Thứ Hai, 30 tháng 10, 2017

Youtube daily can't pay Oct 30 2017

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.

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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

For more infomation >> Can Demarcus Cousins Boogie With Anthony Davis And Make An Underdog Title Run - Duration: 7:21.

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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!

For more infomation >> Alcohol in the sky - when and how much can we drink? And where for free? AeroVlog [ENG+SUBS] - Duration: 3:26.

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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.

For more infomation >> How can you illustrate the expansion of space from the absolute beginning of the universe? - Duration: 4:19.

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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.

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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 ]

For more infomation >> Systemic immunity protects the mind: Can immune checkpoint blockade combat Alzheimer's disease? - Duration: 1:00:13.

-------------------------------------------

'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.

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-------------------------------------------

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

For more infomation >> Batteries Made with Asphalt Can Charge in 5 Minutes - Duration: 2:49.

-------------------------------------------

Hyouka: You can't escape『Kimi ni Matsuwaru Mystery』ED / Ending (FULL HD - 1080p) - Duration: 1:32.

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Can This Family Heal from the Damage of Addiction? - Duration: 1:36.

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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.

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Can a Roblox noob get a girlfriend? - Duration: 8:41.

Today we will see if a roblox noob can get a girlfriend?

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-------------------------------------------

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.

For more infomation >> This video can change your life,with Hindi subtitles(Dont give up) - Duration: 12:52.

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[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.

For more infomation >> [ENGLISH] Writing in the air? This pen can draw in 3D! | Tipeye 3D Pen – Unboxing & Review - Duration: 1:36.

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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.

For more infomation >> How Do We Know That God Can Sympathize with Our Weaknesses? - Duration: 4:25.

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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.

For more infomation >> How heavy a loss love can be | Dean + Cas (+13x03) - Duration: 1:30.

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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.

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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.

For more infomation >> How the States Can Save America - Duration: 5:42.

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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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