out.
If people can make a choice, the same part of the brain that is activated when people
get a piece of food like a piece of chocolate is activated when people have the opportunity
to make a choice.
When people don't have an opportunity to make a choice, when they feel they don't
have control, what is triggered is anxiety.
And so what this means is that giving people a choice—giving people a sense that they
are in the control, that they have agency—is more likely to motivate them, is more likely
to put them in the frame of a reward rather than a loss.
And because control in and of itself is rewarding, a lot of times people will be willing to give
up other kinds of rewards like monetary rewards in order to have control.
For example, in a study that I conducted with my colleagues we gave people the opportunity
to either make choices themselves about random shapes that can give them rewards, or give
another person, an expert, an opportunity to make a choice for them.
And what we found is that people sub-optimally make the decision to keep the agency, to keep
the choice themselves rather than have an expert make the choice for them even if the
expert was more likely to choose the correct thing, to choose a thing that will get them
more money.
So a way to think about it: it's a bit like the stock market.
So a lot of people like to pick their own stocks instead of giving someone else the
opportunity to choose for them—experts are even better, going according to an index.
And the reason that people like to pick their own stocks is because it gives them a sense
of control, it gives them a sense of agency, and that gives them reward.
And many times people realize that there might be a monetary loss.
Some people are overconfident, they think well I'll pick the right thing, and that's
fine, but they still are willing to lose part, to have a monetary loss, to make the choice
themselves.
So in fact in general people prefer to make their own choices, but there are incidents
where people would rather give away their choice.
For example, when the choice is so complicated, the effort is so... so much effort has to
be put into it...
I would rather not do it and give someone else the opportunity to make the choice for
me.
Or for example, under high amounts of stress people sometimes realize that it's better
to have someone else make the choice for them.
Or for example, when making a choice people are afraid that they will regret what they
choose (such as in medical decisions) they sometimes actually prefer to have someone
else make the choice for them.
And in the book I talk about the things that people are scared of the most, and the fears
that we have are not necessarily rational.
So people, for example, a lot of people are scared of flying; so if you look at the numbers
flying is not necessarily the most dangerous thing that you do.
Driving your own car is more dangerous, but people are afraid of flying because one of
the reasons is that once you're in the plane you don't have control anymore, you don't
have control over the plane, you don't have control of anything really of your environment.
So the sense of being in this space where you're losing control completely, giving
it to someone else, is something that people feel anxious about.
Now, they don't want to take control.
I don't want to fly the plane.
I know I will be dead if I fly the plane, but never the less I feel anxious, and I think
that's true in other domains like health.
One of the reasons that being in a hospital is anxiety-provoking, not only because you're
sick—and that's very anxiety provoking—but also because, again, you lose control.
Everyone is making the decision for you, as they should: the doctors and the nurses.
I mean people should have some say, but they realize that the experts are making the choices
for them and that sense of losing control, again, can cause anxiety.
And one thing that studies have shown is that as we age, as we go into older age we lose
some of our control (especially if we go to nursing homes).
Other people make the choices for us and that induces stress on an individual as well, because
no longer can I choose what will I do and when will I do it, and giving people a sense
of control back can help them.
Again, with kids, people tend to tell kids exactly what to do, when to do it and so on,
and kids are not happy with that.
But we could change that: instead of telling the kids, "Well you have to eat your salad,"
maybe say, "Well why don't you create your own salad?
Here are the different ingredients, and put them together—create them."
And one study that we've done showed that when people—and is not only us, we did one
example of this, there's many, many studies showing that—when you create something you
value it more.
So we did a study where people created their own Converse shoes and they liked the Converse
shoes that they created much more than the Converse shoes which looked exactly the same
that someone else created—same color or same shape everything was exactly the same—but
if I created it I liked it more.
Moreover, even if I didn't create it but I thought I created it, I believed I created
it, I wrongly had a memory that I created the shoe, I liked it better.
So if you feel like you have agency in something—whether it's a product, whether is an idea—then
you feel like it's worth more.
And it doesn't actually have to be a true perception, you just have to have a perception
of an agency, a perception of a control in order to value that thing more, and that's
what we've shown in our study looking at how people create shoes and how they value
them.
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