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>>WELCOME TO SYMPOSIUM

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HAVE BEEN MORE DIFFICULT TO

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DEVELOP AND RECENT INVESTMENT

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FROM THE NIH COMMON FUND AND

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RELATED FUNDING AGENCIES TO

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ADDRESS THIS ISSUE HAS RESULTED

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IN THE DEVELOPMENT OF THE NEXT

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GENERATION TOOLS DESIGNED TO

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DEVELOP RATE COMPLEX CA CAR BOW

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HIGH DATE STRUCTURES AND RELATED

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MICRO INTERACTIONS TODAY WE ARE

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EXTREMELY LUCKY TO HAVE SUCH A

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DIVERSE SET OF SPEAKERS TODAY.

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21 AMAZING SCIENTISTS HAVE

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JOINED REPRESENTING A DIVERSE

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REPERTOIRE TO COVER SUCH GROUND

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THAT THIS CROSS ROADS AND YOU

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WILL NOTICE THAT THEIR TALK WILL

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INTERSECT DIFFERENT PIECES OF

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THESE CROSS ROADS AND EXCITING

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FOR HAVING SO MANY EXPERTS ON

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THIS SYMPOSIUM PANEL AND THERE'S

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OVER 800 OF YOU JOINING ON-LINE

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SO THERE'S A WAY JUST SOME

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GROUND RULES, THERE'S A WAY TO

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ASK QUESTIONS.

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OUR SPEAKERS HAVE STRUCTURED

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TALKS AND THERE'S TIME AT THE

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END OF THEIR TALK FOR SOME

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DISCUSSION AND IN ADDITION, IF

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YOU ARE JOINING US IN THE

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VIRTUAL PLATFORM, THERE'S SOME

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WAYS THAT YOU CAN ASK QUESTIONS

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AND THERE'S A POP-UP LIVE

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FEEDBACK ASK A QUESTION.

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TYPE YOUR QUESTION IN THERE AND

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IT WILL BE DIRECTLY ASKED TO THE

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SPEAKERS IN THE ROOM AND IN

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ADDITION IF THEY DON'T HAVE A

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CHANCE TO ASK OR ANSWER YOUR

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QUESTIONS, THE SPEAKER WILL HAVE

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YOUR E-MAIL ADDRESS AND E-MAIL

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YOU AN ANSWER AND IT WILL IF SIL

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TATE A DISCUSSION POST

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SYMPOSIUM.

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THANK YOU FOR JOINING.

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IT'S BEEN REALLY GREAT TO PUT

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THIS TOGETHER WITH MY CO

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ORGANIZERS SEAN STOWWELL UP AT

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THE HOSPITAL AT HARVARD MEDICAL

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SCHOOL AND WE ARE REALLY VERY

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GRATEFUL TO THE COMMON FUND FOR

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FUNDING AND ORGANIZING AND

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HELPING, ESPECIALLY Dr. PAMELA

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MORENO AND THANK YOU, VERY MUCH.

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WE'RE EXCITED TO GET STARTED.

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VICTOR NIZET WILL START US OFF.

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HE IS COMING TO US REALLY EARLY

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IN THE MORNING FROM SAN DIEGO AT

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THE UNIVERSITY OF CALIFORNIA IN

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SAN DIEGO SO THANK YOU VICTOR

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FOR WAKING UP EXTRA EARLY.

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I KNOW YOU ARE AN EARLY RISER

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BUT THANK YOU.

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WE'RE LOOKING FORWARD OF YOUR

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TALK OF BACTERIAL SEPSIS SO

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THANK YOU SO MUCH AND ENJOY YOUR

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TALK.

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>> OK.

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I'D LIKE TO THANK CATHERINE AND

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SEAN FOR THE INVITATION.

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AND I'M A PHYSICIAN SCIENTIST AT

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UC SAN DIEGO AND WE STUDY HOST

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PATHOGEN INTERACTIONS AND INNATE

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IMMUNITY.

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SO, I'M GOING TO TELL YOU A

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LITTLE BIT ABOUT THE PLATELET,

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WHICH IS MAYBE UNDER STUDIED AS

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AN IMMUNE CELL COMPARED TO ITS

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PROMINENT ROLE IN HEMO STAY SIS

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AND THE WORK IS LARGELY LED BY

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THESE TWO IN THE LAB.

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JOSH SUN AND SATOSHI.

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I'M GOING TO TELL YOU TWO

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STORIES ABOUT TRANSLATIONAL

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GLYCOBIOLOGY THAT MIGHT LEAD TO

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DRUG REPURCHASING.

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SO, PLATELETS, ALTHOUGH THEY

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DON'T HAVE A NUCLEUS, HAVE

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GRANULES AND THEY'RE BIO ACTIVE

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MOL ACTUALS THAT PARTICIPATE IN

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CLOTTING INFLAMMATION, BUT THERE

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ARE ALSO CATIONIC PEPTIDES THAT

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HAVE ANTIMICROBIAL ACTIVITIES.

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AND WE HAVE BEEN STUDYING THE

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WAY THAT FRESHLY ISOLATED HUMAN

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PLATELETS INTERACT WITH

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DIFFERENT BACTERIA AND IT'S

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INTERESTING THAT THERE ARE GREAT

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DIFFERENCES IN INDIVIDUAL

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PATHOGENS IN THEIR

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SUSCEPTIBLITY.

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IF YOU RENDER AN ANIMAL, BY

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GIVING THEM A ANTI PLATELET

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ANTIBODY, THEY BECOME

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SIGNIFICANTLY MORE SUSCEPTIBLE

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TO MRSA INFECTION BUT IT HAS NO

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EFFECT ON GROUP B STREP

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INFECTION.

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AND MIXING HUMAN PLATELETS WITH

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BACTERIA, WE CAN SEE THAT MRSA

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GROWTH IS INHIBITED, IN FACT THE

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MRSA ARE KILLED BY THE FRESHLY

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ISOLATED HUMAN PLATELETS AND THE

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GROUP B STREP GROW EVEN FASTER

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THAN THEY WOULD OTHERWISE WHEN

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THEY ARE ENCOUNTERING THE

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PLATELETS.

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AND HERE YOU SEE THAT A MAIN

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REASON FOR GROUP B STREP

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RESISTANCE IS GLYCO BIOLOGICAL

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IN NATURE.

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GROUP B STREP HAS A EXO POLY

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CAPSULE AND ALPHA 2/3 LINK

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TERMINAL ACID IN THE CAP LAR AND

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ON HUMAN CELLS THAT IS OFTEN

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RECOGNIZED ITSELF TO COUNTER

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REGULATE, COMPLIMENT AND OTHER

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IMMUNE ACTIVATION AND YOU CAN

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SEE HERE THAT THE RESISTANCE OF

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THE BACTERIA TO PLATELET KILLING

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DEPENDS ON THE CAPSULE BECAUSE

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IF WE ELIMINATE THE CAP FULL,

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THEY'RE MORE EASILY CLEARED IN

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THE BLOOD AND THIS WAS FULLY

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DEPENDENT ON THE PRESENCE OF

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PLATELETS AND THE CAPSULE MUTANT

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IS MORE SUSCEPTIBLE TO KILLING

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BY HUMAN PLATELETS AND THE

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RELEASE CONTAINING THE

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ANTIMICROBIAL TIDES AND WE CAN

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TREAT WITH A CIALDAISE LEAVING

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THE CAPSULE AND CREATING THIS

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SUSCEPTIBLE TO PLATELET KILLING.

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ALSO, IF YOU TAKE THE PURIFIED

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ANTIMICROBIAL PEPTIDES LIKE

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PLATELET FACTOR 4 AND WE'VE ALSO

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SEEN HUMAN PRESENT IN PLATELET

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GRANULES, THE DEFICIENT MUTANT

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IS MORE SUSCEPTIBLE TO KILLING

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AS DOES THE SIALADATE TREATED

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WILD TYPE BACTERIA.

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IT'S MORE THAN JUST A DIFFERENCE

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IN SUSCEPTIBLITY, WE DISCOVERED

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THE ACID CAPSULE ALSO CONFERS AN

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ABILITY ON THE BACTERIA TO

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SUPPRESS PLATELET ACTIVATION.

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SO IF YOU MEASURE PLATELET

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ACTIVATION BY P SELECTION OR

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GLYCO PROTEIN AND PLATELET

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ACTIVATION YOU SEE THAT THE SIA

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MUTANT LACKING THE CAPSULE AR

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SIGH ALICK ACID -- IT'S
SUPPRESSING

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THE LATE LET ACTIVATION, WHICH

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ARE HERE AND YOU SEE THEM

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ACTIVATING AND DEGRANULATING

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WITH THE SIALIC ACID MUTANT.

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SO, HOW IS THIS WORKING?

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WE HAVE DONE A LOT OF WORK AND

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ONE OF OUR UPCOMING SPEAKERS,

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AMANDA LOUIS, WAS A MAJOR

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CONTRIBUTE OR TO THESE PARADIGMS

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SHOWING THAT GROUP B STREP

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DETACK US SIALIC ACID IS IN

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INHIBITORY SIGNIFICAN SIGLEC ON
THE SURFAC
E

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OF CELLS LIKE MACRO FAGES TO

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INITIATE THROUGH THEIR INTER

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CELLULAR ITE DOMAINS FOSS IF

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TASE ACTIVATION THAT INHIBITS

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PRO INFLAMMATORY SIGNALING

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CASCADES TO IT MIMIC ONE OF THE

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MECHANISMS OF HUMAN HOMEOSTATIC

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IMMUNE REGULATION.

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WE FOUND THAT HUMAN LATE LET'S,

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THIS HADN'T BEEN STUDIED

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EXTENSIVELY, EXPRESS A LOT OF

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THE SAME RECEPTORS IN PARTICULAR

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SIGLEC9 THAT ARE FOUND ON HUMAN

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NEUTRAL FILLS AND MACRO FAGES

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AND THEY ARE ABLE TO BIND TO THE

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PLATELET IN  A SIGNIFICANTLEC

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DEPENDENT MANNER AND HERE YOU

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SEE IN THIS 7.4% PLATELET

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BINDING DROPPING ALL THE WAY

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DOWN TO .9% WHEN YOU ELIMINATE

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THE SIALIC ACID OR BLOCK IT WITH

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AN ANTI BODY.

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WELL, THE BINDING OF THE SEC

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GLEC ON THE PLATELET INHIBITS

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PLATELET ACTIVATION AND WE CAN

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SEE THAT IF WE USE AN ANTI

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SIGLEC ANTIBODY TO BLOCK THE

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ABILITY OF THE BACTERIA, YOU GET

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MORE SIGLEC -- I'M SORRY, MORE

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PLATELET ACTIVATION AND WITH

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MORE PLATELET ACTIVATION YOU

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WILL GET MORE RELEASE OF THE

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ANTIMICROBIAL PEPTIDES.

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HERE YOU SEE THAT IN MIRRORING

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PLATELETS WHICH HAVE SIGLEC E

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WHICH IS SIMILAR TO SIGNIFICANT

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ELECTRIC 9, THEREFORE, THE

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00:11:08,240 --> 00:11:26,040
ABILITY OF THE SO TO SUMMARIZE
THIS FIRST

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STORY, GROUP B, THROUGH IT'S

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SIALIC ACID CAPSULE IS ABLE TO

216
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BLOCK PLATELET ACTIVATION AND

217
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ALSO INHERIT THE ACTIVITY OF THE

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PLATELET PEPTIDES WHICH REN

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DERSE IT ROW CYSTANCE TO

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PLATELET KILLING WHEREAS MRSA IS

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MORE SUSCEPTIBLE.

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SO THE INCREASE ACCEPTABILITY OF

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MRSA IS THE TRANSITION TO OUR

224
00:11:52,040 --> 00:11:53,240
TRANSLATIONAL STORY.

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WE FOUND, IN OUR PATIENT SERIES,

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IN WHICH WE'RE STUDYING

227
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ANTIBIOTIC THERAPY AND SEPSIS

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THAT IF YOU LOCK AT WHAT

229
00:12:03,080 --> 00:12:05,280
CORRELATES TO MORTALITY IN

230
00:12:05,280 --> 00:12:07,880
PATIENTS, IT'S NOT HIGH OR WILL

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00:12:07,880 --> 00:12:09,440
HE WHITE BLOOD CELL COUNT BUT

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LOW PLATELET COUND THAT IS

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STATISTICALLY SIGNIFICANTLY

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ASSOCIATED WITH MORTALITY IN

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PATIENTS WITH A DISEASE FOR

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WHICH MORTALITY IS IN THE 20%

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RANGE AND HAS NOT IMPROVE I
IMPROVED IN

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THE LAST THREE DECADES, EVEN

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WITH ADVANCES IN ICU CARE.

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AND WE HIGHLIGHTED STAFF AUREUC

241
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AND THIS EXAMPLE AND WHEREAS

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IT'S RELATIVELY RESISTANCE TO

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NEWT TRA FILL KILLING IN LABS

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INCLUDING OUR OWN, STUDY ALL

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MECHANISMS FOR THAT SO PLATELETS

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MIGHT BE THE MOST IMPORTANT

247
00:12:54,520 --> 00:12:57,840
IMMUNE CELL IN YOUR BLOOD FOR

248
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STAFF.

249
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AND, WHAT IS INTERESTING IS

250
00:13:00,240 --> 00:13:02,840
THEY'RE GOING MONO A MONO AT

251
00:13:02,840 --> 00:13:03,880
EACH OTHER AND THE PLATELETS

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HAVE THE ABILITY TO KILL THE

253
00:13:06,360 --> 00:13:08,760
STAFF, BUT THE STAPH HAS WEAPONS

254
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TO DEPLOY AGAINST THE PLATELETS.

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WE FOUND, WHEN YOU INFECT A

256
00:13:15,640 --> 00:13:21,160
MOUSE WITH STAPHORIOU IT DRIVES

257
00:13:21,160 --> 00:13:23,800
THE PLATE LESS DOWN AND DRIVING

258
00:13:23,800 --> 00:13:25,680
THE PLATELET DOWN IS A POOR

259
00:13:25,680 --> 00:13:28,200
CONSEQUENCE FOR THE HOST

260
00:13:28,200 --> 00:13:30,840
IMMUNITY BECAUSE WE SHOWED AND

261
00:13:30,840 --> 00:13:39,160
REITERATE HERE THAT EXPERIMENTAL

262
00:13:39,160 --> 00:13:41,320
THROMBOCYTOPENIA IS LESS ABLE TO

263
00:13:41,320 --> 00:13:44,040
CLEAR STAPH AND CLEAR IT IN

264
00:13:44,040 --> 00:13:44,280
VIVO.

265
00:13:44,280 --> 00:13:47,440
WHAT IS DRIVING THE PLATELET

266
00:13:47,440 --> 00:13:50,720
COUNT DOWN, WE FOUND IT'S A

267
00:13:50,720 --> 00:13:52,800
HIGHLY CONSERVED TOXIN STRESSED

268
00:13:52,800 --> 00:13:55,840
BY THE MAJORITY OF STAFF STRAINS

269
00:13:55,840 --> 00:14:00,040
KNOWN AS THE ALPHA TOXIN IN OUR

270
00:14:00,040 --> 00:14:05,240
PATIENT COHORT, THE MORALE ALPHA

271
00:14:05,240 --> 00:14:11,160
TOXIN EXPRESSION THE GREATER OF

272
00:14:11,160 --> 00:14:13,480
THEIR, AND IF MAKE AN ISOGENIC

273
00:14:13,480 --> 00:14:19,120
MUTE AN BACTERIA IN MRSA, WE

274
00:14:19,120 --> 00:14:25,080
FOUND THE DEGREE THE

275
00:14:25,080 --> 00:14:26,560
THROMBOCYTOPENA WAS LESS AND

276
00:14:26,560 --> 00:14:27,840
THAT MUTANT WAS MORE KILLED BY

277
00:14:27,840 --> 00:14:30,320
THE BLOOD OR PURIFIED PLATELETS.

278
00:14:30,320 --> 00:14:36,960
SO, OUR LAB HAS BEEN VERY

279
00:14:36,960 --> 00:14:44,440
INTERESTED IN THEY AR -- THERE
ARE MEDS

280
00:14:44,440 --> 00:14:46,480
THAT HUMANS TAKE THAT TARGET

281
00:14:46,480 --> 00:14:46,840
PLATELETS.

282
00:14:46,840 --> 00:14:48,640
PATIENTS WHO HAVE HAD HEART

283
00:14:48,640 --> 00:14:50,040
ATTACKS OR STROKES AND YOU WANT

284
00:14:50,040 --> 00:14:55,320
TO REDUCE THEIR RISK OF HAVING A

285
00:14:55,320 --> 00:14:59,800
REPEAT EVENT, AS ASPIRIN OR MORE

286
00:14:59,800 --> 00:15:00,720
SOPHISTICATED ANTI-PLATELET

287
00:15:00,720 --> 00:15:00,920
MEDS.

288
00:15:00,920 --> 00:15:06,040
AND WE MIXED EXEMPLARS OF ALL

289
00:15:06,040 --> 00:15:06,640
THESE ANTI-PLATELET MEDS INTO

290
00:15:06,640 --> 00:15:09,840
THE ASSAY OF PLATELET KILLING OF

291
00:15:09,840 --> 00:15:12,240
STAFF AND FOUND THAT ONE CLASS

292
00:15:12,240 --> 00:15:16,160
OF MEDICINE, THE P2Y12

293
00:15:16,160 --> 00:15:18,840
INHIBITORS DRAMATICALLY

294
00:15:18,840 --> 00:15:22,720
INCREASED THE EFFECTIVENESS OF

295
00:15:22,720 --> 00:15:25,440
PLATELET KILLING OF STAPH AND

296
00:15:25,440 --> 00:15:32,440
ROREDUCES THE TOXICITY OF THE

297
00:15:32,440 --> 00:15:34,080
ALPHA TOXIN ON THE PLATELET.

298
00:15:34,080 --> 00:15:38,560
YOU CAN SEE IN VITRO, STHPH,

299
00:15:38,560 --> 00:15:41,160
BASICALLY VAPORIZING PLATELETS

300
00:15:41,160 --> 00:15:45,320
BUT IF YOU HAVE TICAGRELOR THEIR

301
00:15:45,320 --> 00:15:47,600
INTEGRITY IS INTACT IN FACE OF

302
00:15:47,600 --> 00:15:49,640
THE ALPHA TOXIN.

303
00:15:49,640 --> 00:15:55,080
AND IF WE TREATED ANIMALS WITH

304
00:15:55,080 --> 00:15:56,480
TICAGRELOR BEFORE WE GAVE THEM

305
00:15:56,480 --> 00:16:06,280
THE STAPH INFECTION, THIS GOES
BY

306
00:16:06,280 --> 00:16:08,200
BRILLINTA AND IS GIVEN TO

307
00:16:08,200 --> 00:16:10,560
MILLIONS OF AMERICANS, YOU CAN

308
00:16:10,560 --> 00:16:12,960
SEE HERE THE DEGREE IS REDUCED

309
00:16:12,960 --> 00:16:15,480
AND THE ABILITY OF THE BLOOD TO

310
00:16:15,480 --> 00:16:18,040
CLEAR THE PLATELETS AND TO

311
00:16:18,040 --> 00:16:20,040
DEFEND AGAINST STAPH INFECTIONS

312
00:16:20,040 --> 00:16:24,600
IN THE ORGANS IS IMPROVED.

313
00:16:24,600 --> 00:16:31,640
AND HERE YOU SEE LESS DAMAGE.

314
00:16:31,640 --> 00:16:35,320
>> Zahra: TO THE LIVER AND IN

315
00:16:35,320 --> 00:16:36,880
DAMAGEGIVEN A DOSE OF LETHAL

316
00:16:36,880 --> 00:16:39,160
DOSE INFECTION WE SAW

317
00:16:39,160 --> 00:16:41,000
SIGNIFICANT PROTECTION AGAINST

318
00:16:41,000 --> 00:16:43,360
MORTALITY IN THE ABSENCE OF

319
00:16:43,360 --> 00:16:45,920
ANTIBIOTIC THERAPY, JUST BY

320
00:16:45,920 --> 00:16:51,240
ADMINISTERING THIS FDA-APPROVED

321
00:16:51,240 --> 00:16:52,680
ANTI-PLATELET DRUG.

322
00:16:52,680 --> 00:16:54,200
SO A QUIZ THAT I GUESS IS HARD

323
00:16:54,200 --> 00:17:00,400
TO GET AN ANSWER ON-LINE BUT I'M

324
00:17:00,400 --> 00:17:02,520
CURIOUS HOW LONG A PLATELET LAST

325
00:17:02,520 --> 00:17:04,520
IN CIRCULATION.

326
00:17:04,520 --> 00:17:06,040
RED BLOOD CELLS LAST A FEW

327
00:17:06,040 --> 00:17:07,000
MONTHS BUT THE ANSWER TO THIS

328
00:17:07,000 --> 00:17:11,280
QUESTION IS EIGHT OR NINE DAYS.

329
00:17:11,280 --> 00:17:14,000
IT TURNS OUT THERE'S A GLYCO

330
00:17:14,000 --> 00:17:16,840
BIOLOGIC REGULATION TO THIS

331
00:17:16,840 --> 00:17:17,360
PROCESS.

332
00:17:17,360 --> 00:17:18,560
PLATELETS, JUST LIKE MOST OTHER

333
00:17:18,560 --> 00:17:20,400
HUMAN CELLS ARE CAPPED WITH MANY

334
00:17:20,400 --> 00:17:25,080
GLYCO PROTEINS AND THESE HAVE

335
00:17:25,080 --> 00:17:30,280
TERMINAL SIALIC RESIDUE OR

336
00:17:30,280 --> 00:17:34,560
RESIDUE AS THE PLATELET AGES,

337
00:17:34,560 --> 00:17:38,240
THROUGH THE ACTION OF ENDOGENOUS

338
00:17:38,240 --> 00:17:41,840
SOME PRODUCED BY THE PLATELET

339
00:17:41,840 --> 00:17:44,240
ITSELF, THESE TERMINAL SIALIC

340
00:17:44,240 --> 00:17:48,040
ACID RESIDUES ARE REMOVED,

341
00:17:48,040 --> 00:17:50,840
EXPOSING AN UNDERLYING GALACTOSE

342
00:17:50,840 --> 00:17:53,240
WHICH HAS PROTEIN ON THE SURFACE

343
00:17:53,240 --> 00:17:55,920
OF HELP AT SIGHTS IN THE FIRST

344
00:17:55,920 --> 00:18:00,840
LEPTIN DESCRIBED, AT THE NIH IN

345
00:18:00,840 --> 00:18:04,120
FACT, THE ASHWELL-MORELL

346
00:18:04,120 --> 00:18:05,320
RECEPTOR AND THAT'S WHERE

347
00:18:05,320 --> 00:18:09,480
THEY'RE CLEARED IN THE LIFE.

348
00:18:09,480 --> 00:18:09,720
 LIVER.

349
00:18:09,720 --> 00:18:12,200
AS IT AGES IT LOSES THESE SIALIC

350
00:18:12,200 --> 00:18:13,920
ACID AND IT'S CLEARED AND

351
00:18:13,920 --> 00:18:18,360
REPLACED BY NEW PLATELETS FROM

352
00:18:18,360 --> 00:18:22,240
THE MARROW.

353
00:18:22,240 --> 00:18:23,960
STAPH DOESN'T MAKE BUT IT

354
00:18:23,960 --> 00:18:28,840
ACTIVATES THE ENDOGENOUS

355
00:18:28,840 --> 00:18:30,160
ACTIVITY OF PLATELETS, CAUSING

356
00:18:30,160 --> 00:18:36,040
THEM TO MAKE THEMSELVES BALD PRO

357
00:18:36,040 --> 00:18:37,480
PREMATURELY AND THIS DEPENDS ON

358
00:18:37,480 --> 00:18:39,600
THE ACTION OF THE ALPHA TOXIN

359
00:18:39,600 --> 00:18:45,000
AND THIS IS WHAT IS BLOCKED BY

360
00:18:45,000 --> 00:18:49,640
TICAGRELOR SO IN FACT THE

361
00:18:49,640 --> 00:18:53,200
TICAGRELOR IS PREMATURE TICA IN

362
00:18:53,200 --> 00:18:53,760
CLEARANCE OF THE PLATELETS.

363
00:18:53,760 --> 00:18:55,040
THIS IS VERY IMPORTANT BECAUSE

364
00:18:55,040 --> 00:18:58,680
WE ELIMINATE THE ASHWELL-MORELLE

365
00:18:58,680 --> 00:19:02,320
FROM THE LIVER AND THE STAFF

366
00:19:02,320 --> 00:19:04,920
INDUCES NEVER OCCURS AND THE

367
00:19:04,920 --> 00:19:06,640
PLATELET COUNT STAYS HIGH AND

368
00:19:06,640 --> 00:19:09,680
THE ANTI STAPH FUNCTION IS

369
00:19:09,680 --> 00:19:10,840
RETAINED AND THESE KNOCK-OUT

370
00:19:10,840 --> 00:19:16,480
MICE ARE RESISTANCE TO

371
00:19:16,480 --> 00:19:26,600
STAFF-INDUCED SEPSIS BUT THEY'RE

372
00:19:26,600 --> 00:19:31,040
USED IN REDUCING THE SEVERITY OF

373
00:19:31,040 --> 00:19:33,360
INFLUENZA INFECTION AND WE

374
00:19:33,360 --> 00:19:34,560
WONDERED WHETHER WE MIGHT BE

375
00:19:34,560 --> 00:19:41,400
ABLE TO PINO PINOT BENEFIT THIS
BY

376
00:19:41,400 --> 00:19:44,520
BLOCKING THE ACTIVITY SINCE

377
00:19:44,520 --> 00:19:48,200
THESE ARE NOT COMPLETELY SEC FOR

378
00:19:48,200 --> 00:19:50,080
THE BACTERIA ENZYMES BUT ALSO

379
00:19:50,080 --> 00:19:52,000
HAVE ACTIVITY AGAINST THE HOST

380
00:19:52,000 --> 00:19:52,320
ENZYMES.

381
00:19:52,320 --> 00:20:00,640
AND IN FACT, REPURCHASING

382
00:20:00,640 --> 00:20:02,640
OSELTAMIVIR LED TO LESS AND

383
00:20:02,640 --> 00:20:05,320
ANOTHER NON FORM SUED CAL DNA

384
00:20:05,320 --> 00:20:09,640
INHIBITOR, DANA, ALSO HAD A

385
00:20:09,640 --> 00:20:10,640
PROTECTIVE EFFECT IN MICE.

386
00:20:10,640 --> 00:20:12,160
TO SUMMARIZE, WE CAME UP WITH

387
00:20:12,160 --> 00:20:13,920
THIS OBSERVATION THAT PLATELETS

388
00:20:13,920 --> 00:20:16,320
ARE ACTUALLY THE MOST IMPORTANT

389
00:20:16,320 --> 00:20:17,640
CELL IN YOUR BLOOD TO DEFEND

390
00:20:17,640 --> 00:20:21,840
AGAINST THE MOST COMMON SOURCE

391
00:20:21,840 --> 00:20:25,320
OF BACK TO BEEMIA IN THE BLOOD

392
00:20:25,320 --> 00:20:28,640
IN STAPHORIUS THAT KILL THE

393
00:20:28,640 --> 00:20:32,240
STAPH THROUGH ANTIMICROBIAL

394
00:20:32,240 --> 00:20:33,320
PEPTIDES AND THE STAPH IS TRYING

395
00:20:33,320 --> 00:20:36,520
TO DEPLOY A TOXIN THAT CAUSE THE

396
00:20:36,520 --> 00:20:38,800
PLATELETS TO GO BALD AND GET

397
00:20:38,800 --> 00:20:39,600
CLEARED IN THE LIVER AND

398
00:20:39,600 --> 00:20:40,440
UNDERSTANDING THIS PATHWAY

399
00:20:40,440 --> 00:20:42,480
ALLOWS US TO REPURPOSE TWO

400
00:20:42,480 --> 00:20:48,880
COMMON FDA APPROVE DRUGS,

401
00:20:48,880 --> 00:20:50,200
TIKAGOLOR TO IMPROVE OUTCOMES

402
00:20:50,200 --> 00:20:54,640
AND BEE WE'VE BEEN EXPLORING
THIS IN

403
00:20:54,640 --> 00:20:57,040
PATIENTS AND THERE'S ANECDOTAL

404
00:20:57,040 --> 00:21:05,360
CASE REPORTS OF AT STATION OF

405
00:21:05,360 --> 00:21:06,320
TICAGRELOR LEADING TO BLOOD

406
00:21:06,320 --> 00:21:10,240
STREAM CLEARANCE AND RESCUE OF

407
00:21:10,240 --> 00:21:13,400
THE PLATELET COUNT AND ENHANCED

408
00:21:13,400 --> 00:21:14,320
ANTI-PLATELET ACTIVITY AND JUST

409
00:21:14,320 --> 00:21:17,480
PUBLISHED THIS WEEK, A CLINICAL

410
00:21:17,480 --> 00:21:25,000
STUDY LOOKING AT THE OLD SCHOOL

411
00:21:25,000 --> 00:21:26,520
P2Y1 INHIBITOR SHOWING THAT

412
00:21:26,520 --> 00:21:28,760
PATIENTS WHO IN A VERY, VERY

413
00:21:28,760 --> 00:21:31,440
LARGE COHORT WHO HAPPEN TO BE ON

414
00:21:31,440 --> 00:21:34,800
THAT DRUG, HAD DECREASED

415
00:21:34,800 --> 00:21:39,440
INPATIENT AND 30-DAY MORTALITY

416
00:21:39,440 --> 00:21:41,160
COMPARED TO OTHERS.

417
00:21:41,160 --> 00:21:42,560
SO, THAT IS MY TALK.

418
00:21:42,560 --> 00:21:48,240
I WANT TO THANK A LOT OF PEOPLE

419
00:21:48,240 --> 00:21:50,840
INCLUDING MY GLYCOBIOLOGY

420
00:21:50,840 --> 00:21:54,640
MENTORS WHICH INCLUDE JEFF ESCO

421
00:21:54,640 --> 00:21:58,040
AND JAMIE MARTH.

422
00:21:58,040 --> 00:21:59,320
>> EXCELLENT.

423
00:21:59,320 --> 00:22:02,400
THANK YOU FOR A FANTASTIC TALK.

424
00:22:02,400 --> 00:22:07,160
I AM NOT SURE, PAM, I ARE THERE

425
00:22:07,160 --> 00:22:08,440
QUESTIONS?

426
00:22:08,440 --> 00:22:12,280
IF NOT, I CAN ASK YOU A OR IF

427
00:22:12,280 --> 00:22:13,440
OTHERS HAVE A QUESTION.

428
00:22:13,440 --> 00:22:14,720
IF WE HAVE TIME FOR A QUESTION?

429
00:22:14,720 --> 00:22:20,880
>> WE DI DON'T HAVE ANY YET?

430
00:22:20,880 --> 00:22:24,640
I HAVE A QUESTION.

431
00:22:24,640 --> 00:22:26,800
HOW LONG DOES -- DO YOU SEE

432
00:22:26,800 --> 00:22:27,960
RESISTANCE TO THIS?

433
00:22:27,960 --> 00:22:29,280
WILL IT EVENTUALLY BECOME THAT

434
00:22:29,280 --> 00:22:34,040
YOU CAN'T DO THIS

435
00:22:34,040 --> 00:22:34,680
PROPHYLACTICALLY FOREVER?

436
00:22:34,680 --> 00:22:37,840
>> THOSE ARE GOOD QUESTIONS

437
00:22:37,840 --> 00:22:42,400
ABOUT HOST-DIRECTED

438
00:22:42,400 --> 00:22:42,800
THERAPEUTICS.

439
00:22:42,800 --> 00:22:46,200
IN GENERAL IT'S A LITTLE HARDER

440
00:22:46,200 --> 00:22:48,560
FOR A MICROBE TO DEVELOP

441
00:22:48,560 --> 00:22:52,040
RESISTANCE TO AN IMMUNE CELL OR

442
00:22:52,040 --> 00:22:54,640
A, IN THIS CASE THE PLATELET,

443
00:22:54,640 --> 00:22:58,600
THAT HAS BEEN MADE MORE

444
00:22:58,600 --> 00:23:02,040
RESILIENT OR ACTIVATED IN A WAY

445
00:23:02,040 --> 00:23:04,960
TO RELEASE ITS ANTIMICROBIAL

446
00:23:04,960 --> 00:23:07,320
ARSENAL BECAUSE IT'S

447
00:23:07,320 --> 00:23:09,480
MULTIFACETED, RIGHT.

448
00:23:09,480 --> 00:23:10,600
ONE OF THE CORNER STONES OF

449
00:23:10,600 --> 00:23:12,640
AVOIDING ANTIBIOTIC RESIST AS

450
00:23:12,640 --> 00:23:21,840
SOON AS TO USTOUSE IT
SIMULTANEOUSLY TO PU
LL

451
00:23:21,840 --> 00:23:23,760
DIFFERENT DIFFERENT TAG AT THE

452
00:23:23,760 --> 00:23:26,400
TIMING ANTIMICROBIAL AND THAT'S

453
00:23:26,400 --> 00:23:30,240
WHAT A PLATELET IS RELEASING AND

454
00:23:30,240 --> 00:23:31,720
A NEW TRA FILL IS RELEASING IF

455
00:23:31,720 --> 00:23:33,840
IT'S DESIGNED TO ENHANCE THE

456
00:23:33,840 --> 00:23:34,920
RESILIENCE AND THIS WILL BE

457
00:23:34,920 --> 00:23:37,080
OCCURRING IN CONCERT WITH

458
00:23:37,080 --> 00:23:41,800
ANTIBIOTICS, NO ONE WOULD BE

459
00:23:41,800 --> 00:23:51,440
DEPRIVED OF EFFECTIVE.

460
00:23:51,440 --> 00:23:53,320
IT WOULD BE ENGAGING THE IMMUNE

461
00:23:53,320 --> 00:23:55,120
SYSTEM IN A PARTICIPANT AND

462
00:23:55,120 --> 00:23:57,040
IMPROVING TREATMENT OUTCOMES.

463
00:23:57,040 --> 00:23:57,880
>> EXCELLENT.

464
00:23:57,880 --> 00:23:59,680
WE HAVE ONE QUESTION THAT CAME

465
00:23:59,680 --> 00:24:04,800
IN FROM OUR ON-LINE VIEWING

466
00:24:04,800 --> 00:24:05,040
AUDIENCE.

467
00:24:05,040 --> 00:24:07,800
I WONDER WHAT TYPES OF GPS WAS

468
00:24:07,800 --> 00:24:14,280
USED AND SHOW INHIBITED PLATELET

469
00:24:14,280 --> 00:24:19,120
ACTIVATION AND ALL HAVE ALPHA 2,

470
00:24:19,120 --> 00:24:20,040
3 LINKS.

471
00:24:20,040 --> 00:24:24,280
MAYBE SOME SPECIFIC GPC OR CPS9

472
00:24:24,280 --> 00:24:24,640
STRONGER?

473
00:24:24,640 --> 00:24:28,080
>> THAT'S A VERY GOOD QUESTION.

474
00:24:28,080 --> 00:24:30,840
WE ONLY STUDIED THREE ZERO TYPES

475
00:24:30,840 --> 00:24:32,360
OF THE NINE KNOWN BUT TOGETHER

476
00:24:32,360 --> 00:24:35,320
THEY REPRESENT ALMOST 70% OF THE

477
00:24:35,320 --> 00:24:43,400
INVASIVE CASES TYPE 3, TYPE 1-A

478
00:24:43,400 --> 00:24:46,640
AND TYPE 5.

479
00:24:46,640 --> 00:24:50,480
WE SEE THAT ALL GVS ARE

480
00:24:50,480 --> 00:24:52,440
RESISTANT TO PLATELETS BUT WE

481
00:24:52,440 --> 00:24:55,280
ONLY KNOW THAT SIALIC ACID IS

482
00:24:55,280 --> 00:24:55,880
SPECIFICALLY CONTRIBUTING TO

483
00:24:55,880 --> 00:25:01,520
THAT RESISTANCE IN THOSE STRAINS

484
00:25:01,520 --> 00:25:05,440
WHERE WE HAVE ISOGENIC

485
00:25:05,440 --> 00:25:05,720
KNOCKOUTS.

486
00:25:05,720 --> 00:25:08,960
BUT ONE THING THAT IS TRUE, GBS

487
00:25:08,960 --> 00:25:12,120
IN GROUP A STREP GO AVIDLY IN

488
00:25:12,120 --> 00:25:12,640
HUMAN BLOOD.

489
00:25:12,640 --> 00:25:14,480
THEY HAVE NO RESISTANCE.

490
00:25:14,480 --> 00:25:16,440
IT'S AMAZING HOW WE DON'T ALL

491
00:25:16,440 --> 00:25:18,600
DIE WHEN WE GET THESE INFECTIONS

492
00:25:18,600 --> 00:25:20,600
BECAUSE IN THE LABORATORY, OUR

493
00:25:20,600 --> 00:25:25,120
BLOOD HAS NO NEUTRALIZING

494
00:25:25,120 --> 00:25:27,640
ACTIVITIES AND YET, YOU KNOW,

495
00:25:27,640 --> 00:25:30,640
MOST PEOPLE RESIST THESE

496
00:25:30,640 --> 00:25:32,200
INFECTIONS THROUGH MORE

497
00:25:32,200 --> 00:25:35,800
MECHANISMS THAN ARE PRESENT IN

498
00:25:35,800 --> 00:25:36,040
THE BLOOD.

499
00:25:36,040 --> 00:25:36,560
>> GREAT.

500
00:25:36,560 --> 00:25:37,560
THANK YOU SO MUCH.

501
00:25:37,560 --> 00:25:39,360
THAT WAS NICE THAT WE HAD TWO

502
00:25:39,360 --> 00:25:40,720
QUESTIONS FROM EACH SECTION OF

503
00:25:40,720 --> 00:25:41,040
YOUR TALK.

504
00:25:41,040 --> 00:25:42,320
A BEAUTIFUL TALK IN TYING IT

505
00:25:42,320 --> 00:25:44,000
TOGETHER SO NICELY AND THANK YOU

506
00:25:44,000 --> 00:25:45,200
FOR REPURCHASING THOSE ALREADY

507
00:25:45,200 --> 00:25:46,840
USED THERAPEUTICS AND IT'S

508
00:25:46,840 --> 00:25:48,040
AMAZING WORK THAT YOUR GROUP IS

509
00:25:48,040 --> 00:25:49,800
DOING AND THANK YOU FOR LOGGING

510
00:25:49,800 --> 00:25:51,080
ON TODAY TO JOIN OUR TALK.

511
00:25:51,080 --> 00:25:52,480
IT WAS REALLY NICE WORK.

512
00:25:52,480 --> 00:25:54,160
THANK YOU FOR BEING OUT SO EARLY

513
00:25:54,160 --> 00:25:54,560
TOO.

514
00:25:54,560 --> 00:26:01,240
I APPRECIATE IT AND WE'RE GOING

515
00:26:01,240 --> 00:26:02,880
TO SWITCH GEARS TO OUR NEXT

516
00:26:02,880 --> 00:26:06,240
SPEAKER WHO IS LAURA KIESSLING

517
00:26:06,240 --> 00:26:07,800
AND SHE'S GOING TO TALK ABOUT

518
00:26:07,800 --> 00:26:08,360
OUR WORK.

519
00:26:08,360 --> 00:26:13,800
A NICE WAY FROM VICTOR'S TALK.

520
00:26:13,800 --> 00:26:19,000
LEPTIN IS PROBES OF BIOME.

521
00:26:19,000 --> 00:26:20,240
THANK YOU FOR JOINING US.

522
00:26:20,240 --> 00:26:21,720
>> THANK YOU TO THAT ORGANIZERS

523
00:26:21,720 --> 00:26:25,160
FOR PUTTING THIS TOGETHER.

524
00:26:25,160 --> 00:26:28,440
I'M REALLY EXCITED ABOUT TODAY'S

525
00:26:28,440 --> 00:26:28,680
SYMPOSIUM.

526
00:26:28,680 --> 00:26:30,560
SO, AS CATHERINE SAID, I'M GOING

527
00:26:30,560 --> 00:26:34,720
TO TALK TO YOU ABOUT ELECTRIC

528
00:26:34,720 --> 00:26:38,400
TINS AS PROBES AND I WANT TO

529
00:26:38,400 --> 00:26:46,520
START BY

530
00:26:46,520 --> 00:26:48,480
BY -- IT'S ALSO TRUE FOR

531
00:26:48,480 --> 00:26:51,360
BACTERIA AND THIS IS A STREP

532
00:26:51,360 --> 00:26:53,480
PNEUMONIA AND YOU CAN SEE THE

533
00:26:53,480 --> 00:26:55,240
GLYCANS ON THE SURFACE AND WE'VE

534
00:26:55,240 --> 00:26:55,840
JUST HEARD A BEAUTIFUL TALK

535
00:26:55,840 --> 00:27:00,040
ABOUT THE ROLE OF THOSE GLYCANS

536
00:27:00,040 --> 00:27:02,760
IN THE INNATE IMMUNE RESPONSE

537
00:27:02,760 --> 00:27:04,240
AND WE ARE ALSO INTERESTED IN

538
00:27:04,240 --> 00:27:06,440
THAT POINT AND WE'RE INTERESTED

539
00:27:06,440 --> 00:27:09,840
ESPECIALLY IN THE ROLE THAT

540
00:27:09,840 --> 00:27:11,840
LECTINS HAVE TO PLAY SO WHEN YOU

541
00:27:11,840 --> 00:27:15,800
YOU THINK ABOUT HOW WE DECIDE

542
00:27:15,800 --> 00:27:17,840
WHICH MICROBES ARE IN US AND

543
00:27:17,840 --> 00:27:19,560
WHICH ONES WE'LL GET RID OF,

544
00:27:19,560 --> 00:27:22,080
LECTINS ARE THE INTERFACE

545
00:27:22,080 --> 00:27:24,840
BETWEEN THE MICROBES AND OUR

546
00:27:24,840 --> 00:27:25,080
TISSUE.

547
00:27:25,080 --> 00:27:28,360
AND WE CAN ACTUALLY LOOK AT

548
00:27:28,360 --> 00:27:31,560
WHERE THE LOCATION OF LECTINS

549
00:27:31,560 --> 00:27:34,760
ARE VERSUS WHERE WE SEE

550
00:27:34,760 --> 00:27:35,040
INFECTIONS.

551
00:27:35,040 --> 00:27:36,640
YOU CAN SEE THAT THERE'S A

552
00:27:36,640 --> 00:27:38,800
REALLY NICE CORRESPONDENCE.

553
00:27:38,800 --> 00:27:43,040
WE HAVE ELECTRIC KINS A LECTINS
AT THE

554
00:27:43,040 --> 00:27:44,840
INTERFACES WHERE WE FACE

555
00:27:44,840 --> 00:27:46,120
BACTERIAL PATHOGENS BUT OF

556
00:27:46,120 --> 00:27:48,680
COURSE THE SAME PLACES WE FACE

557
00:27:48,680 --> 00:27:53,920
BACTERIAL PATHOGENS WE SPACE

558
00:27:53,920 --> 00:27:54,600
BACTERIAL COMMENCEALS SO THERE'S

559
00:27:54,600 --> 00:27:58,240
A LOT OF INTEREST IN REALLY

560
00:27:58,240 --> 00:28:00,240
UNDERSTANDING HOW THESE

561
00:28:00,240 --> 00:28:01,600
DIFFERENT LECTINS FUNCTION IN

562
00:28:01,600 --> 00:28:04,680
THESE DIFFERENT DISEASE

563
00:28:04,680 --> 00:28:05,680
PROCESSES AND ONE OF THE

564
00:28:05,680 --> 00:28:06,520
SURPRISING THINGS WE FOUND WHEN

565
00:28:06,520 --> 00:28:08,200
WE STARTED LOOKING THAT THE IS

566
00:28:08,200 --> 00:28:12,120
JUST HOW LITTLE THERE IS KNOWN

567
00:28:12,120 --> 00:28:17,240
ABOUT WHAT SPECIFIC MICROBES

568
00:28:17,240 --> 00:28:33,840
THESE ELECTRIC KINS BIND.

569
00:28:33,840 --> 00:28:40,600
IT CAN BLIND ON MICROBES AND

570
00:28:40,600 --> 00:28:43,840
COMPONENTS THAT RESULT IN

571
00:28:43,840 --> 00:28:45,240
FORMATION, FOR EXAMPLE, OF WOMEN

572
00:28:45,240 --> 00:28:50,360
RAINA TACMEMBRANE -- SO THESE
TWO

573
00:28:50,360 --> 00:28:59,040
PROCESSES ALLOW US TO CLEAR

574
00:28:59,040 --> 00:29:00,640
PATHOGENS OR MICROBES THIS

575
00:29:00,640 --> 00:29:01,280
ELECTRIC KIN ENCOUNTERS AND ONE

576
00:29:01,280 --> 00:29:03,000
OF THE QUESTIONS THAT WE HAD IS,

577
00:29:03,000 --> 00:29:05,880
YOU KNOW, THIS IS THE GENERALLY

578
00:29:05,880 --> 00:29:09,040
ACCEPTED ROLE OF LECTINS AND DO

579
00:29:09,040 --> 00:29:10,960
THEY ALL FUNCTION SIMILARLY AND

580
00:29:10,960 --> 00:29:15,080
WHAT ARE THEIR MICROBE

581
00:29:15,080 --> 00:29:15,440
SPECIFICITIES?

582
00:29:15,440 --> 00:29:16,840
SO AS I SAID BEFORE, THAT'S THE

583
00:29:16,840 --> 00:29:18,520
QUESTION THAT WE WANT TO ASK

584
00:29:18,520 --> 00:29:27,080
WHAT IS OUR HUMAN LECTINS

585
00:29:27,080 --> 00:29:28,200
INTERACT TONE.

586
00:29:28,200 --> 00:29:32,440
WE KNOW LECTINS, THE ASSOCIATION

587
00:29:32,440 --> 00:29:36,040
BETWEEN LECTINS AND MICROBES

588
00:29:36,040 --> 00:29:39,920
SEEMS TO HAVE SOME INFLUENCE ON

589
00:29:39,920 --> 00:29:41,120
MICROBIAL BIOME COMPOSITION SO

590
00:29:41,120 --> 00:29:44,120
THIS IS DATA IF YOU KNOCK OUT OR

591
00:29:44,120 --> 00:29:48,760
DELETE MAN OWE BINDING LECTINS

592
00:29:48,760 --> 00:29:50,720
I'VE BEEN DISCUSSION YOU SEE UP

593
00:29:50,720 --> 00:29:52,640
REGULATION OF SOME MICROBES AND

594
00:29:52,640 --> 00:29:56,160
SOME DOWN REGULATION OF OTHERS.

595
00:29:56,160 --> 00:29:58,480
THERE'S ALSO GENOME-WIDE

596
00:29:58,480 --> 00:30:00,640
SEWSIZATION DATA THAT SHOWS THAT

597
00:30:00,640 --> 00:30:02,840
LECTINS CAN BE ASSOCIATED WITH

598
00:30:02,840 --> 00:30:05,040
DISEASES THAT INVOLVE DIS

599
00:30:05,040 --> 00:30:17,000
BIOTICS MIKE CRO HIGH CROW BIOME
HIGH CROW
 BIOME AND WHAT

600
00:30:17,000 --> 00:30:35,480
THESE ARE DOING.

601
00:30:35,480 --> 00:30:40,760
WE FOUND THAT THIS LECTINS IS

602
00:30:40,760 --> 00:30:44,680
HAS A WIDE VARIETY OF MICROBIAL

603
00:30:44,680 --> 00:30:46,040
GLYCANS AND IT'S REALLY NICE FOR

604
00:30:46,040 --> 00:30:50,560
ME BECAUSE WE DID THIS WORK AND

605
00:30:50,560 --> 00:30:52,000
COLLABORATION WITH RICK CUMMINGS

606
00:30:52,000 --> 00:30:53,880
AND SEAN CELL WHO ARE TWO PEOPLE

607
00:30:53,880 --> 00:30:56,240
SPEAKING TODAY SO I'M EXCITED TO

608
00:30:56,240 --> 00:30:57,040
HEAR THEIR TALKS.

609
00:30:57,040 --> 00:31:00,000
WHEN WE LOOKED AT THE

610
00:31:00,000 --> 00:31:02,120
SPECIFICITY, THIS LECTINS BINDS

611
00:31:02,120 --> 00:31:05,800
TO EPITOPE THAT ARE FOUND ON

612
00:31:05,800 --> 00:31:06,840
MICROBIAL GLYCANS AND WE WERE

613
00:31:06,840 --> 00:31:09,080
ABLE TO GET A STRUCTURE SO WE

614
00:31:09,080 --> 00:31:13,640
UNDERSTAND THE SPECIFICITY AND

615
00:31:13,640 --> 00:31:17,640
IF YOU ARE INTERESTED, THERE ARE

616
00:31:17,640 --> 00:31:19,800
PAPERS HIGHLIGHTING THAT.

617
00:31:19,800 --> 00:31:22,080
THIS BINDS TO MICROBIAL SUGARS

618
00:31:22,080 --> 00:31:29,440
AND WE WERE ALSO CURIOUS DOES IT

619
00:31:29,440 --> 00:31:31,400
BIND TO COMMENCE CELLS AND WE

620
00:31:31,400 --> 00:31:36,360
SHOWED BY PAINTING THESE LECTINS

621
00:31:36,360 --> 00:31:40,440
ON TO SLIDES AND THIS IS A MOUSE

622
00:31:40,440 --> 00:31:41,280
SMALL INTESTINE, YOU CAN SEE

623
00:31:41,280 --> 00:31:43,800
THAT THE BACTERIA LIGHT UP AND

624
00:31:43,800 --> 00:31:46,440
WHAT I NEGLECTED TO TELL YOU IS

625
00:31:46,440 --> 00:31:49,680
THIS LEPTIN SAY

626
00:31:49,680 --> 00:31:54,000
CALCIUM-DEPENDENT ELECTRIC TIN

627
00:31:54,000 --> 00:32:03,960
SO WE CAN ADD BDTA AND AND WE
KNOW

628
00:32:03,960 --> 00:32:06,400
THIS LECTIN IS MADE BY CELLS

629
00:32:06,400 --> 00:32:07,880
THAT ARE INVOLVED IN INNATE

630
00:32:07,880 --> 00:32:11,800
IMMUNE DEFENSE.

631
00:32:11,800 --> 00:32:15,280
THESE PENNANT CELLS THAT MAKE

632
00:32:15,280 --> 00:32:15,840
ANTIMICROBIAL PEPTIDES SO WE

633
00:32:15,840 --> 00:32:17,920
KNEW IT HAD THE FEATURES OF AN

634
00:32:17,920 --> 00:32:20,760
INNATE IMMUNE LEPTIN SO WE

635
00:32:20,760 --> 00:32:23,720
WANTED TO STUDY ITS SPECIFICITY

636
00:32:23,720 --> 00:32:25,040
AND I'M GOING TO SHOW YOU A LOT

637
00:32:25,040 --> 00:32:26,920
OF DATA THAT THOSE HUMAN SAMPLES

638
00:32:26,920 --> 00:32:29,800
AND I WANT TO EXPLAIN WHY WE'RE

639
00:32:29,800 --> 00:32:31,440
ESPECIALLY INTERESTED IN LOOKING

640
00:32:31,440 --> 00:32:33,600
AT MIXED COLONIES AND THAT IS

641
00:32:33,600 --> 00:32:35,640
BECAUSE WHEN WE LOOKED AT SINGLE

642
00:32:35,640 --> 00:32:38,400
SPECIES MONO CULTURES, WHICH IS

643
00:32:38,400 --> 00:32:41,600
HOW MANY STUDIES HAVE LEPTIN

644
00:32:41,600 --> 00:32:42,640
SPECIFICITY WERE DETERMINED

645
00:32:42,640 --> 00:32:45,680
RIGHT BINDING TO A SINGLE

646
00:32:45,680 --> 00:32:48,400
SPECIES, WE CAN DETECT BINDING

647
00:32:48,400 --> 00:32:49,960
TO A LOT OF DIFFERENT SPECIES

648
00:32:49,960 --> 00:32:53,040
THAT ARE RELEVANT TO THE HUMAN

649
00:32:53,040 --> 00:32:56,240
GUT AND SO HERE I JUST SHOW TWO

650
00:32:56,240 --> 00:32:57,560
SPECIES WHERE WE DON'T SEE

651
00:32:57,560 --> 00:33:01,640
BINDING SO THIS IS A BACK TA

652
00:33:01,640 --> 00:33:06,480
ROIDY AND WE DO SEE LECTIN

653
00:33:06,480 --> 00:33:10,080
BINDING TO THESE BUT WE SEE

654
00:33:10,080 --> 00:33:11,280
REALLY ROBUST WINDING TO THE

655
00:33:11,280 --> 00:33:13,360
OTHERS SO THAT SUGGESTS THAT IF

656
00:33:13,360 --> 00:33:15,400
WE WERE TO MIX A COLONY TOGETHER

657
00:33:15,400 --> 00:33:16,880
WE COULD SEE BINDING TO THESE

658
00:33:16,880 --> 00:33:24,240
TWO SPECIES, NOT THESE TWO

659
00:33:24,240 --> 00:33:24,480
SPECIES.

660
00:33:24,480 --> 00:33:27,360
THIS IS A OVER LAY OF THE DATA I

661
00:33:27,360 --> 00:33:28,760
SHOWED YOU SO THESE WERE

662
00:33:28,760 --> 00:33:30,440
INDEPENDENT EXPERIMENTS THAT I'M

663
00:33:30,440 --> 00:33:34,240
JUST OVER LAYING AND WHEN WE MIX

664
00:33:34,240 --> 00:33:45,440
TOGETHER AND MAKE A COMMUNITY,

665
00:33:45,440 --> 00:33:48,640
WOOZY THE LECTIN BINDING AND IT

666
00:33:48,640 --> 00:33:50,480
DIDN'T MATTER HOW MUCH LEPTIN WE

667
00:33:50,480 --> 00:33:56,520
ADD WE ONLY SEE BINDING TO THE

668
00:33:56,520 --> 00:33:58,520
RUTER AND I IT'S IN COMMUNITY

669
00:33:58,520 --> 00:34:01,240
AND SO WE WENT ON TO THEN STUDY

670
00:34:01,240 --> 00:34:03,640
THEIR COMMUNITY ACTIVITIES.

671
00:34:03,640 --> 00:34:12,480
SO THE WAY THAT WE'RE GOING TO
DO

672
00:34:12,480 --> 00:34:14,680
THIS IS HE WE'RE FOCUS ON THE

673
00:34:14,680 --> 00:34:16,200
GUT MICROBIOME AND YOU CAN GET

674
00:34:16,200 --> 00:34:19,720
PICTURE BY LOOKING AT HUMAN

675
00:34:19,720 --> 00:34:22,080
STOOL SAMPLES SO WE MAKE LECTINS

676
00:34:22,080 --> 00:34:24,880
AND ALL OF OUR LECTINS ARE HUMAN

677
00:34:24,880 --> 00:34:26,560
LECTINS SO WE'RE THEN GOING TO

678
00:34:26,560 --> 00:34:34,520
COMPARE BINDING BY A FLOW SIGH

679
00:34:34,520 --> 00:34:47,680
TOM TREE.

680
00:34:47,680 --> 00:34:50,120
THIS IS A LECTIN THAT IS THE

681
00:34:50,120 --> 00:34:51,440
BEST STUDIED LECTIN THAT IS

682
00:34:51,440 --> 00:34:55,400
AGAIN INVOLVED IN HOST DEFENSE.

683
00:34:55,400 --> 00:34:58,240
AND THE OTHER REASON WE CHOSE

684
00:34:58,240 --> 00:35:00,200
MAN OWE BINDING LECTIN IS

685
00:35:00,200 --> 00:35:03,760
BECAUSE THEY REALLY HAVE BINDING

686
00:35:03,760 --> 00:35:05,640
SPECIFICITY IN TERMS OF THEIR

687
00:35:05,640 --> 00:35:06,800
SUGAR BINDINGS SO WHAT I'M

688
00:35:06,800 --> 00:35:08,680
SHOWING YOU HERE IS A HEAT MAP

689
00:35:08,680 --> 00:35:12,560
OF MICROBIAL GLYCAN ARRAY DATA

690
00:35:12,560 --> 00:35:14,200
SO WE HAVE THESE BEAUTIFUL GUY

691
00:35:14,200 --> 00:35:16,320
CAN ARRAYS WHERE YOU CAN

692
00:35:16,320 --> 00:35:18,040
MEASURE, AGAIN, BINDING TO

693
00:35:18,040 --> 00:35:20,360
INDIVIDUAL SUGARS ON THE ARRAY

694
00:35:20,360 --> 00:35:22,480
AND THESE ARE THE MICROBIAL GUY

695
00:35:22,480 --> 00:35:25,280
CAN ARRAYS WHICH WHY REALLY

696
00:35:25,280 --> 00:35:28,600
PIONEERED BY THE PAULSON AND

697
00:35:28,600 --> 00:35:30,560
CUMMINGS LAB SO WE USED THESE

698
00:35:30,560 --> 00:35:32,320
AND THEY HAVE VERY DIFFERENT --

699
00:35:32,320 --> 00:35:34,600
THE TWO LECTINS HAVE DIFFERENT

700
00:35:34,600 --> 00:35:37,880
GLYCAN SPECIFICITY SO, IS THIS

701
00:35:37,880 --> 00:35:40,400
MANIFESTED IN THEIR MICROBE

702
00:35:40,400 --> 00:35:41,000
BINDING?

703
00:35:41,000 --> 00:35:44,520
WELL, IF WE TAKE A HUMAN STOOL

704
00:35:44,520 --> 00:35:47,920
SAMPLE AND LABEL HUMAN WITH ONE

705
00:35:47,920 --> 00:35:49,480
COLOR AND MAN OS BINDING WITH

706
00:35:49,480 --> 00:35:51,560
ANOTHER COLOR YOU CAN SEE THESE

707
00:35:51,560 --> 00:35:54,880
ARE CELLS THAT BIND TO MAN OWES

708
00:35:54,880 --> 00:35:57,360
BINDING AND HUMAN ENTA LECTIN

709
00:35:57,360 --> 00:36:00,920
AND TO BOTH AND THERE'S VERY FEW

710
00:36:00,920 --> 00:36:03,520
CELLS THAT SHOW MY COORDINATE

711
00:36:03,520 --> 00:36:04,720
BINDING.

712
00:36:04,720 --> 00:36:06,760
AND SO THIS SPECIFICITY THAT WE

713
00:36:06,760 --> 00:36:09,080
SEE AT THE INDIVIDUAL GLYCAN

714
00:36:09,080 --> 00:36:12,400
LEVEL IS MANIFESTED AT THE

715
00:36:12,400 --> 00:36:13,440
CELLULAR LEVEL.

716
00:36:13,440 --> 00:36:15,720
SO WHAT ORGANISMS ARE THESE

717
00:36:15,720 --> 00:36:16,520
BINDINGS?

718
00:36:16,520 --> 00:36:24,240
AND TO DO THAT, WE COLLABORATED

719
00:36:24,240 --> 00:36:25,200
WITH THE XAVIER AND HOLL MANY

720
00:36:25,200 --> 00:36:27,760
LABS SO THIS IS REALLY LED BY

721
00:36:27,760 --> 00:36:30,000
CHRISTINE ISABELLA AND LYLE

722
00:36:30,000 --> 00:36:32,240
McPHERSON AND MY LAB IN

723
00:36:32,240 --> 00:36:35,200
CONJUNCTION WITH THESE OTHER

724
00:36:35,200 --> 00:36:35,400
LABS.

725
00:36:35,400 --> 00:36:37,280
SO WHEN WE DID IS SINCE WE KNEW

726
00:36:37,280 --> 00:36:39,360
WE COULD IDENTIFY THESE USING

727
00:36:39,360 --> 00:36:42,640
FLOW CYTOMETRY, WE DID SORTS

728
00:36:42,640 --> 00:36:44,760
WHERE WE COULD SORT LECTIN-BOUND

729
00:36:44,760 --> 00:36:46,880
AND LECTIN UNBOUND AND ASK WHAT

730
00:36:46,880 --> 00:36:48,320
IS THE DIFFERENCE BETWEEN THE

731
00:36:48,320 --> 00:36:48,840
SPECIES HERE?

732
00:36:48,840 --> 00:36:51,960
AND SO THE WAY WE DID THAT IS TO

733
00:36:51,960 --> 00:36:54,520
APPLY SHOTGUN SEQUENCES AND META

734
00:36:54,520 --> 00:36:57,760
GENOMIC ANALYSIS TO UNDERSTAND

735
00:36:57,760 --> 00:37:00,200
SPECIES ENRICHMENT.

736
00:37:00,200 --> 00:37:02,280
SO I'M GOING TO SHOW SOME OF OUR

737
00:37:02,280 --> 00:37:05,040
DATA AND SHOW THEM IN A FORM OF

738
00:37:05,040 --> 00:37:07,200
PROBABILITY RATIOS AND

739
00:37:07,200 --> 00:37:10,520
PROBABILITY RATIOS INTRINSICALLY

740
00:37:10,520 --> 00:37:15,880
TAKE INTO ACCOUNT THE ABUNDANCE

741
00:37:15,880 --> 00:37:17,240
OF DIFFERENT SPECIES IN THE

742
00:37:17,240 --> 00:37:18,040
INITIAL INPUT.

743
00:37:18,040 --> 00:37:21,080
AS YOU CAN IMAGINE, IF YOU HAVE

744
00:37:21,080 --> 00:37:23,640
DONORS AND YOU ARE LOOKING AT

745
00:37:23,640 --> 00:37:26,440
THE INPUT YOU DON'T WANT TO BE

746
00:37:26,440 --> 00:37:29,240
BIASED BY, FOR EXAMPLE, A LOT OF

747
00:37:29,240 --> 00:37:31,840
ONE SPECIES THAT THE LECTIN

748
00:37:31,840 --> 00:37:34,200
BINDS SO THESE PROBABILITY

749
00:37:34,200 --> 00:37:36,160
RATIOS TAKE THAT INTO ACCOUNT

750
00:37:36,160 --> 00:37:40,040
AND WHAT THE DATA LOOKS LIKE ARE

751
00:37:40,040 --> 00:37:42,720
THE SIZE OF THE DOT IS THE

752
00:37:42,720 --> 00:37:45,360
ENRICHED FRACTION LIKE WHAT

753
00:37:45,360 --> 00:37:47,640
PREPORTION OF THAT PARTICULAR

754
00:37:47,640 --> 00:37:51,400
SPECIES WAS IN THE FINAL

755
00:37:51,400 --> 00:37:52,240
ENRICHED FRACTION AND THE

756
00:37:52,240 --> 00:37:54,600
PROBABILITY RATIO GIVES YOU A

757
00:37:54,600 --> 00:37:57,760
SENSE OF HOW MUCH WAS ENRICHED

758
00:37:57,760 --> 00:38:00,480
IN THE LECTIN PLUS VERSUS THE

759
00:38:00,480 --> 00:38:02,000
LECTIN MINUS FRACTION.

760
00:38:02,000 --> 00:38:04,240
SO, DATA LIKE THIS SUGGESTS THAT

761
00:38:04,240 --> 00:38:07,080
YOU SEE SOME ENRICHMENT BUT YOU

762
00:38:07,080 --> 00:38:11,440
ALSO SEE A LOT OF THAT

763
00:38:11,440 --> 00:38:12,040
PARTICULAR MICROBE IN THE

764
00:38:12,040 --> 00:38:14,760
NEGATIVE CONTROL AS WELL.

765
00:38:14,760 --> 00:38:16,760
SO AS YOU CAN SEE IF YOU LOOK AT

766
00:38:16,760 --> 00:38:20,720
THIS DATA, AND EACH OF THESE

767
00:38:20,720 --> 00:38:23,440
DIFFERENT SAMPLE IS INDIVIDUAL

768
00:38:23,440 --> 00:38:26,840
HUMAN DONOR AND WE HAVE IN THIS

769
00:38:26,840 --> 00:38:29,440
SAMPLE SET, FIVE PEOPLE THAT ARE

770
00:38:29,440 --> 00:38:31,360
LABELED HEALTHY SO THESE ARE

771
00:38:31,360 --> 00:38:34,760
DONORS THAT HAVE NO DISEASE AND

772
00:38:34,760 --> 00:38:36,920
THE D SAMPLES ARE PEOPLE THAT

773
00:38:36,920 --> 00:38:42,560
HAVE SOME FORM OF IBD OR ULCER

774
00:38:42,560 --> 00:38:42,880
COLITIS.

775
00:38:42,880 --> 00:38:45,160
WE SEE THERE ISN'T VERY HIGH

776
00:38:45,160 --> 00:38:49,200
DONOR SPECIFICITY IN THIS HUMAN

777
00:38:49,200 --> 00:38:50,920
BINDING AND WHAT THESE BACTERIA

778
00:38:50,920 --> 00:38:55,960
HAVE IN COMMON IS THEY'RE RARE.

779
00:38:55,960 --> 00:39:01,040
AND SO HUMAN ENTA LECTIN BINDS

780
00:39:01,040 --> 00:39:06,440
LOW A BUDDANC ABUNDANCE SPECIES
BECAUSE IF

781
00:39:06,440 --> 00:39:08,800
IT'S A LOW ABUNDANCE SPECIES,

782
00:39:08,800 --> 00:39:10,520
RIGHT, I MIGHT HAVE IT BUT YOU

783
00:39:10,520 --> 00:39:14,680
MIGHT NOT SO WE SEE THAT THIS

784
00:39:14,680 --> 00:39:16,720
LECTIN BINDS AGAIN TO THESE RARE

785
00:39:16,720 --> 00:39:21,480
SPECIES AND THIS WAS REALLY

786
00:39:21,480 --> 00:39:24,440
INTERESTING BECAUSE, IT DOESN'T

787
00:39:24,440 --> 00:39:27,920
FIT THAT KIND OF MODEL OF THIS

788
00:39:27,920 --> 00:39:28,920
LECTIN INVOLVED IN DEFENSE

789
00:39:28,920 --> 00:39:30,560
BECAUSE AGAIN THESE ARE RARE

790
00:39:30,560 --> 00:39:32,560
SPECIES AND MANY OF THEM HAVE

791
00:39:32,560 --> 00:39:37,280
BEEN OFFICIAL PROPERTIES.

792
00:39:37,280 --> 00:39:38,760
ONE OF THE THINGS WE NOTED IS

793
00:39:38,760 --> 00:39:41,040
THESE DATA ARE REALLY INTRIGUING

794
00:39:41,040 --> 00:39:44,760
AND EVIDENCE GROWING THAT

795
00:39:44,760 --> 00:39:47,600
INTELLECT ANT CAN DAMPEN IMMUNE

796
00:39:47,600 --> 00:39:48,880
RESPONSES AND TWO PARTICULAR

797
00:39:48,880 --> 00:39:52,760
BACTERIA AND SO WE THINK THAT

798
00:39:52,760 --> 00:39:54,240
BINDING COULD SHIELD THESE

799
00:39:54,240 --> 00:39:56,040
PARTICULAR BACTERIA FROM IMMUNE

800
00:39:56,040 --> 00:39:57,640
CLEARANCE AND ONE THING THAT

801
00:39:57,640 --> 00:39:59,200
I'LL MENTION IS OF COURSE,

802
00:39:59,200 --> 00:40:06,040
HAVING A MORE I DO VERSE DIVERSE
MICROBIOM
E

803
00:40:06,040 --> 00:40:08,640
IS ASSOCIATED WITH BENEFICIAL

804
00:40:08,640 --> 00:40:09,120
HEALTH.

805
00:40:09,120 --> 00:40:11,160
SO THAT SUGGESTED THAT MAYBE ALL

806
00:40:11,160 --> 00:40:17,360
OF THESE LECTINS BIND REALLY

807
00:40:17,360 --> 00:40:19,120
RARE INDIVIDUALS SPECIES SO WE

808
00:40:19,120 --> 00:40:25,840
WANTED TO ASK IS MAN OWES

809
00:40:25,840 --> 00:40:28,640
BINDING LECTIN BROAD, LIKE I

810
00:40:28,640 --> 00:40:29,600
JUST SHOWED YOU.

811
00:40:29,600 --> 00:40:32,680
WHEN WE DID A SIMILAR EXPERIMENT

812
00:40:32,680 --> 00:40:34,600
TO THE ONE I SHOWED YOU WE GOT

813
00:40:34,600 --> 00:40:40,440
DIFFERENT RESULTS WITH THIS

814
00:40:40,440 --> 00:40:40,680
LECTIN.

815
00:40:40,680 --> 00:40:44,840
IT BINDS TO F PRAUSNITZII AND

816
00:40:44,840 --> 00:40:48,160
THIS IS VERY PREVALENT IN THE

817
00:40:48,160 --> 00:40:49,840
HUMAN MICROBIOME AND ITS

818
00:40:49,840 --> 00:40:51,920
ASSOCIATED WITH ROBUST HUMAN

819
00:40:51,920 --> 00:40:56,520
HEALTH AND WE SAW THIS REEL IN

820
00:40:56,520 --> 00:40:58,920
VIRTUALLY ALL OF THE DONORS WITH

821
00:40:58,920 --> 00:41:02,400
THE EXCEPTION OF A FEW PEOPLE

822
00:41:02,400 --> 00:41:12,800
THAT LACK THIS F. PRAUSNITZII.

823
00:41:12,800 --> 00:41:18,360
NOW F. PRAUSNITZII, IS THIS

824
00:41:18,360 --> 00:41:20,000
BINDING TO ALL OF THE ABUNDANT

825
00:41:20,000 --> 00:41:26,880
SPECIES BUT REALLY F.PRAUSNITZII

826
00:41:26,880 --> 00:41:31,160
IS THE ONLY THAT MBL-BOUND.

827
00:41:31,160 --> 00:41:33,760
AND AS I MENTIONED BEFORE, IT'S

828
00:41:33,760 --> 00:41:34,920
INTERESTING TO NOTE THAT WHEN

829
00:41:34,920 --> 00:41:40,320
THAT SPECIES IS NOT THERE IT

830
00:41:40,320 --> 00:41:46,800
BINDS TO A. MUCINIPHILA, IT WAS

831
00:41:46,800 --> 00:41:48,240
ONLY FOUND IN SAMPLES WERE

832
00:41:48,240 --> 00:41:52,280
PEOPLE THAT HAD SOME SORT OF

833
00:41:52,280 --> 00:41:56,640
INFLAMMATORY DISEASE.

834
00:41:56,640 --> 00:41:58,800
AND I GUESS MAYBE I'LL JUST

835
00:41:58,800 --> 00:42:00,120
MENTION HERE, THIS SUGGESTS

836
00:42:00,120 --> 00:42:02,480
THESE KINDS OF LECTIN-BINDING

837
00:42:02,480 --> 00:42:04,000
EXPERIMENTS CAN BE USED TO

838
00:42:04,000 --> 00:42:10,440
SATURDASTARTTO SORT AND
UNDERSTAND AND

839
00:42:10,440 --> 00:42:11,760
DIAGNOSE DIFFERENT DISEASES.

840
00:42:11,760 --> 00:42:39,720
I JUST WANT TO BRIEFLY MENTION,

841
00:42:39,720 --> 00:42:45,400
# H IT WOULIT WOULD HAVE ACCESS
TO THE GUT

842
00:42:45,400 --> 00:42:48,200
AND IN FACT, IN COLORECTAL

843
00:42:48,200 --> 00:42:53,120
CANCER PATIENTS WITH BLOOD IN

844
00:42:53,120 --> 00:43:03,440
THE STOOL, THEY HAVE VERY IT

845
00:43:03,440 --> 00:43:04,680
FELT BUELLLY WITH THE LECTIN

846
00:43:04,680 --> 00:43:07,080
BINDING THAT WE HAVE DETECTED SO

847
00:43:07,080 --> 00:43:08,920
YOU COULD IMAGINE IT DOWN

848
00:43:08,920 --> 00:43:13,640
REGULATING THIS BACTERIUM.

849
00:43:13,640 --> 00:43:18,600
SO WE KNOW A LOT ABOUT HOW TO

850
00:43:18,600 --> 00:43:22,520
PER TISH THESE HOST MICROBE

851
00:43:22,520 --> 00:43:31,760
INTERACTIONS AND THAT THESE

852
00:43:31,760 --> 00:43:33,440
PROTEINS HAVE WE NEED TO

853
00:43:33,440 --> 00:43:34,840
UNDERSTAND THEIR TARGETS AND

854
00:43:34,840 --> 00:43:37,840
I'VE JUST SHOWN YOU TWO OF THESE

855
00:43:37,840 --> 00:43:39,400
MINI LECTINS AND THERE ARE SO

856
00:43:39,400 --> 00:43:47,240
MANY OUT THERE THAT WE COULD USE

857
00:43:47,240 --> 00:43:48,640
TO PROBE AND HOST MICRO

858
00:43:48,640 --> 00:43:50,400
INTERACTIONS AND WE REALLY NEED

859
00:43:50,400 --> 00:43:53,360
THESE NEW KINDS OF TOOLS FOR

860
00:43:53,360 --> 00:43:54,960
PROFILING MICROBIOMES AND WE

861
00:43:54,960 --> 00:43:56,440
HOPE THAT LECTINS WILL BE A PART

862
00:43:56,440 --> 00:43:58,320
OF THAT.

863
00:43:58,320 --> 00:43:59,400
SO, I'VE TRIED TO THANK THE

864
00:43:59,400 --> 00:44:01,200
PEOPLE WHO DID THE WORK

865
00:44:01,200 --> 00:44:02,160
THROUGHOUT THE TALK AND I WANT

866
00:44:02,160 --> 00:44:04,560
TO JUST THANK THE ENTIRE GROUP

867
00:44:04,560 --> 00:44:07,880
AND I WANT TO THANK THE NIH FOR

868
00:44:07,880 --> 00:44:12,040
FUNDING THIS WORK AND AGAIN, THE

869
00:44:12,040 --> 00:44:12,840
ORGANIZERS AND THANK YOU ALL FOR

870
00:44:12,840 --> 00:44:14,560
YOUR ATTENTION AND I'M HAPPY TO

871
00:44:14,560 --> 00:44:17,920
ANSWER QUESTIONS.

872
00:44:17,920 --> 00:44:20,840
>> FANTASTIC TALK.

873
00:44:20,840 --> 00:44:22,640
YOU ALWAYS IMPRESSES US WITH

874
00:44:22,640 --> 00:44:23,840
SOMETHING NEW YOUR LAB IS

875
00:44:23,840 --> 00:44:24,400
ENDURING ON.

876
00:44:24,400 --> 00:44:36,960
QUESTIONS FROM THE AUDIENCE --

877
00:44:36,960 --> 00:44:41,440
WE HAVE A QUESTION.

878
00:44:41,440 --> 00:44:43,120
>> THANK YOU, CATHERINE.

879
00:44:43,120 --> 00:44:45,720
HI, LAURA, THAT WAS A GREAT

880
00:44:45,720 --> 00:44:45,920
TALK.

881
00:44:45,920 --> 00:44:48,400
I'M WONDERING ABOUT YOUR

882
00:44:48,400 --> 00:44:49,840
DIFFERENCES BETWEEN THE TWO

883
00:44:49,840 --> 00:44:51,560
LECTINS AND ONE WAS MORE BROAD

884
00:44:51,560 --> 00:44:53,800
AND ONE WAS MORE SPECIFIC.

885
00:44:53,800 --> 00:44:56,000
SO, DOES THAT, I MEAN,

886
00:44:56,000 --> 00:44:57,600
PRESUMABLY IT GIVES YOU IN SIGHT

887
00:44:57,600 --> 00:44:58,840
INTO THE TYPES OF SUGARS THAT

888
00:44:58,840 --> 00:45:00,400
ARE ON THE SURFACES OR ON

889
00:45:00,400 --> 00:45:01,840
CERTAIN PATHOGENS VERSUS OTHERS?

890
00:45:01,840 --> 00:45:06,120
I MEAN, IS MAN OWES MORE

891
00:45:06,120 --> 00:45:09,080
UBIQUITOUS VERSUS KVO AND THE

892
00:45:09,080 --> 00:45:11,720
OTHER SUGARS OR IS THAT NOT THE

893
00:45:11,720 --> 00:45:13,040
RIGHT EXTRAPOLATION?

894
00:45:13,040 --> 00:45:16,040
>> YEAH, SO, THANK YOU FOR

895
00:45:16,040 --> 00:45:16,480
SAYING THAT.

896
00:45:16,480 --> 00:45:18,160
I WAS GOING TO SAY, I SHOULD

897
00:45:18,160 --> 00:45:20,200
HAVE ENDED MY TALK BY SAYING

898
00:45:20,200 --> 00:45:22,320
THAT THIS ALSO SHOWS HOW

899
00:45:22,320 --> 00:45:24,120
DIFFERENT THE FUNCTIONS OF THESE

900
00:45:24,120 --> 00:45:49,240
LECTINS LIKELY ARE AND AND

901
00:45:49,240 --> 00:45:53,120
THERE'S A TRANSFERASE OR GA TACK

902
00:45:53,120 --> 00:45:55,360
LOW ON THE SURFACE OF THE CELLS

903
00:45:55,360 --> 00:45:58,040
BECAUSE WE ACTUALLY SEE EVEN

904
00:45:58,040 --> 00:46:00,360
THOUGH THEY HAVE THE SUGAR

905
00:46:00,360 --> 00:46:01,640
DENSITIES AND ACCESSIBILITIES OF

906
00:46:01,640 --> 00:46:04,120
THOSE SUGAR ARE REALLY IMPORTANT

907
00:46:04,120 --> 00:46:05,960
AND SO, WE WOULD LIKE TO BE ABLE

908
00:46:05,960 --> 00:46:08,520
TO GO IN AND DO EXACTLY WHAT YOU

909
00:46:08,520 --> 00:46:12,320
ARE SAYING START TO RELATE

910
00:46:12,320 --> 00:46:14,040
SPECIFICALLY SUGARS WITH THE

911
00:46:14,040 --> 00:46:16,640
LECTIN BINDING BUT WE'RE NOT

912
00:46:16,640 --> 00:46:19,960
QUITE THAT FAR YET IN TERMS OF

913
00:46:19,960 --> 00:46:21,600
CAPTURING THE SPECIFIC SUGARS SO

914
00:46:21,600 --> 00:46:23,880
THAT ALSO POINTS TO THE NEED FOR

915
00:46:23,880 --> 00:46:27,320
KNEW TOOLNEW TOOLS WHICH IS
SOMETHING

916
00:46:27,320 --> 00:46:27,840
WE'RE WORKING ON.

917
00:46:27,840 --> 00:46:29,640
>> LOOKING FORWARD TO IT.

918
00:46:29,640 --> 00:46:33,160
>> GREAT QUESTION.

919
00:46:33,160 --> 00:46:42,720
>> AMAZING TALK.

920
00:46:42,720 --> 00:46:43,800
THE FIRST QUESTION WE HAVE FROM

921
00:46:43,800 --> 00:46:46,560
THE ON-LINE AUDIENCE IS FROM

922
00:46:46,560 --> 00:46:48,760
NICOLAS AND HE ASKS, HE IS FROM

923
00:46:48,760 --> 00:46:50,840
VANDER BELT AND WITH SO MANY

924
00:46:50,840 --> 00:46:52,960
LECTINS, WHAT WOULD BE THE BEST

925
00:46:52,960 --> 00:46:55,520
PRIORITIZATION FOR STUDYING TO

926
00:46:55,520 --> 00:46:56,680
PROBE MOST MICROBE INTERACTIONS.

927
00:46:56,680 --> 00:47:00,240
>> YEAH, SO, WE HAVE SOME OTHER

928
00:47:00,240 --> 00:47:02,840
REAL TARGETS LECTINS THAT WE'RE

929
00:47:02,840 --> 00:47:05,320
LOOKING AT AND SO SOME OF THE

930
00:47:05,320 --> 00:47:07,240
LECTINS THAT WERE VERY

931
00:47:07,240 --> 00:47:09,040
INTERESTED IN ARE DRAMATICALLY

932
00:47:09,040 --> 00:47:11,280
ALTERED IN DISEASE AND THAT IS I

933
00:47:11,280 --> 00:47:13,920
THINK A GOOD PRIORITIZATION

934
00:47:13,920 --> 00:47:17,080
STRATEGIES THAT ONE CAN USE.

935
00:47:17,080 --> 00:47:18,520
SO, FOR EXAMPLE, I'LL JUST

936
00:47:18,520 --> 00:47:22,040
MENTION THAT SPD IS THE

937
00:47:22,040 --> 00:47:25,840
LECTIN -- ACTUALLY THE NUMBER

938
00:47:25,840 --> 00:47:31,920
ONE PROTEIN PERTURBED IS IT'S

939
00:47:31,920 --> 00:47:34,600
REALLY IMPORTANT FOR DISEASE AND

940
00:47:34,600 --> 00:47:36,040
I THINK THOSE ARE ONES WE'RE

941
00:47:36,040 --> 00:47:41,840
GOING AFTER FIRST.

942
00:47:41,840 --> 00:47:43,440
>> THERE ARE MORE AND MORE

943
00:47:43,440 --> 00:47:44,440
QUESTIONS COMING IN ON THE CHAT

944
00:47:44,440 --> 00:47:47,840
BUT WE'LL MOVE ON AND I PROMISE

945
00:47:47,840 --> 00:47:49,800
YOU, SHE WILL ANSWER YOU IN YOUR

946
00:47:49,800 --> 00:47:54,000
REMALE-MAIL ADDRESSES.

947
00:47:54,000 --> 00:47:55,120
THANK YOU SO MUCH.

948
00:47:55,120 --> 00:47:57,160
KEEP THE QUESTIONS COMING IN.

949
00:47:57,160 --> 00:47:58,920
THAT'S WHAT MAKES THIS MORE

950
00:47:58,920 --> 00:48:00,640
INTERACTIVE AND FUN SO THANK YOU

951
00:48:00,640 --> 00:48:25,680
FOR AN ENGAGING TALK.

952
00:48:25,680 --> 00:48:29,040
SHE'S GOING TO TALK ABOUT NOVEL

953
00:48:29,040 --> 00:48:36,360
STEP TOE COCKAL GUY CAN BINDING

954
00:48:36,360 --> 00:48:40,080
ADHERENCE.

955
00:48:40,080 --> 00:48:42,640
>> I WANT TO SEE WHAT EVERYONE

956
00:48:42,640 --> 00:48:44,640
IS GOING TO SHARE TODAY SO I'D

957
00:48:44,640 --> 00:48:46,240
LIKE TO START BY THANKING THE

958
00:48:46,240 --> 00:48:48,680
MEMBERS OF THE LAB THAT DID THIS

959
00:48:48,680 --> 00:48:57,160
WORK AND ESPECIALLY MEZ AND

960
00:48:57,160 --> 00:48:58,840
ANIRUDH AND THE ANIMAL MODELING

961
00:48:58,840 --> 00:49:03,200
AND OF COURSE FOR OUR FUNDING.

962
00:49:03,200 --> 00:49:07,840
SO, IT'S AN ORAL COMMENCAL AND

963
00:49:07,840 --> 00:49:09,400
IT'S CONSIDERED TO BE A OR

964
00:49:09,400 --> 00:49:11,720
ALPINE HERE AND SO WHEN WE THINK

965
00:49:11,720 --> 00:49:13,880
ABOUT ORAL PIONEER.

966
00:49:13,880 --> 00:49:17,920
THE SURFACE IS COVERED IN A

967
00:49:17,920 --> 00:49:21,000
PELICAL AND A BACTERIA ARE

968
00:49:21,000 --> 00:49:23,240
THOUGHT TO BIND TO THAT PELICAL

969
00:49:23,240 --> 00:49:25,880
AND EVENTUALLY WE GET THIS

970
00:49:25,880 --> 00:49:28,000
COMPLEX ORAL AND THIS BIO FILM

971
00:49:28,000 --> 00:49:31,840
IS ASSOCIATED WITH DENTAL

972
00:49:31,840 --> 00:49:34,240
CARRIES AND FOR EXAMPLE,

973
00:49:34,240 --> 00:49:36,800
2.5 BILLION ADULTS ARE THOUGHT

974
00:49:36,800 --> 00:49:38,440
TO HAVE UNTREATED DENTAL CARRY

975
00:49:38,440 --> 00:49:41,080
SO THIS IS A SIGNIFICANT ISSUE.

976
00:49:41,080 --> 00:49:46,720
THE STREP OR ALICE CAN CAUSE

977
00:49:46,720 --> 00:49:54,600
SUBACUTE -- WHEN YOU PRESSURE

978
00:49:54,600 --> 00:50:22,040
TEETHAND THEVEGETATION CAN BREAK
OFF AND I
T

979
00:50:22,040 --> 00:50:23,520
CAN GET STUCK IN A SMALLER

980
00:50:23,520 --> 00:50:25,880
VESSEL AND CAUSE A STROKE.

981
00:50:25,880 --> 00:50:28,240
SO, IN THAT ENVIRONMENT, IT'S

982
00:50:28,240 --> 00:50:30,800
THOUGHT THANK YOU TO VICTOR TO

983
00:50:30,800 --> 00:50:33,240
BRING OUR PLATELETS EARLIER,

984
00:50:33,240 --> 00:50:34,680
IT'S A CRITICAL STEP IN THAT

985
00:50:34,680 --> 00:50:37,440
PROPERTY SO EITHER THE BACTERIA

986
00:50:37,440 --> 00:50:39,040
CAN BIND TO THE PLATELETS IN

987
00:50:39,040 --> 00:50:40,360
CIRCULATION AND IT'S LIKE A

988
00:50:40,360 --> 00:50:42,400
TROJAN HORSE TAKING THE BACTERIA

989
00:50:42,400 --> 00:50:45,360
TO THE SITE OF DAMAGE OR CAN

990
00:50:45,360 --> 00:50:48,640
BIND TO THE SITE OF DAMAGE

991
00:50:48,640 --> 00:50:49,200
DIRECTLY.

992
00:50:49,200 --> 00:50:52,040
AND IN BOTH THESE ENVIRONMENTS,

993
00:50:52,040 --> 00:50:53,800
BINDING IS A CRITICAL STEP SO

994
00:50:53,800 --> 00:50:54,440
WE'RE INTERESTED IN

995
00:50:54,440 --> 00:50:55,880
UNDERSTANDING HOW THE BACTERIA

996
00:50:55,880 --> 00:50:59,240
BINDS BECAUSE IF WE THINK WE CAN

997
00:50:59,240 --> 00:51:01,400
WORKOUT OUT THEY BIND WE CAN

998
00:51:01,400 --> 00:51:02,880
REDUCE THE BURDEN OF DISEASE AND

999
00:51:02,880 --> 00:51:05,040
WE BELIEVE SOME OF THE SAME

1000
00:51:05,040 --> 00:51:06,520
MECHANISMS CAN BE IMPORTANT IN

1001
00:51:06,520 --> 00:51:10,520
BOTH ENVIRONMENTS AND IT'S

1002
00:51:10,520 --> 00:51:11,840
ACCIDENTAL THAT STREPTOCOCCUS

1003
00:51:11,840 --> 00:51:14,480
GOES INTO THE SAME BINDING

1004
00:51:14,480 --> 00:51:16,040
MECHANISMS WHICH NOT TO GIVE A

1005
00:51:16,040 --> 00:51:23,760
SPOILER, A CA A IN
CARBOHYDRATES.

1006
00:51:23,760 --> 00:51:26,360
IT WAS RECLASSIFIED ADDITIONAL

1007
00:51:26,360 --> 00:51:27,560
STRAINS WERE ADDED AND IT WAS

1008
00:51:27,560 --> 00:51:29,240
DIVIDED INTO THREE SUB SPECIES

1009
00:51:29,240 --> 00:51:33,960
AND SO JUST FOR CLARITY, I'M

1010
00:51:33,960 --> 00:51:41,320
GOING TO TAKE ABOUT OR ALICE

1011
00:51:41,320 --> 00:51:54,920
TODAY.

1012
00:51:54,920 --> 00:51:57,640
THEY COMBINED A VARIETY OF

1013
00:51:57,640 --> 00:51:59,960
DIFFERENT HOST AND BACTERIAL

1014
00:51:59,960 --> 00:52:02,640
SURFACES AND THEY ARE NAMED FOR

1015
00:52:02,640 --> 00:52:04,080
THE RESPEED SO THESE MAKE UP THE

1016
00:52:04,080 --> 00:52:05,440
MAJORITY OF THE PROTEIN AND

1017
00:52:05,440 --> 00:52:10,480
EVERY OTHER AMINO ACID IS A

1018
00:52:10,480 --> 00:52:13,520
SERINE AND SO THIS FORMS THE

1019
00:52:13,520 --> 00:52:15,360
STORK THAT STRETCHES THE BINDING

1020
00:52:15,360 --> 00:52:18,520
DEMANDS OUT SO WHAT THEY'RE BIND

1021
00:52:18,520 --> 00:52:21,280
IS ACTUALLY THROUGH THE NON

1022
00:52:21,280 --> 00:52:23,240
REPEAT REGION SO IN THAT NON

1023
00:52:23,240 --> 00:52:24,880
REPEAT REGION YOU CAN HAVE

1024
00:52:24,880 --> 00:52:26,480
MODULAR STRUCTURES AND IT TERMS

1025
00:52:26,480 --> 00:52:27,800
THE RECEPTORS THAT IS BOUND SO

1026
00:52:27,800 --> 00:52:32,760
IN THE CASE OF ORAL

1027
00:52:32,760 --> 00:52:33,400
STREPTOCOCCUS, IT BINDS THROUGH

1028
00:52:33,400 --> 00:52:35,120
THESE PROTEINS THAT NON REPEAT

1029
00:52:35,120 --> 00:52:38,600
REGION CONTAINS ONE DOMAIN AND

1030
00:52:38,600 --> 00:52:41,560
UNIQUE DEMAIN SO THE FUNCTION OF

1031
00:52:41,560 --> 00:52:49,600
THE TO BLIND SALIC ACID AND IT

1032
00:52:49,600 --> 00:52:51,520
IT MIGHT BE FOLDING THE SIALIC

1033
00:52:51,520 --> 00:52:53,640
DOMAIN BUT IN OTHER SPECIES,

1034
00:52:53,640 --> 00:52:54,960
THESE ARE PROTEINS THAT HAVE

1035
00:52:54,960 --> 00:52:56,800
BEEN SHOWN TO BE IMPORTANT IN

1036
00:52:56,800 --> 00:52:59,520
VEGETATION FORMATION FOR

1037
00:52:59,520 --> 00:53:02,520
SEVERALLEN DOUGH CAR DIET IS

1038
00:53:02,520 --> 00:53:03,720
PATHOGENS SO IT'S NOT SURPRISING

1039
00:53:03,720 --> 00:53:05,440
WHEN A FEW YEARS AGO WE

1040
00:53:05,440 --> 00:53:10,520
IDENTIFIED A REPEAT PROTEIN THAT

1041
00:53:10,520 --> 00:53:15,440
WE HOLD FAP1 THAT SIGNS ACID SO

1042
00:53:15,440 --> 00:53:18,720
IT'S A REPEAT PROTEIN AND IT

1043
00:53:18,720 --> 00:53:21,320
CONTAINS ONE DOMAIN AND IT ALSO

1044
00:53:21,320 --> 00:53:23,000
CAN HAVE VERY WEAK STRUCTURAL

1045
00:53:23,000 --> 00:53:30,480
SIMILARITY TO A CA CARBOHYDRATE
AND

1046
00:53:30,480 --> 00:53:33,240
IT'S RESURFACE TO SO WE

1047
00:53:33,240 --> 00:53:36,960
PREVIOUSLY PUBLISHED THAT FAP1

1048
00:53:36,960 --> 00:53:39,440
IS IMPORTANT IN WINDING

1049
00:53:39,440 --> 00:53:40,480
PLATELETS SO HERE I'M GOING TO

1050
00:53:40,480 --> 00:53:43,840
SHOW YOU DATA WITH SALIVA AND MY

1051
00:53:43,840 --> 00:53:45,480
LITTLE SCHEMATIC ON THE RIGHT IS

1052
00:53:45,480 --> 00:53:47,840
TO SHOW YOU THE TOOLS WE HAVE.

1053
00:53:47,840 --> 00:53:50,000
IT'S A VAST OVER SIMPLIFICATION.

1054
00:53:50,000 --> 00:53:53,960
SO IF THAT ONE DOES BIND

1055
00:53:53,960 --> 00:53:57,440
TERMINAL SIALIC ACID, IF WE ADD

1056
00:53:57,440 --> 00:54:00,640
A BINDING MODULE, THIS IS FOR A

1057
00:54:00,640 --> 00:54:02,680
SMALL DOMAIN THAT IS

1058
00:54:02,680 --> 00:54:06,120
SPECIFICALLY BIND SIALIC ACID WE

1059
00:54:06,120 --> 00:54:07,880
WOULD BE ABLE TO INHIBIT THE

1060
00:54:07,880 --> 00:54:09,720
BINDING OF ORALISE AND THAT'S

1061
00:54:09,720 --> 00:54:15,080
WHAT WE SEE AND IF WE MAKE A

1062
00:54:15,080 --> 00:54:16,840
FAP1 MUTANT IT WOULD BE IN

1063
00:54:16,840 --> 00:54:17,120
BINDING 2.

1064
00:54:17,120 --> 00:54:19,360
WE WOULD EXPECT IF WE ADD THEM

1065
00:54:19,360 --> 00:54:20,760
TOGETHER, WE REALLY WOULD EXPECT

1066
00:54:20,760 --> 00:54:23,440
TO SEE NO FURTHER REDUCTION IN

1067
00:54:23,440 --> 00:54:27,000
BINDING AND THAT'S ALSO THE CASE

1068
00:54:27,000 --> 00:54:28,800
W KNOW THAT FAP1 IS IMPORTANT

1069
00:54:28,800 --> 00:54:32,480
FOR BINDING SIALIC ACID ON

1070
00:54:32,480 --> 00:54:34,400
PLATELETS AND ON SALIVA.

1071
00:54:34,400 --> 00:54:36,200
OUR QUESTION IS BINDING, I MEAN,

1072
00:54:36,200 --> 00:54:39,080
A LOT OF PEOPLE HAVE IDENTIFIED

1073
00:54:39,080 --> 00:54:40,880
THE PROTEINS AND THERE'S BEEN

1074
00:54:40,880 --> 00:54:48,040
SOME STUDIES IN OR STRP SO IT

1075
00:54:48,040 --> 00:54:51,720
CONSERVED MECHANISM OF ADHESION

1076
00:54:51,720 --> 00:54:56,240
AND WE USE CBM 40 AND WE TOOK

1077
00:54:56,240 --> 00:54:59,040
FIVE ADDITIONAL ISOLATE AND

1078
00:54:59,040 --> 00:55:05,560
SHOWED EACH WAS REDUCED BY CDM40

1079
00:55:05,560 --> 00:55:07,600
AND IT'S JUST TO COMPLICATE

1080
00:55:07,600 --> 00:55:11,120
MATTERS, A LOT OF THESE STRAINS

1081
00:55:11,120 --> 00:55:19,520
CAN UNDERLINE CARBOHYDRATES.

1082
00:55:19,520 --> 00:55:22,280
ONLY TWO OF THE FIVE HAD FAP1 SO

1083
00:55:22,280 --> 00:55:27,200
WE KNEW NOW THAT FINDING SIALIC

1084
00:55:27,200 --> 00:55:29,640
ACID IS CONSERVED AND FAP ONE IS

1085
00:55:29,640 --> 00:55:31,400
NOT AND WE WANTED TO FIND AND

1086
00:55:31,400 --> 00:55:33,640
WHY HAVE A LOT OF TIME TO TELL

1087
00:55:33,640 --> 00:55:35,920
YOU ALL ABOUT IT BUT BASICALLY

1088
00:55:35,920 --> 00:55:43,640
WHAT WE WAS WE MADE A SURFACE

1089
00:55:43,640 --> 00:55:44,320
PROTEINS AND MOST STREPTOCOCCUS

1090
00:55:44,320 --> 00:55:45,840
HAVE BEEN DESCRIBED AND ARE

1091
00:55:45,840 --> 00:55:48,880
FOUND TO THE SURFACE OF THE

1092
00:55:48,880 --> 00:55:53,840
BACTERIA BY SORT ACE A AND WE

1093
00:55:53,840 --> 00:55:56,080
THAT WAS REDUCED IN BINDING SO

1094
00:55:56,080 --> 00:56:00,040
WE CAN DO RELATIVELY COMPARATIVE

1095
00:56:00,040 --> 00:56:04,040
GENOMICS TO COMPARE TRAINS THAT

1096
00:56:04,040 --> 00:56:08,720
HAD FAP1 AND IDENTIFY PRE TEEN

1097
00:56:08,720 --> 00:56:10,160
GENES AND IT WOULD BE DIFFERENT

1098
00:56:10,160 --> 00:56:12,320
AND WE WOULD DO STRUCTURAL

1099
00:56:12,320 --> 00:56:13,640
PREDICTIONS TO SEE IF THEY HAVE

1100
00:56:13,640 --> 00:56:18,680
A DOMAIN OR OTHER THINGS AND YOU

1101
00:56:18,680 --> 00:56:20,080
MIGHT WELL-KNOWN THEY'RE NOT

1102
00:56:20,080 --> 00:56:24,360
EASILY IDENTIFIED BY SEQUENCE

1103
00:56:24,360 --> 00:56:24,640
SIMILARITY.

1104
00:56:24,640 --> 00:56:26,240
IT'S EASIER BY STRUCTURAL

1105
00:56:26,240 --> 00:56:28,240
PREDICTION AND AFTER THAT, WE

1106
00:56:28,240 --> 00:56:34,640
IDENTIFIED WHAT WE CALLED ASAA

1107
00:56:34,640 --> 00:56:36,520
AND ADHESION A AND THIS HAS A

1108
00:56:36,520 --> 00:56:37,840
SIMILAR STRUCTURE IN A WAY BUT

1109
00:56:37,840 --> 00:56:41,680
ALSO IT'S QUITE DIFFERENT AND

1110
00:56:41,680 --> 00:56:43,280
STEED OF REPEATS WE HAVE 42

1111
00:56:43,280 --> 00:56:44,920
REPEATS AND THESE ARE OFTEN

1112
00:56:44,920 --> 00:56:46,240
FOUND DAN TEM IN SURFACE

1113
00:56:46,240 --> 00:56:47,960
PROTEINS AND THEY'VE NOT BEEN

1114
00:56:47,960 --> 00:56:49,680
STUDIED A LOT BUT WHEN ANOTHER

1115
00:56:49,680 --> 00:56:51,040
GROUP ARE COMMONLY EXPRESSED

1116
00:56:51,040 --> 00:56:53,760
SOME OF THESE IN TANDEM THEY

1117
00:56:53,760 --> 00:56:57,120
FORMED AFTER ALPHA ELECTION SO

1118
00:56:57,120 --> 00:57:04,880
WE'RE NOT ABLE THELIX AND
WEBELIEVE IT MAK
ES A FEW RAL AND

1119
00:57:04,880 --> 00:57:07,840
IN THE NON REPEAT REGION, THERE

1120
00:57:07,840 --> 00:57:11,200
ARE TWO UNIQUE DOMAINS IN ASAA

1121
00:57:11,200 --> 00:57:12,840
AND ANOTHER PART OF THAT REGION

1122
00:57:12,840 --> 00:57:15,400
WHICH HAS SOME STRUCTURAL

1123
00:57:15,400 --> 00:57:18,080
SIMILARITIES TO A FAMILY VARIOUS

1124
00:57:18,080 --> 00:57:21,000
ARCHITECTURE DOMAIN AND A CVM SO

1125
00:57:21,000 --> 00:57:23,440
PERHAPS THERE'S MORE THAN ONE

1126
00:57:23,440 --> 00:57:23,880
RECEPTORS.

1127
00:57:23,880 --> 00:57:25,120
SO THEN WE WENT ON TO LOOK AT

1128
00:57:25,120 --> 00:57:28,240
THE FUNCTION OF ASAA AND IF WE

1129
00:57:28,240 --> 00:57:31,080
KNOCK OUT ASAA WE SEE AS WE

1130
00:57:31,080 --> 00:57:33,040
PREDICT, A REDUCTION IN BINDING.

1131
00:57:33,040 --> 00:57:39,120
IF WE USE SIALIC ACID THE STRAIN

1132
00:57:39,120 --> 00:57:42,800
DOES NOT BIND TO AN UNDERLYING

1133
00:57:42,800 --> 00:57:45,000
CARBOHYDRATE AND WE SEE A

1134
00:57:45,000 --> 00:57:49,360
REDUCTION IN BINDING AND IF WE

1135
00:57:49,360 --> 00:57:54,640
THEN USE CELLS AND ASAA WE SEE

1136
00:57:54,640 --> 00:57:56,560
NO FURTHER REDUCTION AND WE ALSO

1137
00:57:56,560 --> 00:58:01,480
SEE BINDING WITH SALIVA TOO.

1138
00:58:01,480 --> 00:58:03,280
WE THEN WERE COMMONLY EXPRESSED

1139
00:58:03,280 --> 00:58:05,840
THE NON REPEAT REGION OF ASAA

1140
00:58:05,840 --> 00:58:08,360
AND SHOWED IT CAN INHIBIT BIND

1141
00:58:08,360 --> 00:58:11,800
NORTH A DOSED MANNER AND TO LOOK

1142
00:58:11,800 --> 00:58:15,280
AT THIS IN A MORE DIRECT WAY, WE

1143
00:58:15,280 --> 00:58:17,200
WERE COMMONLY EXPRESSED THE NON

1144
00:58:17,200 --> 00:58:19,560
REPEAT REGION OF ASAA AND BOUND

1145
00:58:19,560 --> 00:58:22,040
IT TO A PLATE AND THEN ADDED

1146
00:58:22,040 --> 00:58:22,640
PLATELETS AND I DON'T KNOW HOW

1147
00:58:22,640 --> 00:58:25,600
WELL YOU CAN SEE IT BUT

1148
00:58:25,600 --> 00:58:27,840
HOPEFULLY YOU SEE THE DOTS AND

1149
00:58:27,840 --> 00:58:30,760
EACH IS A PLATELET AND THEN IF

1150
00:58:30,760 --> 00:58:33,840
WE TREAT THE PLATELETS WE SEE A

1151
00:58:33,840 --> 00:58:35,200
VAST REDUCTION IN BINDING AND WE

1152
00:58:35,200 --> 00:58:37,960
THEN WANTED TO SHOW IT WAS JUST

1153
00:58:37,960 --> 00:58:44,360
A SIGLEC AS WE PRO DICTIONARY SO

1154
00:58:44,360 --> 00:58:46,240
THAT EXPRESS CAN ALSO BIND

1155
00:58:46,240 --> 00:58:48,520
PLATELETS AND ALSO GREATLY

1156
00:58:48,520 --> 00:58:49,600
REDUCE WITH TREATMENT AND

1157
00:58:49,600 --> 00:58:51,480
BECAUSE BOTH OF THESE PROTEINS

1158
00:58:51,480 --> 00:58:53,720
WERE GTST TAGGED WE USED THAT AS

1159
00:58:53,720 --> 00:58:54,480
A CONTROL.

1160
00:58:54,480 --> 00:58:55,960
AND SO IF WE QUANTIFY THAT DATA

1161
00:58:55,960 --> 00:58:59,440
YOU WITH CLEARLY SEE THAT THE

1162
00:58:59,440 --> 00:59:02,280
SEC GLEC-LIKE AND UNIQUE DOUGH

1163
00:59:02,280 --> 00:59:04,200
MINES BIND IN A SIALIC DEPENDENT

1164
00:59:04,200 --> 00:59:05,600
MANNER SO THEN TO LOOK AT THIS

1165
00:59:05,600 --> 00:59:11,120
IN THE CONTEXT OF THE BACTERIA,

1166
00:59:11,120 --> 00:59:17,080
WHAT MEZ DID SO SHE TAGGED THE

1167
00:59:17,080 --> 00:59:21,200
PROTEIN AND MADE TWO

1168
00:59:21,200 --> 00:59:24,440
DEELECTRICKION TO REMOVE THE

1169
00:59:24,440 --> 00:59:25,960
SIGLEC-LIKE AND UNIQUE DOMAINS

1170
00:59:25,960 --> 00:59:27,440
AND SHOWED THOSE PROTEINS WERE

1171
00:59:27,440 --> 00:59:29,360
STILL EXPRESSED AND ON THE

1172
00:59:29,360 --> 00:59:31,480
SURFACE OF THE BACTERIA, AND WE

1173
00:59:31,480 --> 00:59:41,600
LOOKED AT BINDING.

1174
00:59:41,600 --> 00:59:42,920
SHOWING YOU THEY'RE IMPORTANT

1175
00:59:42,920 --> 00:59:45,800
FOR BINDING SIALIC ACIDS ON THE

1176
00:59:45,800 --> 00:59:46,440
PLATELETS.

1177
00:59:46,440 --> 00:59:47,520
THE PHENOTYPE HERE ISN'T AS

1178
00:59:47,520 --> 00:59:49,920
STRONG AS WE SAW PREVIOUSLY AND

1179
00:59:49,920 --> 00:59:52,720
I THINK THAT'S BECAUSE, WE KNOW

1180
00:59:52,720 --> 00:59:54,440
THAT THE THREE STRAIN DOES NOT

1181
00:59:54,440 --> 00:59:57,360
BIND QUITE AS WELL AND WE THINK

1182
00:59:57,360 --> 00:59:58,800
THAT'S BECAUSE IT'S EFFECTING

1183
00:59:58,800 --> 01:00:03,840
THE FOLDING A LITTLE BIT.

1184
01:00:03,840 --> 01:00:06,240
THAT'S WHY IT LOOKS LESS.

1185
01:00:06,240 --> 01:00:07,760
WITH TODD KITTEN, HE WAS KIND

1186
01:00:07,760 --> 01:00:10,480
ENOUGH TO DO SOME RABBIT MODELS

1187
01:00:10,480 --> 01:00:14,680
FOR US AND WE COULD SEE ABOUT A

1188
01:00:14,680 --> 01:00:15,760
THREE-FOLD REDUCTION IN THE

1189
01:00:15,760 --> 01:00:18,720
NUMBER OF BACTERIA IN THE

1190
01:00:18,720 --> 01:00:19,040
VEGETATION.

1191
01:00:19,040 --> 01:00:20,960
THIS IS IN KEEPING WITH A MOST

1192
01:00:20,960 --> 01:00:23,600
DATA FROM OTHER REPEAT PROTEINS

1193
01:00:23,600 --> 01:00:26,520
IN FACT IT'S MORE OF A REDUCTION

1194
01:00:26,520 --> 01:00:27,600
THAN IS OFTEN OBSERVED.

1195
01:00:27,600 --> 01:00:29,440
WE THINK THE REASON WHY THIS

1196
01:00:29,440 --> 01:00:31,240
REDUCTION ISN'T LARGER IS

1197
01:00:31,240 --> 01:00:32,640
PROBABLY BECAUSE WE'RE EXPOSING

1198
01:00:32,640 --> 01:00:34,200
ADDITIONAL RE SCEPTER ON THE

1199
01:00:34,200 --> 01:00:36,320
SURFACE OF THE BACK TO BE BY

1200
01:00:36,320 --> 01:00:37,720
REMOVING THE FIBER.

1201
01:00:37,720 --> 01:00:41,240
WE SEE IN A ASAA MUTE CAN'T

1202
01:00:41,240 --> 01:00:45,720
INCREASED BINDING TO FIBER.

1203
01:00:45,720 --> 01:00:46,880
WE'RE INTERESTED WHETHER THERE

1204
01:00:46,880 --> 01:00:53,200
WERE ASAA IN OTHER SPECIES.

1205
01:00:53,200 --> 01:00:55,760
THESE COMBINE SIALIC ACID BUT

1206
01:00:55,760 --> 01:00:58,040
THERE ARE OTHERS WE DIDN'T KNOW

1207
01:00:58,040 --> 01:01:03,360
HOW THEY BIND AND SO WE FOUND

1208
01:01:03,360 --> 01:01:06,440
ASAAORTHOLOGS THAT CAN CAUSE.

1209
01:01:06,440 --> 01:01:07,920
I DON'T HAVE THE DATA YET TO

1210
01:01:07,920 --> 01:01:11,040
SHOW YOU, BUT WE TROY TO STUDY

1211
01:01:11,040 --> 01:01:15,200
WHETHER ASAA IS A MEMBER OF A

1212
01:01:15,200 --> 01:01:18,400
FAMILY AND BECAUSE IT'S CLOSEST

1213
01:01:18,400 --> 01:01:20,520
WE CHOSE NATURALLY TRANSFORMAL

1214
01:01:20,520 --> 01:01:22,640
WHEN WE WORK WITH THAT AND IT'S

1215
01:01:22,640 --> 01:01:26,880
ONE STRAIN OF MITIS THAT ENCODES

1216
01:01:26,880 --> 01:01:29,640
TWO POTENTIAL SIALIC

1217
01:01:29,640 --> 01:01:32,240
ACID-BINDING PROTEINS AND WE SEE

1218
01:01:32,240 --> 01:01:38,440
IT IN CODE FAP1 OR ASAA AND IN

1219
01:01:38,440 --> 01:01:43,000
MITIS IT'S MORE COMPLICATED SO

1220
01:01:43,000 --> 01:01:43,840
THIS TRANSCRIPTION WHICH A

1221
01:01:43,840 --> 01:01:46,040
REPEAT PROTEIN THAT'S NOT BEEN

1222
01:01:46,040 --> 01:01:49,480
STUDIED AND ALSO AN ASAA ORTH

1223
01:01:49,480 --> 01:01:56,440
OWE LOG SO ONE OF OUR UNDER

1224
01:01:56,440 --> 01:01:59,640
GRADS.

1225
01:01:59,640 --> 01:02:01,880
OVER ALL, I THINK WE'VE SHOWN

1226
01:02:01,880 --> 01:02:04,520
THAT SIALIC ACID BINDING IS MORE

1227
01:02:04,520 --> 01:02:05,680
COMPLEX THAN PREVIOUSLY

1228
01:02:05,680 --> 01:02:07,240
APPRECIATED SO WE WONDERED IF

1229
01:02:07,240 --> 01:02:11,640
THERE'S OTHER ADDITIONAL SIALIC

1230
01:02:11,640 --> 01:02:12,800
ACID BINDINGS AND SO THESE ARE

1231
01:02:12,800 --> 01:02:14,160
THE TWO THAT I'VE ALREADY TALKED

1232
01:02:14,160 --> 01:02:17,680
ABOUT, ASAA AND THE REPEAT

1233
01:02:17,680 --> 01:02:19,000
PROTEINS AND I DON'T HAVE A LOT

1234
01:02:19,000 --> 01:02:25,920
OF DATA FOR YOU BUT IF WE LIKE

1235
01:02:25,920 --> 01:02:29,520
AT GENOME WE HAVE OTHER SURPASS

1236
01:02:29,520 --> 01:02:30,440
PROTEINS INCLUDING THE ONE THAT

1237
01:02:30,440 --> 01:02:35,640
I'VE ILLUSTRATED HERE WHICH

1238
01:02:35,640 --> 01:02:37,840
INSTEAD OF DOVE 1542 REPEATS HAS

1239
01:02:37,840 --> 01:02:41,160
A TYPICAL REPEATS AND SO WE'RE

1240
01:02:41,160 --> 01:02:43,640
ALSO NOW BECOMING INTERESTED IN

1241
01:02:43,640 --> 01:02:45,760
THIS IDEA THAT A BACTERIA AND I

1242
01:02:45,760 --> 01:02:47,400
DON'T KNOW THAT IT'S A NOVEL

1243
01:02:47,400 --> 01:02:49,000
IDEA, BUT THE IDEA THAT THE

1244
01:02:49,000 --> 01:02:56,640
BACTERIA HAS A PORTFOLIO OF AT

1245
01:02:56,640 --> 01:03:00,280
ADHERENCE SO WE KNOW THERE ARE

1246
01:03:00,280 --> 01:03:03,240
OTHER REPEAT CONTAINING BINDING

1247
01:03:03,240 --> 01:03:19,040
PROTEINS THAT HAVE DIFFERENT SO

1248
01:03:19,040 --> 01:03:20,440
WE CAN HYPOTHESIZE THAT THEY

1249
01:03:20,440 --> 01:03:21,520
HAVE DIFFERENT PROTEINS AND

1250
01:03:21,520 --> 01:03:23,640
THERE'S SOME EVIDENCE THAT THE

1251
01:03:23,640 --> 01:03:25,440
PROTEINS CAN IMPORTANT IN BIO

1252
01:03:25,440 --> 01:03:26,720
FILM FORMATION BUT THERE ARE NOT

1253
01:03:26,720 --> 01:03:28,760
A LOT OF STUDIES OF THOSE

1254
01:03:28,760 --> 01:03:29,840
REPEATS SO ONE OF THE THINGS

1255
01:03:29,840 --> 01:03:31,440
WE'RE INTERESTED TO DO IS TO

1256
01:03:31,440 --> 01:03:35,680
MAKE IC ISOGENIC STRAINS
EXPRESSING

1257
01:03:35,680 --> 01:03:37,840
FAP1 AND ASAA THAT HAVE THE SAME

1258
01:03:37,840 --> 01:03:39,840
BINDING REGION OR NO BINDING

1259
01:03:39,840 --> 01:03:41,600
REGION SO WE CAN STUDY THE

1260
01:03:41,600 --> 01:03:42,720
CONTRIBUTION OF REPEATS SO YOU

1261
01:03:42,720 --> 01:03:44,600
CAN IMAGINE IF A BACTERIA HAS A

1262
01:03:44,600 --> 01:03:46,440
PORTFOLIO OF ADHESIONS AND THEY

1263
01:03:46,440 --> 01:03:50,520
CAN BE DIFFERENT, IT CAN CONFER

1264
01:03:50,520 --> 01:03:51,800
DIFFERENT DISTANCES OUT FROM THE

1265
01:03:51,800 --> 01:03:53,040
SURFACE THAT YOU COMBINE THESE

1266
01:03:53,040 --> 01:03:54,800
DIFFERENT RECEPTORS AND

1267
01:03:54,800 --> 01:03:57,800
DIFFERENT CHARGE, DIFFERENT

1268
01:03:57,800 --> 01:03:58,720
(INAUDIBLE) AND THINGS LIKE THAT

1269
01:03:58,720 --> 01:04:00,720
THAT COULD CHANGE HOW THESE

1270
01:04:00,720 --> 01:04:02,960
BACTERIA BEHAVE.

1271
01:04:02,960 --> 01:04:06,600
IN CONCLUSION, I HOPE I'VE SHOWN

1272
01:04:06,600 --> 01:04:15,360
YOU THE FAP1 AND ASAA AND THESE

1273
01:04:15,360 --> 01:04:17,040
BOTH BIND SIALIC ACID AND WITH

1274
01:04:17,040 --> 01:04:19,640
TODD'S HELP WE SHOWED THAT ASAA

1275
01:04:19,640 --> 01:04:23,040
IS IMPORTANT IN FORMATION OF A

1276
01:04:23,040 --> 01:04:25,240
VEGETATION AND WE'VE SHOWN THAT

1277
01:04:25,240 --> 01:04:29,080
SIALIC ACID BINDING IS MORE

1278
01:04:29,080 --> 01:04:30,360
COMPLEX THAN WE PREVIOUSLY

1279
01:04:30,360 --> 01:04:31,880
APPRECIATED AND WE THINK THAT

1280
01:04:31,880 --> 01:04:34,720
ASAA IS THE FOUNDING MEMBER OF A

1281
01:04:34,720 --> 01:04:36,360
FAMILY OF ADHESIONS AND THE

1282
01:04:36,360 --> 01:04:39,400
OTHER CHARACTERIZED SIALIC EXIST

1283
01:04:39,400 --> 01:04:42,600
IN OUR BACTERIA AND NOW WE'RE

1284
01:04:42,600 --> 01:04:45,640
INTRIGUED OF WHAT THE BIOLOGICAL

1285
01:04:45,640 --> 01:04:47,200
CONSEQUENCES OF THESE ADHESIONS

1286
01:04:47,200 --> 01:04:50,600
AND I'LL TAKE ANY QUESTIONS WITH

1287
01:04:50,600 --> 01:04:51,120
THAT.

1288
01:04:51,120 --> 01:04:51,720
>> EXCELLENT TALK.

1289
01:04:51,720 --> 01:04:55,880
THANK YOU FOR GETTING US INTO OR

1290
01:04:55,880 --> 01:05:00,720
AVENUORAL CAVITY AND THE
BACTERIA

1291
01:05:00,720 --> 01:05:02,240
EXPRESSING THESE RECOGNITION

1292
01:05:02,240 --> 01:05:03,760
PROTEINS OF SIALIC ACIDS SO

1293
01:05:03,760 --> 01:05:04,400
THANK YOU.

1294
01:05:04,400 --> 01:05:05,360
WHAT QUESTIONS DO WE HAVE?

1295
01:05:05,360 --> 01:05:07,240
ARE THERE QUESTIONS COMING IN

1296
01:05:07,240 --> 01:05:07,840
FROM THE CHAT?

1297
01:05:07,840 --> 01:05:09,240
DO OTHER PEOPLE IN THE AUDIENCE

1298
01:05:09,240 --> 01:05:15,320
HAVE QUESTIONS FOR Dr. KING?

1299
01:05:15,320 --> 01:05:17,080
>> I WAS TRYING TO FIND THE

1300
01:05:17,080 --> 01:05:19,880
RAISED HAND IN THE CHAT AND I

1301
01:05:19,880 --> 01:05:22,240
COULDN'T FIGURE OUT.

1302
01:05:22,240 --> 01:05:28,200
I AM REALLY CURIOUS ABOUT

1303
01:05:28,200 --> 01:05:30,440
BINDING TO MUCUS THROUGH THESE

1304
01:05:30,440 --> 01:05:31,120
ADHESIONS AND WHETHER OR NOT

1305
01:05:31,120 --> 01:05:34,560
YOU'VE HAD A CHANCE TO LOOK AT

1306
01:05:34,560 --> 01:05:36,200
THAT BECAUSE THAT WOULD BE AN

1307
01:05:36,200 --> 01:05:37,000
INTERESTING ROLE FOR THEM.

1308
01:05:37,000 --> 01:05:40,920
>> SO WE JUST HAD A PAPER

1309
01:05:40,920 --> 01:05:46,760
ACCEPTED WITH SARAH LINDEN IN

1310
01:05:46,760 --> 01:05:49,560
COPENHAGEN.

1311
01:05:49,560 --> 01:05:51,400
AND SHE LOOKED AT BINDING TO

1312
01:05:51,400 --> 01:05:54,120
MOCK 5A AND 7 ENRICHED FRACTIONS

1313
01:05:54,120 --> 01:05:57,600
AND WE DIDN'T SEE A TON OF

1314
01:05:57,600 --> 01:06:03,280
FINDINGS OF ATCC OR 01577 THE FA

1315
01:06:03,280 --> 01:06:07,560
APPROXIMATE 1 STRAIN EVEN THOUGH

1316
01:06:07,560 --> 01:06:13,840
IT DOES BIND.

1317
01:06:13,840 --> 01:06:16,560
THAT PAPER JUST GOT ACCEPTED SO

1318
01:06:16,560 --> 01:06:18,560
IT SHOULD BE OUT ANY DAY NOW.

1319
01:06:18,560 --> 01:06:23,720
>> YEAH, I THINK MAYBE CAT OR

1320
01:06:23,720 --> 01:06:31,560
EVEN A IS A GOOOR -- ITIS HOW
THEY INFLUEN
CE IT IS

1321
01:06:31,560 --> 01:06:34,720
WHETHER OR NOT YOU SEE THINGS

1322
01:06:34,720 --> 01:06:34,880
TOO.

1323
01:06:34,880 --> 01:06:37,680
>> IN HER SAMPLES, WE MAY BE

1324
01:06:37,680 --> 01:06:39,480
SEEING BINDING TO OTHER FACTORS

1325
01:06:39,480 --> 01:06:41,120
TOO AND HOW MUCH THAT LEADS TO

1326
01:06:41,120 --> 01:06:42,880
CLEARANCE FROM THE ORAL CAVITY

1327
01:06:42,880 --> 01:06:45,600
AND BINDING IN THE ORAL CAVITY

1328
01:06:45,600 --> 01:06:47,960
IS PROBABLY A BALANCE THERE THAT

1329
01:06:47,960 --> 01:06:50,120
YOU ARE SEEING CLEARANCE AND

1330
01:06:50,120 --> 01:06:51,720
ALSO SOME BINDINGS.

1331
01:06:51,720 --> 01:06:57,480
SO, YEAH, IT'S INTRIGUING AND I

1332
01:06:57,480 --> 01:06:59,720
THINK WE WOULD LIKE TO LOOK AT

1333
01:06:59,720 --> 01:07:00,320
MOST STUT HE'D.

1334
01:07:00,320 --> 01:07:01,480
>> SHE'S ON-LINE HERE AND SHE'S

1335
01:07:01,480 --> 01:07:03,640
IN THE CHAT ROOM AND IF YOU WANT

1336
01:07:03,640 --> 01:07:05,720
TO COMMUNICATE WITH CAT OR EVEN

1337
01:07:05,720 --> 01:07:09,440
A OFF LINE AS WELL AS WE'RE

1338
01:07:09,440 --> 01:07:56,840
DOING THIS WHO KNOWS BUT I DON'T

1339
01:07:56,840 --> 01:07:57,240
THINK SO.

1340
01:07:57,240 --> 01:08:00,040
>> AWESOME.

1341
01:08:00,040 --> 01:08:01,920
WELL, THANK YOU FOR AN AMAZING

1342
01:08:01,920 --> 01:08:02,120
TALK.

1343
01:08:02,120 --> 01:08:03,640
THIS IS BEEN A SUPER TREAT SO

1344
01:08:03,640 --> 01:08:06,560
FAR AND STARTING OUT THIS IS

1345
01:08:06,560 --> 01:08:08,200
GREAT.

1346
01:08:08,200 --> 01:08:11,640
WE'RE GOING TO SWITCH GEARS FROM

1347
01:08:11,640 --> 01:08:12,960
EMILY AND SHE'S COMING FROM

1348
01:08:12,960 --> 01:08:13,640
HARVARD UNIVERSITY AND SHE'S

1349
01:08:13,640 --> 01:08:15,320
GOING TO TALK TO US ABOUT HER

1350
01:08:15,320 --> 01:08:18,560
WORK ON ENZYME DISCOVERY IN THE

1351
01:08:18,560 --> 01:08:22,280
HUMAN MICROBIOME.

1352
01:08:22,280 --> 01:08:23,720
IF YOU FOR JOINING US AND I

1353
01:08:23,720 --> 01:08:25,080
APPRECIATE YOU COMING AT THE

1354
01:08:25,080 --> 01:08:27,000
INTERSECTION OF MICROBIOME

1355
01:08:27,000 --> 01:08:28,160
METABOLISM AND GLYCO SCIENCE SO

1356
01:08:28,160 --> 01:08:29,240
THANK YOU SO MUCH FOR JOINING

1357
01:08:29,240 --> 01:08:30,680
AND WE'RE LOOKING FORWARD TO

1358
01:08:30,680 --> 01:08:31,040
YOUR TALK.

1359
01:08:31,040 --> 01:08:32,600
>> THANK YOU SO MUCH CATHERINE

1360
01:08:32,600 --> 01:08:33,320
AND THANK YOU TO ALL THE

1361
01:08:33,320 --> 01:08:34,920
ORGANIZERS FOR IN INVITING ME TO

1362
01:08:34,920 --> 01:08:36,920
BE PART OF THIS INTERESTING

1363
01:08:36,920 --> 01:08:37,280
SYMPOSIUM.

1364
01:08:37,280 --> 01:08:42,560
AND I'M EXCITED TO BE HERE.

1365
01:08:42,560 --> 01:08:45,680
SO, WE ARE INTERESTED BECAUSE OF

1366
01:08:45,680 --> 01:08:48,160
THE RICH CHEMISTRY THAT THEY

1367
01:08:48,160 --> 01:08:48,560
PERFORM.

1368
01:08:48,560 --> 01:08:50,360
SO WE THINK THAT THESE ORGANISMS

1369
01:08:50,360 --> 01:08:51,800
REALLY PROVIDE SOME AMAZING

1370
01:08:51,800 --> 01:08:55,360
OPPORTUNITIES FOR THE DISCOVERY

1371
01:08:55,360 --> 01:08:59,280
OF NEW CHEM TRE CHEMISTRY AND
METABOLISM

1372
01:08:59,280 --> 01:09:02,040
BUT WE'RE FASCINATED BY THE

1373
01:09:02,040 --> 01:09:03,120
BIOLOGICAL ROLES THAT IT PLAYS

1374
01:09:03,120 --> 01:09:06,560
IN HUMAN ASSOCIATED MICROBIAL

1375
01:09:06,560 --> 01:09:06,840
COMMUNITIES.

1376
01:09:06,840 --> 01:09:09,280
SO MICROBIAL METABOLISM EXPANDS

1377
01:09:09,280 --> 01:09:12,440
THE CHEMISTRY OF THE HUMAN BODY

1378
01:09:12,440 --> 01:09:13,360
AND MEDIATES IMPORTANT

1379
01:09:13,360 --> 01:09:14,560
INTERACTIONS WITH THE HOST.

1380
01:09:14,560 --> 01:09:16,880
BUT ARE UNDERSTANDING OF THE

1381
01:09:16,880 --> 01:09:20,240
BIOLOGICAL CONSEQUENCES IS STILL

1382
01:09:20,240 --> 01:09:21,080
LIMITED.

1383
01:09:21,080 --> 01:09:25,040
MOST GUT MICROBIAL METABOLIC

1384
01:09:25,040 --> 01:09:26,280
ACTIVITY HAVEN'T BEEN LINKED TO

1385
01:09:26,280 --> 01:09:29,200
GENES OR ENZYMES AND BOTH GENES

1386
01:09:29,200 --> 01:09:31,000
AND METABOLITES ARE

1387
01:09:31,000 --> 01:09:33,800
UNCHARACTERIZED AND FINALLY, WE

1388
01:09:33,800 --> 01:09:36,840
HAVEN'T YET MANY OF THE

1389
01:09:36,840 --> 01:09:37,480
MOLECULAR MECHANISMS BY WHICH

1390
01:09:37,480 --> 01:09:39,160
THEY EFFECT THE HEALTH OF THE

1391
01:09:39,160 --> 01:09:44,400
HOST AND OTHER MEMBERS OF THE

1392
01:09:44,400 --> 01:09:47,240
MICRO BIOME SO THESE QUESTIONS

1393
01:09:47,240 --> 01:09:48,560
REALLY INTRIGUE MY LAB AND OUR

1394
01:09:48,560 --> 01:09:50,040
GOAL IS TO USE CHEMICAL

1395
01:09:50,040 --> 01:09:50,960
KNOWLEDGE AND APPROACHES TO TROY

1396
01:09:50,960 --> 01:09:54,240
TO DO THINGS LIKE DISCOVER NEW

1397
01:09:54,240 --> 01:09:55,960
METABOLIC ACTIVITIES AND ENZYMES

1398
01:09:55,960 --> 01:10:00,440
FROM THE HUMAN MICROBIOME AND TO

1399
01:10:00,440 --> 01:10:02,240
DECIPHER HOW THEY INFLUENCE HOST

1400
01:10:02,240 --> 01:10:10,160
BIOLOGY AND OTHER MICROBES.

1401
01:10:10,160 --> 01:10:14,760
WE HOPE IT WILL REVEAL INSIGHTS

1402
01:10:14,760 --> 01:10:17,640
INTO MICROBIOME AND PAVE THE WAY

1403
01:10:17,640 --> 01:10:19,840
FOR THERAPEUTIC INTERVENTIONS.

1404
01:10:19,840 --> 01:10:21,600
MOST OF OUR WORK HAS FOCUSED ON

1405
01:10:21,600 --> 01:10:24,080
THE HUMAN GUT MICROBIOME SO OVER

1406
01:10:24,080 --> 01:10:25,240
THE LAST 10 YEARS WE'VE STUDIED

1407
01:10:25,240 --> 01:10:27,640
A WIDE RANGE OF MET BOL

1408
01:10:27,640 --> 01:10:29,360
DETECTIVE TEASE THAT HAVE

1409
01:10:29,360 --> 01:10:31,640
EXPANDED OUR UNDERSTANDING OF

1410
01:10:31,640 --> 01:10:35,840
ENZYMES FROM THESE ORGANISMS AND

1411
01:10:35,840 --> 01:10:37,920
REVEALED CORRELATION S WITH

1412
01:10:37,920 --> 01:10:38,280
HUMAN HEATH.

1413
01:10:38,280 --> 01:10:41,440
WE HAVE DISCOVERED HOW A GROUP

1414
01:10:41,440 --> 01:10:45,120
OF UNCUL TURD GUT BACTERIA

1415
01:10:45,120 --> 01:10:46,040
METABOLIZED CHOLESTEROL LOWERING

1416
01:10:46,040 --> 01:10:47,720
LEVELS OF THIS DISEASE

1417
01:10:47,720 --> 01:10:49,720
ASSOCIATED MOLECULE AND WE'VE

1418
01:10:49,720 --> 01:10:51,720
UNDISCOVERED GUT BACTERIA THAT

1419
01:10:51,720 --> 01:10:53,840
METABOLIZE THE PARKINSON'S

1420
01:10:53,840 --> 01:10:56,440
DISEASE AND REDUCING ITS BIO

1421
01:10:56,440 --> 01:10:58,920
AVAILABILITY AND WE'VE ALSO

1422
01:10:58,920 --> 01:11:01,240
DESCRIBED HOW GUT BACTERIA MAKE

1423
01:11:01,240 --> 01:11:03,600
THE COMPLEX DAMAGING NATURAL

1424
01:11:03,600 --> 01:11:05,960
PRODUCT LINKED TO COLORECTAL

1425
01:11:05,960 --> 01:11:09,000
CANCER BUT GIVEN THE THEME OF

1426
01:11:09,000 --> 01:11:10,000
TODAY'S SYMPOSIUM, I ACTUALLY

1427
01:11:10,000 --> 01:11:12,720
WANT TO TELL YOU ABOUT A NEW

1428
01:11:12,720 --> 01:11:14,240
STORY, THIS IS OUR FIRST EFFORTS

1429
01:11:14,240 --> 01:11:17,360
TO KIND OF MOVE BEYOND THE GUT

1430
01:11:17,360 --> 01:11:19,160
AND INVESTIGATE ENZYMES FROM THE

1431
01:11:19,160 --> 01:11:22,280
AND THIS IS ALL ALSO OF OUR

1432
01:11:22,280 --> 01:11:23,240
FIRST ADVENTURES INTO THE

1433
01:11:23,240 --> 01:11:24,800
DISCOVERY AND CHARACTERIZATION

1434
01:11:24,800 --> 01:11:27,840
OF CARBOHYDRATE METABOLIZING

1435
01:11:27,840 --> 01:11:29,280
ENZYMES.

1436
01:11:29,280 --> 01:11:31,920
SO THE HUMAN BIKE ROW BIOME IS

1437
01:11:31,920 --> 01:11:33,960
DIFFERENT THAN THE HUMAN GUT.

1438
01:11:33,960 --> 01:11:38,520
THE HEALTH ASSOCIATED STATE IS

1439
01:11:38,520 --> 01:11:41,320
TYPICALLY DOMINATED BY A SINGLE

1440
01:11:41,320 --> 01:11:44,760
SPECIES OF LACTOBACILLU IS AND

1441
01:11:44,760 --> 01:11:47,760
THEY LOWER THE PH OF THE

1442
01:11:47,760 --> 01:11:50,000
CERVICAL VAGINAL ENVIRONMENT BUT

1443
01:11:50,000 --> 01:11:52,200
THIS COMMUNITY CAN TRANSITION TO

1444
01:11:52,200 --> 01:11:56,080
A MORE DIVERSE GROUP OF

1445
01:11:56,080 --> 01:11:57,520
ANTI-ROBES AND THIS IS

1446
01:11:57,520 --> 01:12:01,840
ASSOCIATED WITH AN ELEVATION OF

1447
01:12:01,840 --> 01:12:04,440
PH AND THIS CHANGE IN COMMUNITY

1448
01:12:04,440 --> 01:12:05,960
COMPOSITION AS ASSOCIATED WITH

1449
01:12:05,960 --> 01:12:08,920
CHANGES IN THE CERVICAL VAGINAL

1450
01:12:08,920 --> 01:12:13,160
ENVIRONMENT AND THE DEROGATION

1451
01:12:13,160 --> 01:12:13,840
OF MUCUS AS WELL AS HEALTH

1452
01:12:13,840 --> 01:12:17,720
CONDITIONS INCLUDING BACTERIAL,

1453
01:12:17,720 --> 01:12:20,520
HIGHER RISK FOR PRE TERM BIRTH

1454
01:12:20,520 --> 01:12:25,000
AND STI ACQUISITION SO WE DON'T

1455
01:12:25,000 --> 01:12:27,800
UNDERSTAND WHAT PROMOTES

1456
01:12:27,800 --> 01:12:34,560
DOMINANCE OR THE FACTORS

1457
01:12:34,560 --> 01:12:35,920
FACILITATE THIS TO A DIVERSE

1458
01:12:35,920 --> 01:12:36,240
COMMUNITY.

1459
01:12:36,240 --> 01:12:37,840
THIS LACK OF KNOWLEDGE LIMITS

1460
01:12:37,840 --> 01:12:40,960
OUR ABILITY TO INTERVENE

1461
01:12:40,960 --> 01:12:42,000
THERAPEUTICALLY AND HASN'T BEEN

1462
01:12:42,000 --> 01:12:44,400
A MAJOR ADVANCE IN THE TREATMENT

1463
01:12:44,400 --> 01:12:51,800
OF BACTERIAL ADVANTAGE ENOSIS.

1464
01:12:51,800 --> 01:13:05,160
SO THIS EFFECTS A COULD THIS

1465
01:13:05,160 --> 01:13:06,560
CHANGE IF WE HAVE A BETTER

1466
01:13:06,560 --> 01:13:09,280
UNDERSTANDING OF VAGINAL

1467
01:13:09,280 --> 01:13:11,640
BACTERIA AND WE COULD IDENTIFY

1468
01:13:11,640 --> 01:13:12,960
METABOLIC ACTIVITIES AND ENZYMES

1469
01:13:12,960 --> 01:13:15,320
THAT SUPPORT VAGINAL BACTERIA IN

1470
01:13:15,320 --> 01:13:16,400
DIFFERENT COMMUNITIES OR THAT

1471
01:13:16,400 --> 01:13:19,640
ENABLE THE TRANSITION BETWEEN

1472
01:13:19,640 --> 01:13:20,720
THESE DIFFERENT COMMUNITIES AND

1473
01:13:20,720 --> 01:13:22,840
AGAIN, MOST IMPORTANTLY IF WE

1474
01:13:22,840 --> 01:13:24,440
UNDERSTAND THE FUNCTIONS AND THE

1475
01:13:24,440 --> 01:13:28,240
MECHANISMS BY WHICH HOST AND

1476
01:13:28,240 --> 01:13:30,040
OTHER MEMBERS OF THE COMMUNITY

1477
01:13:30,040 --> 01:13:31,960
CAN RELEVERAGE THAT INFORMATION

1478
01:13:31,960 --> 01:13:34,680
SO THERAPEUTIC DEVELOPMENT SO

1479
01:13:34,680 --> 01:13:37,240
TODAY, I HOPE TO GIVE THESE ARE

1480
01:13:37,240 --> 01:13:38,160
INTERESTING QUESTIONS TO EXPLORE

1481
01:13:38,160 --> 01:13:39,920
AND WE'RE STILL AT AN EARLY

1482
01:13:39,920 --> 01:13:42,240
STAGE BUT I HOPE THIS WILL

1483
01:13:42,240 --> 01:13:43,840
ILLUSTRATE HOW CHEMISTRY CAN

1484
01:13:43,840 --> 01:13:46,240
PLAY A KEY ROLE IN THESE EFFORTS

1485
01:13:46,240 --> 01:13:47,600
AND PARTICULARLY, HOW IT'S

1486
01:13:47,600 --> 01:13:49,960
IMPORTANT THAT WE DISCOVER AND

1487
01:13:49,960 --> 01:13:55,400
CHARACTERIZE ENZYMES FROM THIS

1488
01:13:55,400 --> 01:13:55,640
COMMUNITY.

1489
01:13:55,640 --> 01:13:57,680
THIS IS THE WORK OF TWO

1490
01:13:57,680 --> 01:13:59,040
TRAINEES, A POSTDOC IN THE LAB

1491
01:13:59,040 --> 01:14:00,800
AND A GRADUATE STUDENT AND WE'VE

1492
01:14:00,800 --> 01:14:05,360
WORKED TOGETHER ON THIS PROJECT

1493
01:14:05,360 --> 01:14:07,040
WITH SETH AND SETH WILL TALK

1494
01:14:07,040 --> 01:14:10,040
LATER ON TODAY.

1495
01:14:10,040 --> 01:14:13,160
AND CAROLYN MITCHELL IS ANOTHER

1496
01:14:13,160 --> 01:14:14,240
KEY COLLABORATOR AND WE'RE PART

1497
01:14:14,240 --> 01:14:19,440
OF A LARGER VAGINAL MICROBIOME

1498
01:14:19,440 --> 01:14:20,960
CONSORTIUM FOUNDED BY THE GATES

1499
01:14:20,960 --> 01:14:21,520
FOUNDATION.

1500
01:14:21,520 --> 01:14:22,760
THIS PROJECT BEGAN WITH AN

1501
01:14:22,760 --> 01:14:25,000
INTEREST IN UNDERSTANDING HOW

1502
01:14:25,000 --> 01:14:29,360
VAGINAL BACTERIA ACCESSED AROUND

1503
01:14:29,360 --> 01:14:31,840
IMPORTANT CARBON SOURCE.

1504
01:14:31,840 --> 01:14:36,360
GLYCO GINA ACCUMULATIO GENE
ACCUMULATES AN
D IT'S

1505
01:14:36,360 --> 01:14:39,640
AN IMPORTANT NUTRIENT SOURCE FOR

1506
01:14:39,640 --> 01:14:40,640
VAGINAL BACTERIA AND NOW OF

1507
01:14:40,640 --> 01:14:43,640
COURSE IN ORDER FOR BACTERIA TO

1508
01:14:43,640 --> 01:14:45,000
ACCESS GLUCOSE FROM GLYCO AGAIN

1509
01:14:45,000 --> 01:14:49,920
THEY NEED TO HYDRO GUYS THIS TO

1510
01:14:49,920 --> 01:15:03,720
SMALLER PRODUCTS AND THEY WERE

1511
01:15:03,720 --> 01:15:04,800
UNSUCCESSFUL AND THIS RACED THE

1512
01:15:04,800 --> 01:15:06,080
QUESTION OF WHAT TYPE OF ENZYMES

1513
01:15:06,080 --> 01:15:13,840
MIGHT BE RESPONSIBLE FOR GLYCO

1514
01:15:13,840 --> 01:15:14,680
GLYCOGEN BREAKDOWN IN THE

1515
01:15:14,680 --> 01:15:15,840
VAGINAL ENVIRONMENT.

1516
01:15:15,840 --> 01:15:16,920
THERE'S BEEN EVIDENCE SUPPORTING

1517
01:15:16,920 --> 01:15:25,760
A ROLE NOR HUMAN USING ALLY A

1518
01:15:25,760 --> 01:15:27,240
AND STUT HE'D CORRELATION

1519
01:15:27,240 --> 01:15:33,960
BETWEEN THE ABUNDANCE OF THIS

1520
01:15:33,960 --> 01:15:44,040
ENZYME IT WAS SUPPORTED THAT

1521
01:15:44,040 --> 01:15:47,280
THEY RETAINED HIGH GLYCOGEN

1522
01:15:47,280 --> 01:15:52,640
ACTIVITY EVEN AT PH4 HAVE

1523
01:15:52,640 --> 01:15:55,360
ACTIVITY SO THIS HINTED AT THE

1524
01:15:55,360 --> 01:15:58,840
POTENTIAL RELEVANCE OF BACTERIAL

1525
01:15:58,840 --> 01:16:00,360
ACTIVITY AND IN DEED THE LAST

1526
01:16:00,360 --> 01:16:01,840
FEW YEARS HAVE SEEN SOME REALLY

1527
01:16:01,840 --> 01:16:03,280
GREAT ADVANCES IN OUR

1528
01:16:03,280 --> 01:16:05,320
UNDERSTANDING OF GLYCOGEN

1529
01:16:05,320 --> 01:16:10,320
METABOLISM BY VAGINAL BACTERIA

1530
01:16:10,320 --> 01:16:13,960
AND IN 2019 COURT LAB PERFORMED

1531
01:16:13,960 --> 01:16:18,360
AN ANALYSIS OF STRAINS AND

1532
01:16:18,360 --> 01:16:21,040
ASSOCIATED WITH DOMINATED VERSUS

1533
01:16:21,040 --> 01:16:24,640
STRAINS THAT WERE PRESENT IN

1534
01:16:24,640 --> 01:16:26,640
MORE DIVERSE DIS BIOTICS

1535
01:16:26,640 --> 01:16:27,840
COMMUNITIES AND THIS ANALYSIS

1536
01:16:27,840 --> 01:16:29,320
SHOWED FOR THE FIRST TIME THAT

1537
01:16:29,320 --> 01:16:31,840
ACTUALLY A LARGE FRACTION OF AND

1538
01:16:31,840 --> 01:16:34,560
STRAINS IN THEIR PANEL COULD IN

1539
01:16:34,560 --> 01:16:36,840
DEED GROW ON GLYCOGEN CONTAINED

1540
01:16:36,840 --> 01:16:46,080
MEDIA AND THEY PERFORMED

1541
01:16:46,080 --> 01:16:49,960
INCLUDING A GLYCOGEN METABOLISM

1542
01:16:49,960 --> 01:16:53,400
A TYPE 1 THEY NAMED AND IT HAS A

1543
01:16:53,400 --> 01:16:58,240
CENTRAL DOMAIN AND HAS A SIGNAL

1544
01:16:58,240 --> 01:16:59,840
PEPTIDE AND DOMAIN PREDICTED

1545
01:16:59,840 --> 01:17:03,520
ASSOCIATION S WITH THE BACK

1546
01:17:03,520 --> 01:17:19,080
TERRAL S AND IS EXTRA IN

1547
01:17:19,080 --> 01:17:21,000
ADVANTAGE VAGINAL FLUIDS AND

1548
01:17:21,000 --> 01:17:22,920
THEY HAVE METABOLISMING ACTIVITY

1549
01:17:22,920 --> 01:17:34,600
USING THE PAGE AND THEY SEQUENCE

1550
01:17:34,600 --> 01:17:36,560
DETECTED SEQUENCE SO THIS

1551
01:17:36,560 --> 01:17:38,800
ANALYSIS IMPLICATES BOTH HUMAN

1552
01:17:38,800 --> 01:17:44,880
AND BACTERIAL ENZYMES AND BUT

1553
01:17:44,880 --> 01:17:46,560
WHILE THESE HAVE GREATLY

1554
01:17:46,560 --> 01:17:48,360
ADVANCED OUR UNDERSTANDING OF

1555
01:17:48,360 --> 01:17:50,240
ENZYMES FOR METABOLISM A MAJOR

1556
01:17:50,240 --> 01:17:52,480
GAP IN ALL OF THESE WAS A LACK

1557
01:17:52,480 --> 01:17:54,240
OF BIOCHEMICAL CHARACTERIZATION

1558
01:17:54,240 --> 01:17:56,120
OF THESE ENZYMES.

1559
01:17:56,120 --> 01:17:58,960
AND SO THESE WERE THE QUESTIONS

1560
01:17:58,960 --> 01:18:00,480
THAT MY GROUP HAVE STARTED THIS

1561
01:18:00,480 --> 01:18:00,880
PROJECT.

1562
01:18:00,880 --> 01:18:03,600
CAN THESE ENZYMES REALLY

1563
01:18:03,600 --> 01:18:11,400
BREAKDOWN GUY C GLYCO AGAIN AND
GROWTH

1564
01:18:11,400 --> 01:18:13,040
ON GLYCOGEN.

1565
01:18:13,040 --> 01:18:18,120
WE HAD OUR OWN SEARCH SO WE HAD

1566
01:18:18,120 --> 01:18:21,280
VAGINAL BACTERIA USING THAT

1567
01:18:21,280 --> 01:18:24,240
SEQUENCE AS A QUERY SO WE WERE

1568
01:18:24,240 --> 01:18:25,480
LOOKING SPECIFICALLY FOR

1569
01:18:25,480 --> 01:18:28,920
PROTEINS THAT CONTAIN PREDICTED

1570
01:18:28,920 --> 01:18:31,400
SNAP PEPTIDES THAN AN EXTRA

1571
01:18:31,400 --> 01:18:36,200
CELLULAR AND WE FOUND 69

1572
01:18:36,200 --> 01:18:37,760
POTENTIAL AND INTERESTINGLY, WE

1573
01:18:37,760 --> 01:18:39,560
FOUND THESE SEQUENCES WERE

1574
01:18:39,560 --> 01:18:43,400
PRESENT IN MANY SPECIES BEYOND

1575
01:18:43,400 --> 01:18:50,560
SO IT INCLUDES GARDNER ELLA

1576
01:18:50,560 --> 01:18:52,120
STRAINS AND -- AND SO YOU WILL

1577
01:18:52,120 --> 01:18:54,960
NOTE THAT DIVERSITY IN THE

1578
01:18:54,960 --> 01:18:57,560
ENZYME SEQUENCES AND THE DOMAIN

1579
01:18:57,560 --> 01:18:59,480
ARRANGEMENTS, WHILE ALL OF THE

1580
01:18:59,480 --> 01:19:02,080
ENZYMES HAVE ONE PREDICTED

1581
01:19:02,080 --> 01:19:03,840
DOMAIN THERE'S LARGE VARIATIONS

1582
01:19:03,840 --> 01:19:07,240
IN THE LENGTH AND DOMAINS

1583
01:19:07,240 --> 01:19:08,880
PRESENT IN THESE DIFFERENT

1584
01:19:08,880 --> 01:19:13,040
ENZYMES AND THE PROTEINS HAVE

1585
01:19:13,040 --> 01:19:15,080
CARBOHYDRATE FINDINGS AND

1586
01:19:15,080 --> 01:19:18,160
INTERESTINGLY THE GARDNER ELLA

1587
01:19:18,160 --> 01:19:20,600
HAS TWO MLA DOMAINS AND SO OVER

1588
01:19:20,600 --> 01:19:22,000
ALL THIS INITIAL ANALYSIS

1589
01:19:22,000 --> 01:19:24,360
SUGGESTED THAT A VARIETY OF

1590
01:19:24,360 --> 01:19:26,600
VAGINAL BACTERIA MIGHT

1591
01:19:26,600 --> 01:19:30,240
POTENTIALLY HAVE ENZYMES CAPABLE

1592
01:19:30,240 --> 01:19:33,680
OF METABOLIZING GLYCOGEN.

1593
01:19:33,680 --> 01:19:35,560
WE WANTED TO UNDERSTAND HOW

1594
01:19:35,560 --> 01:19:37,080
THESE ENZYMES WORKED IN MORE

1595
01:19:37,080 --> 01:19:42,360
DOUGH TAIDETAIL SO WE EXPRESSED
THESE

1596
01:19:42,360 --> 01:19:44,040
PROTEINS IN E. COLI WITHOUT

1597
01:19:44,040 --> 01:19:46,640
THEIR PEPTIDES AND WE BEGAN TO

1598
01:19:46,640 --> 01:19:48,640
STUDY THEIR ACTIVITIES.

1599
01:19:48,640 --> 01:19:50,640
SO, FIRST WE EXAMINED IF THEY

1600
01:19:50,640 --> 01:19:52,800
COULD SUPPORT BACTERIAL GROWTH

1601
01:19:52,800 --> 01:19:57,320
ON GLYCOGEN AND SO TO DO THIS WE

1602
01:19:57,320 --> 01:20:00,720
IRON YOU BATED A STRAIN THAT IS

1603
01:20:00,720 --> 01:20:02,400
MISSING THE POOL A GENE.

1604
01:20:02,400 --> 01:20:07,240
THIS IS A NATURALLY LACKS THIS

1605
01:20:07,240 --> 01:20:09,040
GENE.

1606
01:20:09,040 --> 01:20:10,880
WITH INDIVIDUAL PURIFIED ENZYMES

1607
01:20:10,880 --> 01:20:13,840
AND MONITORED THE EFFECTS ON

1608
01:20:13,840 --> 01:20:16,000
GROWTH IN GLYCOGEN CONTAINING

1609
01:20:16,000 --> 01:20:17,760
MEDIUM AND WE SEE THAT IN DEED,

1610
01:20:17,760 --> 01:20:24,760
ADD NORTH THE PURIFIED

1611
01:20:24,760 --> 01:20:25,360
L.CRISPATUS FROM A DIFFERENT

1612
01:20:25,360 --> 01:20:28,040
STRAIN ALLOWS THIS STRAIN TO

1613
01:20:28,040 --> 01:20:33,800
GROW WELL ON GLYCOGEN ADDING THE

1614
01:20:33,800 --> 01:20:35,040
PULAEN GAME DOES NOT SUPPORT

1615
01:20:35,040 --> 01:20:37,760
GROWTH SO WE TESTED THE OTHER

1616
01:20:37,760 --> 01:20:38,840
PROTEINS IN THIS AS SAY AND

1617
01:20:38,840 --> 01:20:46,320
FOUND THAT IT'S NOT JUST THE

1618
01:20:46,320 --> 01:20:48,480
L.CRISPATUS THEY CAN ALL SUPPORT

1619
01:20:48,480 --> 01:20:51,560
BACTERIAL GROWTH ON GLYCO AGAIN.

1620
01:20:51,560 --> 01:20:52,760
POTENTIALLY IMPLICATING THEM ALL

1621
01:20:52,760 --> 01:20:54,760
IN THIS ACTIVITY.

1622
01:20:54,760 --> 01:20:56,880
SO WE NEXT SOUGHT TO GAIN MORE

1623
01:20:56,880 --> 01:21:04,240
DETAILED INFORMATION ABOUT THE

1624
01:21:04,240 --> 01:21:06,800
ENZYME SPECIFICITY WITH GLYCOGEN

1625
01:21:06,800 --> 01:21:09,400
SO WE CHARTER THE PARAMETERS OF

1626
01:21:09,400 --> 01:21:11,200
THESE DIFFERENT ENZYMES OF

1627
01:21:11,200 --> 01:21:12,840
DIFFERENT SUBSTRATES THAT

1628
01:21:12,840 --> 01:21:16,600
CONTAIN DIFFERENT TYPES SO WE

1629
01:21:16,600 --> 01:21:17,920
LOCKED AT WE SEE SOME

1630
01:21:17,920 --> 01:21:19,200
INTERESTING DIFFERENCE THIS IS

1631
01:21:19,200 --> 01:21:21,680
SPECIFICITY SO, ALL OF THE

1632
01:21:21,680 --> 01:21:24,480
ENZYMES CAN DEGRADE AND SOME OF

1633
01:21:24,480 --> 01:21:29,160
THEM ARE UNABLE TO METABOLIZE

1634
01:21:29,160 --> 01:21:30,560
LINKAGES AND I ALSO WANT TO

1635
01:21:30,560 --> 01:21:32,840
POINT OUT THE DIFFERENCES IN

1636
01:21:32,840 --> 01:21:34,520
ACTIVITIES BETWEEN ENZYMES FROM

1637
01:21:34,520 --> 01:21:37,560
DIFFERENT ORGANISMS AND THE

1638
01:21:37,560 --> 01:21:39,320
GARDNER ELLA ENZYME STANDING OUT

1639
01:21:39,320 --> 01:21:42,520
AS BEING MUCH MORE ACTIVE THAN

1640
01:21:42,520 --> 01:21:46,520
ENZYMES FROM SOME OF THE OTHER

1641
01:21:46,520 --> 01:21:48,680
SPECIES LIKE LACK TOE BASIL IS

1642
01:21:48,680 --> 01:21:51,120
AND THIS IS INTERESTING TO THINK

1643
01:21:51,120 --> 01:21:51,360
ABOUT.

1644
01:21:51,360 --> 01:21:54,240
IT SUGGESTS GARNER ELLA MAY

1645
01:21:54,240 --> 01:21:58,160
METABOLIZE GLYCOGEN MUCH MORE

1646
01:21:58,160 --> 01:21:59,840
EXTENSIVELY AND GARDNER ELLA IS

1647
01:21:59,840 --> 01:22:03,560
KNOWN TO POSSESS OTHER TYPES OF

1648
01:22:03,560 --> 01:22:06,400
OFEN GYMS VERY NOTABLY THEY HAVE

1649
01:22:06,400 --> 01:22:07,920
SIGHAL DATES ENZYMES AND WE'LL

1650
01:22:07,920 --> 01:22:10,320
HEAR MORE ABOUT SOME OF THESE

1651
01:22:10,320 --> 01:22:12,880
GARDNER ELLA ENZYMES TODAY IN

1652
01:22:12,880 --> 01:22:14,320
AMANDA LOUIS' TALK.

1653
01:22:14,320 --> 01:22:17,160
SO WE MEASURED ALL OF THESE

1654
01:22:17,160 --> 01:22:19,400
ENZYME PARAMETERS AND A PH OF

1655
01:22:19,400 --> 01:22:21,640
5.4, WHAT ABOUT ENZYME ACTIVITY

1656
01:22:21,640 --> 01:22:24,240
AT LOWER PH VALUES THAT MAY

1657
01:22:24,240 --> 01:22:26,960
BETTER REFLECT THE PH ASSOCIATED

1658
01:22:26,960 --> 01:22:30,560
WITH A LACK OF BA LIS DOMINATED

1659
01:22:30,560 --> 01:22:30,840
COMMUNITY.

1660
01:22:30,840 --> 01:22:32,240
WELL HERE WE OBSERVED SOMETHING

1661
01:22:32,240 --> 01:22:35,240
VERY INTRIGUING SO, WHEN WE

1662
01:22:35,240 --> 01:22:38,280
VARIED PH AND MEASUREDDEN TIME

1663
01:22:38,280 --> 01:22:40,480
AND THE ENZYME GENERALLY

1664
01:22:40,480 --> 01:22:41,880
RETAINED MUCH MORE OF THEIR

1665
01:22:41,880 --> 01:22:44,680
ACTIVITIES AT LOWER PH VALUES

1666
01:22:44,680 --> 01:22:46,680
THAN ENZYMES FROM OTHER

1667
01:22:46,680 --> 01:22:48,360
ORGANISMS SO WE THINK THIS COULD

1668
01:22:48,360 --> 01:22:50,840
INDICATE THESE EXTRA CELLULAR

1669
01:22:50,840 --> 01:22:53,880
ENZYMES MIGHT BE ADAPTED IN AN

1670
01:22:53,880 --> 01:22:54,640
ACIDIC ENVIRONMENT AND SUGGESTS

1671
01:22:54,640 --> 01:22:57,080
THAT VAGINAL PH COULD HAVE AN

1672
01:22:57,080 --> 01:22:59,080
IMPORTANT INFLUENCE ON ENZYME

1673
01:22:59,080 --> 01:23:00,720
ACTIVITY AND SO NEXT WE WANTED

1674
01:23:00,720 --> 01:23:02,640
TO CHARACTERIZE THE SPECIFIC

1675
01:23:02,640 --> 01:23:04,440
BREAKDOWN PRODUCTS GENERATED BY

1676
01:23:04,440 --> 01:23:06,400
DIFFERENT BACTERIAL ENZYMES AND

1677
01:23:06,400 --> 01:23:08,520
COMPARE THAT TO THE ACTIVITY OF

1678
01:23:08,520 --> 01:23:11,800
THE HUMAN SAL A VARY AM A LACE.

1679
01:23:11,800 --> 01:23:13,920
AND SO, WE'RE CHARACTERIZING

1680
01:23:13,920 --> 01:23:15,480
DIFFERENT BREAKDOWN PRODUCTS BY

1681
01:23:15,480 --> 01:23:16,640
LCMS AND WE SEE THAT THE

1682
01:23:16,640 --> 01:23:19,040
PRODUCTS GENERATED BY THE

1683
01:23:19,040 --> 01:23:20,600
BACTERIAL ENZYMES DIFFER BETWEEN

1684
01:23:20,600 --> 01:23:22,880
DIFFERENT ORGANISMS AND ALSO,

1685
01:23:22,880 --> 01:23:25,120
DIFFER FROM THE PRODUCT

1686
01:23:25,120 --> 01:23:28,400
DISTRIBUTION OF THE HUMAN

1687
01:23:28,400 --> 01:23:31,040
ENZYMES AND HERE WE LOOK AT

1688
01:23:31,040 --> 01:23:33,160
PRODUCTS THAT ARE GENERATED WITH

1689
01:23:33,160 --> 01:23:37,400
WE INCUBATE THESE AND WE DID

1690
01:23:37,400 --> 01:23:43,480
THIS EXPERIMENT WITH POLULIN AND

1691
01:23:43,480 --> 01:23:44,800
THERE'S DISTINCT DIFFERENCE AND

1692
01:23:44,800 --> 01:23:50,600
WHEN USING A SUBSTRATE AND IT IS

1693
01:23:50,600 --> 01:23:52,480
LINKAGES WE SEE ALL BACTERIA

1694
01:23:52,480 --> 01:23:55,720
ENZYMES CAN METABOLIZE THIS

1695
01:23:55,720 --> 01:23:58,320
SUBSTRATE AND THE HUMAN ENZYME

1696
01:23:58,320 --> 01:24:01,160
CANNOT SO THIS IS ACTUALLY A

1697
01:24:01,160 --> 01:24:02,240
VERY SIGNIFICANT OBSERVATION

1698
01:24:02,240 --> 01:24:05,240
BECAUSE IT SUGGESTS THAT

1699
01:24:05,240 --> 01:24:07,280
PULLULAN'S ACTIVITY MIGHT

1700
01:24:07,280 --> 01:24:10,360
POTENTIALLY BE USED AS A MARKER

1701
01:24:10,360 --> 01:24:14,400
OF BACTERIAL ENZYMES IN COMPLEX

1702
01:24:14,400 --> 01:24:18,160
HUMAN MICROBIOME SAMPLES.

1703
01:24:18,160 --> 01:24:21,000
SO WITH THIS IN MIND, WE HAVE

1704
01:24:21,000 --> 01:24:21,920
STARTED TO SECRETARY QUESTION OF

1705
01:24:21,920 --> 01:24:23,600
WHETHER THESE BACTERIAL ENZYMES

1706
01:24:23,600 --> 01:24:28,480
ARE PRESENT IN CERVICAL LAVAGE

1707
01:24:28,480 --> 01:24:30,240
SAMPLES AND THEY HAVE A ROLE IN

1708
01:24:30,240 --> 01:24:33,840
HELPING US TO ACCESS THESE

1709
01:24:33,840 --> 01:24:34,200
SAMPLES.

1710
01:24:34,200 --> 01:24:36,680
WE DID JUST ATTEMPTED TO DETECT

1711
01:24:36,680 --> 01:24:38,720
HUMAN AM A LACE IN ASSUMER MUTE

1712
01:24:38,720 --> 01:24:43,320
ANTS USING ALI SA AND WE

1713
01:24:43,320 --> 01:24:45,080
VERIFIED WE COULD DETECT THIS

1714
01:24:45,080 --> 01:24:47,920
ENZYME IN OUR SAMPLE AND WE ALSO

1715
01:24:47,920 --> 01:24:49,640
FOUND THAT THERE'S NO CROSS

1716
01:24:49,640 --> 01:24:51,240
REACTIVITY WITH ANY OF OUR

1717
01:24:51,240 --> 01:24:55,280
PURIFIED MICROBIAL.

1718
01:24:55,280 --> 01:24:59,760
SO WE SEE VARYING LEVELS OF THE

1719
01:24:59,760 --> 01:25:03,000
HUMAN AM A LISTEN SIM.

1720
01:25:03,000 --> 01:25:06,400
NEXT WE WANTED TO MEASURE

1721
01:25:06,400 --> 01:25:07,880
GLYCOGEN DEGRADATION AND YOU

1722
01:25:07,880 --> 01:25:10,400
LOOKED AT THIS AT VARIOUS PHs

1723
01:25:10,400 --> 01:25:11,560
AND WE SEE GENERALLY THAT

1724
01:25:11,560 --> 01:25:15,600
THERE'S A CORRELATION BETWEEN

1725
01:25:15,600 --> 01:25:18,680
AMALYSE ACTIVITY AND THE LEVEL

1726
01:25:18,680 --> 01:25:23,520
OF HUMAN AMALYSE AND WE FOUND IN

1727
01:25:23,520 --> 01:25:25,280
ONE OF OUR SAMPLES HIGHLIGHTED

1728
01:25:25,280 --> 01:25:27,720
HERE THERE'S ENHANCED ACTIVITY

1729
01:25:27,720 --> 01:25:52,400
AND THIS REALLY DOESN'T SEE --
SO,

1730
01:25:52,400 --> 01:25:55,840
WE ARE HERE AGAIN USING LCMS FOR

1731
01:25:55,840 --> 01:25:58,600
THE PRODUCTION OF MULTI TRY OWES

1732
01:25:58,600 --> 01:26:00,640
FROM THE VAGINAL SAMPLES AND WE

1733
01:26:00,640 --> 01:26:01,960
OBSERVED VARIOUS LEVELS OF

1734
01:26:01,960 --> 01:26:03,120
PRODUCT FORMATION WHEN THESE

1735
01:26:03,120 --> 01:26:05,800
SAMPLES ARE INCUBATED WITH GLYCO

1736
01:26:05,800 --> 01:26:07,040
AGAIN BUT WE SEE A REALLY

1737
01:26:07,040 --> 01:26:09,520
DIFFERENT PATTERN OF METABOLISM

1738
01:26:09,520 --> 01:26:11,280
WHEN WE INCUBATE THESE SAL POPS

1739
01:26:11,280 --> 01:26:14,960
WITH PULLULAN SO THE HUMAN

1740
01:26:14,960 --> 01:26:17,160
ENZYME CAN'T METABOLIZE THIS

1741
01:26:17,160 --> 01:26:18,720
SUBSTRATE IN THE EXACT SAME

1742
01:26:18,720 --> 01:26:21,400
SAMPLE THAT RETAINED ACTIVITIES

1743
01:26:21,400 --> 01:26:25,840
AT LOW PH, WE SEE SUBSTANTIAL

1744
01:26:25,840 --> 01:26:29,160
PRODUCTION OF MULTO TRY OWES

1745
01:26:29,160 --> 01:26:31,000
FROM PULLULAN SO WE THINK AT

1746
01:26:31,000 --> 01:26:34,240
THIS OBSERVATION MAY DEMONSTRATE

1747
01:26:34,240 --> 01:26:37,040
THAT ENZYMES ARE PRESENT IN THIS

1748
01:26:37,040 --> 01:26:37,280
SAMPLE.

1749
01:26:37,280 --> 01:26:40,120
NOW THERE'S IMPORTANT CAVEATS.

1750
01:26:40,120 --> 01:26:41,960
IT'S A SMALL NUMBER OF SAMPLES.

1751
01:26:41,960 --> 01:26:43,560
WE WERE WORKING WITH SAMPLES

1752
01:26:43,560 --> 01:26:45,240
THAT WERE NOT SEQUENCES SO WE

1753
01:26:45,240 --> 01:26:46,880
DON'T KNOW WHICH ORGANISMS ARE

1754
01:26:46,880 --> 01:26:49,240
PRESENT THIS THESE SAMPLES SO A

1755
01:26:49,240 --> 01:26:50,280
GOAL WE'RE WORKING TOWARDS RIGHT

1756
01:26:50,280 --> 01:26:54,320
NOW IS REALLY INVESTIGATING A

1757
01:26:54,320 --> 01:26:55,880
LARGER NUMBER OF SAMPLES TO

1758
01:26:55,880 --> 01:27:00,120
REALLY TRY TO PINPOINT WHICH

1759
01:27:00,120 --> 01:27:03,400
ENZYMES ARE RESPONSIBLE FOR THIS

1760
01:27:03,400 --> 01:27:03,680
ACTIVITY.

1761
01:27:03,680 --> 01:27:06,400
BUT, TO START TO WRAP-UP, I HOPE

1762
01:27:06,400 --> 01:27:08,640
THAT THIS SHORT STORY HAS SHOWN

1763
01:27:08,640 --> 01:27:10,400
HOW UNDERSTANDING BACTERIAL

1764
01:27:10,400 --> 01:27:12,680
ENZYMES CAN BEGIN TO HELP US

1765
01:27:12,680 --> 01:27:17,640
GAIN  A MECHANISTIC
UNDERSTANDING

1766
01:27:17,640 --> 01:27:20,560
OF MICROBIOMES SO UNDERSTANDING

1767
01:27:20,560 --> 01:27:23,040
ENZYMES AND LINKING IT BACK TO

1768
01:27:23,040 --> 01:27:24,440
GENES, REALLY IMPROVES OUR

1769
01:27:24,440 --> 01:27:27,320
ABILITY TO START ANALYZING

1770
01:27:27,320 --> 01:27:29,280
MICROBIAL GENOME AND MIKE OWE

1771
01:27:29,280 --> 01:27:30,840
BIOME SEQUENCING DATA AND MAKE

1772
01:27:30,840 --> 01:27:34,560
ACCURATE PREDICTIONS ABOUT

1773
01:27:34,560 --> 01:27:35,840
SPECIFIC MICROBIAL FUNCTIONS.

1774
01:27:35,840 --> 01:27:39,360
BIO CHEMICALLY CHARACTERIZING

1775
01:27:39,360 --> 01:27:40,840
ENZYMES PROVIDE KEY INSIGHTS

1776
01:27:40,840 --> 01:27:42,240
INTO ENVIRONMENTAL FACTORS THAT

1777
01:27:42,240 --> 01:27:44,520
MIGHT INFLUENCE METABOLISM SO

1778
01:27:44,520 --> 01:27:53,560
THINGS LIKE PH AND FINALLY,

1779
01:27:53,560 --> 01:27:55,320
UNDERSTANDING ENZYMES CAN HELP

1780
01:27:55,320 --> 01:27:57,720
US AND EITHER THROUGH DEVELOPING

1781
01:27:57,720 --> 01:27:58,920
INHIBITORS OF SPECIFIC ENZYMES

1782
01:27:58,920 --> 01:28:04,480
OR THROUGH HELPING US SELECT AND

1783
01:28:04,480 --> 01:28:07,320
SO THESE TYPES OF STRATEGIES MAY

1784
01:28:07,320 --> 01:28:09,240
BE USEFUL IN THE SHORT TERM FOR

1785
01:28:09,240 --> 01:28:19,920
HELPING US STUDY SO KNOWLEDGE OF

1786
01:28:19,920 --> 01:28:23,000
THESE AMYLASES IN DIFFERENT

1787
01:28:23,000 --> 01:28:27,760
STRAINS HAVE HELPED THE SELECT

1788
01:28:27,760 --> 01:28:29,040
THE STRAINS FOR POTENTIAL

1789
01:28:29,040 --> 01:28:30,840
DEVELOPMENT OF THESE TYPES OF

1790
01:28:30,840 --> 01:28:34,640
PROBIOTICS INTERVENTIONS.

1791
01:28:34,640 --> 01:28:36,760
WHILE I FOCUSED ON ONE FAMILY OF

1792
01:28:36,760 --> 01:28:37,920
ENZYMES TODAY, WE'RE EXCITE

1793
01:28:37,920 --> 01:28:40,040
TODAY A PLOY THIS WORK FLOW TO

1794
01:28:40,040 --> 01:28:42,400
OTHER TYPES OF VAGINAL

1795
01:28:42,400 --> 01:28:45,640
BACTERIAEL ENZYMES.

1796
01:28:45,640 --> 01:28:47,440
SO, FROM AN EVEN BIGGER PICTURE

1797
01:28:47,440 --> 01:28:49,080
PERSPECTIVE, I THINK THIS WORK

1798
01:28:49,080 --> 01:28:54,880
HIGHLIGHTS SOME VERY IMPORTANT

1799
01:28:54,880 --> 01:28:58,240
PITFALLS OF MICROBIOME SEQUENCES

1800
01:28:58,240 --> 01:29:00,040
RELIES ON AUTOMATED ANNOTATIONS

1801
01:29:00,040 --> 01:29:01,280
AND IT'S IMPORTANT TO REMEMBER

1802
01:29:01,280 --> 01:29:04,720
THAT THESE ANNOTATIONS ARE

1803
01:29:04,720 --> 01:29:05,320
FREQUENTLY INCORRECT SO MORE

1804
01:29:05,320 --> 01:29:07,920
OVER I THINK THAT THIS STORY

1805
01:29:07,920 --> 01:29:09,360
PARTICULARLY HIGHLIGHTS THEIR

1806
01:29:09,360 --> 01:29:12,640
IMPORTANT FEATURES OF ENZYME AND

1807
01:29:12,640 --> 01:29:13,960
PROTEIN FUNCTION THAT CAN'T

1808
01:29:13,960 --> 01:29:16,880
READILY BE PREDICTED FROM

1809
01:29:16,880 --> 01:29:17,840
SEQUENCES DATA ALONE.

1810
01:29:17,840 --> 01:29:20,800
THINGS LIKE THE PH TOLERANCE OF

1811
01:29:20,800 --> 01:29:22,600
THE ENZYMES OR ENHANCED ACTIVITY

1812
01:29:22,600 --> 01:29:25,240
OF THE GARDNER ELLA ENZYME SO

1813
01:29:25,240 --> 01:29:26,760
THIS REALLY SPEAKS TO THE NEED

1814
01:29:26,760 --> 01:29:31,160
TO INTEGRATE BIO CHEMISTRY TO

1815
01:29:31,160 --> 01:29:32,080
MICROBIOME STUDIES.

1816
01:29:32,080 --> 01:29:34,240
I WILL THANK MY RESEARCH GROUP

1817
01:29:34,240 --> 01:29:35,960
AND OR COLLABORATORS AND I

1818
01:29:35,960 --> 01:29:36,640
HIGHLIGHTED THE SPECIFIC

1819
01:29:36,640 --> 01:29:42,600
STUDENTS WHO CONTRIBUTED TO THIS

1820
01:29:42,600 --> 01:29:42,920
PROJECT.

1821
01:29:42,920 --> 01:29:44,720
I'M GRATEFUL TO EVERYONE IN THE

1822
01:29:44,720 --> 01:29:47,560
LAB AND THANK THE MEMBERS OF THE

1823
01:29:47,560 --> 01:29:49,320
CONSORTIUM AND THE GATES

1824
01:29:49,320 --> 01:29:50,760
FOUNDATION FOR FUNDING AND I

1825
01:29:50,760 --> 01:29:52,200
WOULD BE HAPPY TO ANSWER ANY

1826
01:29:52,200 --> 01:29:52,800
QUESTIONS.

1827
01:29:53,680 --> 01:29:54,760
>> EXCELLENT TALK AND I'M GLAD

1828
01:29:54,760 --> 01:29:58,040
THAT WE'RE GETTING YOU INTO THE

1829
01:29:58,040 --> 01:29:59,840
CARBOHYDRATE PART OF GLYCAN SO

1830
01:29:59,840 --> 01:30:00,840
PERFECT THAT WAS AWESOME.

1831
01:30:00,840 --> 01:30:02,560
THANK YOU SO MUCH.

1832
01:30:02,560 --> 01:30:04,320
WE HAVE QUESTIONS FROM THE -- WE

1833
01:30:04,320 --> 01:30:05,320
HAVE ONE.

1834
01:30:05,320 --> 01:30:07,400
AMANDA LOUIS, IF YOU WANT TO ASK

1835
01:30:07,400 --> 01:30:08,920
YOU CAN ASK IF NOT I CAN ASK YOU

1836
01:30:08,920 --> 01:30:09,640
FOR YOU.

1837
01:30:09,640 --> 01:30:11,160
IT'S SUPPOSE TO YOU.

1838
01:30:11,160 --> 01:30:12,800
>> I CAN ASK.

1839
01:30:12,800 --> 01:30:14,120
GREAT TALK, EMILY.

1840
01:30:14,120 --> 01:30:15,040
>> THANK YOU.

1841
01:30:15,040 --> 01:30:19,960
>> SO I WONDER THE OLD IDEA

1842
01:30:19,960 --> 01:30:22,560
USING GLYCOGEN AS A PRE BIOTICS

1843
01:30:22,560 --> 01:30:26,480
AND IT'S A GOOD IDEA.

1844
01:30:26,480 --> 01:30:28,000
>> IT'S A GREAT QUESTION.

1845
01:30:28,000 --> 01:30:29,480
YOU HAVE TO CONSIDER THE

1846
01:30:29,480 --> 01:30:32,360
IMPLICATIONS OF DOING THAT IN A

1847
01:30:32,360 --> 01:30:33,520
COMMUNITY CONTEXT AND CERTAINLY

1848
01:30:33,520 --> 01:30:35,560
I THINK IF YOU HAVE A COMMUNITY

1849
01:30:35,560 --> 01:30:39,520
THAT IS DOMINATED BY GARDNER

1850
01:30:39,520 --> 01:30:42,840
ELLA WITHOUT SOME SORT OF

1851
01:30:42,840 --> 01:30:43,880
MANIPULATING THE ENVIRONMENT I

1852
01:30:43,880 --> 01:30:44,840
WOULD BE A LITTLE BIT CONCERNED

1853
01:30:44,840 --> 01:30:47,040
ABOUT THAT, GIVEN THAT I THINK

1854
01:30:47,040 --> 01:30:51,040
THAT GARDNER EARLY I ELLA IS
LIKELY TO

1855
01:30:51,040 --> 01:30:52,840
USE THAT SUBSTRATE MORE

1856
01:30:52,840 --> 01:30:54,720
EFFICIENTLY THAN THE ORGANISMS

1857
01:30:54,720 --> 01:30:56,720
THAT YOU WOULD PERHAPS LIKE TO

1858
01:30:56,720 --> 01:30:58,680
ENCOURAGE TO GROW.

1859
01:30:58,680 --> 01:31:00,640
>> EMILY, YOU'VE ENCOURAGED LOTS

1860
01:31:00,640 --> 01:31:02,400
OF TALK FROM THE QUESTIONS ON

1861
01:31:02,400 --> 01:31:03,800
OUR ON-LINE COMMUNITY.

1862
01:31:03,800 --> 01:31:07,760
SO, WE HAVE A QUESTION FROM

1863
01:31:07,760 --> 01:31:09,400
DANIEL WHO ASKED S. THERE ANY

1864
01:31:09,400 --> 01:31:11,800
DATABASE TOOL WE CAN USE TO FIND

1865
01:31:11,800 --> 01:31:13,680
POTENTIAL BACTERIAL ENZYMES OR

1866
01:31:13,680 --> 01:31:15,600
GENES THAT PRODUCE CERTAIN

1867
01:31:15,600 --> 01:31:16,040
METABOLITES?

1868
01:31:16,040 --> 01:31:19,040
>> SO THERE'S A NUMBER OF TOOLS,

1869
01:31:19,040 --> 01:31:20,440
I THINK PARTICULARLY DEVELOPED

1870
01:31:20,440 --> 01:31:23,520
IN THE CONTEXT OF WANTING TO

1871
01:31:23,520 --> 01:31:25,160
PROBE THE HUMAN GUT MICROBIOME

1872
01:31:25,160 --> 01:31:26,640
SO IT DEPENDS ON WHAT YOU LOOK

1873
01:31:26,640 --> 01:31:34,240
FOR SO A LOT OF THE TOOLS THAT I

1874
01:31:34,240 --> 01:31:36,000
THINK COULD BE -- MOST FAMILIAR

1875
01:31:36,000 --> 01:31:40,800
WITH FOCUS IN ON THE NATURAL

1876
01:31:40,800 --> 01:31:42,240
PRODUCTS SPACE SO THE GROUP

1877
01:31:42,240 --> 01:31:46,640
THAT'S DEVELOPED SOME GREAT WEB

1878
01:31:46,640 --> 01:31:48,240
BASED TOOLS AND TOOLS THAT ALLOW

1879
01:31:48,240 --> 01:31:50,200
TO JUST IDENTIFY THINGS THAT

1880
01:31:50,200 --> 01:31:52,920
LOOK LIKE GENE CLUSTERS THAT

1881
01:31:52,920 --> 01:31:55,040
ENCODE ENZYMES IN GUT BACTERIA

1882
01:31:55,040 --> 01:32:01,400
AND SO IT IS SORT OF HELPED

1883
01:32:01,400 --> 01:32:02,520
POTENTIALLY USE GENOMIC CONTEXT

1884
01:32:02,520 --> 01:32:04,280
SO I'M NOT AS FAMILIAR WITH

1885
01:32:04,280 --> 01:32:08,840
TOOLS AVAILABLE TO HELP DISCOVER

1886
01:32:08,840 --> 01:32:10,160
CARBOHYDRATE ENZYMES BUT THEY'RE

1887
01:32:10,160 --> 01:32:11,520
OBVIOUSLY REALLY IMPORTANT AND

1888
01:32:11,520 --> 01:32:12,640
I'M SURE THERE'S SOME REALLY

1889
01:32:12,640 --> 01:32:14,400
GREAT RESOURCE THIS IS THAT

1890
01:32:14,400 --> 01:32:14,640
SPACE.

1891
01:32:14,640 --> 01:32:17,160
>> WE'RE GETTING LOTS OF

1892
01:32:17,160 --> 01:32:20,880
QUESTIONS ON-LINE BUT IN A TEEN
NADINE HAS

1893
01:32:20,880 --> 01:32:21,640
A QUESTION.

1894
01:32:21,640 --> 01:32:24,240
>> SURE.

1895
01:32:24,240 --> 01:32:26,320
I JUST HAVE A MECHANIC NICE TICK

1896
01:32:26,320 --> 01:32:26,600
QUESTION.

1897
01:32:26,600 --> 01:32:28,600
FOR THE ONE THAT HAS A HIGH

1898
01:32:28,600 --> 01:32:33,920
ACTIVITY THAT THE DVAGINILIS AND

1899
01:32:33,920 --> 01:32:34,720
KNOWING WHAT YOU KNOW ABOUT THE

1900
01:32:34,720 --> 01:32:35,840
MECHANISM OR THE STRUCTURES

1901
01:32:35,840 --> 01:32:37,480
OFFER WHATEVER, IT IS OBVIOUS

1902
01:32:37,480 --> 01:32:39,720
WHY THAT IS SO MUCH MORE ACTIVE?

1903
01:32:39,720 --> 01:32:41,360
WHAT DO YOU KNOW, I GUESS,

1904
01:32:41,360 --> 01:32:41,600
FROM --

1905
01:32:41,600 --> 01:32:43,200
>> WELL, SO THE INTRIGUING THING

1906
01:32:43,200 --> 01:32:46,320
TO ME ABOUT THAT ENZYME IS IT'S

1907
01:32:46,320 --> 01:32:51,120
THE ONE THAT HAS TWO ALPHA AMO

1908
01:32:51,120 --> 01:32:52,880
LACE DOMAIN AND IF YOU MUTATE

1909
01:32:52,880 --> 01:32:55,240
JUST ONE YOU LOSE GREATER THAN

1910
01:32:55,240 --> 01:32:56,560
90% OF THE ACTIVITY.

1911
01:32:56,560 --> 01:32:58,520
IT'S DEAD IF YOU MUTATE TWO

1912
01:32:58,520 --> 01:33:00,400
DOMAINS BUT THE LOSS OF ACTIVITY

1913
01:33:00,400 --> 01:33:01,960
WHEN YOU MUTATE JUST ONE OF

1914
01:33:01,960 --> 01:33:04,760
THOSE DOMAINS, SPEAKS TO PERHAPS

1915
01:33:04,760 --> 01:33:05,960
COORDINATION BETWEEN THE TWO

1916
01:33:05,960 --> 01:33:08,840
DOMAINS AND SO I WONDER IF

1917
01:33:08,840 --> 01:33:09,640
THAT'S POSSIBLY SOMETHING THAT

1918
01:33:09,640 --> 01:33:11,680
IS LINKED TO THE INCREASED

1919
01:33:11,680 --> 01:33:13,640
DEFICIENCY OF THAT PARTICULAR

1920
01:33:13,640 --> 01:33:13,880
ENZYME.

1921
01:33:13,880 --> 01:33:16,440
>> THANK YOU.

1922
01:33:16,440 --> 01:33:18,240
SO EMILY THERE'S A VARIETY OF

1923
01:33:18,240 --> 01:33:19,640
QUESTIONS IN THE CHAT BUT DUE TO

1924
01:33:19,640 --> 01:33:21,520
THE INTEREST OF TIME, WE'RE

1925
01:33:21,520 --> 01:33:22,680
GOING TO -- I CAN E-MAIL THOSE

1926
01:33:22,680 --> 01:33:24,720
TO YOU AND YOU CAN READ THEM

1927
01:33:24,720 --> 01:33:25,560
YOURSELVES AND ALL OF THE SEE

1928
01:33:25,560 --> 01:33:29,040
MALES ARE-MAILS ARE ASSOCIATED
WITH THE

1929
01:33:29,040 --> 01:33:32,440
QUESTIONS THERE SO YOU CAN

1930
01:33:32,440 --> 01:33:34,680
RESPOND BACK AT YOUR LEISURE.

1931
01:33:34,680 --> 01:33:36,840
KEEP THE QUESTIONS FROM THE

1932
01:33:36,840 --> 01:33:38,840
ON-LINE PART IT MAKES IT MORE

1933
01:33:38,840 --> 01:33:39,760
INTERACTIVE AND FUN SO THANK YOU

1934
01:33:39,760 --> 01:33:41,080
FOR THE PARTICIPATION AND

1935
01:33:41,080 --> 01:33:41,800
FANTASTIC TALK.

1936
01:33:41,800 --> 01:33:42,480
THANK YOU FOR THAT.

1937
01:33:42,480 --> 01:33:43,560
I REALLY APPRECIATE YOU TELLING

1938
01:33:43,560 --> 01:33:45,760
US THAT NEW WORK COMING OUT OF

1939
01:33:45,760 --> 01:33:46,840
YOUR LAB.

1940
01:33:46,840 --> 01:33:56,440
OUR NEXT SPEAKER IS DARIA

1941
01:33:56,440 --> 01:33:57,640
PICANTINO AND ALCOHOLISM AT THE

1942
01:33:57,640 --> 01:33:59,800
NIH AND SHE'S A POSTDOC TO BAL

1943
01:33:59,800 --> 01:34:00,880
FELLOW AND SHE'S GOING TO TALK

1944
01:34:00,880 --> 01:34:05,560
ABOUT HER WORK ON THE GUT

1945
01:34:05,560 --> 01:34:06,560
MICROBE IN ALCOHOL USE DISORDER

1946
01:34:06,560 --> 01:34:07,960
SO REALLY DIVERSE TALKS THIS

1947
01:34:07,960 --> 01:34:10,040
MORNING SO THANK YOU FOR JOINING

1948
01:34:10,040 --> 01:34:10,240
TODAY.

1949
01:34:10,240 --> 01:34:12,080
>> THANK YOU SO MUCH CATHERINE.

1950
01:34:12,080 --> 01:34:19,920
I'M GOING TO SHARE MY SCREEN.

1951
01:34:19,920 --> 01:34:21,640
SO -- GREAT.

1952
01:34:21,640 --> 01:34:28,480
I'M JUST GOING TO MINIMIZE HERE.

1953
01:34:28,480 --> 01:34:28,880
PERFECT.

1954
01:34:28,880 --> 01:34:30,000
SO THANK YOU CATHERINE AND THANK

1955
01:34:30,000 --> 01:34:31,920
YOU EVERYONE FOR HAVING ME

1956
01:34:31,920 --> 01:34:32,120
TODAY.

1957
01:34:32,120 --> 01:34:35,560
I'M REALLY EXCITED TO PRESENT

1958
01:34:35,560 --> 01:34:40,360
THE WORK IN THE PAST FOR YEARS

1959
01:34:40,360 --> 01:34:46,040
SO I'M STILL CARRYING OUT AT CPN

1960
01:34:46,040 --> 01:34:51,880
LAB AND IT'S PSYCHO LAB BY Dr.

1961
01:34:51,880 --> 01:34:53,160
LYNN AND TODAY I'M GOING TO

1962
01:34:53,160 --> 01:34:55,400
PRESENT OUR WORK ON THE GUT

1963
01:34:55,400 --> 01:34:58,320
MICROBIOME IN ALCOHOL USE

1964
01:34:58,320 --> 01:35:00,720
DISORDER FROM BENCH TO BED.

1965
01:35:00,720 --> 01:35:03,520
SO WHAT WE DO IS BASICALLY TAKE

1966
01:35:03,520 --> 01:35:06,400
ADVANTAGE OF THE HIGHLY

1967
01:35:06,400 --> 01:35:07,400
TRANSITIONAL NATURE OF THE LAB

1968
01:35:07,400 --> 01:35:09,920
TO PHYSICALLY DEVELOP NEW

1969
01:35:09,920 --> 01:35:12,640
TREATMENTS FOR ALCOHOL DISORDER

1970
01:35:12,640 --> 01:35:16,320
BY STUDYING THE GAP MICROBIOME

1971
01:35:16,320 --> 01:35:19,960
AND MA LAB LOAM.

1972
01:35:19,960 --> 01:35:21,640
WE START AND WE MOVE FORWARD AS

1973
01:35:21,640 --> 01:35:28,080
YOU CAN SEE HERE FROM NON HUMAN

1974
01:35:28,080 --> 01:35:29,480
PRIMATES AND WE MOVED TO HUMANS

1975
01:35:29,480 --> 01:35:30,920
AND THIS IS THE LAST STUDY WE

1976
01:35:30,920 --> 01:35:32,560
WRAPPED UP DURING THE PANDEMIC

1977
01:35:32,560 --> 01:35:34,720
AND WE'RE BASICALLY ANALYZING

1978
01:35:34,720 --> 01:35:37,360
THE DATA AS I'M SPEAKING RIGHT

1979
01:35:37,360 --> 01:35:39,160
NOW SO IT'S VERY EXCITING AND

1980
01:35:39,160 --> 01:35:42,560
I'LL SHOW SOME PRELIMINARY

1981
01:35:42,560 --> 01:35:42,800
RESULTS.

1982
01:35:42,800 --> 01:35:46,600
WHAT IS THE REASON WHY WE ARE

1983
01:35:46,600 --> 01:35:49,600
KIND OF FOLLOWING THIS -- WHAT

1984
01:35:49,600 --> 01:35:54,040
IS THE RATIONAL BEHIND THIS?

1985
01:35:54,040 --> 01:35:56,040
THE RATIONAL IS WE'D LIKE TO

1986
01:35:56,040 --> 01:35:58,720
IDENTIFY SOME COMMON MICROBIAL

1987
01:35:58,720 --> 01:36:01,640
ACTS OR METABOLITES BETWEEN THE

1988
01:36:01,640 --> 01:36:03,240
THREE SPECIES THAT HAVE A

1989
01:36:03,240 --> 01:36:05,240
POTENTIAL OF FUNCTION OF ALCOHOL

1990
01:36:05,240 --> 01:36:07,440
AND DRINKING AND THIS IDEAL

1991
01:36:07,440 --> 01:36:11,040
SCENARIO OBVIOUSLY COULD

1992
01:36:11,040 --> 01:36:12,000
REPRESENT LIKE THE STARTING

1993
01:36:12,000 --> 01:36:13,760
POINT TO DEVELOP A NOVEL

1994
01:36:13,760 --> 01:36:15,320
TREATMENT FOR ALCOHOL ABUSE

1995
01:36:15,320 --> 01:36:16,680
DISORDER SO THIS IS BASICALLY

1996
01:36:16,680 --> 01:36:18,600
WHAT WE'RE FOCUSING ON NOW.

1997
01:36:18,600 --> 01:36:22,520
SO, LET ME GIVE YOU A LITTLE BIT

1998
01:36:22,520 --> 01:36:23,400
OF BACKGROUND.

1999
01:36:23,400 --> 01:36:25,040
SO, WE WERE BASICALLY DOING IS

2000
01:36:25,040 --> 01:36:27,840
STUDYING THE EFFECTS OF

2001
01:36:27,840 --> 01:36:32,600
EXCESSIVE ALCOHOL DRINKING ON

2002
01:36:32,600 --> 01:36:37,240
THE GUT AND MICRO OWN AND IT

2003
01:36:37,240 --> 01:36:40,440
INCLUDES BASICALLY A COMBINATION

2004
01:36:40,440 --> 01:36:42,240
OF BINGE DRINKING AND HEAVY

2005
01:36:42,240 --> 01:36:42,520
DRINKING.

2006
01:36:42,520 --> 01:36:44,960
BINGE DRINKING CAN BE THOUGHT

2007
01:36:44,960 --> 01:36:47,520
ABOUT DRINKING TOO MUCH TOO FAST

2008
01:36:47,520 --> 01:36:49,240
AND THE DEFINITION IS BASICALLY

2009
01:36:49,240 --> 01:36:51,720
FIVE OR MORE DRINKS FOR MEN THAT

2010
01:36:51,720 --> 01:36:54,560
ARE CONSUMED ON ONE OCCASION AND

2011
01:36:54,560 --> 01:36:57,160
BY ONE OCCASION WE MEAN TWO

2012
01:36:57,160 --> 01:36:59,920
HOURS AND IN WOMEN IT'S FOUR OR

2013
01:36:59,920 --> 01:37:01,440
MORE DRINKS CONSUMED ON ONE

2014
01:37:01,440 --> 01:37:04,200
OCCASION SO WITHIN THESE TWO

2015
01:37:04,200 --> 01:37:06,520
HOURS AND ANOTHER DRINKING IS

2016
01:37:06,520 --> 01:37:11,880
THAT DRINKING THIS FAST AND IN

2017
01:37:11,880 --> 01:37:23,600
THIS MUCH -- AS I SAID THERE'S

2018
01:37:23,600 --> 01:37:25,400
ANOTHER COMPONENT WHICH IS HEAVY

2019
01:37:25,400 --> 01:37:26,760
DRINKING SO DRINKING TOO MUCH

2020
01:37:26,760 --> 01:37:28,640
TOO OFTEN, AGAIN, I'M GOING TO

2021
01:37:28,640 --> 01:37:30,640
ROW FER TO THE NIAAA DEFINITION

2022
01:37:30,640 --> 01:37:32,600
AND HEAVY DRINKING WHICH IS 15

2023
01:37:32,600 --> 01:37:35,400
OR MORE DRINKS ON AN AVERAGE PER

2024
01:37:35,400 --> 01:37:38,840
WEEK FOR MEN AND EIGHT OR MORE

2025
01:37:38,840 --> 01:37:43,400
DRINKS ON AVERAGE PER WEEK FOR

2026
01:37:43,400 --> 01:37:43,960
WOMEN.

2027
01:37:43,960 --> 01:37:46,040
SO, THIS IS A BIT OF NUMBERS.

2028
01:37:46,040 --> 01:37:49,640
SO, TO SHOW YOU HOW EXCESSIVE

2029
01:37:49,640 --> 01:37:52,840
ALCOHOL USE AFFECTS THE U.S.

2030
01:37:52,840 --> 01:37:53,160
POPULATION.

2031
01:37:53,160 --> 01:37:55,440
SO BINGE DRINKING IN THE U.S.

2032
01:37:55,440 --> 01:37:58,400
EFFECTS ALMOST 26% OF PEOPLE

2033
01:37:58,400 --> 01:38:02,720
OVER 18 YEARS OF AGE.

2034
01:38:02,720 --> 01:38:04,280
AS FOR THE ALCOHOL USE DISORDER

2035
01:38:04,280 --> 01:38:07,840
SO THE PROPER DIAGNOSIS SO BINGE

2036
01:38:07,840 --> 01:38:13,320
DRINK ASKING DRINKING IS A HABIT
THAT HAS

2037
01:38:13,320 --> 01:38:15,920
CRITERIA AND 14.5 MILLION OF

2038
01:38:15,920 --> 01:38:17,240
INDIVIDUALS IN THE U.S. ARE

2039
01:38:17,240 --> 01:38:20,720
AFFECTED BY THIS DISORDER SO

2040
01:38:20,720 --> 01:38:23,920
IT'S A PUBLIC-HEALTH PROBLEM.

2041
01:38:23,920 --> 01:38:27,120
AS FOR ALCOHOL RELATED DEATHS,

2042
01:38:27,120 --> 01:38:29,400
THE NUMBER IS VERY HIGH SO

2043
01:38:29,400 --> 01:38:32,080
95,000 PEOPLE DIE FROM

2044
01:38:32,080 --> 01:38:34,040
ALCOHOL-RELATED CAUSES ANNUALLY.

2045
01:38:34,040 --> 01:38:37,280
ALCOHOL RELATED CAUSES ENCLOUD

2046
01:38:37,280 --> 01:38:39,400
ACUTE CAUSES AND THIS MAY BE

2047
01:38:39,400 --> 01:38:42,720
TRAGIC ACCIDENTS, MAYBE

2048
01:38:42,720 --> 01:38:44,800
SELF-INFLECTED INJURIES,

2049
01:38:44,800 --> 01:38:46,440
VIOLENCE, BUT WE ALSO HAVE A LOT

2050
01:38:46,440 --> 01:38:48,640
OF CHRONIC CAUSES AND ABOUT THE

2051
01:38:48,640 --> 01:38:51,800
THE MOST WELL-KNOWN IS OBVIOUSLY

2052
01:38:51,800 --> 01:39:00,440
LIVER SIG CIROSIS AND
DYSFUNCTION OF

2053
01:39:00,440 --> 01:39:02,120
THE CARDIOVASCULAR SYSTEMS AND

2054
01:39:02,120 --> 01:39:04,000
LOTS OF CANCERS AND SO ON.

2055
01:39:04,000 --> 01:39:04,960
IT'S WORTH MENTIONING BECAUSE

2056
01:39:04,960 --> 01:39:08,480
THE NUMBER DOESN'T GIVE THE IDEA

2057
01:39:08,480 --> 01:39:11,800
BUT 95,000 MEANS 1/10 U.S.

2058
01:39:11,800 --> 01:39:13,800
CITIES AND TOYS FROM AN ALCOHOL

2059
01:39:13,800 --> 01:39:16,160
RELATED CAUSE AND THIS NUMBER IS

2060
01:39:16,160 --> 01:39:18,480
NOT HIGHER THAN OPIOID-RELATED

2061
01:39:18,480 --> 01:39:20,600
DEATHS SO OPIOID-RELATED DEATHS

2062
01:39:20,600 --> 01:39:21,760
IS HALF.

2063
01:39:21,760 --> 01:39:24,960
DESPITE WE'RE LIVING AN OPIOID

2064
01:39:24,960 --> 01:39:26,560
EPIDEMIC SO THIS IS JUST TO GIVE

2065
01:39:26,560 --> 01:39:31,960
AN IDEA THAT ALCOHOL IS

2066
01:39:31,960 --> 01:39:32,240
PREVALENT.

2067
01:39:32,240 --> 01:39:36,160
SO, IN TERMS OF ECONOMIC WE CAN

2068
01:39:36,160 --> 01:39:41,600
SEE HERE THAT EACH YEAR ALCOHOL

2069
01:39:41,600 --> 01:39:42,680
CAUSES 249 BILLION COST TO THE

2070
01:39:42,680 --> 01:39:49,760
HEALING CARHEALTH-CARE SYSTEM
AND THE MAIN

2071
01:39:49,760 --> 01:39:52,520
COST DERIVES FROM WORK-PLACE

2072
01:39:52,520 --> 01:39:54,080
PRODUCTIVITY A DISRUPTION OF

2073
01:39:54,080 --> 01:39:56,400
WORK AND THEN OTHER COMPONENTS

2074
01:39:56,400 --> 01:39:59,960
ARE JUSTICE HEALTHCARE AND

2075
01:39:59,960 --> 01:40:02,680
BASICALLY TRAFFIC RELATED

2076
01:40:02,680 --> 01:40:03,160
INCIDENTS.

2077
01:40:03,160 --> 01:40:04,960
SO, BACK TO OUR RESEARCH.

2078
01:40:04,960 --> 01:40:07,000
AS I SAID BEFORE, EXCESSIVE

2079
01:40:07,000 --> 01:40:10,720
ALCOHOL USE SO A COMBINATION,

2080
01:40:10,720 --> 01:40:11,400
BINGE AND HEAVY ALCOHOL DRINKING

2081
01:40:11,400 --> 01:40:13,000
SO DRINKING TOO MUCH AND TOO

2082
01:40:13,000 --> 01:40:14,560
OFTEN IS KNOWN TO PRODUCE

2083
01:40:14,560 --> 01:40:19,840
CHANGES IN THE FECAL MICRO BIOME

2084
01:40:19,840 --> 01:40:22,200
IN RODENTS AND HUMANS.

2085
01:40:22,200 --> 01:40:24,280
IT DOESN'T GO IN THE SAME LINE

2086
01:40:24,280 --> 01:40:27,240
SO WE CAN SEE SOME STUDIES

2087
01:40:27,240 --> 01:40:28,840
HIGHLIGHTING AN INCREASE OR

2088
01:40:28,840 --> 01:40:32,880
DECREASE OF CERTAIN MICROBIAL

2089
01:40:32,880 --> 01:40:33,760
SPECIES AND OTHERS SHOW

2090
01:40:33,760 --> 01:40:35,440
DIFFERENT RESULTS, IT'S HARD TO

2091
01:40:35,440 --> 01:40:37,760
FIND A WAY TO PUT THE PIECES OF

2092
01:40:37,760 --> 01:40:38,560
THE PUZZLE TOGETHER AND THAT'S

2093
01:40:38,560 --> 01:40:42,680
WHY WE TRIED TO DO SOME STUDIES

2094
01:40:42,680 --> 01:40:46,440
OURSELF AND SO WE STARTED FROM

2095
01:40:46,440 --> 01:40:48,680
ROARODENTS.

2096
01:40:48,680 --> 01:40:51,040
THIS WAS BASICALLY OUR STARTING

2097
01:40:51,040 --> 01:40:53,560
POINT AND WE BASICALLY GENERATED

2098
01:40:53,560 --> 01:40:56,720
SOME PROMISING ALTHOUGH VERY

2099
01:40:56,720 --> 01:40:58,520
PRELIMINARY DATA ON ALCOHOL

2100
01:40:58,520 --> 01:41:01,280
BINGE-LIKE EXPOSURE IN MALE RATS

2101
01:41:01,280 --> 01:41:05,720
IN COLLABORATION AND NIAAA AS AN

2102
01:41:05,720 --> 01:41:07,760
EXPLORATORY AIM PART OF A LARGER

2103
01:41:07,760 --> 01:41:12,240
STUD TEE ON WILD TYPE FOR THE

2104
01:41:12,240 --> 01:41:15,000
BRAIN RECEPTORS WE INVESTIGATED

2105
01:41:15,000 --> 01:41:16,520
GUT MICROBIAL DIVERSITY WHICH

2106
01:41:16,520 --> 01:41:21,360
MEASURE THE DIVERSITY WITHIN AND

2107
01:41:21,360 --> 01:41:22,040
IN BETWEEN.

2108
01:41:22,040 --> 01:41:23,040
WHAT DID WE FIND?

2109
01:41:23,040 --> 01:41:25,560
AS WE CAN SEE HERE, LET'S FOCUS

2110
01:41:25,560 --> 01:41:27,440
ON THE FIGURE ON THE LEFT.

2111
01:41:27,440 --> 01:41:32,040
SO WE FOUND THAT THE GUT HIGH

2112
01:41:32,040 --> 01:41:34,840
CROW ALPHA DIVERSITY INDEX WHICH

2113
01:41:34,840 --> 01:41:37,240
IS AS I SAID ON THE LEFT, SHOWED

2114
01:41:37,240 --> 01:41:40,520
A SIGNIFICANT DECREASE IN BOTH

2115
01:41:40,520 --> 01:41:42,240
THE SELF-ADMINISTRATION, THE

2116
01:41:42,240 --> 01:41:44,120
DIVERSITY IN THE

2117
01:41:44,120 --> 01:41:45,560
SELF-ADMINISTRATION BY THE

2118
01:41:45,560 --> 01:41:49,160
RODENTS OF A SWEET SOLUTION AND

2119
01:41:49,160 --> 01:41:50,920
SWEET END ALCOHOL SOLUTION

2120
01:41:50,920 --> 01:41:54,360
COMPARED TO THE BASELINE AND

2121
01:41:54,360 --> 01:41:58,200
THEN WHEN WE MOVED TO THE RIGHT

2122
01:41:58,200 --> 01:42:03,920
PART OF THE FIGURE SO WE MOVE TO

2123
01:42:03,920 --> 01:42:05,240
THE GUT MICROBIAL DIVERSITY AND

2124
01:42:05,240 --> 01:42:07,840
MET BY AN ANALYSIS OF DISTANCES

2125
01:42:07,840 --> 01:42:13,080
WHAT WE SEE HERE IS THAT THERE'S

2126
01:42:13,080 --> 01:42:16,000
A CLEAR SEPARATION BETWEEN THE

2127
01:42:16,000 --> 01:42:17,640
ALCOHOL SWEET SOLUTION

2128
01:42:17,640 --> 01:42:20,240
SELF-ADMINISTRATION COMPARED TO

2129
01:42:20,240 --> 01:42:20,960
THE NON ALCOHOLIC SWEET SOLUTION

2130
01:42:20,960 --> 01:42:22,040
AND THE BASELINE.

2131
01:42:22,040 --> 01:42:27,480
WHICH ACCOUNTS FOR 22.4% OF

2132
01:42:27,480 --> 01:42:30,720
DEFISDEFICIENCIES.

2133
01:42:30,720 --> 01:42:32,520
THESE FINDINGS ARE TO HIGHLIGHT

2134
01:42:32,520 --> 01:42:34,640
THE IMPORTANCE AND THESE

2135
01:42:34,640 --> 01:42:37,200
FINDINGS POINT TO THE FACT THAT

2136
01:42:37,200 --> 01:42:39,840
RODENTS WHO DRINK ALCOHOL HAVE A

2137
01:42:39,840 --> 01:42:42,080
DES TRA MENTAL DECREASE IN BOTH

2138
01:42:42,080 --> 01:42:45,640
ALPHA AND BETA DIVERSITY SO WE

2139
01:42:45,640 --> 01:42:49,040
KNOW THAT LIKE FOR NORMAL GUT,

2140
01:42:49,040 --> 01:42:51,040
THERE HAS TO BE A HIGH DIVERSITY

2141
01:42:51,040 --> 01:42:53,600
OF BACTERIAL SPECIES SO WHAT

2142
01:42:53,600 --> 01:42:55,240
WE'RE SEEING HERE IS OBVIOUS LOW

2143
01:42:55,240 --> 01:43:00,800
A NEGATIVE CONDITION, IN WHICH

2144
01:43:00,800 --> 01:43:03,640
ALCOHOL REDUCES THE DIVERSITY.

2145
01:43:03,640 --> 01:43:05,640
SO, THEN WHAT WE DID IS WE, AS I

2146
01:43:05,640 --> 01:43:07,200
SAID BEFORE, WE MOVED FORWARD

2147
01:43:07,200 --> 01:43:10,360
WITH NON HUMAN PRIMATES AND WE

2148
01:43:10,360 --> 01:43:11,560
THOUGHT IT WOULD BE IMPORTANT

2149
01:43:11,560 --> 01:43:13,520
BECAUSE THERE ARE VERY FEW

2150
01:43:13,520 --> 01:43:14,640
STUDIES, THERE ARE ONLY TWO

2151
01:43:14,640 --> 01:43:18,480
STUDIES WHICH WERE CONDUCTED IN

2152
01:43:18,480 --> 01:43:22,280
MAY AND WE DECIDED TO PROCEED

2153
01:43:22,280 --> 01:43:25,840
WITH PRIME IT'S A FOR A SERIOUS

2154
01:43:25,840 --> 01:43:33,560
REASON THAT AND WE TRANSLATED

2155
01:43:33,560 --> 01:43:39,400
THE MODEL IN CHRONIC ALCOHOL IN

2156
01:43:39,400 --> 01:43:46,560
COLLABORATION WITH STUDY MADE

2157
01:43:46,560 --> 01:43:49,160
POSSIBLE AND WE INVESTIGATED FOR

2158
01:43:49,160 --> 01:43:50,240
THE FIRST TIME THE CHRONIC

2159
01:43:50,240 --> 01:43:56,000
EXCESSIVE ALCOHOL DRINKING WITH

2160
01:43:56,000 --> 01:43:58,240
CHANGES IN THE GUT MICRO WE USED

2161
01:43:58,240 --> 01:44:02,000
ALL OF THEM AND SO, WHAT DID WE

2162
01:44:02,000 --> 01:44:04,440
HAVE, SO WE HAD STUDIED THREE

2163
01:44:04,440 --> 01:44:07,400
GROUPS OF BABOONS SO WE HAVE

2164
01:44:07,400 --> 01:44:09,400
LSTL IS WHAT WE CALL THE

2165
01:44:09,400 --> 01:44:11,520
LONG-TERM DRINKING GROUPS SO

2166
01:44:11,520 --> 01:44:14,040
THIS GROUP BASICALLY CHRONICALLY

2167
01:44:14,040 --> 01:44:15,720
DRANK ALCOHOL EVERYDAY OF THE

2168
01:44:15,720 --> 01:44:18,240
WEEK SO SEVEN DAYS OUT OF SEVEN

2169
01:44:18,240 --> 01:44:20,240
FOR OVER 10 YEARS AND THEN WE

2170
01:44:20,240 --> 01:44:23,000
HAD THE SHORT TERM ALCOHOL

2171
01:44:23,000 --> 01:44:27,720
DRINKING GROUP THAT CHRONICALLY

2172
01:44:27,720 --> 01:44:28,960
DRANK ALCOHOL EVERY DAY FOR TWO

2173
01:44:28,960 --> 01:44:29,640
OR THROW YEARS.

2174
01:44:29,640 --> 01:44:31,760
I WOULD CALL IT RELATIVE SHORT

2175
01:44:31,760 --> 01:44:33,440
TERM BECAUSE IT'S NOT SO SHORT

2176
01:44:33,440 --> 01:44:35,200
TERM.

2177
01:44:35,200 --> 01:44:39,040
AND THEN WE HAD OUR CONTROL

2178
01:44:39,040 --> 01:44:39,960
GROUP THAT DRANK AND I'M GOING

2179
01:44:39,960 --> 01:44:44,240
TO SHOW YOU HERE AND THAT IS

2180
01:44:44,240 --> 01:44:46,600
BASICALLY AN ORANGE FLAVORED

2181
01:44:46,600 --> 01:44:50,680
DRINK AND CALORIES AS ALCOHOL

2182
01:44:50,680 --> 01:44:56,000
BUT NOT ALCOHOLIC AND THEY DRANK

2183
01:44:56,000 --> 01:44:58,640
FOR EIGHT YEARS AND WE DECIDED

2184
01:44:58,640 --> 01:45:00,720
TO STUDY THIS THREE GROUPS IN

2185
01:45:00,720 --> 01:45:03,640
TWO CONDITIONS SO WE BASICALLY

2186
01:45:03,640 --> 01:45:05,640
STUDIED THESE THREE GROUPS IN

2187
01:45:05,640 --> 01:45:07,760
THREE CONSECUTIVE DAYS OF ACTIVE

2188
01:45:07,760 --> 01:45:09,440
DRINKING AND THEN, THESE DAYS

2189
01:45:09,440 --> 01:45:12,840
WERE FOLLOWED BY THREE

2190
01:45:12,840 --> 01:45:14,520
CONSECUTIVE OF SHORT TERM

2191
01:45:14,520 --> 01:45:16,320
ACCIDENTS AND MOVING FORWARD,

2192
01:45:16,320 --> 01:45:18,480
SO, I'M GOING TO EXPLAIN A

2193
01:45:18,480 --> 01:45:24,800
LITTLE BIT WHY WE CHOSE BABOONS,

2194
01:45:24,800 --> 01:45:26,720
BACK BOONES IN CAPTIVITY HAVE A

2195
01:45:26,720 --> 01:45:28,400
CHANGE IN THEIR MICROBIOME

2196
01:45:28,400 --> 01:45:30,680
BECAUSE IT COMES SIMILAR TO THAT

2197
01:45:30,680 --> 01:45:32,560
IN HUMANS SO IT HAS THIS EFFECT

2198
01:45:32,560 --> 01:45:37,680
AND THE SECOND REASON IS THAT

2199
01:45:37,680 --> 01:45:39,360
THE GUT MICROBIOME OF BABOONS IS

2200
01:45:39,360 --> 01:45:41,240
THE CLOSEST TO THE HUMAN SPECIES

2201
01:45:41,240 --> 01:45:46,800
COMPARED TO APES AND MONKEYS SO

2202
01:45:46,800 --> 01:45:49,200
IT OFFERS A CLEAR ADVANTAGE AND

2203
01:45:49,200 --> 01:45:53,400
ANOTHER REASON IS THAT THE BACK

2204
01:45:53,400 --> 01:46:01,960
BOONES METABOLIZE COMPARED TO

2205
01:46:01,960 --> 01:46:07,400
STUDIES WHO HAVE AND THEY ALLOW

2206
01:46:07,400 --> 01:46:09,200
LONG-TERM EXPOSURE TO ALCOHOL IN

2207
01:46:09,200 --> 01:46:12,080
WELL CONTROLLED EXPERIMENTAL

2208
01:46:12,080 --> 01:46:14,320
CONDITIONS THAT OBVIOUSLY CANNOT

2209
01:46:14,320 --> 01:46:22,360
BE IN HUMAN STUDIES THIS THIS IS

2210
01:46:22,360 --> 01:46:24,680
ANOTHER ADVANTAGE AND IN TERMS

2211
01:46:24,680 --> 01:46:26,520
OF THE BALLOON MODEL WE USED,

2212
01:46:26,520 --> 01:46:28,320
IT'S BASED ON A VALIDATED

2213
01:46:28,320 --> 01:46:29,840
SCHEDULE OF REINFORCEMENT

2214
01:46:29,840 --> 01:46:31,960
PROCEDURE AND IT'S CONSISTENT

2215
01:46:31,960 --> 01:46:34,440
WITH NOT A AAA DEFINITION OF

2216
01:46:34,440 --> 01:46:35,480
HEAVY AND BINGE DRINKING IN

2217
01:46:35,480 --> 01:46:38,120
HUMANS SO IT'S HEAVY AND BINGE

2218
01:46:38,120 --> 01:46:41,200
DRANKING ACID DESIGNED THEM FOR.

2219
01:46:41,200 --> 01:46:43,800
DRINKING TOO MUCH TOO FAST AND

2220
01:46:43,800 --> 01:46:46,480
TOO OFTEN.

2221
01:46:46,480 --> 01:46:48,160
SECOND, THERE'S SPECIFICITY WAS

2222
01:46:48,160 --> 01:46:53,480
TESTED IN ALCOHOL VERSUS AND IF

2223
01:46:53,480 --> 01:46:55,960
I WAITED MEDICATION DEVELOP FOR

2224
01:46:55,960 --> 01:47:00,640
ALCOHOL DISORDER AND STUDIES ON

2225
01:47:00,640 --> 01:47:01,920
THROW DRUGS.

2226
01:47:01,920 --> 01:47:05,080
AND IMPORTANCE HERE IS IS ONE OF

2227
01:47:05,080 --> 01:47:06,840
THE THROW FDA APPROVED

2228
01:47:06,840 --> 01:47:08,040
MEDICATION FOR ALCOHOL USE

2229
01:47:08,040 --> 01:47:09,840
DISORDER AND THE OTHER

2230
01:47:09,840 --> 01:47:11,640
MEDICATIONS ALTHOUGH THEY'RE NOT

2231
01:47:11,640 --> 01:47:14,520
APPROVED BY THE FDA HAVE SHOWN

2232
01:47:14,520 --> 01:47:18,280
INCREDIBLE EFFICACY IN THEM

2233
01:47:18,280 --> 01:47:20,480
EFFECTED BY ALCOHOL USE DISORDER

2234
01:47:20,480 --> 01:47:22,040
SO WE CAN SEE THE CLINICAL

2235
01:47:22,040 --> 01:47:28,440
IMPORTANCE OF THIS POINT AND SO

2236
01:47:28,440 --> 01:47:29,320
IN TERMS OF THE ONE PART IS

2237
01:47:29,320 --> 01:47:33,400
INTERESTING TO NOTE THE BA BONES

2238
01:47:33,400 --> 01:47:35,040
WERE MALE AND THEY DID NOT

2239
01:47:35,040 --> 01:47:35,840
DIFFER IN TERMS OF SIGNIFICANT

2240
01:47:35,840 --> 01:47:38,400
IN TERMS OF AGE OR WEIGHT AND

2241
01:47:38,400 --> 01:47:39,880
ALSO WHAT I WANTED TO HIGHLIGHT

2242
01:47:39,880 --> 01:47:42,920
IS THAT THE LIVER ENZYME, THE

2243
01:47:42,920 --> 01:47:45,840
LIVER FUNCTION TEST WAS NORMAL.

2244
01:47:45,840 --> 01:47:49,000
MEANING THEY DID NOT SHOW ANY

2245
01:47:49,000 --> 01:47:51,880
ALTERATION THAT CAN MIMIC

2246
01:47:51,880 --> 01:47:53,520
ALCOHOL AND LIVER CONDITIONS IN

2247
01:47:53,520 --> 01:48:01,040
HUMANS SO THEY WERE HEALTHY BACK

2248
01:48:01,040 --> 01:48:03,040
BONES AND WHEN THEY DRANK IN

2249
01:48:03,040 --> 01:48:04,920
THEIR TWO HOUR PERIOD IN THE

2250
01:48:04,920 --> 01:48:10,520
TRAINED SCHEDULE O SCHEDULE OF
PROCEDURE

2251
01:48:10,520 --> 01:48:12,080
THEY RECEIVED OVER .08 TO MAKE

2252
01:48:12,080 --> 01:48:15,720
SURE THEY WERE ACTUALLY BINGE

2253
01:48:15,720 --> 01:48:16,280
DRINKING.

2254
01:48:16,280 --> 01:48:18,000
SO THIS IS WHAT WE SEE, THIS IS

2255
01:48:18,000 --> 01:48:23,560
WHAT WE SEE IN TERMS OF GUT

2256
01:48:23,560 --> 01:48:24,400
MICRO BIOME.

2257
01:48:24,400 --> 01:48:26,960
WHAT WE SEE IN THE LEFT SIDE OF

2258
01:48:26,960 --> 01:48:30,600
THE FIGURE IS THE ALPHA

2259
01:48:30,600 --> 01:48:31,920
DIVERSITY SO GUT MICROBIAL IS

2260
01:48:31,920 --> 01:48:33,880
MEASURED BY THE SHANNON

2261
01:48:33,880 --> 01:48:35,040
DIVERSITY INDEX AND

2262
01:48:35,040 --> 01:48:37,320
SIGNIFICANTLY DECREASED AFTER

2263
01:48:37,320 --> 01:48:40,480
LONG-TERM ALCOHOL DRINKING WHEN

2264
01:48:40,480 --> 01:48:42,600
COMPARED TO, AS WE CAN SEE HERE,

2265
01:48:42,600 --> 01:48:44,400
TO THE ALCOHOL SHORT-TERM

2266
01:48:44,400 --> 01:48:47,080
DRINKING WHICH IS IN THE MIDDLE

2267
01:48:47,080 --> 01:48:48,600
IN TANG ON THE LEFT.

2268
01:48:48,600 --> 01:48:51,840
AND BASICALLY, WHAT WE CAN SEE

2269
01:48:51,840 --> 01:48:53,400
HERE IS THAT THERE ARE NO

2270
01:48:53,400 --> 01:48:55,040
SIGNIFICANT DIFFERENCES IN TANG

2271
01:48:55,040 --> 01:48:56,280
AND ALCOHOL SHORT TERM.

2272
01:48:56,280 --> 01:48:58,520
CONTRARILY TO OUR EXPECTATIONS,

2273
01:48:58,520 --> 01:48:59,920
WE THOUGHT THAT TWO OR THREE

2274
01:48:59,920 --> 01:49:02,520
YEARS OF DRINKING OF ALCOHOL

2275
01:49:02,520 --> 01:49:08,040
DRINKING WOULD BE STILL KIND OF

2276
01:49:08,040 --> 01:49:11,280
CONTRIBUTED TO BASICALLY

2277
01:49:11,280 --> 01:49:12,920
INDUCING A DECREASE IN DIVERSITY

2278
01:49:12,920 --> 01:49:18,880
AND WE DID NOT FIND THAT.

2279
01:49:18,880 --> 01:49:20,080
WHAT WE CAN SEE IN TERMS OF THE

2280
01:49:20,080 --> 01:49:23,240
TWO CONDITIONS WE STUDIED, THE

2281
01:49:23,240 --> 01:49:32,040
THREE GROUPS OF BABOONS AND

2282
01:49:32,040 --> 01:49:33,680
THREE DAYS OF SHORT TERM

2283
01:49:33,680 --> 01:49:34,840
ABSTINENCE WERE NOT SUFFICIENT

2284
01:49:34,840 --> 01:49:38,520
TO RESTORE THE NORMAL MICROBIOME

2285
01:49:38,520 --> 01:49:41,040
AND IT WOULD BE INTERESTING TO

2286
01:49:41,040 --> 01:49:43,560
PROLONG THE ABSTINENCE AND SEE

2287
01:49:43,560 --> 01:49:46,640
IF THE MICRO BUY OWN IN THE

2288
01:49:46,640 --> 01:49:47,640
LONG-TERM GROUP RETURNS TO

2289
01:49:47,640 --> 01:49:52,760
NORMAL AND WHAT WE SEE HERE ON

2290
01:49:52,760 --> 01:49:55,600
THE RIGHT, IS THE GUT DIVERSITY

2291
01:49:55,600 --> 01:49:59,240
AND WHAT WE CAN SEE AS MEASURED

2292
01:49:59,240 --> 01:50:01,440
BY THE BRAY-CURTIS SIMILARITY

2293
01:50:01,440 --> 01:50:04,040
THAT SUGGESTION THAT BASICALLY

2294
01:50:04,040 --> 01:50:05,040
THE ALCOHOL LONG-TERM GROUP IN

2295
01:50:05,040 --> 01:50:09,200
RED WHICH IS IN RED, AND THE

2296
01:50:09,200 --> 01:50:11,320
TANG GROUP IN BLUE, ARE

2297
01:50:11,320 --> 01:50:12,200
DIFFERENT.

2298
01:50:12,200 --> 01:50:14,840
ACCOUNTING FOR 8.3% OF THE

2299
01:50:14,840 --> 01:50:15,120
DIFFERENCES.

2300
01:50:15,120 --> 01:50:17,120
AND AGAIN THE TWO CONDITIONS SO

2301
01:50:17,120 --> 01:50:19,360
DRINKING AND ABSENCE DID NOT

2302
01:50:19,360 --> 01:50:21,400
EXHIBIT DIFFERENT COMMUNITY

2303
01:50:21,400 --> 01:50:22,760
STRUCTURES AND POSSIBLY AGAIN

2304
01:50:22,760 --> 01:50:24,920
BECAUSE THESE THREE DAYS OF

2305
01:50:24,920 --> 01:50:27,520
ABSENTEEISM DID NOT MAKE ANY

2306
01:50:27,520 --> 01:50:33,600
IMPACT ON THE STRUCTURE OF OUR

2307
01:50:33,600 --> 01:50:33,920
MICRO IMPACTS.

2308
01:50:33,920 --> 01:50:39,480
WE CAN SEE THE RESULTS OF OUR

2309
01:50:39,480 --> 01:50:46,240
METMET SO WE USED MODELS TO

2310
01:50:46,240 --> 01:50:48,440
INVESTIGATE WHICH METABOLISM

2311
01:50:48,440 --> 01:50:50,360
WERE IN THE GROUP FOR A

2312
01:50:50,360 --> 01:50:51,560
CONDITION INTERACTION AND AS WE

2313
01:50:51,560 --> 01:50:53,640
CAN SEE AS SHOWN IN THIS HEAT

2314
01:50:53,640 --> 01:50:56,840
MAP, WE FOUND 66 METABOLITES TO

2315
01:50:56,840 --> 01:50:58,600
BE SIGNIFICANTLY DIFFERENT IN

2316
01:50:58,600 --> 01:51:01,160
THE LONG-TERM ALCOHOL DRINKING

2317
01:51:01,160 --> 01:51:03,960
ON THE LEFT IN RED, COMPARED TO

2318
01:51:03,960 --> 01:51:04,760
THE SHORT-TERM ALCOHOL DRINKING

2319
01:51:04,760 --> 01:51:07,920
GROUP WHICH IS IN GREN IN THE

2320
01:51:07,920 --> 01:51:09,080
MIDDLE AND THE TANG GROUP WHICH

2321
01:51:09,080 --> 01:51:12,560
IS THE LAST ONE.

2322
01:51:12,560 --> 01:51:14,600
AGAIN, THERE WERE NO SIGNIFICANT

2323
01:51:14,600 --> 01:51:17,160
DIFFERENCES BETWEEN THE TWO

2324
01:51:17,160 --> 01:51:19,360
CONDITIONS SO THAT FOCUSES ARE

2325
01:51:19,360 --> 01:51:20,720
NOT SHOWING THEM HERE AND THE

2326
01:51:20,720 --> 01:51:23,840
TWO CONDITIONS DRINKING AND

2327
01:51:23,840 --> 01:51:26,640
SHORT TERM ACCIDENTS.

2328
01:51:26,640 --> 01:51:28,560
WHICH WERE THE METABOLITES THAT

2329
01:51:28,560 --> 01:51:29,560
WHY SIGNIFICANTLY DIFFERENT IN

2330
01:51:29,560 --> 01:51:31,440
THE LONG-TERM ALCOHOL DRINKING

2331
01:51:31,440 --> 01:51:34,320
GROUP COMPARED TO THE OTHER TWO?

2332
01:51:34,320 --> 01:51:36,560
WE SAW THAT THERE WAS AN

2333
01:51:36,560 --> 01:51:42,520
INCREASED IN METABOLITES RELATED

2334
01:51:42,520 --> 01:51:44,240
TO GMDYSBIOSIS AND BRANCH CHAIN

2335
01:51:44,240 --> 01:51:47,360
AMINO ACIDS, FATTY ACIDS,

2336
01:51:47,360 --> 01:51:53,200
CENTRAL ENERGY METABOLITES AND

2337
01:51:53,200 --> 01:51:53,800
PENTOSE MET TAB LIGHTS AND WE

2338
01:51:53,800 --> 01:51:56,400
SAW AMINO AS SITS AND AGAIN,

2339
01:51:56,400 --> 01:51:58,040
THESE PROBABLY MEANS THAT THE

2340
01:51:58,040 --> 01:52:02,520
ALCOHOL, THE LONG-TERM ALCOHOL

2341
01:52:02,520 --> 01:52:07,040
DRINKING GROUP HAD A GREATER

2342
01:52:07,040 --> 01:52:08,880
DAMAGE OF THE CAUSE COMPARED TO

2343
01:52:08,880 --> 01:52:13,800
THE SHORT-TERM ALCOHOL DRINKING

2344
01:52:13,800 --> 01:52:14,000
GROUP.

2345
01:52:14,000 --> 01:52:16,480
SO LAST BUT NOT LEAST THIS IS

2346
01:52:16,480 --> 01:52:20,240
OUR STUDY IN HUMANS AND

2347
01:52:20,240 --> 01:52:23,760
BASICALLY WE USED THE FINDINGS

2348
01:52:23,760 --> 01:52:29,320
FROM THE BABOON STUDY IN

2349
01:52:29,320 --> 01:52:31,440
INDIVIDUALS WITH ALCOHOL USE

2350
01:52:31,440 --> 01:52:32,920
DISORDER AND WHAT DID WE HAVE

2351
01:52:32,920 --> 01:52:33,280
HERE?

2352
01:52:33,280 --> 01:52:37,080
WE HAD THREE GROUPS OF

2353
01:52:37,080 --> 01:52:37,680
PARTICIPANTS.

2354
01:52:37,680 --> 01:52:39,840
WE HAD ABSTINENT INDIVIDUALS

2355
01:52:39,840 --> 01:52:42,800
WITH ALCOHOL USE DISORDER.

2356
01:52:42,800 --> 01:52:44,040
THESE INDIVIDUALS USED TO BE

2357
01:52:44,040 --> 01:52:46,240
HEAVY DRINKERS BUT THEY HAD

2358
01:52:46,240 --> 01:52:48,560
STOPPED DRINKING FOR AT LEAST

2359
01:52:48,560 --> 01:52:50,360
SIX WEEKS AND OF THESE SIX

2360
01:52:50,360 --> 01:52:53,880
WEEKS, FOUR WEEKS WERE SPENT IN

2361
01:52:53,880 --> 01:52:56,960
THE NIHAAA INPATIENT UNIT AND

2362
01:52:56,960 --> 01:52:58,320
THEY WERE DISCHARGED AND AT

2363
01:52:58,320 --> 01:52:59,880
LEAST TWO WEEKS WERE SPENT IN

2364
01:52:59,880 --> 01:53:02,440
THEIR NORMAL DAILY LIVES.

2365
01:53:02,440 --> 01:53:04,040
AND THE REASON WE WANTED THAT IS

2366
01:53:04,040 --> 01:53:05,240
BECAUSE WE WANTED THEM TO RETURN

2367
01:53:05,240 --> 01:53:07,920
TO THEIR NORMAL DIET, I DON'T

2368
01:53:07,920 --> 01:53:09,880
KNOW, PHYSICAL EXERCISE AND ANY

2369
01:53:09,880 --> 01:53:12,040
OTHER CONDITION.

2370
01:53:12,040 --> 01:53:13,800
THEN WE HAD THE CURRENTLY HEAVY

2371
01:53:13,800 --> 01:53:15,680
DRINKING INDIVIDUALS WITH AUD SO

2372
01:53:15,680 --> 01:53:18,400
THIS INDIVIDUALS WERE NOT

2373
01:53:18,400 --> 01:53:20,160
SEEKING TREATMENT.

2374
01:53:20,160 --> 01:53:21,160
THEY DRANK HEAVY AND THEY JUST

2375
01:53:21,160 --> 01:53:23,040
CAME TO OUR OUT PATIENT UNIT,

2376
01:53:23,040 --> 01:53:24,680
JUST FOR THE PURPOSE OF THE

2377
01:53:24,680 --> 01:53:25,040
STUDY.

2378
01:53:25,040 --> 01:53:26,680
AND THEN WE HAD WHAT WE CALL THE

2379
01:53:26,680 --> 01:53:28,320
HEALTHY CONTROLS BUT IT'S MORE

2380
01:53:28,320 --> 01:53:30,600
PRO PRE TO CALL THEM NON-AUD

2381
01:53:30,600 --> 01:53:31,760
CONTROLS IN THAT THEY DID NOT

2382
01:53:31,760 --> 01:53:33,400
HAVE A DIAGNOSIS OF CURRENT OR

2383
01:53:33,400 --> 01:53:35,560
FAST AUD AND I ALSO HAVE TO

2384
01:53:35,560 --> 01:53:37,680
MENTION IN REALITY, THAT ALL

2385
01:53:37,680 --> 01:53:40,040
THESE THREE GROUPS OF

2386
01:53:40,040 --> 01:53:41,800
PARTICIPANTS WERE HEALTHY AND

2387
01:53:41,800 --> 01:53:46,560
THAT WE EXCLUDED ANY ALCOHOL

2388
01:53:46,560 --> 01:53:48,320
ASSOCIATED DISEASE, WE EXCLUDED

2389
01:53:48,320 --> 01:53:51,320
MAJOR HEALTH PROBLEMS, MAJOR

2390
01:53:51,320 --> 01:53:51,800
PSYCHIATRIC PROBLEMS.

2391
01:53:51,800 --> 01:53:53,640
SO I WOULD SAY THEY WERE ALL

2392
01:53:53,640 --> 01:53:55,320
PRETTY HEALTHY.

2393
01:53:55,320 --> 01:53:58,480
NO DIABETES AND SO ON.

2394
01:53:58,480 --> 01:54:00,760
SO, THESE ARE THE -- AND

2395
01:54:00,760 --> 01:54:02,520
OBVIOUSLY I FORGOT TO TELL YOU

2396
01:54:02,520 --> 01:54:06,480
OBVIOUSLY NO INTAKE OF

2397
01:54:06,480 --> 01:54:08,280
PROBIOTICS, ANTIBIOTICS OR ANY

2398
01:54:08,280 --> 01:54:09,400
MEDICATIONS THAT CAN INFLUENCE

2399
01:54:09,400 --> 01:54:13,800
THE MICRO.

2400
01:54:13,800 --> 01:54:15,240
WE CAN SEE ALREADY THAT THERE

2401
01:54:15,240 --> 01:54:17,240
WERE NO SIGNIFICANT DIFFERENCES

2402
01:54:17,240 --> 01:54:19,680
IN TERMS OF GENDER, RACE,

2403
01:54:19,680 --> 01:54:24,560
ETHNICITY, AGE, AND THE THREE

2404
01:54:24,560 --> 01:54:25,760
GROUPS WERE COMPARABLE IN TERMS

2405
01:54:25,760 --> 01:54:28,480
OF SOCIAL DEMOGRAPHICS AND WHICH

2406
01:54:28,480 --> 01:54:31,280
WAS KIND OF IMPORTANT FOR US,

2407
01:54:31,280 --> 01:54:32,640
ALTHOUGH WE DIDN'T REALLY LOOK

2408
01:54:32,640 --> 01:54:32,880
FOR THAT.

2409
01:54:32,880 --> 01:54:35,800
WE WERE KIND OF LUCKY.

2410
01:54:35,800 --> 01:54:37,400
THIS IS WHAT WE FOUND.

2411
01:54:37,400 --> 01:54:38,360
SO I'M SHOWING THIS FOR THE

2412
01:54:38,360 --> 01:54:42,520
FIRST TIME BECAUSE AS I SAID, WE

2413
01:54:42,520 --> 01:54:50,560
REANALYZED IN MICROBIOME AND --

2414
01:54:50,560 --> 01:54:52,160
THIS WAS NOT WHAT WE EXPECTED.

2415
01:54:52,160 --> 01:54:54,040
AS WE CAN SEE HERE, WE HAVE THE

2416
01:54:54,040 --> 01:54:55,640
CURRENT DRINKER, THE PEOPLE THAT

2417
01:54:55,640 --> 01:55:02,560
WE HAD EXPECTED TO ACTUALLY HAVE

2418
01:55:02,560 --> 01:55:05,040
DETRIMENTAL DECREASE OF THE

2419
01:55:05,040 --> 01:55:06,120
MICROBIOME OR DIVERSITY AS SHOWN

2420
01:55:06,120 --> 01:55:09,000
IN THE LEFT, WELL, THEY DID NOT

2421
01:55:09,000 --> 01:55:09,600
HAVE THAT.

2422
01:55:09,600 --> 01:55:10,640
BASICALLY THEY DID NOT FOLLOW

2423
01:55:10,640 --> 01:55:15,960
THE RESULTS OF THE RODENTS AND

2424
01:55:15,960 --> 01:55:19,280
BABONE STUDIES WHERE ALCOHOL IS

2425
01:55:19,280 --> 01:55:21,160
IN GUT MICROBIOME DIVERSITY.

2426
01:55:21,160 --> 01:55:23,600
WE SEE THE OPPOSITE.

2427
01:55:23,600 --> 01:55:25,880
BASICALLY OUR CURRENT DRINKERS

2428
01:55:25,880 --> 01:55:29,040
HAVE AN ALPHA DIVERSITY

2429
01:55:29,040 --> 01:55:30,680
SIGNIFICANTLY HIGHER THAN THE

2430
01:55:30,680 --> 01:55:33,160
ABSTINENCE GROUP AND THE HEALTHY

2431
01:55:33,160 --> 01:55:33,560
CONTROLS.

2432
01:55:33,560 --> 01:55:38,440
AS I SAY, ALSO, BRAINSTORMING

2433
01:55:38,440 --> 01:55:41,200
WITH OUR COLLEAGUES, OUR

2434
01:55:41,200 --> 01:55:44,960
COLLEAGUES MICROBIOLOGIST IS

2435
01:55:44,960 --> 01:55:47,440
THAT A HIGHER ALPHA DIVERSITY

2436
01:55:47,440 --> 01:55:49,680
DOES NOT NECESSARILY MEAN A

2437
01:55:49,680 --> 01:55:52,200
BETTER GUT MIKE RE BIOME, A

2438
01:55:52,200 --> 01:55:53,360
HEALTHIER GUT MICROBIOME BECAUSE

2439
01:55:53,360 --> 01:55:55,040
IT COULD BE THE RESULT OF

2440
01:55:55,040 --> 01:55:57,960
INSULTS THAT CAUSE A DIS BIO SIS

2441
01:55:57,960 --> 01:55:59,080
BUT IT'S JUST THE DIRECTION OF

2442
01:55:59,080 --> 01:56:01,360
THE CHANGE THAT IS DIFFERENT.

2443
01:56:01,360 --> 01:56:03,480
IN FACT, WHAT WE CAN SEE THAT IS

2444
01:56:03,480 --> 01:56:05,360
THE ALPHA DIVERSITY OF HEALTHY

2445
01:56:05,360 --> 01:56:07,080
CONTROLS IN ABSTINENCE IS

2446
01:56:07,080 --> 01:56:07,320
NORMAL.

2447
01:56:07,320 --> 01:56:09,080
IT IS ABNORMAL IN CURRENT

2448
01:56:09,080 --> 01:56:11,040
DRINKERS BUT WE HAVE TO SEE WHY

2449
01:56:11,040 --> 01:56:13,480
THE DIRECTION IS DIFFERENT,

2450
01:56:13,480 --> 01:56:19,960
COMPARED TO RODENT AND BABOONS.

2451
01:56:19,960 --> 01:56:21,560
IN TERMS OF BETTER DIVERSITY,

2452
01:56:21,560 --> 01:56:24,040
WHAT WE CAN SEE HERE IN TERMS OF

2453
01:56:24,040 --> 01:56:26,240
IS THE SIMILARITY IS THAT

2454
01:56:26,240 --> 01:56:31,840
THERE'S A KIND OF OVERLAP

2455
01:56:31,840 --> 01:56:32,680
NUCLEAR DISTINCTION BETWEEN THE

2456
01:56:32,680 --> 01:56:35,840
THREE GROUPS ALTHOUGH THE

2457
01:56:35,840 --> 01:56:36,720
HEALTHY CONTROLS, YEAH -- I

2458
01:56:36,720 --> 01:56:39,560
WOULD SAY THERE'S AN OVERLAP

2459
01:56:39,560 --> 01:56:41,640
WITH THE TWO AXIS EXPLAINING

2460
01:56:41,640 --> 01:56:46,200
ONLY A COMBINED 18% AND 18.1% OF

2461
01:56:46,200 --> 01:56:48,640
THE BETA TA DIVERSITY.

2462
01:56:48,640 --> 01:56:53,400
WE HAVE NOT ANALYZED THE MA TAB

2463
01:56:53,400 --> 01:56:54,680
A LOAM YET BUT I WOULD LIKE TO

2464
01:56:54,680 --> 01:56:56,720
SAY THAT IN ORDER TO PROPERLY

2465
01:56:56,720 --> 01:56:58,800
UNDERSTAND WHAT HAPPENS TO THE

2466
01:56:58,800 --> 01:57:00,040
MICROBIOME IN HUMANS, JUST

2467
01:57:00,040 --> 01:57:01,880
BECAUSE OF WHAT I MENTIONED

2468
01:57:01,880 --> 01:57:06,480
EARLIER, THERE ARE SO MANY COM

2469
01:57:06,480 --> 01:57:08,200
THINGS PRESENT WHEN STUDYING

2470
01:57:08,200 --> 01:57:10,240
HUMANS WE'RE ACTUALLY ANALYZING

2471
01:57:10,240 --> 01:57:12,400
ALL THE DATA WE HAVE AS REGARDS

2472
01:57:12,400 --> 01:57:13,360
TO NUTRITION AS WE CAN SEE HERE

2473
01:57:13,360 --> 01:57:15,040
ON THE RIGHT.

2474
01:57:15,040 --> 01:57:16,840
BECAUSE OBVIOUSLY WE WANT TO SEE

2475
01:57:16,840 --> 01:57:19,040
IF THERE ARE A SIGNIFICANT

2476
01:57:19,040 --> 01:57:20,920
DIFFERENCES IN NUTRITION BETWEEN

2477
01:57:20,920 --> 01:57:21,320
OUR THREE GROUPS.

2478
01:57:21,320 --> 01:57:23,880
WE'RE STUDYING LEVELS OF

2479
01:57:23,880 --> 01:57:25,320
PHYSICAL EXERCISE, ALTHOUGH AS I

2480
01:57:25,320 --> 01:57:29,280
SAID BEFORE, WE EXCLUDED MAJOR

2481
01:57:29,280 --> 01:57:30,680
PSYCHO PATHOLOGICAL DISORDERS

2482
01:57:30,680 --> 01:57:34,000
AND WE'RE STILL LOOKING AT OUR

2483
01:57:34,000 --> 01:57:34,920
QUESTIONNAIRES THAT MAY

2484
01:57:34,920 --> 01:57:37,040
HIGHLIGHT DIFFERENCE AND

2485
01:57:37,040 --> 01:57:38,640
DEPRESSION OR ANY OTHER SIGH

2486
01:57:38,640 --> 01:57:40,040
LOGICAL FEATURES, AND THEN WE

2487
01:57:40,040 --> 01:57:42,040
OBVIOUSLY WANTED, AS YOU CAN SEE

2488
01:57:42,040 --> 01:57:44,440
HERE, UP HERE, THIS LADY AND

2489
01:57:44,440 --> 01:57:47,720
THIS SORT OF DOME, THIS IS THE

2490
01:57:47,720 --> 01:57:52,840
MEASURE OF THE META, THE

2491
01:57:52,840 --> 01:57:56,480
METABOLISM AND WHETHER THEY ARE

2492
01:57:56,480 --> 01:57:57,800
NOT BEHIND ANY PHYSICAL ACTIVITY

2493
01:57:57,800 --> 01:57:59,800
AND HERE ON THE RIGHT, WE HAVE

2494
01:57:59,800 --> 01:58:02,440
THIS AND WE DID IT FOR THE POEM

2495
01:58:02,440 --> 01:58:05,920
TO BASICALLY HAVE AN IDEA OF HOW

2496
01:58:05,920 --> 01:58:08,120
THE AMOUNT OF FAT IN THE BODY,

2497
01:58:08,120 --> 01:58:16,000
WE KNOW THAT INTRA DOMINAL FAT

2498
01:58:16,000 --> 01:58:17,080
AND IT'S ANOTHER IMPORTANT

2499
01:58:17,080 --> 01:58:20,440
FACTOR THAT WE KNOW TO BE

2500
01:58:20,440 --> 01:58:24,840
ASSOCIATED WITH THIS GUT

2501
01:58:24,840 --> 01:58:26,240
DISBIOSIS AND THIS IS SOMETHING

2502
01:58:26,240 --> 01:58:27,960
THAT WE'RE ALSO INVESTIGATING

2503
01:58:27,960 --> 01:58:28,960
THROUGH OUR PROBE METHOD AND

2504
01:58:28,960 --> 01:58:30,440
THIS IS BASICALLY WHAT WE'RE

2505
01:58:30,440 --> 01:58:31,640
TRYING DO NOW.

2506
01:58:31,640 --> 01:58:34,080
WITH ALL THESE ELEMENTS AND KIND

2507
01:58:34,080 --> 01:58:37,760
OF SEE IF IT MAKES SENSE TO HAVE

2508
01:58:37,760 --> 01:58:39,280
THEM AS CO VARIANTS WHILE WE

2509
01:58:39,280 --> 01:58:41,600
STUDY THE MICROBIOME AND WE'RE

2510
01:58:41,600 --> 01:58:43,840
GOING TO TRY TO CORRELATE ALL

2511
01:58:43,840 --> 01:58:46,280
THESE MEASURES WITH A BUY PO

2512
01:58:46,280 --> 01:58:48,640
BEHAVIORAL MEASURES WITH CRAVING

2513
01:58:48,640 --> 01:58:53,760
MEASURE IN OUR BAR SETTING AT

2514
01:58:53,760 --> 01:58:54,360
THE NIH.

2515
01:58:54,360 --> 01:58:56,240
I WANT TO THANK YOU AND FIRST OF

2516
01:58:56,240 --> 01:58:59,080
ALL I WANT TO ACKNOWLEDGE ALL MY

2517
01:58:59,080 --> 01:58:59,400
COLLEAGUES.

2518
01:58:59,400 --> 01:59:03,360
THIS STUDY WAS FUNDED BY JOINT

2519
01:59:03,360 --> 01:59:07,960
FUNDING BY THE NIDA, NIAAA AND I

2520
01:59:07,960 --> 01:59:09,280
COULDN'T HAVE THEM SO MANY DATA

2521
01:59:09,280 --> 01:59:10,680
AND I COULDN'T HAVE DONE WITH

2522
01:59:10,680 --> 01:59:15,320
THEM AND OBVIOUSLY WITH MY

2523
01:59:15,320 --> 01:59:17,560
MENTOR AND OUR COLLABORATORS AND

2524
01:59:17,560 --> 01:59:18,720
ANYWAY, THANK YOU SO MUCH FOR

2525
01:59:18,720 --> 01:59:26,960
YOUR TIME AND

2526
01:59:26,960 --> 01:59:29,640
>> THANK YOU FOR A GREAT TALK

2527
01:59:29,640 --> 01:59:31,400
THINKING ABOUT ANOTHER DYNAMIC

2528
01:59:31,400 --> 01:59:35,400
OF THE MICROBIOME, THAT IS

2529
01:59:35,400 --> 01:59:35,840
ALCOHOL.

2530
01:59:35,840 --> 01:59:39,520
WE'LL LOOK FOR QUESTIONS FROM 

2531
01:59:39,520 --> 01:59:40,440
THE ONLINE QUESTIONS AND

2532
01:59:40,440 --> 01:59:45,160
AUDIENCE IN THE ZOOM ROOM TOO.

2533
01:59:45,160 --> 01:59:48,040
AND I GUESS I HAVE A QUESTION IF

2534
01:59:48,040 --> 01:59:49,960
NO ONE ELSE HAS ONE.

2535
01:59:49,960 --> 01:59:51,720
DREW, PERFECT, I WILL LET YOU

2536
01:59:51,720 --> 01:59:52,720
HAVE A VOICE.

2537
01:59:52,720 --> 01:59:56,720
>> I DID HAVE ONE QUESTION.

2538
01:59:56,720 --> 01:59:59,480
CURIOUS, DID YOU EVER DO

2539
01:59:59,480 --> 02:00:04,640
SAMPLING AT DIFFERENT POINTS IN

2540
02:00:04,640 --> 02:00:07,960
THE G.I. TRACT?

2541
02:00:07,960 --> 02:00:17,240
IT GETS ABSORBED DIFFERENTLY

2542
02:00:17,240 --> 02:00:20,040
PROXIMALLY OR DISTALLY.

2543
02:00:20,040 --> 02:00:21,440
>> UNFORTUNATELY NOT.

2544
02:00:21,440 --> 02:00:23,800
WE DO HAVE MEASURES OF

2545
02:00:23,800 --> 02:00:25,880
INTESTINAL PROBABILITY, WHEN YOU

2546
02:00:25,880 --> 02:00:30,920
ON A US, AS I SAID, A 4-PROBE

2547
02:00:30,920 --> 02:00:34,440
TEST, WHERE WE'RE TRYING TO SEE

2548
02:00:34,440 --> 02:00:35,880
IF PERMEABILITY CHANGES GOING

2549
02:00:35,880 --> 02:00:38,240
FROM THE STOMACH TO THE COLON.

2550
02:00:38,240 --> 02:00:43,360
BUT OBVIOUSLY WE DON'T HAVE

2551
02:00:43,360 --> 02:00:44,240
UNFORTUNATELY THE GUT

2552
02:00:44,240 --> 02:00:46,480
MICROBIOME.

2553
02:00:46,480 --> 02:00:54,920
THAT WOULD HAVE BEEN AMAZING.

2554
02:00:54,920 --> 02:00:57,520
>> WE WANT AN ACTIVE ONLINE

2555
02:00:57,520 --> 02:00:57,840
GROUP.

2556
02:00:57,840 --> 02:01:00,840
SO A QUESTION, WILL YOUR GROUP

2557
02:01:00,840 --> 02:01:03,040
DIFFERENTIATE COHORTS OF HIGHLY

2558
02:01:03,040 --> 02:01:04,840
SENSITIVE PEOPLE OR SPECTRUM,

2559
02:01:04,840 --> 02:01:06,640
PEOPLE WITH AUTOIMMUNE DISEASES?

2560
02:01:06,640 --> 02:01:07,320
SHE SAYS GREAT WORK.

2561
02:01:07,320 --> 02:01:10,440
>> THANK YOU SO MUCH FOR THE

2562
02:01:10,440 --> 02:01:11,720
QUESTION. 

2563
02:01:11,720 --> 02:01:17,640
THIS IS VERY INTERESTING. 

2564
02:01:17,640 --> 02:01:20,760
IF BY AUTOIMMUNE DISEASES, WE

2565
02:01:20,760 --> 02:01:22,480
MEAN DISEASES THAT ARE

2566
02:01:22,480 --> 02:01:25,240
DIAGNOSED, WE EXCLUDED AS I SAID

2567
02:01:25,240 --> 02:01:27,560
BEFORE ANY MAJOR DISEASE BECAUSE

2568
02:01:27,560 --> 02:01:29,760
THAT WOULD HAVE COMPLICATED.

2569
02:01:29,760 --> 02:01:32,840
WE'RE ALREADY TRYING TO

2570
02:01:32,840 --> 02:01:36,520
EXTRAPOLATE, TRYING TO BASICALLY

2571
02:01:36,520 --> 02:01:37,280
ALREADY SIGNIFY THE COVARIATE,

2572
02:01:37,280 --> 02:01:38,760
WHAT HAPPENS IN THE HUMAN WORLD.

2573
02:01:38,760 --> 02:01:42,320
SO I WOULD SAY NO.

2574
02:01:42,320 --> 02:01:45,760
WE EXCLUDED THOSE DISEASES

2575
02:01:45,760 --> 02:01:46,080
UNFORTUNATELY.

2576
02:01:46,080 --> 02:01:49,880
BUT OTHERWISE IT'S REALLY HARD

2577
02:01:49,880 --> 02:01:51,320
TO SAY WHAT IS DUE TO THAT AND

2578
02:01:51,320 --> 02:01:54,040
WHAT IS DUE TO ALCOHOL.

2579
02:01:54,040 --> 02:01:55,480
ALCOHOL DOESN'T CAUSE THE SAME

2580
02:01:55,480 --> 02:02:00,560
EFFECT IN HUMANS COMPARED TO

2581
02:02:00,560 --> 02:02:02,000
RODENTS AND BABOONS, IT'S

2582
02:02:02,000 --> 02:02:03,240
ALREADY VERY DIFFERENT.

2583
02:02:03,240 --> 02:02:04,360
>> THANK YOU.

2584
02:02:04,360 --> 02:02:06,040
AND THERE'S LOTS OF QUESTIONS IN

2585
02:02:06,040 --> 02:02:06,520
THE CHAT.

2586
02:02:06,520 --> 02:02:11,840
DUE TO THE INTEREST OF TIME I

2587
02:02:11,840 --> 02:02:14,840
WILL E-MAIL AND YOU'LL HAVE A

2588
02:02:14,840 --> 02:02:19,480
CHANCE TO E-MAIL THE QUESTIONER

2589
02:02:19,480 --> 02:02:19,680
BACK.

2590
02:02:19,680 --> 02:02:21,320
IT'S IMPORTANT TO GO A LITTLE

2591
02:02:21,320 --> 02:02:22,960
OVER TIME TO KEEP THE DISCUSSION

2592
02:02:22,960 --> 02:02:24,720
PERIOD GOING, THE COOL PART

2593
02:02:24,720 --> 02:02:25,640
ABOUT DOING THIS.

2594
02:02:25,640 --> 02:02:28,960
WE RECOGNIZE WE'RE OVER TIME AND

2595
02:02:28,960 --> 02:02:30,080
WE'RE ETCHING INTO THE LUNCH

2596
02:02:30,080 --> 02:02:31,680
HOUR, THAT WILL BE OKAY BECAUSE

2597
02:02:31,680 --> 02:02:33,040
WE ARE ONLINE.

2598
02:02:33,040 --> 02:02:38,040
YOU CAN GO AS YOU PLEASE.

2599
02:02:38,040 --> 02:02:40,240
ALSO, THESE ARE BEING RECORDED

2600
02:02:40,240 --> 02:02:41,800
AND ARCHIVED AT THE NIH LIBRARY,

2601
02:02:41,800 --> 02:02:44,360
YOU CAN VIEW THEM AFTER TODAY.

2602
02:02:44,360 --> 02:02:48,200
KEEP THAT IN MIND AS YOU'RE

2603
02:02:48,200 --> 02:02:50,840
LOOKING AT THE CLOCK.

2604
02:02:50,840 --> 02:02:53,440
SWITCHING GEARS, SEAN WILL

2605
02:02:53,440 --> 02:02:59,840
INTRODUCE THE NEXT SPEAKER. 

2606
02:02:59,840 --> 02:03:01,840
>> NEXT MARIO FELDMAN FROM WASH

2607
02:03:01,840 --> 02:03:02,000
U.

2608
02:03:02,000 --> 02:03:03,200
TAKE IT AWAY.

2609
02:03:03,200 --> 02:03:04,880
>> THANK YOU VERY MUCH.

2610
02:03:04,880 --> 02:03:07,720
CAN YOU SEE MY SLIDES?

2611
02:03:07,720 --> 02:03:08,000
>> YES.

2612
02:03:08,000 --> 02:03:08,440
>> PERFECT.

2613
02:03:08,440 --> 02:03:08,680
THANK YOU.

2614
02:03:08,680 --> 02:03:10,400
IT'S A PLEASURE TO BE HERE,

2615
02:03:10,400 --> 02:03:12,040
LEARNING ABOUT THINGS I NEVER

2616
02:03:12,040 --> 02:03:15,040
THOUGHT I WOULD BE HEARING.

2617
02:03:15,040 --> 02:03:15,600
VERY COOL.

2618
02:03:15,600 --> 02:03:19,440
BUT TODAY I'M GOING TO TALK

2619
02:03:19,440 --> 02:03:26,000
ABOUT OUR WORK ON BACTERIAL

2620
02:03:26,000 --> 02:03:26,800
VESICLES AND DEGRADATION OF

2621
02:03:26,800 --> 02:03:28,280
POLYSACCHARIDES IN THE GUT.

2622
02:03:28,280 --> 02:03:43,480
IT'S KNOWN FOR MANY YEARS 

2623
02:03:43,480 --> 02:03:46,520
BACTERIA AND VESICLES, OUTER

2624
02:03:46,520 --> 02:03:51,560
MEMBRANE CONFORMS VESICLES,

2625
02:03:51,560 --> 02:03:52,120
TRAPPING PROTEINS.

2626
02:03:52,120 --> 02:03:53,880
SO, THOSE VESICLES HAVE BEEN

2627
02:03:53,880 --> 02:03:58,520
PROPOSED TO HAVE A LOT OF ROLES

2628
02:03:58,520 --> 02:04:00,280
IN BACTERIAL PHYSIOLOGY.

2629
02:04:00,280 --> 02:04:04,640
THEY ARE PROPOSED TO PLAY A ROLE

2630
02:04:04,640 --> 02:04:07,640
IN TRANSFER, IMMUNOMODULATION,

2631
02:04:07,640 --> 02:04:23,840
DELIVERY OF FACTORS, DELIVERY OF

2632
02:04:23,840 --> 02:04:24,520
ANTI-MICROBIALS.

2633
02:04:24,520 --> 02:04:30,240
AS I TOLD YOU BEFORE, THIS HAS

2634
02:04:30,240 --> 02:04:32,080
BEEN DESCRIBED IN THE '60s,

2635
02:04:32,080 --> 02:04:37,960
1960s, YOU CAN SEE IN THIS

2636
02:04:37,960 --> 02:04:42,720
IMAGE, THEY WERE HAVING A LOT OF

2637
02:04:42,720 --> 02:04:43,560
INTEREST, FINDING A GOOD

2638
02:04:43,560 --> 02:04:44,840
MECHANISM TO UNDERSTAND HOW

2639
02:04:44,840 --> 02:04:47,200
THESE THINGS ARE MADE.

2640
02:04:47,200 --> 02:04:52,000
THAT LED TO THE CONTROVERSY IN

2641
02:04:52,000 --> 02:05:00,760
THE FIELD, REAL THINGS,

2642
02:05:00,760 --> 02:05:02,600
MICROSCOPY, TODAY 50% OF

2643
02:05:02,600 --> 02:05:03,720
MICROBIOLOGISTS BELIEVE THESE

2644
02:05:03,720 --> 02:05:07,040
ARE REAL THINGS, THE OTHER HALF

2645
02:05:07,040 --> 02:05:07,960
THINGS IT'S ARTIFACTS.

2646
02:05:07,960 --> 02:05:13,880
SO WHAT DO WE KNOW ABOUT THE

2647
02:05:13,880 --> 02:05:17,640
MECHANISMS OF HOW THE BACTERIAL

2648
02:05:17,640 --> 02:05:23,800
VESICLES ARE FORMED, HOW MUCH IS

2649
02:05:23,800 --> 02:05:24,000
KNOWN.

2650
02:05:24,000 --> 02:05:29,640
IN THE '80s, IT WAS PROPOSED

2651
02:05:29,640 --> 02:05:34,120
THAT THERE WAS SOME PEPTO

2652
02:05:34,120 --> 02:05:37,280
GLYCANS, OUTER MEMBRANE, A BASIC

2653
02:05:37,280 --> 02:05:37,840
MECHANISM.

2654
02:05:37,840 --> 02:05:40,840
IF YOU WONDER HOW WE LEARN IN 40

2655
02:05:40,840 --> 02:05:41,840
YEARS OF RESEARCH, UNFORTUNATELY

2656
02:05:41,840 --> 02:05:44,080
THE ONLY THING WE'VE LEARNED IS

2657
02:05:44,080 --> 02:05:45,120
TO MAKE BETTER DRAWINGS BECAUSE

2658
02:05:45,120 --> 02:05:45,880
IT'S THE SAME.

2659
02:05:45,880 --> 02:05:48,720
THIS IS FROM THE LAST REVIEW.

2660
02:05:48,720 --> 02:05:50,280
AS YOU CAN SEE HERE THERE'S NOT

2661
02:05:50,280 --> 02:05:55,000
MUCH MORE INFORMATION.

2662
02:05:55,000 --> 02:05:59,000
SOMEHOW OUTER MEMBRANE IS

2663
02:05:59,000 --> 02:05:59,240
DETACHED.

2664
02:05:59,240 --> 02:06:01,840
THAT'S WHERE WE ARE NOW.

2665
02:06:01,840 --> 02:06:03,720
SOME MECHANISMS HAVE BEEN

2666
02:06:03,720 --> 02:06:08,600
PROPOSED IN DIFFERENT BACTERIA,

2667
02:06:08,600 --> 02:06:10,360
BUT NOT UNIVERSAL.

2668
02:06:10,360 --> 02:06:14,480
PEOPLE THINK MAYBE THOSE 

2669
02:06:14,480 --> 02:06:18,880
MECHANISMS ARE NOT REAL BECAUSE

2670
02:06:18,880 --> 02:06:21,800
ALL INVOLVE STABILIZATION.

2671
02:06:21,800 --> 02:06:24,640
SO DESPITE WE DON'T KNOW MUCH OF

2672
02:06:24,640 --> 02:06:28,120
HOW THEY ARE MADE, A LOT OF

2673
02:06:28,120 --> 02:06:30,200
PAPERS TALKING ABOUT ROLES OF

2674
02:06:30,200 --> 02:06:34,520
ALL THIS IN THIS CASE I'M GOING

2675
02:06:34,520 --> 02:06:35,960
TO TALK ABOUT BACTEROIDES.

2676
02:06:35,960 --> 02:06:38,520
IN THE MICROBIOME THESE ARE

2677
02:06:38,520 --> 02:06:53,840
FOUND TO HAVE DIFFERENT ROLES 

2678
02:06:53,840 --> 02:06:56,440
FROM PROTECTION TO

2679
02:06:56,440 --> 02:06:58,040
POLYSACCHARIDES.

2680
02:06:58,040 --> 02:07:03,040
ALL THOSE PAPERS HAVE USED

2681
02:07:03,040 --> 02:07:05,680
VESICLES, NOBODY KNOWS HOW MANY

2682
02:07:05,680 --> 02:07:08,640
ARE PRODUCED, ALSO BACTERIA HAS

2683
02:07:08,640 --> 02:07:09,840
BEEN GROWN AT 37 DEGREES,

2684
02:07:09,840 --> 02:07:11,120
WHATEVER TEMPERATURE THEY ARE

2685
02:07:11,120 --> 02:07:13,440
USING, WE DON'T KNOW REALLY HOW

2686
02:07:13,440 --> 02:07:16,600
MUCH THAT REALLY REFLECTS THE

2687
02:07:16,600 --> 02:07:16,880
COMPOSITION.

2688
02:07:16,880 --> 02:07:18,800
THAT'S WHAT WE WANT TO TRY TO

2689
02:07:18,800 --> 02:07:25,720
SHOW YOU TODAY. 

2690
02:07:25,720 --> 02:07:30,840
SO, BACTEROIDES ARE MEMBERS OF

2691
02:07:30,840 --> 02:07:32,160
THE MICROBIOME AND PRODUCE THIS,

2692
02:07:32,160 --> 02:07:34,480
IT'S REALLY A GOOD MODEL TO

2693
02:07:34,480 --> 02:07:37,800
INVESTIGATE HOW THESE THINGS ARE

2694
02:07:37,800 --> 02:07:38,000
MADE.

2695
02:07:38,000 --> 02:07:40,760
THE FIRST THING WE HAVE DONE

2696
02:07:40,760 --> 02:07:46,120
SEVERAL YEARS AGO WAS TO

2697
02:07:46,120 --> 02:07:46,760
CHARACTERIZE PROTEINS PRESENT

2698
02:07:46,760 --> 02:07:56,720
THERE AND COMPARE TO PROTEINS IN

2699
02:07:56,720 --> 02:07:58,040
THE OUTER MEMBRANE.

2700
02:07:58,040 --> 02:07:59,720
THE POSITION OF OUTER MEMBRANE

2701
02:07:59,720 --> 02:08:01,440
IS COMPLETELY DIFFERENT.

2702
02:08:01,440 --> 02:08:05,640
THERE'S A PROCESSER OF

2703
02:08:05,640 --> 02:08:05,920
SELECTION.

2704
02:08:05,920 --> 02:08:10,200
SOME PROTEINS CHOSEN, FOR 

2705
02:08:10,200 --> 02:08:13,640
EXAMPLE, YOU CAN SEE SOME

2706
02:08:13,640 --> 02:08:16,640
PROTEINS NOT GOING TO THE OMV.

2707
02:08:16,640 --> 02:08:18,520
FOR EXAMPLE, THIS PROTEIN.

2708
02:08:18,520 --> 02:08:26,040
THIS IS TELLING US A CLEAR

2709
02:08:26,040 --> 02:08:27,440
PROCESS HERE.

2710
02:08:27,440 --> 02:08:28,480
THE SECOND THING WE REALLY FOUND

2711
02:08:28,480 --> 02:08:30,640
THAT WE WERE NOT EXPECTING WAS

2712
02:08:30,640 --> 02:08:41,920
TO FIND A LOT OF HYDRO LYTIC 

2713
02:08:41,920 --> 02:08:42,200
ENZYMES.

2714
02:08:42,200 --> 02:08:49,000
THERE ARE DIFFERENT ENZYMES 

2715
02:08:49,000 --> 02:08:50,120
INVOLVED IN DEGRADATION, TRUE

2716
02:08:50,120 --> 02:08:51,240
FOR BACTEROIDES.

2717
02:08:51,240 --> 02:08:52,640
THESE ARE SOMETHING THE BACTERIA

2718
02:08:52,640 --> 02:08:58,960
IS TRYING TO DO WITH PURPOSE. 

2719
02:08:58,960 --> 02:09:04,160
WE VALIDATED THE PROTEOMIC DATA

2720
02:09:04,160 --> 02:09:04,840
BY WESTERN BLOT.

2721
02:09:04,840 --> 02:09:07,400
WE SEE MOST OF THE PROTEINS

2722
02:09:07,400 --> 02:09:13,200
LOCALIZE IN THE OUTER MEMBRANE.

2723
02:09:13,200 --> 02:09:15,840
IF YOU TAKE ANOTHER PROTEIN IN

2724
02:09:15,840 --> 02:09:17,720
THE ANALYSIS, ENRICHED IN OUTER

2725
02:09:17,720 --> 02:09:19,560
MEMBRANE, DOESN'T GO TO ALL

2726
02:09:19,560 --> 02:09:22,480
THIS.  HERE WE HAVE ANOTHER

2727
02:09:22,480 --> 02:09:24,440
BATCH OF MARKERS, NIECE ARE

2728
02:09:24,440 --> 02:09:26,440
OMVs, ALWAYS SOMETHING IN THE

2729
02:09:26,440 --> 02:09:30,040
MEMBRANE BECAUSE PROTEIN HAS TO

2730
02:09:30,040 --> 02:09:30,960
BE IN THE MEMBRANE.

2731
02:09:30,960 --> 02:09:32,520
AND THEN WE HAVE PROTEINS HERE

2732
02:09:32,520 --> 02:09:36,960
THAT ARE IN THE OUTER MEMBRANE,

2733
02:09:36,960 --> 02:09:40,200
EXCLUDED FROM THE VESICLES.

2734
02:09:40,200 --> 02:09:48,080
AND HERE EXAMPLE OF WHAT ARE

2735
02:09:48,080 --> 02:09:51,720
THOSE FOUND, ALL OF THOSE ARE

2736
02:09:51,720 --> 02:09:59,840
LIPOPROTEINS, SUPPOSED TO BE

2737
02:09:59,840 --> 02:10:01,440
LOCALIZED INTO MEMBRANES.

2738
02:10:01,440 --> 02:10:09,720
MANY OF THESE HYDROLASES, THESE

2739
02:10:09,720 --> 02:10:17,720
ARE PROTEINS ENCODED USUALLY IN

2740
02:10:17,720 --> 02:10:21,880
ONE, AND THEY HAVE SEVERAL

2741
02:10:21,880 --> 02:10:26,040
HYDROLASES, A CHANNEL ALLOWS THE

2742
02:10:26,040 --> 02:10:30,320
POLYSACCHARIDES TO BE IMPORTED.

2743
02:10:30,320 --> 02:10:33,960
SO MANY PROTEINS THAT WE FIND IN

2744
02:10:33,960 --> 02:10:36,440
ALL THESE ARE ACTUALLY PART OF

2745
02:10:36,440 --> 02:10:36,640
THIS.

2746
02:10:36,640 --> 02:10:47,400
NEE WE A LOT OF LIPOPROTEINS.

2747
02:10:47,400 --> 02:10:51,960
THIS IS VERY IMPORTANT TO

2748
02:10:51,960 --> 02:10:54,520
CONSIDER THAT THE PULs

2749
02:10:54,520 --> 02:11:02,560
CONSTITUTE 20% OF GENOME OF

2750
02:11:02,560 --> 02:11:03,800
THESE BACTEROIDES.

2751
02:11:03,800 --> 02:11:12,680
HOW BACTERIA MANAGE TO DEGRADE

2752
02:11:12,680 --> 02:11:13,640
AS POLYSACCHARIDES.

2753
02:11:13,640 --> 02:11:20,040
AND ONE VERY INTERESTING WORK

2754
02:11:20,040 --> 02:11:21,200
PUBLISHED SHOWED THAT ONE

2755
02:11:21,200 --> 02:11:22,600
BACTERIUM CAN SUPPORT THE GROWTH

2756
02:11:22,600 --> 02:11:34,640
OF ANOTHER. 

2757
02:11:34,640 --> 02:11:38,840
OUTER MEMBRANE VESICLES, THE

2758
02:11:38,840 --> 02:11:40,480
OTHER BACTERIUM HAS LACTOSE, NOW

2759
02:11:40,480 --> 02:11:40,840
CAN GROW.

2760
02:11:40,840 --> 02:11:43,840
THIS IS NOT JUST ONE EXAMPLE SO

2761
02:11:43,840 --> 02:11:47,960
EACH OF THESE MEMBERS OF THE

2762
02:11:47,960 --> 02:11:48,880
MICROBIOME CAN PRODUCE ALL THESE

2763
02:11:48,880 --> 02:11:51,840
THAT CAN SUPPORT THE GROWTH OF

2764
02:11:51,840 --> 02:11:53,640
DIFFERENT ONES DEPENDING ON THE

2765
02:11:53,640 --> 02:11:54,640
CONDITION.

2766
02:11:54,640 --> 02:11:58,520
IT'S A COLLABORATION.

2767
02:11:58,520 --> 02:12:02,480
AND I WOULD PROPOSE VESICLES ARE

2768
02:12:02,480 --> 02:12:03,440
ACTUALLY PARTICLES.

2769
02:12:03,440 --> 02:12:09,760
NOW I WANT TO SHOW NO DATA BY

2770
02:12:09,760 --> 02:12:14,040
MARIANA IN MY LAB, TWO AIMS.

2771
02:12:14,040 --> 02:12:18,400
VISUALIZATION OF OUTER MEMBRANE

2772
02:12:18,400 --> 02:12:19,400
VESICLES EMPLOYING MARKERS, CAN

2773
02:12:19,400 --> 02:12:26,640
WE VISUALIZE THIS?

2774
02:12:26,640 --> 02:12:33,480
THEY NEED OXYGEN TO GROW,

2775
02:12:33,480 --> 02:12:34,240
BACTEROIDES IS ANAEROBIC

2776
02:12:34,240 --> 02:12:36,120
CONDITIONS, WE NEED TO GIVE SOME

2777
02:12:36,120 --> 02:12:37,520
TIME EXPOSED TO OXYGEN TO GROW,

2778
02:12:37,520 --> 02:12:39,640
THAT CAUSES SOME ISSUES TO THE

2779
02:12:39,640 --> 02:12:41,000
METABOLISM OF THE BACTERIUM.

2780
02:12:41,000 --> 02:12:43,080
BUT WE MANAGED TO GET GOOD DATA

2781
02:12:43,080 --> 02:12:44,120
ON THAT.

2782
02:12:44,120 --> 02:12:47,160
I'M GOING INTO MORE IN THE ROLE

2783
02:12:47,160 --> 02:12:50,640
OF THE OMV IN DEGRADATION OF

2784
02:12:50,640 --> 02:12:53,840
POLYSACCHARIDES.

2785
02:12:53,840 --> 02:13:00,000
IN THE FIRST IMAGE, YOU HAVE

2786
02:13:00,000 --> 02:13:03,080
INULINASE, ONE PROTEIN, A MARKER

2787
02:13:03,080 --> 02:13:04,520
WE FOUND, PROTEOMICS, AND THE

2788
02:13:04,520 --> 02:13:06,080
FIRST THING YOU CAN SEE IS WHERE

2789
02:13:06,080 --> 02:13:11,560
THE MARKERS GO TO THE OMVs ARE

2790
02:13:11,560 --> 02:13:14,880
FOUND IN PARTICULAR LOCI, THE 

2791
02:13:14,880 --> 02:13:20,320
ONES IN OUTER MEMBRANE, YOU CAN

2792
02:13:20,320 --> 02:13:24,200
SEE THE PROTEINS MOSTLY TO

2793
02:13:24,200 --> 02:13:24,400
OMVs.

2794
02:13:24,400 --> 02:13:26,040
IN THIS PARTICULAR SLIDE WE'RE

2795
02:13:26,040 --> 02:13:39,800
NOT SO HAPPY WITH OXYGEN.

2796
02:13:39,800 --> 02:13:42,200
ALLOW US TO SEE WHERE THIS FORM.

2797
02:13:42,200 --> 02:13:43,800
WE HAVE SEPARATE EXPRESSION,

2798
02:13:43,800 --> 02:13:45,240
WHAT HAPPENS WHEN WE CO-EXPRESS

2799
02:13:45,240 --> 02:13:46,520
THE TWO MARKERS?

2800
02:13:46,520 --> 02:13:50,800
THAT'S WHAT YOU CAN SEE HERE IN

2801
02:13:50,800 --> 02:13:52,920
GREEN, OUTER MEMBRANE VESICLE

2802
02:13:52,920 --> 02:13:54,880
MARKER, WE SEE VESICLES IN THIS

2803
02:13:54,880 --> 02:13:55,200
EXPERIMENT.

2804
02:13:55,200 --> 02:13:56,760
IN RED WE DON'T SEE ANY

2805
02:13:56,760 --> 02:13:57,440
VESICLES.

2806
02:13:57,440 --> 02:13:58,240
THAT'S OKAY.

2807
02:13:58,240 --> 02:14:00,040
THIS IS A MARKER OF THE

2808
02:14:00,040 --> 02:14:00,280
MEMBRANE.

2809
02:14:00,280 --> 02:14:05,960
WHAT YOU SEE IN THE IMAGE

2810
02:14:05,960 --> 02:14:09,400
COMBINED, BACTERIA HAS TWO

2811
02:14:09,400 --> 02:14:12,440
COLORS, OMVs ARE ONLY SHOWING

2812
02:14:12,440 --> 02:14:13,040
THE GREEN.

2813
02:14:13,040 --> 02:14:15,440
SO RECAPITULATING WHAT WE SAW ON

2814
02:14:15,440 --> 02:14:22,040
THE MASS SPEC, THIS PROTEIN

2815
02:14:22,040 --> 02:14:26,960
REALLY GOES TO OMVs IN THE

2816
02:14:26,960 --> 02:14:29,400
CELLS, STILL SHOWING PHENOTYPES.

2817
02:14:29,400 --> 02:14:32,520
SO THAT'S WHAT YOU EXPECT IF

2818
02:14:32,520 --> 02:14:33,720
OMVs ARE REAL BUT ANOTHER

2819
02:14:33,720 --> 02:14:44,600
POINT WOULD WHAT IF WE EXPRESS 

2820
02:14:44,600 --> 02:14:46,760
TWO DIFFERENT MARKERS OF OMVs?

2821
02:14:46,760 --> 02:14:49,920
WE HAVE TWO MARKERS.

2822
02:14:49,920 --> 02:14:50,960
PRETTY MUCH EVERY VESICLE THERE

2823
02:14:50,960 --> 02:14:54,960
IS SEEN BY THE TWO COLORS.

2824
02:14:54,960 --> 02:14:57,520
SO INDICATING THESE DOTS WE SEE

2825
02:14:57,520 --> 02:15:06,200
ARE REACTING TO BOTH OMV

2826
02:15:06,200 --> 02:15:08,600
MARKERS. 

2827
02:15:08,600 --> 02:15:09,840
SO REALLY THEY CO-LOCALIZE.

2828
02:15:09,840 --> 02:15:11,000
AND NOW WE'RE GOING TO SEE

2829
02:15:11,000 --> 02:15:12,440
MOVIES.

2830
02:15:12,440 --> 02:15:14,400
THIS IS VERY CHALLENGING BECAUSE

2831
02:15:14,400 --> 02:15:16,800
AGAIN OXYGEN WILL NOT ALLOW US

2832
02:15:16,800 --> 02:15:18,360
TO SEE A LOT.

2833
02:15:18,360 --> 02:15:21,080
YOU CAN SEE HERE THE VESICLES

2834
02:15:21,080 --> 02:15:23,200
COMING OUT WITH THE OMV MARKER,

2835
02:15:23,200 --> 02:15:25,040
WHERE IT'S NOT VISIBLE WITH

2836
02:15:25,040 --> 02:15:26,640
OUTER MEMBRANE MARKERS.

2837
02:15:26,640 --> 02:15:29,800
YOU CAN SEE VESICLE COMING OUT

2838
02:15:29,800 --> 02:15:33,200
OF THE CELL. 

2839
02:15:33,200 --> 02:15:36,960
AND WE HAVE ANOTHER IMAGE, THIS

2840
02:15:36,960 --> 02:15:38,520
HAS MOVEMENT THAT WE'RE GOING TO

2841
02:15:38,520 --> 02:15:38,760
CORRECT.

2842
02:15:38,760 --> 02:15:41,640
YOU CAN SEE AS WELL HERE VESICLE

2843
02:15:41,640 --> 02:15:43,960
COMING OUT OF THE CELL, NOT

2844
02:15:43,960 --> 02:15:46,640
VISIBLE IN THE RED CHANNEL, THE

2845
02:15:46,640 --> 02:15:48,520
OUTER MEMBRANE MARKER.

2846
02:15:48,520 --> 02:15:50,600
SO, THIS IS ACTUALLY THE FIRST

2847
02:15:50,600 --> 02:15:55,920
TIME THAT VESICLES CAN BE SEEN

2848
02:15:55,920 --> 02:15:59,360
BY LIVE MICROSCOPY.

2849
02:15:59,360 --> 02:16:01,640
NOW I'M GOING TO SWITCH GEARS

2850
02:16:01,640 --> 02:16:05,520
AND WE'RE GOING TO SEE HOW --

2851
02:16:05,520 --> 02:16:07,960
NOW THAT WE KNOW THESE ARE REAL,

2852
02:16:07,960 --> 02:16:09,800
THESE THINGS WE FOUND INITIALLY

2853
02:16:09,800 --> 02:16:12,760
IN THE MASS SPEC ACTUALLY WE CAN

2854
02:16:12,760 --> 02:16:16,160
SEE THEM AS WE EXPECT FOR THE

2855
02:16:16,160 --> 02:16:18,800
PROCESS, WE WONDER HOW DOES ALL

2856
02:16:18,800 --> 02:16:27,880
THIS CHANGE THE COMPOSITION 

2857
02:16:27,880 --> 02:16:28,120
CHANGE?

2858
02:16:28,120 --> 02:16:30,440
WE CULTURED BACTEROIDES, GROW IN

2859
02:16:30,440 --> 02:16:32,400
MINIMUM MEDIA ADDING DIFFERENT

2860
02:16:32,400 --> 02:16:32,800
POLYSACCHARIDES.

2861
02:16:32,800 --> 02:16:37,720
YOU CAN SEE FIRST ALREADY THE 

2862
02:16:37,720 --> 02:16:39,960
COMPOSITION CHANGES LIKE THIS

2863
02:16:39,960 --> 02:16:44,040
ONE LEVAN, HEPARIN.

2864
02:16:44,040 --> 02:16:45,320
DIFFERENT PROTEINS, MANNAN, THE

2865
02:16:45,320 --> 02:16:46,440
PRICE HERE IS MUCIN.

2866
02:16:46,440 --> 02:16:47,680
MAYBE IT'S NOT A SURPRISE.

2867
02:16:47,680 --> 02:16:49,720
WE DON'T HAVE MANY OF THESE,

2868
02:16:49,720 --> 02:16:55,160
THEY ARE MORE LIKE HAVING LESS

2869
02:16:55,160 --> 02:16:55,920
PROTEINS.

2870
02:16:55,920 --> 02:17:02,280
SO, IT'S NOT A PATHOGEN.

2871
02:17:02,280 --> 02:17:08,160
THEY CAN GROW BUT ARE NOT SO

2872
02:17:08,160 --> 02:17:08,840
HAPPY.

2873
02:17:08,840 --> 02:17:13,480
SO THEN WE DID PROTEOMICS FOR

2874
02:17:13,480 --> 02:17:13,920
THESE.

2875
02:17:13,920 --> 02:17:15,840
I'M GOING TO TRY TO EXPLAIN WITH

2876
02:17:15,840 --> 02:17:18,320
ONE OF THE CASES.

2877
02:17:18,320 --> 02:17:26,560
WE HAVE THE COMPOSITION OF THE

2878
02:17:26,560 --> 02:17:28,400
OMV, FOR THE DIFFERENT ONES.

2879
02:17:28,400 --> 02:17:31,760
IN RED THESE ARE ENRICHED TO

2880
02:17:31,760 --> 02:17:33,160
THIS PARTICULAR CONDITION.

2881
02:17:33,160 --> 02:17:35,480
THESE PROTEINS ARE PARTICULARLY

2882
02:17:35,480 --> 02:17:37,440
ENRICHED IN OMVs, A BATCH OF

2883
02:17:37,440 --> 02:17:42,520
PROTEINS MISSING PRESENT IN ALL 

2884
02:17:42,520 --> 02:17:46,000
THE OTHER CONDITIONS ABSENT IN

2885
02:17:46,000 --> 02:17:47,600
LEVAN, SHOWING THE COMPOSITION

2886
02:17:47,600 --> 02:17:49,720
IS DIFFERENT, A BUNCH OF

2887
02:17:49,720 --> 02:17:50,480
PROTEINS ARE ENRICHED IN OMVs,

2888
02:17:50,480 --> 02:17:52,240
WE WANT TO SEE WHERE THEY ARE,

2889
02:17:52,240 --> 02:18:02,720
WELL, HAVING RED HERE, THESE ARE

2890
02:18:02,720 --> 02:18:03,040
LIPOPROTEINS.

2891
02:18:03,040 --> 02:18:08,480
WHEN YOU WANT TO SEE A GOOD 

2892
02:18:08,480 --> 02:18:11,320
MATCH WITH PREVIOUS WORK, DATA

2893
02:18:11,320 --> 02:18:16,320
SHOWING THESE WERE INDUCED, NOW

2894
02:18:16,320 --> 02:18:18,600
WE SHOW EXPRESSION, PROTEINS

2895
02:18:18,600 --> 02:18:21,040
ENRICHED TO OUTER MEMBRANE

2896
02:18:21,040 --> 02:18:21,320
VESICLES.

2897
02:18:21,320 --> 02:18:23,840
I'M TRYING TO SHOW ALL THE DATA

2898
02:18:23,840 --> 02:18:24,120
COMPARED.

2899
02:18:24,120 --> 02:18:25,880
AS YOU CAN SEE FOR EACH

2900
02:18:25,880 --> 02:18:33,640
PARTICULAR NUTRIENT THERE'S A 

2901
02:18:33,640 --> 02:18:34,520
GROUP OF HYDROLASES ENRICHED,

2902
02:18:34,520 --> 02:18:45,520
MORE IN MANNOSE THAN ANY OTHER 

2903
02:18:45,520 --> 02:18:46,480
CONDITION.

2904
02:18:46,480 --> 02:18:51,840
HEPARIN GLUCOSE, HYALURONIC

2905
02:18:51,840 --> 02:18:52,640
ACID, DIFFERENT GROUPS.

2906
02:18:52,640 --> 02:18:55,960
I DON'T KNOW, WE TRY TO AVOID

2907
02:18:55,960 --> 02:18:58,000
USING OMVs WITH MUCIN.

2908
02:18:58,000 --> 02:19:01,360
MOST THINGS ARE MISSING, A FEW

2909
02:19:01,360 --> 02:19:01,960
STUFF THERE, WHAT ALLOWS

2910
02:19:01,960 --> 02:19:04,480
BACTERIA TO GROW IN MUCIN, NOT

2911
02:19:04,480 --> 02:19:06,640
WHAT THEY REALLY WANT TO DO IN

2912
02:19:06,640 --> 02:19:08,120
THIS CASE.

2913
02:19:08,120 --> 02:19:10,920
ANOTHER POSSIBLE INTERPRETATION

2914
02:19:10,920 --> 02:19:12,960
WHERE MANNOSE, HEPARIN,

2915
02:19:12,960 --> 02:19:18,240
HYALURONIC ACID AND STARCH ARE

2916
02:19:18,240 --> 02:19:20,840
ALL SIMPLE POLYSACCHARIDES, THEY

2917
02:19:20,840 --> 02:19:23,120
HAVE TWO DIFFERENT SUGARS WHICH

2918
02:19:23,120 --> 02:19:26,640
FAVOR ACTION OF PARTICULAR GENE,

2919
02:19:26,640 --> 02:19:29,880
THE MUCIN IS MATCHING, SO REALLY

2920
02:19:29,880 --> 02:19:31,440
THAT'S ALSO NOT SENSING THE

2921
02:19:31,440 --> 02:19:33,200
SIGNAL NOT WORKING AS WELL.

2922
02:19:33,200 --> 02:19:36,560
AND THIS IS ANOTHER WAY TO

2923
02:19:36,560 --> 02:19:40,720
PRESENT IT IN WHICH HERE IS THE

2924
02:19:40,720 --> 02:19:42,120
PLOT SHOWING PROTEINS ENRICHED

2925
02:19:42,120 --> 02:19:44,160
FOR EACH, TO THE RIGHT, AND

2926
02:19:44,160 --> 02:19:46,360
PROTEINS ENRICHED IN THE OUTER

2927
02:19:46,360 --> 02:19:51,080
MEMBRANES TO THE LEFT.

2928
02:19:51,080 --> 02:19:53,000
RED PROTEINS ARE ALL

2929
02:19:53,000 --> 02:19:54,840
LIPOPROTEINS THAT CONTAIN A

2930
02:19:54,840 --> 02:19:57,560
SIGNAL THAT I'M GOING TO SHOW

2931
02:19:57,560 --> 02:20:00,720
YOU IN A SECOND, IN THE LEFT

2932
02:20:00,720 --> 02:20:08,200
WHAT WE GET HERE IN BLUE THESE

2933
02:20:08,200 --> 02:20:14,120
ARE MEMBRANE PROTEINS, IN YELLOW

2934
02:20:14,120 --> 02:20:15,240
THESE ARE LIPOPROTEINS THAT

2935
02:20:15,240 --> 02:20:16,200
DON'T HAVE THE SIGNAL THAT I'M

2936
02:20:16,200 --> 02:20:18,160
GOING TO SHOW YOU IN A SECOND.

2937
02:20:18,160 --> 02:20:20,640
ALL THESE PROTEINS IN RED NOT

2938
02:20:20,640 --> 02:20:28,360
ONLY HAVE THE FUNCTION OF

2939
02:20:28,360 --> 02:20:29,920
LIPOPROTEINS, THEY CONTAIN A

2940
02:20:29,920 --> 02:20:41,680
SIGNAL THAT TARGETS TO OMVs.

2941
02:20:41,680 --> 02:20:43,320
THERE ARE NEGATIVELY CHARGED

2942
02:20:43,320 --> 02:20:46,880
AMINO ACID, EVIDENCE TO REMOVE

2943
02:20:46,880 --> 02:20:48,080
THESE MOTIF, THESE PROTEINS WILL

2944
02:20:48,080 --> 02:20:50,000
NOT GO TO THE OMV ANYMORE.

2945
02:20:50,000 --> 02:20:50,920
PROTEINS THAT REMAIN IN THE

2946
02:20:50,920 --> 02:20:53,240
CELLS DON'T HAVE THAT SIGNAL.

2947
02:20:53,240 --> 02:20:58,480
SO CLEARLY HERE THIS IS PART OF

2948
02:20:58,480 --> 02:20:59,840
THE PROCESS.

2949
02:20:59,840 --> 02:21:01,240
VERY DIRECTED PROCESS WITH A

2950
02:21:01,240 --> 02:21:02,360
CLEAR GOAL.

2951
02:21:02,360 --> 02:21:03,720
I'M GOING TO TRY TO SUMMARIZE

2952
02:21:03,720 --> 02:21:07,440
WHAT I JUST TOLD YOU IN ONE

2953
02:21:07,440 --> 02:21:07,800
FIGURE.

2954
02:21:07,800 --> 02:21:10,080
WHAT WE THINK IS HAPPENING IN

2955
02:21:10,080 --> 02:21:16,480
THE PRESENCE OF SPECIFIC

2956
02:21:16,480 --> 02:21:21,600
POLYSACCHARIDES BACTERIA WILL

2957
02:21:21,600 --> 02:21:22,120
SENSE, FRUCTOSE, HEPARIN,

2958
02:21:22,120 --> 02:21:23,720
INDUCED SPECIFIC POOLS WHICH

2959
02:21:23,720 --> 02:21:25,800
ALSO ACTUALLY KNOWN THIS PART

2960
02:21:25,800 --> 02:21:32,520
HAS BEEN SHOWN BEFORE BY OTHER

2961
02:21:32,520 --> 02:21:33,040
GROUPS.

2962
02:21:33,040 --> 02:21:34,560
LIPOPROTEINS THAT ARE HERE THEY

2963
02:21:34,560 --> 02:21:37,360
ARE GOING INTO THE MEMBRANE,

2964
02:21:37,360 --> 02:21:40,480
SOMEHOW MAKE IT ACROSS THE OUTER

2965
02:21:40,480 --> 02:21:41,240
MEMBRANE.

2966
02:21:41,240 --> 02:21:42,880
EXPOSED TO THE SURFACE.

2967
02:21:42,880 --> 02:21:46,240
AND THEY ARE RECRUITING SPECIFIC

2968
02:21:46,240 --> 02:21:48,720
FOCI, WHAT YOU SEE HERE, OMB IS

2969
02:21:48,720 --> 02:21:50,440
GOING TO BE GENERATED, VERY

2970
02:21:50,440 --> 02:21:51,920
DYNAMIC, SOME IMAGES WE CAN SEE

2971
02:21:51,920 --> 02:21:54,560
THEY ARE MOVING AROUND.

2972
02:21:54,560 --> 02:21:57,240
SO THIS PROCESS OF TRANSLOCATION

2973
02:21:57,240 --> 02:22:03,520
IS MEDIATED BY LESS SIGNAL,

2974
02:22:03,520 --> 02:22:04,600
COMPOSED BY NEGATIVE CHARGE

2975
02:22:04,600 --> 02:22:07,640
AMINO ACIDS. 

2976
02:22:07,640 --> 02:22:10,640
WHAT HAPPENED THEN IS THE

2977
02:22:10,640 --> 02:22:16,920
MECHANISM, NOW WHAT ARE THE

2978
02:22:16,920 --> 02:22:18,760
FACTORS THAT ARE RECRUITING TO

2979
02:22:18,760 --> 02:22:22,480
THE FOCI, QUESTIONS WE WANT TO

2980
02:22:22,480 --> 02:22:23,280
ANSWER RIGHT NOW.

2981
02:22:23,280 --> 02:22:24,840
VESICLES ARE FORMED.

2982
02:22:24,840 --> 02:22:30,000
YOU CAN SEE WITH SPECIFIC

2983
02:22:30,000 --> 02:22:30,560
MARKERS.

2984
02:22:30,560 --> 02:22:32,040
OMV, THE COMPOSITION, DIFFERENT

2985
02:22:32,040 --> 02:22:40,640
MARKERS IN THE CELLS. 

2986
02:22:40,640 --> 02:22:55,680
NOW A LOT GLYCOSIDIC, DEGRADE

2987
02:22:55,680 --> 02:22:56,040
POLYSACCHARIDE.

2988
02:22:56,040 --> 02:22:58,520
ALSO YOU'RE GOING TO HAVE A TALK

2989
02:22:58,520 --> 02:23:01,160
LATER SHOWING PATHOGENS CAN ALSO

2990
02:23:01,160 --> 02:23:04,960
BENEFIT BY ACTIVITY OF THE OUTER

2991
02:23:04,960 --> 02:23:06,840
MEMBRANE VESICLES FROM

2992
02:23:06,840 --> 02:23:07,320
BACTEROIDES.

2993
02:23:07,320 --> 02:23:09,880
TAKEHOME MESSAGES I HOPE YOU

2994
02:23:09,880 --> 02:23:13,080
WILL REMEMBER AFTER THIS IS THAT

2995
02:23:13,080 --> 02:23:16,440
ALL THESE, THE FIRST TIME WE

2996
02:23:16,440 --> 02:23:22,520
HAVE IT PROVED IT'S NOT AN

2997
02:23:22,520 --> 02:23:25,880
ARTIFACT. 

2998
02:23:25,880 --> 02:23:33,560
HIGHLY ORCHESTRATED PROCESS. 

2999
02:23:33,560 --> 02:23:44,200
BACTEROIDES PACKS 

3000
02:23:44,200 --> 02:23:51,480
GLYCOSYLHYDROLASE. 

3001
02:23:51,480 --> 02:23:58,440
I THINK THAT BASICALLY OUR WORK 

3002
02:23:58,440 --> 02:24:01,760
AND THE GROUP, OMVs CONTRIBUTE

3003
02:24:01,760 --> 02:24:02,960
TO GUT HOMEOSTASIS.

3004
02:24:02,960 --> 02:24:06,440
THE ONLY THING LEFT IS TO THANK

3005
02:24:06,440 --> 02:24:25,520
THE PEOPLE IN MY GROUP.

3006
02:24:25,520 --> 02:24:28,920
THE WORK IS BASED ON TWO

3007
02:24:28,920 --> 02:24:33,960
PREVIOUS POSTDOCS IN MY LAB.

3008
02:24:33,960 --> 02:24:35,600
AND OUR COLLABORATOR FOR

3009
02:24:35,600 --> 02:24:37,760
PROTEOMICS, AND I THANK YOU FOR

3010
02:24:37,760 --> 02:24:39,760
YOUR ATTENTION.

3011
02:24:39,760 --> 02:24:40,920
>> THANK YOU.

3012
02:24:40,920 --> 02:24:42,400
WE GET QUESTIONS COMING FROM THE

3013
02:24:42,400 --> 02:24:42,960
ONLINE GROUP.

3014
02:24:42,960 --> 02:24:46,560
DO YOU SEE EVIDENCE WHERE YOU

3015
02:24:46,560 --> 02:24:48,360
MIX BACTERIAL CULTURES OR

3016
02:24:48,360 --> 02:24:50,240
SPECIES WITH OTHER BACTERIA OR

3017
02:24:50,240 --> 02:24:51,440
HOST CELLS?

3018
02:24:51,440 --> 02:24:56,440
>> ACTUALLY I WOULD LIKE TO TELL

3019
02:24:56,440 --> 02:25:01,640
YOU NO BUT YES.

3020
02:25:01,640 --> 02:25:06,560
WE SEE TIMES BACTERIA WITH

3021
02:25:06,560 --> 02:25:08,400
VESICLES, FROM ONE BACTERIUM TO

3022
02:25:08,400 --> 02:25:09,960
ANOTHER SO I DON'T KNOW IF

3023
02:25:09,960 --> 02:25:11,360
THAT'S ARTIFACT OR REALLY

3024
02:25:11,360 --> 02:25:11,760
HAPPENING.

3025
02:25:11,760 --> 02:25:18,560
SOME PEOPLE HAVE FOUND EVIDENCE

3026
02:25:18,560 --> 02:25:28,720
IN OTHER BACTERIA, ONE BACTERIUM

3027
02:25:28,720 --> 02:25:29,440
CAN PROVIDE.

3028
02:25:29,440 --> 02:25:33,360
THIS IS EVEN MORE MYSTERIOUS

3029
02:25:33,360 --> 02:25:42,600
THAN WHAT WE'RE ALREADY DOING.

3030
02:25:42,600 --> 02:25:50,640
>> SETH AND WARREN?

3031
02:25:50,640 --> 02:25:52,600
>> MARIO, NICE TO MEET YOU.

3032
02:25:52,600 --> 02:25:54,880
I'M SETH. 

3033
02:25:54,880 --> 02:25:55,960
THANKS FOR THE ACKNOWLEDGMENTS.

3034
02:25:55,960 --> 02:25:58,720
I'M GOING TO ASK QUESTIONS

3035
02:25:58,720 --> 02:26:00,320
BECAUSE I WONDERED FOR A WHILE.

3036
02:26:00,320 --> 02:26:04,440
I'LL ASK A QUESTION TO AN EXPERT

3037
02:26:04,440 --> 02:26:06,640
IN OMVs, HOW FAR DO THEY GO?

3038
02:26:06,640 --> 02:26:09,440
AND DO YOU THINK THEY HAVE

3039
02:26:09,440 --> 02:26:09,840
SPECIAL BIOPHYSICAL

3040
02:26:09,840 --> 02:26:15,200
CHARACTERISTICS THAT ALLOW THEM

3041
02:26:15,200 --> 02:26:18,080
TO TRAVEL THROUGH PERHAPS MUCUS?

3042
02:26:18,080 --> 02:26:19,640
>> THERE IS WORK SHOWING THAT

3043
02:26:19,640 --> 02:26:22,560
THEY CAN GO FAR, ONE OF THE

3044
02:26:22,560 --> 02:26:24,560
ADVANTAGES OF PACKING HYDROLASES

3045
02:26:24,560 --> 02:26:25,120
IN OMV.

3046
02:26:25,120 --> 02:26:33,600
WHY PUT THEM IN OMVs?

3047
02:26:33,600 --> 02:26:35,240
WELL, YOU ONLY CARE FOR YOU, IT

3048
02:26:35,240 --> 02:26:37,440
WOULD BE EFFICIENT TO GET ONLY

3049
02:26:37,440 --> 02:26:39,600
AT THE MEMBRANE, I CAN ONLY

3050
02:26:39,600 --> 02:26:41,040
CATCH WHATEVER COMES NEXT TO ME.

3051
02:26:41,040 --> 02:26:46,760
WHEREAS IF I PUT AN OMV THERE,

3052
02:26:46,760 --> 02:26:50,560
OMV CAN DIFFUSE, FIND

3053
02:26:50,560 --> 02:26:55,720
POLYSACCHARIDES, DEGRADE THEM,

3054
02:26:55,720 --> 02:26:58,040
THE SACCHARIDES, SUGARS WILL

3055
02:26:58,040 --> 02:27:00,040
ACTUALLY DIFFUSE MORE.

3056
02:27:00,040 --> 02:27:07,640
HIGHLY DIFFUSIBLE IN SOME CASES 

3057
02:27:07,640 --> 02:27:09,880
PROBABLY OR MORE PATHOGENIC

3058
02:27:09,880 --> 02:27:11,040
BACTEROIDES CAN PROBABLY

3059
02:27:11,040 --> 02:27:13,120
PENETRATE AND REACH FARTHER

3060
02:27:13,120 --> 02:27:14,040
YEAH.

3061
02:27:14,040 --> 02:27:16,320
THAT, THAT'S ONE OF THE KNOWN

3062
02:27:16,320 --> 02:27:17,240
ADVANTAGES OF THE OMVs, THEY

3063
02:27:17,240 --> 02:27:20,400
CAN GO FAR, THEY ARE VERY SMALL,

3064
02:27:20,400 --> 02:27:21,880
THEY CAN GET WHERE BACTERIA

3065
02:27:21,880 --> 02:27:23,040
CANNOT GET.

3066
02:27:23,040 --> 02:27:24,880
WE TRIED TO DO EXPERIMENTS ON

3067
02:27:24,880 --> 02:27:25,640
ANIMALS, STILL CHALLENGING FOR

3068
02:27:25,640 --> 02:27:26,800
US NOW.

3069
02:27:26,800 --> 02:27:28,840
WE NOW CAN SEE THEM AND WE HOPE

3070
02:27:28,840 --> 02:27:32,880
TO BE ABLE TO GO INTO ANIMAL

3071
02:27:32,880 --> 02:27:35,040
STUDIES AND CAN SEE THESE OMVs

3072
02:27:35,040 --> 02:27:39,360
TO SEE WHERE THEY GO.

3073
02:27:39,360 --> 02:27:40,880
WE TRY WITH ORGANOIDS AS WELL.

3074
02:27:40,880 --> 02:27:42,840
NOW THAT WE HAVE THE TOOLS THESE

3075
02:27:42,840 --> 02:27:43,840
ARE QUESTIONS WE WANT TO ANSWER

3076
02:27:43,840 --> 02:27:47,920
BUT IT WILL TAKE A WHILE.

3077
02:27:47,920 --> 02:27:54,560
>> THANKS FOR THAT COOL SCIENCE

3078
02:27:54,560 --> 02:27:57,520
CUREOUTS  CURIOUS WHETHER OR NOT

3079
02:27:57,520 --> 02:27:58,640
UP LOOKED AT METABOLITES IN THE

3080
02:27:58,640 --> 02:28:00,160
OMVs BECAUSE THAT COULD BE

3081
02:28:00,160 --> 02:28:02,960
ANOTHER WAY THEY COULD SIGNAL

3082
02:28:02,960 --> 02:28:06,080
AND BE VALUABLE AS CARRIERS.

3083
02:28:06,080 --> 02:28:09,080
>> WE HAVEN'T DONE IT.

3084
02:28:09,080 --> 02:28:10,640
THE MAIN REASON WHY, I THINK IT

3085
02:28:10,640 --> 02:28:12,800
WOULD CHANGE SO MUCH COMPOSITION

3086
02:28:12,800 --> 02:28:14,320
BASED ON HOW WE GROW THE

3087
02:28:14,320 --> 02:28:14,640
BACTERIA.

3088
02:28:14,640 --> 02:28:16,240
I DON'T KNOW IF THEY ARE GOING

3089
02:28:16,240 --> 02:28:19,600
TO REFLECT WHAT REALLY HAPPENS

3090
02:28:19,600 --> 02:28:23,440
IN THE ANIMAL MODELS. 

3091
02:28:23,440 --> 02:28:24,720
OR IN THE HUMAN.

3092
02:28:24,720 --> 02:28:28,160
WE CAN AT LEAST START AND SEE IF

3093
02:28:28,160 --> 02:28:31,040
THERE'S SOMETHING DIFFERENT THAN

3094
02:28:31,040 --> 02:28:32,080
THE OTHER COMPONENTS.

3095
02:28:32,080 --> 02:28:33,360
MY CONCERN IS THIS.

3096
02:28:33,360 --> 02:28:38,200
SOME OF THE WORK HAS BEEN DONE

3097
02:28:38,200 --> 02:28:42,440
WITH ALL THESE AND IMMUNOLOGY,

3098
02:28:42,440 --> 02:28:44,560
RANDOM AMOUNTS, I DON'T KNOW HOW

3099
02:28:44,560 --> 02:28:46,600
MUCH THEIR EFFECT, NOW WE KNOW,

3100
02:28:46,600 --> 02:28:50,200
DEPENDING HOW YOU GROW OMVs

3101
02:28:50,200 --> 02:28:52,000
WITH A COMPLETELY DIFFERENT

3102
02:28:52,000 --> 02:28:53,280
COMPOSITION, YEAH, SOMETHING WE

3103
02:28:53,280 --> 02:28:55,760
CAN HOPEFULLY ADDRESS IN THE

3104
02:28:55,760 --> 02:28:57,400
FUTURE IN MORE REALISTIC

3105
02:28:57,400 --> 02:28:58,400
CONDITIONS OF GROWTH.

3106
02:28:58,400 --> 02:29:00,840
>> ONE MORE QUESTION FROM THE

3107
02:29:00,840 --> 02:29:01,400
ONLINE.

3108
02:29:01,400 --> 02:29:03,400
I DON'T WANT THEM TO FEEL

3109
02:29:03,400 --> 02:29:04,040
EXCLUDED.

3110
02:29:04,040 --> 02:29:07,520
WE HAVE A BUNCH OF QUESTIONS SO

3111
02:29:07,520 --> 02:29:08,520
PLEASE CONTINUE TO HAVE

3112
02:29:08,520 --> 02:29:10,760
QUESTIONS, WE CAN ANSWER OFFLINE

3113
02:29:10,760 --> 02:29:12,240
AS WELL.

3114
02:29:12,240 --> 02:29:15,040
HELEN DUKE, QUESTION IS ARE YOU

3115
02:29:15,040 --> 02:29:18,840
ABLE TO PROBE GENOMES

3116
02:29:18,840 --> 02:29:20,760
TRANSCRIPTOMES USING GENETIC

3117
02:29:20,760 --> 02:29:23,840
MARKERS OR CHANGE IN SPECIFIC

3118
02:29:23,840 --> 02:29:24,600
TRANSCRIPTIONAL ACTIVITIES?

3119
02:29:24,600 --> 02:29:29,600
>> IF I'M ABLE TO PROBE GENOMES?

3120
02:29:29,600 --> 02:29:31,120
USING EPIGENETIC MARKER OR

3121
02:29:31,120 --> 02:29:32,360
CHANGE SPECIFIC -- WE DON'T KNOW

3122
02:29:32,360 --> 02:29:32,640
YET.

3123
02:29:32,640 --> 02:29:34,360
WE HOPE IN THE FUTURE ONCE WE

3124
02:29:34,360 --> 02:29:40,280
KNOW A LITTLE BIT MORE. 

3125
02:29:40,280 --> 02:29:43,680
THAT'S THE BIG QUESTION FOR ME.

3126
02:29:43,680 --> 02:29:46,240
I'M NOT A MICROBIOME PERSON, I'M

3127
02:29:46,240 --> 02:29:47,240
A BACTERIA PERSON.

3128
02:29:47,240 --> 02:29:54,160
SO NO, WE ONLY HAVE A CARGO.

3129
02:29:54,160 --> 02:29:57,040
WE REALLY WANT TO KNOW NOW TO

3130
02:29:57,040 --> 02:29:57,640
INVESTIGATE MACHINERY AND

3131
02:29:57,640 --> 02:29:58,640
HOPEFULLY MAY BE ABLE TO ANSWER

3132
02:29:58,640 --> 02:30:01,280
QUESTIONS, IF I INTERPRET THAT

3133
02:30:01,280 --> 02:30:02,600
CORRECTLY.

3134
02:30:02,600 --> 02:30:04,000
>> SOUNDS GREAT.

3135
02:30:04,000 --> 02:30:04,320
THANKS, MARIO.

3136
02:30:04,320 --> 02:30:06,440
FOR TIME'S SAKE WE'LL MOVE ON.

3137
02:30:06,440 --> 02:30:08,840
PLEASE PUT YOUR QUESTIONS WITH

3138
02:30:08,840 --> 02:30:10,360
YOUR E-MAIL ADDRESSES, THAT WILL

3139
02:30:10,360 --> 02:30:14,480
ALLOW SPEAKERS TO  REACH OUT AND

3140
02:30:14,480 --> 02:30:16,040
ANSWER QUESTIONS.

3141
02:30:16,040 --> 02:30:19,640
WE APPRECIATE EVERYONE'S

3142
02:30:19,640 --> 02:30:22,400
INVOLVEMENT. 

3143
02:30:22,400 --> 02:30:26,080
NEXT IS FIKRI AVCI, UNIVERSITY

3144
02:30:26,080 --> 02:30:27,840
OF GEORGIA, GLYCAN MEDIATED

3145
02:30:27,840 --> 02:30:32,160
IMMUNOREGULATION IN HEALTH AND

3146
02:30:32,160 --> 02:30:34,560
DISEASE.

3147
02:30:34,560 --> 02:30:39,680
 

3148
02:30:39,680 --> 02:30:56,720
 

3149
02:30:56,720 --> 02:30:59,920
 

3150
02:30:59,920 --> 02:31:01,360
>> THANK YOU FOR THE INVITATION

3151
02:31:01,360 --> 02:31:04,040
AND PUTTING TOGETHER THIS

3152
02:31:04,040 --> 02:31:05,840
FANTASTIC SYMPOSIUM TODAY.

3153
02:31:05,840 --> 02:31:08,760
I'M GOING TO SHARE ARE YOU TWO

3154
02:31:08,760 --> 02:31:11,840
OF OUR UNPUBLISHED SHORT STORIES

3155
02:31:11,840 --> 02:31:13,120
PERTAINING TO GLYCAN MEDIATED

3156
02:31:13,120 --> 02:31:15,240
IMMUNOREGULATION IN HEALTH AND

3157
02:31:15,240 --> 02:31:15,440
DISEASE.

3158
02:31:15,440 --> 02:31:17,880
FIRST WILL HAVE TO DO WITH THE

3159
02:31:17,880 --> 02:31:21,480
DISEASE WHICH IS GOING TO BE

3160
02:31:21,480 --> 02:31:24,640
BREAST CANCER, SECOND STORY,

3161
02:31:24,640 --> 02:31:26,080
EVEN SHORTER, TO DEAL WITH

3162
02:31:26,080 --> 02:31:30,640
PRELIMINARY DATA ON HOW GLYCANS

3163
02:31:30,640 --> 02:31:33,680
MAY INDUCE HOMEOSTASIS IN THE

3164
02:31:33,680 --> 02:31:35,240
GUT, GUT MICROBIOME.

3165
02:31:35,240 --> 02:31:44,200
SO THE FIRST STORY HAS TO DO 

3166
02:31:44,200 --> 02:31:53,760
WITH TN ANTIGEN. ANTIGEN, ROLE

3167
02:31:53,760 --> 02:32:00,640
IN IMMUNE EVASION IN BREAST

3168
02:32:00,640 --> 02:32:02,160
CANCER.

3169
02:32:02,160 --> 02:32:05,080
IT IS PARTICULARLY ON MUCIN 1,

3170
02:32:05,080 --> 02:32:08,160
HERE YOU SEE A NUMBER OF THOSE

3171
02:32:08,160 --> 02:32:13,400
HYPO GLYCOSYLATION EVENTS IN THE

3172
02:32:13,400 --> 02:32:14,680
CANCER CELL, ANTIGEN IS

3173
02:32:14,680 --> 02:32:22,200
BASICALLY THIS SUGAR UNIT.

3174
02:32:22,200 --> 02:32:32,520
SO, THIS IS  AN NCI PILOT

3175
02:32:32,520 --> 02:32:38,080
PROJECT, BASED ON MULTIPLE

3176
02:32:38,080 --> 02:32:40,520
CRITERIA, NOT POST-TRANSLATIONAL

3177
02:32:40,520 --> 02:32:46,560
EVENTS RESULTING IN ANTIGENS.

3178
02:32:46,560 --> 02:32:54,760
THE OTHER IS ACTUAL LECTIN, IN

3179
02:32:54,760 --> 02:33:00,560
MICE IT'S EITHER MGL 2

3180
02:33:00,560 --> 02:33:02,120
MACROPHAGE GALACTOSE LECTIN 2 OR

3181
02:33:02,120 --> 02:33:09,040
1B THAT BINDS TO TN ANTIGEN,

3182
02:33:09,040 --> 02:33:19,280
DEVELOP WELL ESTABLISHED, 

3183
02:33:19,280 --> 02:33:21,240
LITERATURE DEMONSTRATES

3184
02:33:21,240 --> 02:33:24,360
INTERACTIONS LEAD TO REACTION.

3185
02:33:24,360 --> 02:33:25,880
HOMEOSTASIS OF T CELLS.

3186
02:33:25,880 --> 02:33:30,840
WITH THE TWO IMPORTANT PLAYERS

3187
02:33:30,840 --> 02:33:34,640
WE HYPOTHESIZE ABERRANT TUMOR

3188
02:33:34,640 --> 02:33:38,760
GLYCOSYLATION IN THIS CASE

3189
02:33:38,760 --> 02:33:40,160
INDUCES ACCUMULATION OF TN

3190
02:33:40,160 --> 02:33:50,160
INDUCED CELLS IN BREAST TUMOR 

3191
02:33:50,160 --> 02:33:50,640
MICROENVIRONMENT, AND

3192
02:33:50,640 --> 02:33:58,000
INTERACTION LEADS TO TUMOR

3193
02:33:58,000 --> 02:33:58,600
IMMUNE EVASION.

3194
02:33:58,600 --> 02:34:05,840
WE USED MOUSE BREAST CANCER

3195
02:34:05,840 --> 02:34:09,520
MODEL, BY INJECTING CANCER CELL

3196
02:34:09,520 --> 02:34:12,400
LINE CELLS, EXPRESS TN ANTIGEN,

3197
02:34:12,400 --> 02:34:19,200
WE WANT TO LOOK AT TUMOR

3198
02:34:19,200 --> 02:34:21,560
MICROENVIRONMENT, WHETHER CELLS

3199
02:34:21,560 --> 02:34:23,640
ACCUMULATE. 

3200
02:34:23,640 --> 02:34:32,040
WE OBSERVED B CELL POPULATION TO

3201
02:34:32,040 --> 02:34:34,360
OUR SURPRISE, PREDOMINANTLY OR

3202
02:34:34,360 --> 02:34:50,440
MAYBE ALL THESE ASSOCIATED WITH 

3203
02:34:50,440 --> 02:34:54,560
MYELOID CELLS.

3204
02:34:54,560 --> 02:34:55,840
 

3205
02:34:55,840 --> 02:35:02,040
 

3206
02:35:02,040 --> 02:35:04,160
WE WERE ATTRIBUTING CELLS

3207
02:35:04,160 --> 02:35:05,240
IMMUNOREGULATORY FUNCTIONS,

3208
02:35:05,240 --> 02:35:08,440
WANTED TO SEE WHETHER THEY HAVE

3209
02:35:08,440 --> 02:35:13,440
REGULATORY B CELL MARKERS, CD24,

3210
02:35:13,440 --> 02:35:17,040
CD1D AND SEVERAL OTHER MARKERS,

3211
02:35:17,040 --> 02:35:21,240
THEY DO SHOW SOME MARKERS, AS

3212
02:35:21,240 --> 02:35:21,440
WELL.

3213
02:35:21,440 --> 02:35:29,560
AND WE ALSO WANTED TO LOOK AT

3214
02:35:29,560 --> 02:35:31,680
DISEASED B CELLS.

3215
02:35:31,680 --> 02:35:33,200
IN GENERAL, NOT ALWAYS,

3216
02:35:33,200 --> 02:35:36,920
ASSOCIATED WITH IMMUNE

3217
02:35:36,920 --> 02:35:37,920
SUPPRESSIVE FUNCTION.

3218
02:35:37,920 --> 02:35:39,880
SO WE'RE CONTINUING TO

3219
02:35:39,880 --> 02:35:43,160
CHARACTERIZE CELLS AS PART OF

3220
02:35:43,160 --> 02:35:44,520
THE CHARACTERIZATION, TRANSCRIPT

3221
02:35:44,520 --> 02:35:51,840
OMIC ANALYSIS OF CELLS, WE 

3222
02:35:51,840 --> 02:35:55,360
COMPARE, BUT THEN WE KNEW THEY

3223
02:35:55,360 --> 02:35:59,280
WOULD BE VASTLY DIFFERENT FROM

3224
02:35:59,280 --> 02:36:02,600
ONE ANOTHER AS YOU CAN SEE IN

3225
02:36:02,600 --> 02:36:03,560
DIFFERENTIALLY EXPRESSED GENES

3226
02:36:03,560 --> 02:36:14,120
THOUSANDS ARE DIFFERENTIALLY

3227
02:36:14,120 --> 02:36:14,400
EXPRESSED.

3228
02:36:14,400 --> 02:36:21,240
ALMOST ALL IN THE TUMOR

3229
02:36:21,240 --> 02:36:22,200
MICROENVIRONMENT, SEPARATED THEM

3230
02:36:22,200 --> 02:36:23,600
INTO LOW AND HIGH GROUPS.

3231
02:36:23,600 --> 02:36:26,640
AND THEN COMPARED THOSE TWO

3232
02:36:26,640 --> 02:36:27,920
POPULATIONS, THAT'S WHAT YOU'RE

3233
02:36:27,920 --> 02:36:29,240
SEEING IN HERE.

3234
02:36:29,240 --> 02:36:32,760
WE WANTED TO CARRY OUT OUR

3235
02:36:32,760 --> 02:36:34,840
ANALYSIS, USING THOSE

3236
02:36:34,840 --> 02:36:36,800
POPULATIONS BECAUSE WE FELT LIKE

3237
02:36:36,800 --> 02:36:42,600
THEY ARE THE CLOSEST, WITH ONLY

3238
02:36:42,600 --> 02:36:46,240
CD301B EXPRESSION THAT WAS

3239
02:36:46,240 --> 02:36:46,640
DIFFERENT.

3240
02:36:46,640 --> 02:36:48,440
IN MANY PROCESSES AND EVENTS

3241
02:36:48,440 --> 02:36:53,440
WE'VE SEEN EXPRESSED GENES BUT

3242
02:36:53,440 --> 02:36:54,560
HAVE BEEN INTERESTED.

3243
02:36:54,560 --> 02:36:58,040
IN THIS VOLCANO PLOT OBSERVED

3244
02:36:58,040 --> 02:37:07,240
SOME INTERESTING GENES THAT ARE

3245
02:37:07,240 --> 02:37:07,600
ASSOCIATED WITH

3246
02:37:07,600 --> 02:37:08,520
IMMUNOREGULATION, EXPRESS HIGH

3247
02:37:08,520 --> 02:37:26,360
POPULATIONS AS OPPOSED TO LOW

3248
02:37:26,360 --> 02:37:26,840
POPULATIONS.

3249
02:37:26,840 --> 02:37:28,800
WE SHALL CONTINUING OUR ANALYSIS

3250
02:37:28,800 --> 02:37:32,840
BUT WE WANTED TO SEE WHETHER TO

3251
02:37:32,840 --> 02:37:35,160
TEST OUR HYPOTHESIS THE CELLS,

3252
02:37:35,160 --> 02:37:37,520
AND ACCUMULATION IN THE TUMOR

3253
02:37:37,520 --> 02:37:38,160
MICROENVIRONMENT, HAS ANYTHING

3254
02:37:38,160 --> 02:37:41,040
TO DO WITH IMMUNE EVASION AND

3255
02:37:41,040 --> 02:37:42,560
THEREFORE THE TUMOR GROWTH.

3256
02:37:42,560 --> 02:37:47,440
AND THIS IS AGAIN A PRELIMINARY

3257
02:37:47,440 --> 02:37:51,360
DATA, PERFORMED BY USING

3258
02:37:51,360 --> 02:37:54,680
TRANSGENIC MICE, IN CD301B,

3259
02:37:54,680 --> 02:37:57,360
VERSUS WILDTYPE MOUSE, OBSERVED

3260
02:37:57,360 --> 02:38:00,320
VERY SIGNIFICANT DECREASE IN

3261
02:38:00,320 --> 02:38:03,440
TUMOR VOLUME WHEN THE CD301B IS

3262
02:38:03,440 --> 02:38:06,600
NO LONGER EXPRESSED ON THOSE

3263
02:38:06,600 --> 02:38:12,440
CELLS IN THE TUMOR

3264
02:38:12,440 --> 02:38:12,920
MICROENVIRONMENT.

3265
02:38:12,920 --> 02:38:14,800
THESE CELLS ARE IN FACT PLAYING

3266
02:38:14,800 --> 02:38:26,280
THE ROLE OF IMMUNE EVASION CELL 

3267
02:38:26,280 --> 02:38:26,840
POPULATION.

3268
02:38:26,840 --> 02:38:28,880
THIS IS A VERY BROAD SLIDE,

3269
02:38:28,880 --> 02:38:31,640
STILL THIS IS THE WORK IN

3270
02:38:31,640 --> 02:38:40,200
PROGRESS BUT ONE OBSERVATION 

3271
02:38:40,200 --> 02:39:00,680
MADE US VERY EXCITED. 

3272
02:39:00,680 --> 02:39:08,040
THE OTHER SIDE OF THE STORY HAS

3273
02:39:08,040 --> 02:39:10,560
TO DO WITH TN.

3274
02:39:10,560 --> 02:39:13,200
WE WANTED TO MODULATE TN

3275
02:39:13,200 --> 02:39:18,040
EXPRESSION LEVELS AND FOR THAT 

3276
02:39:18,040 --> 02:39:20,560
WE MAPPED OUT COSMC, IMPORTANT

3277
02:39:20,560 --> 02:39:22,440
FOR ELONGATION OF THE

3278
02:39:22,440 --> 02:39:23,080
OLIGOSACCHARIDE CHAINS, AND BY

3279
02:39:23,080 --> 02:39:28,040
DOING THAT WE WERE ABLE TO

3280
02:39:28,040 --> 02:39:30,240
GENERATE WHAT WE CALL TN HIGH

3281
02:39:30,240 --> 02:39:33,040
CELL LINE, AS YOU CAN SEE BY

3282
02:39:33,040 --> 02:39:35,280
PROBING THE TN ANTIBODY OBSERVED

3283
02:39:35,280 --> 02:39:41,040
HIGH TN EXPRESSION ON THESE

3284
02:39:41,040 --> 02:39:43,960
CELLS.

3285
02:39:43,960 --> 02:39:45,920
WE'RE BEGINNING TO EXPLORE

3286
02:39:45,920 --> 02:39:52,240
DIFFERENTIAL EXPRESSION, AND

3287
02:39:52,240 --> 02:39:53,640
THEIR ROLES IN ACCUMULATION,

3288
02:39:53,640 --> 02:39:56,200
ALSO TUMOR GROWTH AND

3289
02:39:56,200 --> 02:39:56,640
PROGRESSION.

3290
02:39:56,640 --> 02:40:14,440
AND THIS IS DATA AGAIN, TN LOW 

3291
02:40:14,440 --> 02:40:15,840
OR HIGH CELL LINES.

3292
02:40:15,840 --> 02:40:19,280
THERE SEEMS TO BE CORRELATION

3293
02:40:19,280 --> 02:40:25,200
BETWEEN THE TWO.

3294
02:40:25,200 --> 02:40:27,480
WE'RE ALSO -- WE'VE OBTAINED

3295
02:40:27,480 --> 02:40:32,200
TRANSGENIC MOUSE LINE THAT'S

3296
02:40:32,200 --> 02:40:37,280
EXPRESSING HUMAN MUCIN 1 WITH TN

3297
02:40:37,280 --> 02:40:39,280
EXPRESSION, INDUCE WITH

3298
02:40:39,280 --> 02:40:41,200
CARCINOGEN WE COMPARED WILDTYPE

3299
02:40:41,200 --> 02:40:48,640
MICE WITH TRANSGENIC MICE AND

3300
02:40:48,640 --> 02:40:49,240
OBSERVED NON-TRANSGENIC MICE

3301
02:40:49,240 --> 02:40:50,760
SURVIVED AT LOWER RATE THAN

3302
02:40:50,760 --> 02:40:52,440
WILDTYPE MICE.

3303
02:40:52,440 --> 02:41:03,360
AGAIN SUGGESTING THAT THE TN

3304
02:41:03,360 --> 02:41:06,120
ANTIGEN IS IMPORTANT IN CANCER

3305
02:41:06,120 --> 02:41:06,560
PROGRESSION.

3306
02:41:06,560 --> 02:41:09,440
IN THIS PARTICULAR EXPERIMENT WE

3307
02:41:09,440 --> 02:41:18,440
LOOKED AT ACCUMULATION OF CD19+

3308
02:41:18,440 --> 02:41:22,520
CELLS AND, AGAIN, LOWER SURVIVAL

3309
02:41:22,520 --> 02:41:26,600
AND HIGHER ACCUMULATION OF 

3310
02:41:26,600 --> 02:41:29,240
CD301B IN THE PRESENCE WERE

3311
02:41:29,240 --> 02:41:30,040
ASSOCIATED ALTOGETHER.

3312
02:41:30,040 --> 02:41:34,840
AGAIN, THIS IS SOME UNPUBLISHED

3313
02:41:34,840 --> 02:41:38,160
RESULTS FOR A PROJECT WHICH

3314
02:41:38,160 --> 02:41:44,320
WE'RE SO FAR SHOWING THAT THERE

3315
02:41:44,320 --> 02:41:46,040
IS A LYMPHOCYTE POPULATION IN

3316
02:41:46,040 --> 02:41:48,040
THE BREAST TUMOR ENVIRONMENT BUT

3317
02:41:48,040 --> 02:41:53,760
I DON'T FIND BY CD301B

3318
02:41:53,760 --> 02:41:59,200
EXPRESSION AND THESE  TN

3319
02:41:59,200 --> 02:42:02,120
EXPRESSION ON CANCER CELLS IS

3320
02:42:02,120 --> 02:42:15,680
CORRELATED WITH THESE CELLS AND 

3321
02:42:15,680 --> 02:42:17,840
CANCER GROWTH.

3322
02:42:17,840 --> 02:42:21,480
WE'RE CONTINUING TO CHARACTERIZE

3323
02:42:21,480 --> 02:42:24,240
THESE POPULATION OF CELLS.

3324
02:42:24,240 --> 02:42:26,320
AND WE HAVE SO MANY QUESTIONS,

3325
02:42:26,320 --> 02:42:29,200
I'M GUESSING YOU DO TOO, TO

3326
02:42:29,200 --> 02:42:34,200
DETERMINE MECHANISMS ASSOCIATED

3327
02:42:34,200 --> 02:42:35,880
WITH THIS INTERACTION AND WE'RE

3328
02:42:35,880 --> 02:42:39,320
HOPING TO TAKE IT FROM THOSE

3329
02:42:39,320 --> 02:42:40,680
MECHANISTIC WORKS INTO

3330
02:42:40,680 --> 02:42:42,240
TRANSLATABLE TRANSLATIONAL

3331
02:42:42,240 --> 02:42:46,280
RESEARCH WHERE WE CAN OVERCOME

3332
02:42:46,280 --> 02:42:49,240
CANCER PROGRESSION THROUGH

3333
02:42:49,240 --> 02:42:53,120
INHIBITING THIS CD 301B

3334
02:42:53,120 --> 02:42:54,120
INTERACTION, IN HUMANS.

3335
02:42:54,120 --> 02:42:59,240
SO THAT LEADS ME TO MY SECOND

3336
02:42:59,240 --> 02:43:01,240
ONE-SLIDE STORY THAT HAS TO DO

3337
02:43:01,240 --> 02:43:02,200
WITH GLYCAN MEDIATED REGULATION

3338
02:43:02,200 --> 02:43:14,120
OF IMMUNE RESPONSES IN THE GUT

3339
02:43:14,120 --> 02:43:14,600
MICROBIOME.

3340
02:43:14,600 --> 02:43:19,440
HAVING SEEN TN ANTIGEN IN TUMOR

3341
02:43:19,440 --> 02:43:21,440
CELLS, RECRUITING IMMUNE CELLS

3342
02:43:21,440 --> 02:43:23,680
IN THE TUMOR MICROENVIRONMENT

3343
02:43:23,680 --> 02:43:25,240
AND LEADING THEM TO FURTHER

3344
02:43:25,240 --> 02:43:27,440
GROWTH OF THE TUMOR WE ASKED

3345
02:43:27,440 --> 02:43:29,240
OURSELVES WOULD THESE CELLS HAVE

3346
02:43:29,240 --> 02:43:37,280
ANY USE IN THE HOMEOSTASIS OF

3347
02:43:37,280 --> 02:43:37,920
IMMUNE SYSTEM?

3348
02:43:37,920 --> 02:43:42,600
AND WE LOOKED AT THE GUT

3349
02:43:42,600 --> 02:43:43,800
MICROBIOME AND COMPARTMENTS IN

3350
02:43:43,800 --> 02:43:49,280
THE GUT WHETHER CELLS ARE 

3351
02:43:49,280 --> 02:43:54,560
INTERACTING WITH THE SYMBIOTIC

3352
02:43:54,560 --> 02:43:57,080
BACTERIA, WHETHER THEY INDUCE

3353
02:43:57,080 --> 02:43:58,680
REGULATORY TYPE AND THEREFORE

3354
02:43:58,680 --> 02:43:59,160
HOMEOSTASIS.

3355
02:43:59,160 --> 02:44:08,240
FOR THAT WE LOOKED, EXPRESSION

3356
02:44:08,240 --> 02:44:13,880
IN THE GUT IN COMPARTMENTS WE'VE

3357
02:44:13,880 --> 02:44:18,000
SEEN AN INCREASED CD301B

3358
02:44:18,000 --> 02:44:20,840
EXPRESSION IN SPF MICE AND

3359
02:44:20,840 --> 02:44:22,120
WANTED TO SEE WHETHER THEIR

3360
02:44:22,120 --> 02:44:30,160
PRESENCE HAD ANYTHING TO DO WITH

3361
02:44:30,160 --> 02:44:31,920
IMMUNE SYSTEM HOMEOSTASIS, AND

3362
02:44:31,920 --> 02:44:41,040
DID THAT THROUGH MODEL, DEPLETE

3363
02:44:41,040 --> 02:44:43,840
CD301 B+ CELLS SEE DIFFERENCE IN

3364
02:44:43,840 --> 02:44:47,040
SURVIVAL THAT DEMONSTRATED CELLS

3365
02:44:47,040 --> 02:44:52,440
ARE VERY IMPORTANT FOR 

3366
02:44:52,440 --> 02:44:55,440
PREVENTING AUTOIMMUNE BIAS IN

3367
02:44:55,440 --> 02:44:56,840
THE GUT COMPARTMENTS.

3368
02:44:56,840 --> 02:45:11,360
WE'RE NOW LOOKING AT COMPARING

3369
02:45:11,360 --> 02:45:12,440
WILDTYPE VERSUS CD3 01B,

3370
02:45:12,440 --> 02:45:16,320
ENHANCED IN THE PRESENCE OF CD3O

3371
02:45:16,320 --> 02:45:17,800
1B+ CELLS OR NOT, THIS IS STILL

3372
02:45:17,800 --> 02:45:20,560
ONGOING WORK FOR US.

3373
02:45:20,560 --> 02:45:27,640
THEY SAME TIME WE'RE USING

3374
02:45:27,640 --> 02:45:30,200
ANTI-TN ANTIBODY, TRYING TO

3375
02:45:30,200 --> 02:45:31,480
IDENTIFY OR ZOOM IN TO

3376
02:45:31,480 --> 02:45:38,200
PARTICULAR SPECIES THAT ARE

3377
02:45:38,200 --> 02:45:39,440
ACTUALLY LEADING TO THIS

3378
02:45:39,440 --> 02:45:41,400
INTERACTION THAT LEADS TO WHAT

3379
02:45:41,400 --> 02:45:44,320
IS OBSERVED IN COLITIS.

3380
02:45:44,320 --> 02:45:51,920
WITH THAT, WE THINK THAT CD301B

3381
02:45:51,920 --> 02:45:53,240
MICROBIOME OR MICRO FLUORIDE

3382
02:45:53,240 --> 02:45:54,520
INTERACTION LEAD TO HOMEO

3383
02:45:54,520 --> 02:46:01,240
STAYSES,  HOMEOSTASIS, YOU GET

3384
02:46:01,240 --> 02:46:01,760
INFLAMMATORY DISEASES AND

3385
02:46:01,760 --> 02:46:03,960
POTENTIALLY CANCER DUE TO THOSE

3386
02:46:03,960 --> 02:46:06,040
INFLAMMATORY PROCESSES.

3387
02:46:06,040 --> 02:46:09,520
AND THAT'S OUR OWN HYPOTHESIS.

3388
02:46:09,520 --> 02:46:14,920
HAVING SAID THAT, WE'RE MOVING

3389
02:46:14,920 --> 02:46:15,960
TO EMORY UNIVERSITY MEDICAL

3390
02:46:15,960 --> 02:46:17,640
SCHOOL IN A MONTH, THIS PROJECT

3391
02:46:17,640 --> 02:46:20,440
IS UP FOR GRABS, NOBODY IS

3392
02:46:20,440 --> 02:46:22,400
WORKING ON THIS.

3393
02:46:22,400 --> 02:46:24,240
AND I HEARD THAT THERE ARE 800

3394
02:46:24,240 --> 02:46:25,600
OR SO PEOPLE WATCHING THIS SO IF

3395
02:46:25,600 --> 02:46:27,440
ANYONE IS INTERESTED IN WORKING

3396
02:46:27,440 --> 02:46:31,440
ON THIS PROJECT PLEASE CONTACT 

3397
02:46:31,440 --> 02:46:31,640
ME.

3398
02:46:31,640 --> 02:46:38,000
WITH THAT, I'D LIKE TO THANK 

3399
02:46:38,000 --> 02:46:45,800
AMY IN MY LAB, HELPING WITH

3400
02:46:45,800 --> 02:46:58,520
BIOINFORMATICS ON THE MICROBIOME

3401
02:46:58,520 --> 02:46:58,840
PROJECT.

3402
02:46:58,840 --> 02:47:10,080
SANDRA PROVIDED MICE AND AKIKO

3403
02:47:10,080 --> 02:47:12,360
PROVIDED CD301B TRANSGENIC MICE.

3404
02:47:12,360 --> 02:47:16,680
>> WHEN YOU LOOK AT KNOCKOUT

3405
02:47:16,680 --> 02:47:18,040
MICE, JUST IN GENERAL, IMMUNE

3406
02:47:18,040 --> 02:47:21,720
RESPONSE, DO YOU SEE DIFFERENCE

3407
02:47:21,720 --> 02:47:23,200
IN B CELL RESPONSE,

3408
02:47:23,200 --> 02:47:24,840
INFLAMMATION, ANTIBODY TITERS IN

3409
02:47:24,840 --> 02:47:26,240
GENERAL FOLLOWING TRADITIONAL

3410
02:47:26,240 --> 02:47:26,520
CHALLENGES?

3411
02:47:26,520 --> 02:47:28,160
>> I THINK PUBLISHED WORK ON

3412
02:47:28,160 --> 02:47:33,200
THAT ONE, SHE HAS ACTUALLY

3413
02:47:33,200 --> 02:47:38,040
SHOWN, STILL NOT KNOWN THESE B 

3414
02:47:38,040 --> 02:47:40,520
CELLS WERE ACTUALLY CD301B+,

3415
02:47:40,520 --> 02:47:43,280
IT'S ALWAYS BEEN ASSOCIATED WITH

3416
02:47:43,280 --> 02:47:44,160
MACROPHAGES.

3417
02:47:44,160 --> 02:47:44,440
>> RIGHT.

3418
02:47:44,440 --> 02:47:48,880
>> AND SHE HAS SHOWN REDUCEED

3419
02:47:48,880 --> 02:48:02,360
ANTIBODY MEDIATED IMMUNITY.

3420
02:48:02,360 --> 02:48:03,120
>> OKAY.

3421
02:48:03,120 --> 02:48:09,040
I DON'T SEE QUESTIONS IN THE

3422
02:48:09,040 --> 02:48:09,480
CHAT.

3423
02:48:09,480 --> 02:48:10,800
MAYBE WE'LL MOVE ON.

3424
02:48:10,800 --> 02:48:12,360
IF YOU HAVE QUESTIONS, PLEASE

3425
02:48:12,360 --> 02:48:16,240
PUT THEM INTO THE CHAT AND WITH 

3426
02:48:16,240 --> 02:48:20,520
YOUR E-MAIL ADDRESS, PEOPLE CAN

3427
02:48:20,520 --> 02:48:20,840
RESPOND.

3428
02:48:20,840 --> 02:48:21,440
>> SHOOT ME AN E-MAIL.

3429
02:48:21,440 --> 02:48:22,360
>> WE APPRECIATE IT.

3430
02:48:22,360 --> 02:48:23,600
WONDERFUL TALK.

3431
02:48:23,600 --> 02:48:24,160
BEAUTIFUL WORK.

3432
02:48:24,160 --> 02:48:24,600
>> THANK YOU.

3433
02:48:24,600 --> 02:48:32,120
>> WE'RE GOING TO MOVE ON TO

3434
02:48:32,120 --> 02:48:36,760
DREW KIRALY FROM MOUNT SINAI TO

3435
02:48:36,760 --> 02:48:39,840
TALK ABOUT MANIPULATIONS, I'M

3436
02:48:39,840 --> 02:48:41,360
TRANSITIONING GLASSES,

3437
02:48:41,360 --> 02:48:46,320
MANIPULATIONS OF GUT MICROBIOME

3438
02:48:46,320 --> 02:48:46,600
DIVERSITY.

3439
02:48:46,600 --> 02:48:47,760
>> CAN EVERYONE HEAR ME AND SEE

3440
02:48:47,760 --> 02:48:50,240
MY SLIDES?

3441
02:48:50,240 --> 02:48:50,640
>> LOOKS GREAT.

3442
02:48:50,640 --> 02:48:52,240
>> SO THANK YOU TO THE

3443
02:48:52,240 --> 02:48:54,600
ORGANIZERS FOR INVITING ME AND

3444
02:48:54,600 --> 02:48:55,960
THANK YOU TO EVERYONE WATCHING

3445
02:48:55,960 --> 02:49:05,840
ONLINE, EXCITED TO TAKE PART IN

3446
02:49:05,840 --> 02:49:06,640
IMPRESSIVE SYMPOSIUM AND HOPE I

3447
02:49:06,640 --> 02:49:07,440
HAVE A CONTRIBUTION.

3448
02:49:07,440 --> 02:49:09,480
I WAS HOPING I WOULD HAVE SOME

3449
02:49:09,480 --> 02:49:10,240
INTERESTING NEW DATA AND WASN'T

3450
02:49:10,240 --> 02:49:12,560
SURE IT WOULD BE OUT YET SO I

3451
02:49:12,560 --> 02:49:16,720
GAVE A  GENERIC TITLE BUT WE GOT

3452
02:49:16,720 --> 02:49:19,080
NEW DATA SO I'M GOING TO

3453
02:49:19,080 --> 02:49:20,920
TRANSITION AND SACRIFICE POLISH

3454
02:49:20,920 --> 02:49:23,640
ON THE TALK TO SHOW SOME REALLY

3455
02:49:23,640 --> 02:49:26,280
NEW AND EXCITING THINGS.

3456
02:49:26,280 --> 02:49:28,200
PRETTY MUCH EVERYTHING IN THE

3457
02:49:28,200 --> 02:49:31,840
INTRODUCTION IS UNPUBLISH AND 

3458
02:49:31,840 --> 02:49:33,560
UNPRESENTED BEFORE BY ME.

3459
02:49:33,560 --> 02:49:35,120
MORE SPECIFICALLY WE'LL LOOK AT

3460
02:49:35,120 --> 02:49:38,680
EFFECTS OF THE GUT MICROBIOME 

3461
02:49:38,680 --> 02:49:44,560
AND HOW IT REGULATES FENTANYL

3462
02:49:44,560 --> 02:49:46,560
SEEKING BEHAVIOR AND SYNAPTIC

3463
02:49:46,560 --> 02:49:53,360
PROTEOMICS IN THE VENTRAL

3464
02:49:53,360 --> 02:49:55,440
STRIATUM, IMPORTANT IN REWARD IN

3465
02:49:55,440 --> 02:49:56,680
OPIOID USE DISORDER.

3466
02:49:56,680 --> 02:49:58,040
NO CONFLICTS OF INTEREST RELATED

3467
02:49:58,040 --> 02:49:58,440
TO THE PRESENTATION.

3468
02:49:58,440 --> 02:50:01,080
MANY IN THE ROOM ARE AWARE,

3469
02:50:01,080 --> 02:50:04,240
OPIOID USE DISORDER IS A MAJOR

3470
02:50:04,240 --> 02:50:07,840
PUBLIC HEALTH PROBLEM.

3471
02:50:07,840 --> 02:50:08,960
ESTIMATES ARE SOMEWHAT DIFFICULT

3472
02:50:08,960 --> 02:50:11,240
BUT CURRENT BEST GUESS, THIS IS

3473
02:50:11,240 --> 02:50:15,880
A CONDITION AFFECTING MORE THAN 

3474
02:50:15,880 --> 02:50:22,440
16 MILLION PEOPLE WORLDWIDE.

3475
02:50:22,440 --> 02:50:24,040
OVERDOSE IS ON THE RISE.

3476
02:50:24,040 --> 02:50:28,400
SOME MOST RECENT DATA FROM NIDA

3477
02:50:28,400 --> 02:50:30,000
ABOUT RATES OF OVERDOSE, DRUG

3478
02:50:30,000 --> 02:50:31,840
OVERDOSES, IN THE UNITED STATES,

3479
02:50:31,840 --> 02:50:33,240
WITH A NUMBER OF OVERDOSES PER

3480
02:50:33,240 --> 02:50:34,840
YEAR ON THE Y-AXIS.

3481
02:50:34,840 --> 02:50:38,520
YOU CAN SEE THIS LIGHT BLUE LINE

3482
02:50:38,520 --> 02:50:41,640
HERE, SYNTHETIC OPIOIDS ARE THE

3483
02:50:41,640 --> 02:50:45,760
METHADONES, PRIMARILY FENTANYL. 

3484
02:50:45,760 --> 02:50:47,120
IN RECENT YEARS HAVING 50,000+

3485
02:50:47,120 --> 02:50:50,000
OVERDOSES DUE TO FENTANYL AND

3486
02:50:50,000 --> 02:50:50,360
SIMILAR OPIOIDS.

3487
02:50:50,360 --> 02:50:52,640
THIS IS SOMETHING THAT EARLY

3488
02:50:52,640 --> 02:50:54,520
DATA SUGGESTS THAT COVID

3489
02:50:54,520 --> 02:50:58,240
PANDEMIC HAS ACTUALLY BEEN 

3490
02:50:58,240 --> 02:50:59,040
EXACERBATING THIS PHENOMENON,

3491
02:50:59,040 --> 02:51:01,560
THAT THE ISOLATION, OTHER

3492
02:51:01,560 --> 02:51:02,360
FACTORS, HAVE BEEN DRIVING

3493
02:51:02,360 --> 02:51:02,840
INCREASED OVERDOSES.

3494
02:51:02,840 --> 02:51:04,960
IF ANYTHING THIS IS A PROBLEM

3495
02:51:04,960 --> 02:51:12,200
CURRENTLY GETTING WORSE, NOT

3496
02:51:12,200 --> 02:51:12,440
BETTER.

3497
02:51:12,440 --> 02:51:13,960
I'M A PHYSICIAN-SCIENTIST, A

3498
02:51:13,960 --> 02:51:14,280
PSYCHIATRIST.

3499
02:51:14,280 --> 02:51:15,360
WHAT'S DIFFICULT FOR ME TREATING

3500
02:51:15,360 --> 02:51:20,200
PATIENTS, I HAVE NO GOOD WAY OF

3501
02:51:20,200 --> 02:51:23,680
RISK STRATIFYING FOR RELAPSE OR 

3502
02:51:23,680 --> 02:51:25,360
UNDERSTANDING RISK OF BECOMING

3503
02:51:25,360 --> 02:51:27,280
DEPENDENT WHEN STARTING USE OF

3504
02:51:27,280 --> 02:51:28,040
OPIOIDS.

3505
02:51:28,040 --> 02:51:30,840
MULTIPLE GOOD TREATMENT OPTIONS,

3506
02:51:30,840 --> 02:51:33,240
STILL INSUFFICIENT FOR A LOT OF

3507
02:51:33,240 --> 02:51:34,520
PATIENTS.

3508
02:51:34,520 --> 02:51:35,080
PATIENTS HAVE DIFFICULT

3509
02:51:35,080 --> 02:51:36,080
TOLERATING, MAINTAINING, A

3510
02:51:36,080 --> 02:51:37,240
NUMBER OF SIDE EFFECTS.

3511
02:51:37,240 --> 02:51:38,640
WORKING TO IDENTIFY WAYS TO RISK

3512
02:51:38,640 --> 02:51:40,520
STRATIFY AND TREAT PATIENTS IS A

3513
02:51:40,520 --> 02:51:42,160
CRITICAL NEED FOR THE FIELD.

3514
02:51:42,160 --> 02:51:43,920
I WOULD ARGUE SOCIETY AT LARGE

3515
02:51:43,920 --> 02:51:52,080
GIVEN THE MAGNITUDE OF THE

3516
02:51:52,080 --> 02:51:53,760
PROBLEM.

3517
02:51:53,760 --> 02:52:00,000
WE'VE BEEN  FOCUSING ON THE GUT

3518
02:52:00,000 --> 02:52:00,280
MICROBIOME.

3519
02:52:00,280 --> 02:52:02,120
OPIOID FITS WELL.

3520
02:52:02,120 --> 02:52:04,000
RECEPTORS ARE EXPRESSED HIGHLY

3521
02:52:04,000 --> 02:52:06,120
THROUGHOUT THE GUT.

3522
02:52:06,120 --> 02:52:08,160
THERE HAVE BEEN STUDIES SHOWING

3523
02:52:08,160 --> 02:52:11,240
HIGH DOSE LONG-TERM OPIOID USE

3524
02:52:11,240 --> 02:52:17,160
CAN AFFECT COMPOSITION AND

3525
02:52:17,160 --> 02:52:17,640
METABOLOMIC MICROBIOME.

3526
02:52:17,640 --> 02:52:21,040
WE'VE BEEN DOING WORK LOOKING AT

3527
02:52:21,040 --> 02:52:22,040
HOW METABOLITES CAN SIGNAL TO

3528
02:52:22,040 --> 02:52:27,680
THE BRAIN AND HAVE WAYS

3529
02:52:27,680 --> 02:52:29,040
IMPORTANT FOR BEHAVIOR.

3530
02:52:29,040 --> 02:52:31,400
WE'RE LOOKING AT COMPLEX

3531
02:52:31,400 --> 02:52:34,880
INTERACTIONS THAT EXIST BETWEEN

3532
02:52:34,880 --> 02:52:37,240
THE COMMENSAL MICROBIOME AND THE

3533
02:52:37,240 --> 02:52:38,560
INTESTINAL IMMUNE SYSTEM THAT

3534
02:52:38,560 --> 02:52:39,280
CAN DRIVE BEHAVIORS.

3535
02:52:39,280 --> 02:52:43,240
TODAY WE'RE GOING TO TALK ABOUT

3536
02:52:43,240 --> 02:52:44,840
SIMILAR MODELING, DRILLING DOWN

3537
02:52:44,840 --> 02:52:49,200
ON WHAT SOME MICROBIOME EFFECTS

3538
02:52:49,200 --> 02:52:52,840
ARE ON OPIOID USE DISORDER.

3539
02:52:52,840 --> 02:52:54,840
THE MODEL WE'RE USING RELATIVELY

3540
02:52:54,840 --> 02:52:58,000
SIMPLE, A BIT OF A BROAD

3541
02:52:58,000 --> 02:52:59,600
APPROACH, A LARGE MICROBIOME

3542
02:52:59,600 --> 02:53:01,080
KNOCKDOWN ASKING THE QUESTION OF

3543
02:53:01,080 --> 02:53:05,240
IF YOU HAVE A MARKEDLY REDUCED

3544
02:53:05,240 --> 02:53:06,360
PRESENCE OF THESE NORMAL

3545
02:53:06,360 --> 02:53:08,000
BACTERIA IN THE GUT HOW WILL

3546
02:53:08,000 --> 02:53:15,080
THAT AFFECT REGULATION OF BRAIN 

3547
02:53:15,080 --> 02:53:18,360
AND BEHAVIOR LONG TERM.

3548
02:53:18,360 --> 02:53:21,080
WE'RE DOING A HOME CAGE MODEL, A

3549
02:53:21,080 --> 02:53:24,400
COCKTAIL THROUGH HOME CAGE

3550
02:53:24,400 --> 02:53:25,840
DRINKING WATER, ANTIBIOTICS THAT

3551
02:53:25,840 --> 02:53:27,760
ARE BROAD SPECTRUM AND POORLY

3552
02:53:27,760 --> 02:53:29,720
ABSORBED WITH THE HOPE THE

3553
02:53:29,720 --> 02:53:31,720
ANTIBIOTICS WILL GO THROUGH AND

3554
02:53:31,720 --> 02:53:34,840
KNOCK DOWN MICROBIOME HAVING

3555
02:53:34,840 --> 02:53:42,520
MINIMAL OFF-TARGET EFFECTS BY

3556
02:53:42,520 --> 02:53:43,640
ABSORPTION.

3557
02:53:43,640 --> 02:53:48,960
WE'RE USING NEOMICKEN,

3558
02:53:48,960 --> 02:53:52,080
BACITRACIN AND VANCOMYCIN.

3559
02:53:52,080 --> 02:54:01,120
WE GET GREATER THAN 90%

3560
02:54:01,120 --> 02:54:02,000
REDUCTION, WE'RE INTERESTED IN

3561
02:54:02,000 --> 02:54:04,800
BEHAVIOR AND HOW DOES THIS

3562
02:54:04,800 --> 02:54:05,480
REGULATE BEHAVIORAL RESPONSE,

3563
02:54:05,480 --> 02:54:08,320
WE'VE SPENT A GREAT DEAL OF TIME

3564
02:54:08,320 --> 02:54:11,520
TRYING TO ENSURE THAT THIS IS

3565
02:54:11,520 --> 02:54:13,960
WHERE THE ANIMALS ARE HEALTHY

3566
02:54:13,960 --> 02:54:16,000
AND BEHAVING RELATIVELY NORMALLY

3567
02:54:16,000 --> 02:54:18,440
AT BASELINE BEFORE WE GIVE

3568
02:54:18,440 --> 02:54:21,040
FURTHER MANIPULATION.

3569
02:54:21,040 --> 02:54:22,120
WE'VE IDENTIFIED COCKTAIL,

3570
02:54:22,120 --> 02:54:24,040
ANIMALS WILL DRINK SOLUTION

3571
02:54:24,040 --> 02:54:25,600
NORMALLY, NO DIFFERENCE OF

3572
02:54:25,600 --> 02:54:26,840
TREATMENT OF WATER CONTROLS, HOW

3573
02:54:26,840 --> 02:54:29,040
MUCH ANTIBIOTIC ANIMALS ARE

3574
02:54:29,040 --> 02:54:29,280
DRINKING.

3575
02:54:29,280 --> 02:54:31,240
WE SEE NORMAL BODY WEIGHT GROWTH

3576
02:54:31,240 --> 02:54:32,320
OVER TIME INCLUDING PERIODS UP

3577
02:54:32,320 --> 02:54:36,160
TO SIX WEEKS OR LONGER ON

3578
02:54:36,160 --> 02:54:36,440
ANTIBIOTICS.

3579
02:54:36,440 --> 02:54:37,200
WE'VE LOOKED AT LOCOMOTOR

3580
02:54:37,200 --> 02:54:39,040
ACTIVITY TO MAKE SURE ANIMALS

3581
02:54:39,040 --> 02:54:41,080
ARE MOVING NORMALLY AT BASELINE

3582
02:54:41,080 --> 02:54:43,480
AND SEE AGAIN UP TO EVEN 6 WEEKS

3583
02:54:43,480 --> 02:54:45,240
OF ANTIBIOTICS THERE'S NO

3584
02:54:45,240 --> 02:55:03,560
DIFFERENCE BETWEEN THE TWO 

3585
02:55:03,560 --> 02:55:03,800
GROUPS.

3586
02:55:03,800 --> 02:55:05,360
I'M SHOWING MORPHINE BUT MOSTLY

3587
02:55:05,360 --> 02:55:06,560
TALKING ABOUT FENTANYLS TODAY,

3588
02:55:06,560 --> 02:55:08,720
NO CHANGES IN LEVELS OF

3589
02:55:08,720 --> 02:55:11,200
INJECTION IN SERUM OR BRAIN ARE

3590
02:55:11,200 --> 02:55:12,400
OPIOIDS OR METABOLITES, SO

3591
02:55:12,400 --> 02:55:15,440
EFFECTS ARE NOT SIMPLY DUE TO

3592
02:55:15,440 --> 02:55:17,360
CHANGES IN AVAILABILITY OF THE

3593
02:55:17,360 --> 02:55:17,960
DRUGS.

3594
02:55:17,960 --> 02:55:22,640
WE'VE DONE CONTROL FOR

3595
02:55:22,640 --> 02:55:25,440
INFLAMMATORY RESPONSE, BUT WHAT

3596
02:55:25,440 --> 02:55:26,840
WE'VE CONVINCED OURSELVES SOME

3597
02:55:26,840 --> 02:55:28,640
WORK WE PUBLISHED ALREADY, WE

3598
02:55:28,640 --> 02:55:32,200
HAVE THE SYSTEM WHERE WE'RE

3599
02:55:32,200 --> 02:55:33,600
ROBUSTLY KNOCKING DOWN

3600
02:55:33,600 --> 02:55:35,040
MICROBIOME, AND HAVE AN ANIMAL

3601
02:55:35,040 --> 02:55:39,640
RELATIVELY NORMAL AND HEALTHY AT

3602
02:55:39,640 --> 02:55:39,920
BASELINE.

3603
02:55:39,920 --> 02:55:40,560
SOME PREVIOUSLY PUBLISHED WORK

3604
02:55:40,560 --> 02:55:42,880
WAS TO IDENTIFY SOME EARLY

3605
02:55:42,880 --> 02:55:46,080
EFFECTS OF MICROBIOME ON DRUG

3606
02:55:46,080 --> 02:55:47,600
SEEKING BEHAVIORS RELEVANT TO

3607
02:55:47,600 --> 02:55:48,440
OPIOID USE DISORDER.

3608
02:55:48,440 --> 02:55:50,000
THIS IS A MOUSE STUDY, ANIMALS

3609
02:55:50,000 --> 02:55:51,960
ON ANTIBIOTICS FOR TWO WEEKS.

3610
02:55:51,960 --> 02:56:00,280
WE DID THIS MEASURE OF DRUG 

3611
02:56:00,280 --> 02:56:01,440
PREFERENCE, CONDITIONED PLACE

3612
02:56:01,440 --> 02:56:04,840
PREFERENCE, AN APPARATUS WITH

3613
02:56:04,840 --> 02:56:06,600
TWO CHAMBERS, EACH DAY SALINE IN

3614
02:56:06,600 --> 02:56:08,240
THE MORNING, OPIOID IN THE

3615
02:56:08,240 --> 02:56:09,640
AFTERNOON, CONFINED TO THE OTHER

3616
02:56:09,640 --> 02:56:10,960
SIDE, LAST DAY OPEN THE DOORS

3617
02:56:10,960 --> 02:56:13,320
AND SEE HOW MUCH TIME THEY SPEND

3618
02:56:13,320 --> 02:56:16,840
ON EACH SIDE, INDEX OF DRUG

3619
02:56:16,840 --> 02:56:17,120
PREFERENCE.

3620
02:56:17,120 --> 02:56:19,160
WHAT WE SAW AND PUBLISHED

3621
02:56:19,160 --> 02:56:22,480
EARLIER ON MICROBIOME DEPLETION

3622
02:56:22,480 --> 02:56:24,480
LED TO MARKED REDUCTION AND

3623
02:56:24,480 --> 02:56:32,320
FORMATION OF CONDITIONED PLACE 

3624
02:56:32,320 --> 02:56:33,120
PREFERENCE.

3625
02:56:33,120 --> 02:56:38,680
HIGHER DOSE, DECREASED PREACH 

3626
02:56:38,680 --> 02:56:40,240
-- PREFERENCE.

3627
02:56:40,240 --> 02:56:42,280
TRIED GOING HIGHER WITH EVEN

3628
02:56:42,280 --> 02:56:44,320
LARGER DOSE OF MORPHINE VERSUS

3629
02:56:44,320 --> 02:56:47,480
STRONGER PREFERENCE IN CONTROL

3630
02:56:47,480 --> 02:56:48,920
ANIMALS HERE, ANIMALS LACKING

3631
02:56:48,920 --> 02:56:50,000
MICROBIOME FORMED NO PREFERENCE

3632
02:56:50,000 --> 02:56:50,720
FOR THIS DRUG.

3633
02:56:50,720 --> 02:56:52,680
THAT WAS KIND OF INTERESTING.

3634
02:56:52,680 --> 02:56:54,480
IN COMBINATION WE'VE BEEN

3635
02:56:54,480 --> 02:56:57,240
LOOKING AT A NUMBER OF PAPERS

3636
02:56:57,240 --> 02:57:00,000
SUGGESTING THAT CHANGES IN THE

3637
02:57:00,000 --> 02:57:01,280
MICROBIOME AND METABOLITES CAN

3638
02:57:01,280 --> 02:57:01,880
AFFECT TRANSCRIPTIONAL

3639
02:57:01,880 --> 02:57:03,600
REGULATION IN THE BRAIN SO IN

3640
02:57:03,600 --> 02:57:05,880
THE SAME PAPER WE ALSO PERFORMED

3641
02:57:05,880 --> 02:57:14,560
RNA SEQUENCING OF THE VENTRAL

3642
02:57:14,560 --> 02:57:21,240
STRIATUM, NUCLEUS ACCUMBENS.

3643
02:57:21,240 --> 02:57:23,640
AND WE FOUND ANIMALS WITH THE

3644
02:57:23,640 --> 02:57:28,320
MICROBIOME KNOCKED DOWN TREATED

3645
02:57:28,320 --> 02:57:29,040
WITH MORPHINE ARE DYSREGULATED

3646
02:57:29,040 --> 02:57:29,440
GENE EXPRESSION.

3647
02:57:29,440 --> 02:57:34,040
THIS IS A VOLCANO PLOT COMPARING

3648
02:57:34,040 --> 02:57:34,560
MORPHINE-PAIRED GROUPS,

3649
02:57:34,560 --> 02:57:36,800
DYSREGULATION OF THOUSANDS OF

3650
02:57:36,800 --> 02:57:42,360
GENES EVEN COMPARED TO

3651
02:57:42,360 --> 02:57:43,040
MORPHINE-TREATED CONTROLS.

3652
02:57:43,040 --> 02:57:46,200
THIS IS AFFECTING CELLULAR

3653
02:57:46,200 --> 02:57:50,200
PATHWAYS AS DIVERSE AS CHROMATIN

3654
02:57:50,200 --> 02:57:50,680
MODIFICATION, EPIGENETIC

3655
02:57:50,680 --> 02:58:05,240
REGULATION, CELL ADHESION, GLIAL

3656
02:58:05,240 --> 02:58:06,560
PATHWAYS, NEUROGENESIS, WE'VE

3657
02:58:06,560 --> 02:58:09,000
BEEN MOVING TOWARD MODELS WITH

3658
02:58:09,000 --> 02:58:22,440
HIGHER TRANSLATIONAL RELEVANCE.

3659
02:58:22,440 --> 02:58:23,440
HOW DO MICROBIOME MANIPULATIONS

3660
02:58:23,440 --> 02:58:25,840
DRIVE DRUG SEEKING IN

3661
02:58:25,840 --> 02:58:26,560
TRANSLATIONALLY RELEVANT MODELS?

3662
02:58:26,560 --> 02:58:34,000
ARE MOW ELECTRIC ALREADY CHAINS 

3663
02:58:34,000 --> 02:58:35,280
-- MOLECULAR CHANGES IN THE

3664
02:58:35,280 --> 02:58:37,240
BRAIN EXHIBITED AT PROTEIN

3665
02:58:37,240 --> 02:58:37,440
LEVEL?

3666
02:58:37,440 --> 02:58:40,040
I'LL ADDRESS THAT IN THE LAST

3667
02:58:40,040 --> 02:58:41,480
TEN MINUTES HERE.

3668
02:58:41,480 --> 02:58:44,040
THE WAY WE'RE MODELING SUBSTANCE

3669
02:58:44,040 --> 02:58:46,560
USE DISORDER IN THE RODENT,

3670
02:58:46,560 --> 02:58:50,200
HIGHER RELEVANCE, WITH DRUG SELF

3671
02:58:50,200 --> 02:58:51,920
ADMINISTRATION, WE TAKE ANIMALS,

3672
02:58:51,920 --> 02:58:53,400
IMPLANT WITH CATHETER, TRAIN

3673
02:58:53,400 --> 02:58:55,240
THEM TO LEVER PRESS FOR

3674
02:58:55,240 --> 02:58:56,840
INFUSIONS OF A DRUG.

3675
02:58:56,840 --> 02:59:00,240
THIS ALLOWS US TO LOOK AT HOW

3676
02:59:00,240 --> 02:59:01,440
ANIMALS ACQUIRE DRUG-TAKING

3677
02:59:01,440 --> 02:59:03,040
BEHAVIORS AND MORE IMPORTANTLY

3678
02:59:03,040 --> 02:59:04,520
AND MORE RELEVANT FOR ADDICTION

3679
02:59:04,520 --> 02:59:07,720
MODELS LOOK AT DRUG SEEKING WITH

3680
02:59:07,720 --> 02:59:08,760
RESPONSES, CHANGING HOW MANY

3681
02:59:08,760 --> 02:59:10,440
TIMES ANIMALS HAVE TO PRESS THE

3682
02:59:10,440 --> 02:59:14,360
LEVER TO GET INFUSION OF DRUGS.

3683
02:59:14,360 --> 02:59:17,200
AND ALSO WE CAN LOOK AT MODELS

3684
02:59:17,200 --> 02:59:20,160
OF RELAPSE, TEACH ANIMALS TO

3685
02:59:20,160 --> 02:59:21,440
SELF-ADMINISTER, PUT THEM IN

3686
02:59:21,440 --> 02:59:22,640
HOME CAGE FOR ABSTINENCE AND

3687
02:59:22,640 --> 02:59:30,640
RETURN THEM TO MODELS OF DRUG RE

3688
02:59:30,640 --> 02:59:39,280
RE RELAPSE.

3689
02:59:39,280 --> 02:59:43,920
FOR BEHAVIORAL EXPERIMENTS, 

3690
02:59:43,920 --> 02:59:44,640
SIMILAR TO PUBLISHED WORK,

3691
02:59:44,640 --> 02:59:50,000
CONTROLLED WATER OR ANTIBIOTICS

3692
02:59:50,000 --> 02:59:56,320
FOR TWO WEEKS, TRAIN TO

3693
02:59:56,320 --> 02:59:57,360
SELF-ADMINISTER FENTANYL, TO

3694
02:59:57,360 --> 03:00:00,640
TRAIN THEM TO LEVER PRESS TO GET

3695
03:00:00,640 --> 03:00:02,240
AN INFUSION OF DRUG.

3696
03:00:02,240 --> 03:00:04,240
AND WE SPEND TIME BECAUSE WE

3697
03:00:04,240 --> 03:00:07,360
WANTED TWO GROUPS TO START ON

3698
03:00:07,360 --> 03:00:09,000
EQUAL FOOTING AFTER

3699
03:00:09,000 --> 03:00:10,240
SELF-ADMINISTRATION, TO LEARN TO

3700
03:00:10,240 --> 03:00:11,400
ADMINISTER EQUALLY.

3701
03:00:11,400 --> 03:00:17,720
SO WHEN WE USE THIS INTERMEDIATE

3702
03:00:17,720 --> 03:00:21,040
DOSE WE SEE BOTH CONTROL AND

3703
03:00:21,040 --> 03:00:21,840
MICROBIOME DEPLETED ANIMALS

3704
03:00:21,840 --> 03:00:23,640
LEARN BEHAVIOR EQUALLY, EACH

3705
03:00:23,640 --> 03:00:28,200
GETTING ABOUT 30 INFUSIONS PER 

3706
03:00:28,200 --> 03:00:30,560
SESSION BY THE END, THIS IS A

3707
03:00:30,560 --> 03:00:32,800
ROBUST DOSE OF FENTANYL WHERE

3708
03:00:32,800 --> 03:00:35,040
THEY ARE RESPONDING NICELY FOR

3709
03:00:35,040 --> 03:00:35,840
IT.

3710
03:00:35,840 --> 03:00:38,280
WE CAN TAKE THIS ACQUISITION AND

3711
03:00:38,280 --> 03:00:42,240
TRANSITION TO SOME MORE COMPLEX

3712
03:00:42,240 --> 03:00:44,280
TASKS, INTERROGATE DRUG-SEEKING

3713
03:00:44,280 --> 03:00:46,520
BEHAVIOR.

3714
03:00:46,520 --> 03:00:48,600
FIRST THING IS INCREASED FIXED

3715
03:00:48,600 --> 03:00:49,600
RATIO, WE CAN NOW INCREASE THE

3716
03:00:49,600 --> 03:00:51,760
NUMBER OF TIMES THEY HAVE TO

3717
03:00:51,760 --> 03:00:53,760
PRESS THE LEVER TO GET DRUGS.

3718
03:00:53,760 --> 03:00:58,520
WE SEE WHEN WE INCREASE THAT TO 

3719
03:00:58,520 --> 03:01:02,960
TWO PRESSES PER INFUSION,

3720
03:01:02,960 --> 03:01:04,240
ANIMALS DON'T HAVE MUCH OF A

3721
03:01:04,240 --> 03:01:04,600
DIFFERENCE.

3722
03:01:04,600 --> 03:01:06,480
WE MAKE THEM WORK HARDER AND SEE

3723
03:01:06,480 --> 03:01:08,640
A SEPARATION OF GROUPS.

3724
03:01:08,640 --> 03:01:10,040
ANTIBIOTIC ANIMALS HAD TO PRESS

3725
03:01:10,040 --> 03:01:12,080
THREE TIMES TO GET INFUSION,

3726
03:01:12,080 --> 03:01:14,720
START TO PRESS AT HIGHER LEVELS

3727
03:01:14,720 --> 03:01:15,440
TO ACHIEVE INFUSIONS.

3728
03:01:15,440 --> 03:01:20,880
AS WE MAKE IT EVEN HARDER, TO

3729
03:01:20,880 --> 03:01:22,480
GET INFUSIONS, PRESS FIVE TIMES

3730
03:01:22,480 --> 03:01:24,720
TO GET A SINGLE INFUSION,

3731
03:01:24,720 --> 03:01:25,640
ANTIBIOTIC ANIMALS ARE WORKING

3732
03:01:25,640 --> 03:01:29,240
MUCH HARDER TO GET INFUSIONS OF

3733
03:01:29,240 --> 03:01:29,640
OPIOIDS.

3734
03:01:29,640 --> 03:01:33,000
SUGGESTING AS WE DO THIS MORE

3735
03:01:33,000 --> 03:01:36,320
COME BEHAVIOR WE SEE INCREASE IN

3736
03:01:36,320 --> 03:01:38,000
DRUG-SEEKING BEHAVIOR.

3737
03:01:38,000 --> 03:01:39,320
WE PERFORMED ANOTHER EXPERIMENT,

3738
03:01:39,320 --> 03:01:41,040
PROGRESSIVE RATIO, WITHIN A

3739
03:01:41,040 --> 03:01:41,680
SINGLE SESSION WE PROGRESSIVELY

3740
03:01:41,680 --> 03:01:43,160
INCREASE HOW MANY TIMES ANIMALS

3741
03:01:43,160 --> 03:01:44,880
PRESS THE LEVER TO GET A SINGLE

3742
03:01:44,880 --> 03:01:46,520
INFUSION OF DRUG AND LOOK AND

3743
03:01:46,520 --> 03:01:49,240
SEE HOW MANY TIMES THEY WILL

3744
03:01:49,240 --> 03:01:54,160
WORK OR PRESS TO GET EVEN ONE

3745
03:01:54,160 --> 03:01:54,560
INFUSION.

3746
03:01:54,560 --> 03:01:57,040
OVER A SESSION CONTROL ANIMALS

3747
03:01:57,040 --> 03:01:59,000
WILL PRESS, ON THE LAST TIME,

3748
03:01:59,000 --> 03:02:02,080
ABOUT 25 TIMES TO GET SINGLE

3749
03:02:02,080 --> 03:02:02,360
INFUSION.

3750
03:02:02,360 --> 03:02:03,120
THEY EVENTUALLY GIVE UP BECAUSE

3751
03:02:03,120 --> 03:02:06,440
IT'S TOO HARD TO GET IT.

3752
03:02:06,440 --> 03:02:08,520
WE SEE OUR MICROBIOME DEPLETED

3753
03:02:08,520 --> 03:02:13,120
ANIMALS WORK MUCH HARDER TO GET 

3754
03:02:13,120 --> 03:02:14,480
SINGLE INFUSIONS, 50 TIMES OR

3755
03:02:14,480 --> 03:02:16,440
MORE TO GET THE SINGLE INFUSION.

3756
03:02:16,440 --> 03:02:19,200
WE'RE STARTING TO SEE HOW THIS

3757
03:02:19,200 --> 03:02:23,320
MICROBIOME MANIPULATION IS 

3758
03:02:23,320 --> 03:02:25,040
AFFECTING THESE DRUG-SEEKING

3759
03:02:25,040 --> 03:02:25,600
BEHAVIORS.

3760
03:02:25,600 --> 03:02:27,080
GOING TO ACTIVE ADMINISTRATION

3761
03:02:27,080 --> 03:02:33,000
MOVING TO THE RELAPSE MODEL.

3762
03:02:33,000 --> 03:02:35,160
MICROBIOME KNOCKDOWN PERIOD,

3763
03:02:35,160 --> 03:02:36,680
ANIMALS TRAINED TO

3764
03:02:36,680 --> 03:02:37,200
SELF-ADMINISTER EQUALLY.

3765
03:02:37,200 --> 03:02:38,120
AFTER THEY LEARN BEHAVIOR THEY

3766
03:02:38,120 --> 03:02:40,280
GO BACK TO HOME CAGE FOR TWO

3767
03:02:40,280 --> 03:02:41,960
WEEKS, TWO WEEKS OF ABSTINENCE,

3768
03:02:41,960 --> 03:02:44,800
PUT THEM BACK IN THE BOX AND DO

3769
03:02:44,800 --> 03:02:45,600
REINSTATEMENT TASKS.

3770
03:02:45,600 --> 03:02:47,760
WE PUT THEM IN THE BOX, NO DRUG

3771
03:02:47,760 --> 03:02:49,520
AVAILABLE BUT LEVERS THEY

3772
03:02:49,520 --> 03:02:50,360
PREVIOUSLY PRESSED ARE THERE.

3773
03:02:50,360 --> 03:02:56,440
AND SO WE CAN SEE HOW MUCH BEING

3774
03:02:56,440 --> 03:02:57,640
REEXPOSED MAKES THEM PRESS THE

3775
03:02:57,640 --> 03:03:00,000
LEVER TO TRY TO RECEIVE

3776
03:03:00,000 --> 03:03:00,240
INFUSIONS.

3777
03:03:00,240 --> 03:03:04,640
SIMILAR PATTERN TO WHAT WE SAW

3778
03:03:04,640 --> 03:03:05,960
WITH THE INCREASED RATIO,

3779
03:03:05,960 --> 03:03:08,200
PUTTING THEM BACK IN THE BOX

3780
03:03:08,200 --> 03:03:10,520
MICROBIOME DEPLETED ANIMALS ARE

3781
03:03:10,520 --> 03:03:11,440
PRESSING MUCH MORE FREQUENTLY ON

3782
03:03:11,440 --> 03:03:13,240
THE LEVER THAT WAS PREVIOUSLY

3783
03:03:13,240 --> 03:03:14,440
ASSOCIATED WITH DRUG EVEN THOUGH

3784
03:03:14,440 --> 03:03:18,200
NO DRUG IS BEING DELIVERED.

3785
03:03:18,200 --> 03:03:19,800
AFTER THIS SESSION WE TURN ON

3786
03:03:19,800 --> 03:03:21,400
ONE OF THE CUE LIGHTS TURNED ON

3787
03:03:21,400 --> 03:03:23,400
WHEN THE ANIMALS RECEIVED

3788
03:03:23,400 --> 03:03:26,520
INFUSION OF DRUG TO SEE IF THAT

3789
03:03:26,520 --> 03:03:28,960
WOULD FURTHER SPUR DRUG SEEKING

3790
03:03:28,960 --> 03:03:30,000
BEHAVIORS AND THE ANTIBIOTIC

3791
03:03:30,000 --> 03:03:31,760
ANIMALS CONTINUE TO PRESS MORE

3792
03:03:31,760 --> 03:03:37,440
FOR THE DRUG ASSOCIATED CUE, NO

3793
03:03:37,440 --> 03:03:40,280
DRUG IS COMING.

3794
03:03:40,280 --> 03:03:46,640
WE SEE HOW MUCH ANIMALS PRESS

3795
03:03:46,640 --> 03:03:47,760
OVER BOTH SESSIONS, TO SEPARATE

3796
03:03:47,760 --> 03:03:49,640
EARLY ON IN THE SLOPE OF THE

3797
03:03:49,640 --> 03:03:50,520
ANTIBIOTIC ANIMALS CONTINUES TO

3798
03:03:50,520 --> 03:03:51,800
BE HIGHER THROUGHOUT THE

3799
03:03:51,800 --> 03:03:52,840
SESSION.

3800
03:03:52,840 --> 03:03:54,960
EVEN OVER THE COURSE OF THE

3801
03:03:54,960 --> 03:03:56,520
HOUR-LONG SESSION WE'RE SEEING

3802
03:03:56,520 --> 03:03:59,400
ANTIBIOTIC ANIMALS AS YOU ADD

3803
03:03:59,400 --> 03:04:00,920
MORE DRUG ASSOCIATED CUES

3804
03:04:00,920 --> 03:04:03,000
CONTINUE TO PRESS AT HIGHER

3805
03:04:03,000 --> 03:04:05,680
LEVELS, INTERESTING AND

3806
03:04:05,680 --> 03:04:06,680
SOMETHING WE'RE DELVING INTO.

3807
03:04:06,680 --> 03:04:09,720
BUT ONE OF WHICH IS TRY AND

3808
03:04:09,720 --> 03:04:11,600
FIGURE OUT MOLECULAR

3809
03:04:11,600 --> 03:04:14,280
UNDERPINNINGS, SO I MENTIONED

3810
03:04:14,280 --> 03:04:16,960
EARLIER THAT WE HAVE DONE

3811
03:04:16,960 --> 03:04:18,800
TRANSCRIPTOMIC ANALYSIS, WORKING

3812
03:04:18,800 --> 03:04:21,120
WITH THE PROTEOMICS SCORE TO DO

3813
03:04:21,120 --> 03:04:22,520
QUANTITATIVE ANALYSIS IN THE

3814
03:04:22,520 --> 03:04:26,440
BRAIN SO WE'RE TAKING ANIMALS

3815
03:04:26,440 --> 03:04:30,400
FROM EXPERIMENTS, DISSECTING

3816
03:04:30,400 --> 03:04:34,680
NUCLEUS ACCUMBENS, VENTRAL 

3817
03:04:34,680 --> 03:04:35,720
STRIATUM, PERFORMING

3818
03:04:35,720 --> 03:04:38,640
QUANTITATIVE PROTEOMIC ANALYSIS

3819
03:04:38,640 --> 03:04:40,640
USING MASS SPECTROMETRY, NO

3820
03:04:40,640 --> 03:04:45,280
LONGER A NEW METHOD, DATA

3821
03:04:45,280 --> 03:04:46,280
INDEPENDENT METHOD FOR MASS

3822
03:04:46,280 --> 03:04:54,560
SPECTROMETRY, A WAY TO TRY AND 

3823
03:04:54,560 --> 03:04:56,520
MAKE THIS LESS BIASED, THE

3824
03:04:56,520 --> 03:04:59,040
PEPTIDES ARE GROUPED BY MASS TO

3825
03:04:59,040 --> 03:05:01,520
CHARGE RATIO AND INDIVIDUAL MASS

3826
03:05:01,520 --> 03:05:05,200
TO CHARGE RATIO, ALLOWS US TO

3827
03:05:05,200 --> 03:05:06,720
GET MORE DETECTION OF SOME

3828
03:05:06,720 --> 03:05:08,120
PROTEINS EXPRESSED AT LOWER

3829
03:05:08,120 --> 03:05:10,840
LEVELS RATHER THAN ONLY THOSE

3830
03:05:10,840 --> 03:05:14,560
PEPTIDES SAMPLED AT HIGH LEVELS.

3831
03:05:14,560 --> 03:05:16,640
WHEN WE DID THIS WE LOOKED AT A

3832
03:05:16,640 --> 03:05:17,440
NUMBER OF GROUPS.

3833
03:05:17,440 --> 03:05:21,440
THIS IS JUST A VOLCANO PLOT

3834
03:05:21,440 --> 03:05:23,240
LOOKING AT DIFFERENT GROUPS.

3835
03:05:23,240 --> 03:05:28,280
FOR THOSE NOT FAMILIAR, THE

3836
03:05:28,280 --> 03:05:30,040
X-AXIS IS LOOKING AT LOG FOLD

3837
03:05:30,040 --> 03:05:31,320
CHANGE, UP OR DOWN.

3838
03:05:31,320 --> 03:05:34,040
AND THEN THE Y-AXIS IS THE

3839
03:05:34,040 --> 03:05:35,240
NEGATIVE LOG 10 P-VALUE, LOOKING

3840
03:05:35,240 --> 03:05:37,680
AT THIS, KIND OF THE BIGGER THE

3841
03:05:37,680 --> 03:05:42,560
ERUPTION, THE MORE PROTEINS ARE

3842
03:05:42,560 --> 03:05:43,080
REGULATED.

3843
03:05:43,080 --> 03:05:49,640
WE SEE SOME PROTEINS CHANGING IN

3844
03:05:49,640 --> 03:05:52,800
THE NUCLEUS ACCUMBENS.

3845
03:05:52,800 --> 03:05:59,240
OUR EFFECTS IN WATER FENTANYL 

3846
03:05:59,240 --> 03:06:01,120
CONTROLS ARE MORE ROBUST, 300

3847
03:06:01,120 --> 03:06:01,960
PROTEINS UP OR DOWNREGULATED.

3848
03:06:01,960 --> 03:06:08,320
AND WHEN WE LOOK AT INTERACTION,

3849
03:06:08,320 --> 03:06:10,040
SIMILAR TO TRANSCRIPTOMIC DATA,

3850
03:06:10,040 --> 03:06:13,520
ADD IN FENTANYL SEE REGULATION 

3851
03:06:13,520 --> 03:06:14,560
OF SIGNIFICANTLY MORE PROTEINS.

3852
03:06:14,560 --> 03:06:18,040
HE'S ARE HOT OFF THE PRESS DATA,

3853
03:06:18,040 --> 03:06:20,280
DIGGING INTO IT NOW.

3854
03:06:20,280 --> 03:06:25,440
I WANTED TO GIVE SOME DETAIL AND

3855
03:06:25,440 --> 03:06:28,080
PATHWAY ANALYSIS WE'VE BEEN

3856
03:06:28,080 --> 03:06:28,360
DOING.

3857
03:06:28,360 --> 03:06:32,040
LOOKING AT MOST SIGNIFICANT

3858
03:06:32,040 --> 03:06:35,920
PATHWAYS, YOU CAN SEE IF YOU

3859
03:06:35,920 --> 03:06:39,560
LOOK AT GENE ONTOLOGY-TYPE

3860
03:06:39,560 --> 03:06:40,160
PATHWAY ANALYSIS, NEGATIVE LOG

3861
03:06:40,160 --> 03:06:41,960
10 P-VALUE, ANYTHING BEYOND IS

3862
03:06:41,960 --> 03:06:43,320
STATISTICALLY SIGNIFICANT.

3863
03:06:43,320 --> 03:06:45,400
WHAT WE SEE HERE, THIS IS WHAT

3864
03:06:45,400 --> 03:06:50,600
WE EXPECTED, WE SEE EFFECTS MORE

3865
03:06:50,600 --> 03:06:52,080
ROBUST IN ANTIBIOTIC ANIMALS,

3866
03:06:52,080 --> 03:06:53,840
SIMILAR PATHWAYS REGULATED.

3867
03:06:53,840 --> 03:06:55,440
YOU EXPECT SYNAPTIC PROTEINS

3868
03:06:55,440 --> 03:06:58,600
REGULATED IN ANIMALS RECEIVING

3869
03:06:58,600 --> 03:07:01,280
FENTANYL BUT SEEING A MORE

3870
03:07:01,280 --> 03:07:03,240
SIGNIFICANT ENRICHMENT IN

3871
03:07:03,240 --> 03:07:05,480
ANIMALS LACKING MICROBIOME,

3872
03:07:05,480 --> 03:07:06,520
SIMILAR WITH METABOLIC

3873
03:07:06,520 --> 03:07:08,720
PROCESSES, THINGS WE WOULD

3874
03:07:08,720 --> 03:07:10,560
EXPECT THAT THE MICROBIOME AND

3875
03:07:10,560 --> 03:07:13,880
CHANGES IN METABOLITES REACHING

3876
03:07:13,880 --> 03:07:16,120
THE BRAIN ARE AFFECTING CELLULAR

3877
03:07:16,120 --> 03:07:18,400
METABOLISM IN RESPONSE TO DRUGS.

3878
03:07:18,400 --> 03:07:22,440
WE DO PATHWAY ANALYSIS, TAKING

3879
03:07:22,440 --> 03:07:23,880
INTO ACCOUNT VECTOR OF THE OR

3880
03:07:23,880 --> 03:07:26,920
DIRECTION OF CHANGE, THERE ARE A

3881
03:07:26,920 --> 03:07:30,640
NUMBER OF PATHWAYS CHANGING IN

3882
03:07:30,640 --> 03:07:34,040
OPPOSITE DIRECTIONS BETWEEN THE

3883
03:07:34,040 --> 03:07:34,520
GROUPS.

3884
03:07:34,520 --> 03:07:37,600
PROTEINS ARE INCREASED MORE SO

3885
03:07:37,600 --> 03:07:39,960
IN ANTIBIOTIC ANIMALS, DECREASED

3886
03:07:39,960 --> 03:07:45,240
IN WATER FENTANYL, SIMILAR WITH

3887
03:07:45,240 --> 03:07:46,480
PKA AND INTRACELLULAR CASCADES.

3888
03:07:46,480 --> 03:07:48,080
THIS IS SOMETHING THAT'S REALLY

3889
03:07:48,080 --> 03:07:48,840
INTERESTING.

3890
03:07:48,840 --> 03:07:54,240
I WANT TO ON THE LAST SLIDE DIG

3891
03:07:54,240 --> 03:07:54,840
OUT SYNAPTIC RELATED PROTEINS,

3892
03:07:54,840 --> 03:07:56,320
TO LOOK BETWEEN THE GROUPS AND

3893
03:07:56,320 --> 03:07:58,600
SEE WHAT KIND OF OVERLAP.

3894
03:07:58,600 --> 03:08:01,880
IF YOU LOOK AT PROTEINS FROM

3895
03:08:01,880 --> 03:08:07,760
THIS SYNAPSE LOCALIZATION GENE

3896
03:08:07,760 --> 03:08:10,480
ONTOLOGY, WE SEE SIGNIFICANT

3897
03:08:10,480 --> 03:08:12,800
OVERLAP. 

3898
03:08:12,800 --> 03:08:16,120
THERE ARE A NUMBER THERE ARE

3899
03:08:16,120 --> 03:08:17,840
UNIQUE WITH FDR CORRECTION.

3900
03:08:17,840 --> 03:08:20,760
WHEN WE START TO LOOK AT THE

3901
03:08:20,760 --> 03:08:22,520
STRING ANALYSIS TO SEE HOW THESE

3902
03:08:22,520 --> 03:08:25,760
DIRECT, WE SEE WATER FENTANYL

3903
03:08:25,760 --> 03:08:28,200
ANIMALS HAVE SMALLER INTERACTIVE

3904
03:08:28,200 --> 03:08:32,200
NETWORK OF SIGNIFICANTLY

3905
03:08:32,200 --> 03:08:34,400
REGULATED SYNAPTIC PROTEINS.

3906
03:08:34,400 --> 03:08:35,960
ANTIBIOTIC ANIMALS HAVE LARGER

3907
03:08:35,960 --> 03:08:36,200
CHANGE.

3908
03:08:36,200 --> 03:08:38,080
PRE AND POST SYNAPTIC PROTEINS,

3909
03:08:38,080 --> 03:08:39,440
BOTH ARE HAVING EFFECTS ON

3910
03:08:39,440 --> 03:08:44,360
EITHER SIDE OF THE SYNAPSE.

3911
03:08:44,360 --> 03:08:46,640
TO FINISH WITH WORKING MODEL,

3912
03:08:46,640 --> 03:08:47,840
THIS IS MORE EPIGENETICALLY

3913
03:08:47,840 --> 03:08:49,560
GEARED BUT STILL WORKS, OUR IDEA

3914
03:08:49,560 --> 03:08:53,160
HERE IS WITH NORMAL MICROBIOME

3915
03:08:53,160 --> 03:08:53,680
IT'S IMPORTANT HOMEOSTATIC

3916
03:08:53,680 --> 03:08:55,120
REGULATOR OF PRETTY MUCH EVERY

3917
03:08:55,120 --> 03:08:57,440
SYSTEM THROUGHOUT THE BODY, BY

3918
03:08:57,440 --> 03:09:01,840
PRODUCTION OF NORMAL SHORT CHAIN

3919
03:09:01,840 --> 03:09:02,640
FATTY ACIDS YOU GET APPROPRIATE

3920
03:09:02,640 --> 03:09:05,040
GENE EXPRESSION WHICH HELPS WITH

3921
03:09:05,040 --> 03:09:07,880
BEHAVIORAL REGULATION AND IF WE

3922
03:09:07,880 --> 03:09:09,400
DEPLETE MICROBIOME WE'RE

3923
03:09:09,400 --> 03:09:11,840
DEPLETING HOMEOSTATIC FORCE OF

3924
03:09:11,840 --> 03:09:13,080
METABOLITES THAT IT'S PRODUCING,

3925
03:09:13,080 --> 03:09:18,560
DYSREGULATED GENE AND PROTEIN

3926
03:09:18,560 --> 03:09:21,600
EXPRESSION, ABERRANT BEHAVER AND

3927
03:09:21,600 --> 03:09:22,440
SYNAPTIC PLASTICITY.

3928
03:09:22,440 --> 03:09:34,160
I'D LIKE TO THANK THOSE IN MY

3929
03:09:34,160 --> 03:09:38,640
LAB.

3930
03:09:38,640 --> 03:09:42,120
I WOULD LIKE TO -- I'M MOVING IN

3931
03:09:42,120 --> 03:09:43,760
THE NEAR FUTURE, WE'RE MOVING TO

3932
03:09:43,760 --> 03:09:46,080
WAKE FOREST SCHOOL OF MEDICINE

3933
03:09:46,080 --> 03:09:46,840
BEGINNING IN JUNE, WE'RE LOOKING

3934
03:09:46,840 --> 03:09:53,440
TO HIRE PEOPLE AT ALL LEVELS,

3935
03:09:53,440 --> 03:09:54,680
TECHNICIANS, POSTDOCTORAL

3936
03:09:54,680 --> 03:10:00,480
FELLOWS, GRADUATE STUDENTS, IF 

3937
03:10:00,480 --> 03:10:02,000
ANYONE IS INTERESTED HAVE THEM

3938
03:10:02,000 --> 03:10:03,280
GET IN TOUCH WITH ME.

3939
03:10:03,280 --> 03:10:09,440
>> WE HAVE A FEW QUESTIONS.

3940
03:10:09,440 --> 03:10:13,280
HOW DID YOU DECIDE THE DRUG

3941
03:10:13,280 --> 03:10:14,200
AMOUNT?

3942
03:10:14,200 --> 03:10:14,880
I DID BEHAVIORAL STUDIES,

3943
03:10:14,880 --> 03:10:15,800
STRUGGLE TO LEARN HOW MUCH OF

3944
03:10:15,800 --> 03:10:21,800
THE DRUG WE COULD USE TO SHOW

3945
03:10:21,800 --> 03:10:24,920
GOOD LOCOMOTION EFFECTS.

3946
03:10:24,920 --> 03:10:25,880
>> YEAH, WHEN WE'RE STARTING A

3947
03:10:25,880 --> 03:10:28,320
NEW PROJECT WE DO A

3948
03:10:28,320 --> 03:10:31,480
DOSE-RESPONSE CURVE, WITH THE

3949
03:10:31,480 --> 03:10:32,720
CONDITION PLACED PREFERENCE,

3950
03:10:32,720 --> 03:10:33,840
USING PREVIOUSLY PUBLISHED DOSES

3951
03:10:33,840 --> 03:10:36,920
DID DOSE RANGE FROM 2 1/2

3952
03:10:36,920 --> 03:10:38,040
MILLIGRAMS PER KILOGRAM TO 15,

3953
03:10:38,040 --> 03:10:40,320
SEEING WHERE WE SEE THE EFFECTS.

3954
03:10:40,320 --> 03:10:42,400
THAT'S WHAT WE DO WITH ANY

3955
03:10:42,400 --> 03:10:43,240
BEHAVIORAL PHARMACOLOGY THING

3956
03:10:43,240 --> 03:10:46,640
LIKE THIS, START WITH DOSE RANGE

3957
03:10:46,640 --> 03:10:47,520
AND GO FROM THERE.

3958
03:10:47,520 --> 03:10:50,240
>> THANK YOU FOR THE

3959
03:10:50,240 --> 03:10:50,560
PRESENTATION.

3960
03:10:50,560 --> 03:10:54,760
HAVE YOU PERFORMED FECAL

3961
03:10:54,760 --> 03:10:55,400
MICROBIOME TRANSPLANTATION

3962
03:10:55,400 --> 03:10:57,440
EXPERIMENTS TO REVERSE IMPACT OF

3963
03:10:57,440 --> 03:10:57,720
DEPLETION?

3964
03:10:57,720 --> 03:10:59,640
>> YES, GREAT QUESTION.

3965
03:10:59,640 --> 03:11:01,520
WE'RE WORKING ON THE TRANSPLANT,

3966
03:11:01,520 --> 03:11:04,240
THAT'S KIND OF SORT OF WORKING

3967
03:11:04,240 --> 03:11:06,400
BUT THAT'S EARLIER DAYS.

3968
03:11:06,400 --> 03:11:07,040
WE HAVEN'T DONE AS MUCH

3969
03:11:07,040 --> 03:11:10,240
PROBIOTICS BUT A NUMBER OF

3970
03:11:10,240 --> 03:11:11,560
THINGS WITH METABOLITE

3971
03:11:11,560 --> 03:11:12,840
SUPPLEMENTATION, PARTICULARLY

3972
03:11:12,840 --> 03:11:15,200
SHORT CHAIN FATTY ACIDS,

3973
03:11:15,200 --> 03:11:15,800
REVERSED EFFECTS, WE HAVEN'T

3974
03:11:15,800 --> 03:11:18,680
DONE IT IN THE

3975
03:11:18,680 --> 03:11:19,400
SELF-ADMINISTRATION YET BUT

3976
03:11:19,400 --> 03:11:21,200
THAT'S THE AVENUE WE'VE BEEN

3977
03:11:21,200 --> 03:11:23,040
MAKING MORE SO THAN PROBIOTICS

3978
03:11:23,040 --> 03:11:25,840
SO FAR.

3979
03:11:25,840 --> 03:11:28,720
>> A RELATED QUESTION, SO

3980
03:11:28,720 --> 03:11:29,800
PATIENTS, I DO HEMATOLOGY,

3981
03:11:29,800 --> 03:11:32,440
SICKLE CELL DISEASE EARLY ON,

3982
03:11:32,440 --> 03:11:40,520
THEY ARE GETTING EARLY ON IN 

3983
03:11:40,520 --> 03:11:41,080
LIFE PENICILLIN, PERTURBING

3984
03:11:41,080 --> 03:11:42,240
MICROBIOME, I DON'T KNOW IF

3985
03:11:42,240 --> 03:11:43,520
THERE'S ANYONE THAT'S LOOKED

3986
03:11:43,520 --> 03:11:46,960
BACK TO SEE, NOT EVERYONE IS ON

3987
03:11:46,960 --> 03:11:53,200
PROPHYLAXIS, WHETHER THERE'S 

3988
03:11:53,200 --> 03:11:54,760
CORRELATION BETWEEN PATIENTS WHO

3989
03:11:54,760 --> 03:11:55,920
ARE ACTUALLY ON PROPHYLACTIC

3990
03:11:55,920 --> 03:11:57,920
MEASURE IN TERMS OF ORAL

3991
03:11:57,920 --> 03:11:59,360
ANTIBIOTICS AND GETTING OPIOIDS

3992
03:11:59,360 --> 03:12:00,640
AND WHETHER THAT HAS ANY

3993
03:12:00,640 --> 03:12:05,440
INFLUENCE ON THE CHANCE THEY

3994
03:12:05,440 --> 03:12:07,040
WILL DEVELOP UNFORTUNATELY

3995
03:12:07,040 --> 03:12:07,520
ADDICTIVE BEHAVIORS?

3996
03:12:07,520 --> 03:12:08,720
>> GREAT QUESTION.

3997
03:12:08,720 --> 03:12:10,720
WE'VE BEEN TRYING TO LOOK IN THE

3998
03:12:10,720 --> 03:12:11,800
CLINICAL LITERATURE, HAVEN'T

3999
03:12:11,800 --> 03:12:13,440
BEEN SUCCESSFUL SO FAR, I'VE

4000
03:12:13,440 --> 03:12:15,040
BEEN HOPING TO GET SOME MORE

4001
03:12:15,040 --> 03:12:18,400
STUDIES GOING IN THAT.

4002
03:12:18,400 --> 03:12:25,240
I WOULD SAY BECCA, THE 

4003
03:12:25,240 --> 03:12:27,200
I NSTRUCTOR, HER K AWARD IS

4004
03:12:27,200 --> 03:12:29,240
LOOKING AT SUBSEQUENT MODELS OF

4005
03:12:29,240 --> 03:12:32,320
OPIOID USE DISORDER AND SEES

4006
03:12:32,320 --> 03:12:34,040
LASTING EFFECTS IN THE ANIMAL

4007
03:12:34,040 --> 03:12:35,520
MODEL, THERE'S SMOKE IF NOT

4008
03:12:35,520 --> 03:12:35,840
FIRE.

4009
03:12:35,840 --> 03:12:37,560
>> VERY COOL TALK.

4010
03:12:37,560 --> 03:12:40,000
WE'LL MOVE ON, A FEW MORE

4011
03:12:40,000 --> 03:12:41,000
QUESTIONS IF YOU COULD ANSWER IN

4012
03:12:41,000 --> 03:12:42,360
THE CHAT THAT WOULD BE

4013
03:12:42,360 --> 03:12:42,720
FANTASTIC.

4014
03:12:42,720 --> 03:12:45,520
>> OF COURSE.

4015
03:12:45,520 --> 03:12:48,160
>> NEXT SPEAKER STEPHAN RUHL,

4016
03:12:48,160 --> 03:12:52,200
UNIVERSITY OF BUFFALO, STRAIGHT

4017
03:12:52,200 --> 03:13:06,520
FROM THE MOUTH, NATURAL

4018
03:13:06,520 --> 03:13:08,240
GLYCAN-BINDING TOOLS.

4019
03:13:08,240 --> 03:13:14,280
I'M TRYING TO GROW  -- GO ON

4020
03:13:14,280 --> 03:13:16,640
SCREEN SHARE.

4021
03:13:16,640 --> 03:13:17,600
THIS SHOULD WORK.

4022
03:13:17,600 --> 03:13:19,840
I WOULD LIKE TO BRING THE

4023
03:13:19,840 --> 03:13:27,200
ATTENTION BACK TO THE ORAL

4024
03:13:27,200 --> 03:13:29,320
CAVITY FROM THE GUT BECAUSE IT'S

4025
03:13:29,320 --> 03:13:31,160
BASICALLY ONE CONTINUUM.

4026
03:13:31,160 --> 03:13:33,760
I WOULD LIKE TO EMPHASIZE THAT

4027
03:13:33,760 --> 03:13:36,360
THE MICROBIOME AND ORAL CAVITY

4028
03:13:36,360 --> 03:13:40,200
IS ONE OF THE MOST RICHEST

4029
03:13:40,200 --> 03:13:42,840
MICROBIOME IN MAMMALIAN HOSTS.

4030
03:13:42,840 --> 03:13:44,360
IT IS CONNECTED WITH THE GUT

4031
03:13:44,360 --> 03:13:46,720
MICROBIOME BECAUSE IT'S ALL ONE

4032
03:13:46,720 --> 03:13:47,200
CONTINUUM.

4033
03:13:47,200 --> 03:13:49,040
AND IT HAS BEEN KNOWN FOR QUITE

4034
03:13:49,040 --> 03:13:54,560
A LONG TIME AT LEAST SINCE THE

4035
03:13:54,560 --> 03:13:57,600
'70s AND '80s THAT GLYCAN

4036
03:13:57,600 --> 03:14:03,120
MEDIATED INTERACTIONS PLAY A BIG

4037
03:14:03,120 --> 03:14:04,640
ROLE IN THE BINDING OF MICROBES

4038
03:14:04,640 --> 03:14:07,440
TO EACH OTHER AND ALSO IN THE

4039
03:14:07,440 --> 03:14:18,640
BINDING OF MICROBES HE BINDING

4040
03:14:18,640 --> 03:14:20,200
OF MICROBES TO HOST SURFACES.

4041
03:14:20,200 --> 03:14:23,840
IS 

4042
03:14:23,840 --> 03:14:32,040
SALIVA PLAYS AN IMPORTANT ROLE. 

4043
03:14:32,040 --> 03:14:44,320
THEY BIND WITH PROTEIN ADHESINS

4044
03:14:44,320 --> 03:14:45,720
TO GLYCANS.

4045
03:14:45,720 --> 03:14:50,040
GLYCAN BINDING CAN MEDIATE 

4046
03:14:50,040 --> 03:14:51,600
BINDING TO NEIGHBORING BACTERIA,

4047
03:14:51,600 --> 03:15:03,280
AND BEGINNING THE INITIATION OF

4048
03:15:03,280 --> 03:15:05,160
BIOFILMS THROUGH MICROADHESION,

4049
03:15:05,160 --> 03:15:11,600
A BUILDUP  OF COMMUNITIES AND

4050
03:15:11,600 --> 03:15:12,600
EVENTUALLY BIOFILMS.

4051
03:15:12,600 --> 03:15:16,840
MICROBES CAN BIND TO EPITHELIAL

4052
03:15:16,840 --> 03:15:20,520
SURFACES VIA GLYCAN MEDIATED

4053
03:15:20,520 --> 03:15:21,240
DIRECTIONS.

4054
03:15:21,240 --> 03:15:26,320
THEY CAN ALSO CAUSE

4055
03:15:26,320 --> 03:15:27,720
AGLUTENNATION, BEFORE THE

4056
03:15:27,720 --> 03:15:31,200
MICROBES REACH HOST SURFACES,

4057
03:15:31,200 --> 03:15:48,560
THEY BECOME AGLUTENNATED WHICH 

4058
03:15:48,560 --> 03:15:49,440
MAY REPRESENT BACTERIAL

4059
03:15:49,440 --> 03:15:52,240
CLEARANCE. 

4060
03:15:52,240 --> 03:15:53,560
THEY CAN DECORATE THEMSELVES,

4061
03:15:53,560 --> 03:15:55,440
DIETARY REQUIREMENTS, ALSO MAY

4062
03:15:55,440 --> 03:15:57,680
SHIELD FROM HOST IMMUNE SYSTEM,

4063
03:15:57,680 --> 03:16:01,760
KIND OF A BACTERIAL MIMICRY,

4064
03:16:01,760 --> 03:16:04,160
COVERING THEMSELVES WITH HOST

4065
03:16:04,160 --> 03:16:04,560
MOLECULES.

4066
03:16:04,560 --> 03:16:07,840
LASTLY MICROBES ARE IMPORTANT

4067
03:16:07,840 --> 03:16:12,560
FOR INTERACTION WITH PHAGOCYTES.

4068
03:16:12,560 --> 03:16:26,880
MOSTLY NEUTROPHILS, STEMMING 

4069
03:16:26,880 --> 03:16:27,880
FROM THE GINGIVAL FLUID.

4070
03:16:27,880 --> 03:16:31,520
THE FIRST TIME MY LABORATORY

4071
03:16:31,520 --> 03:16:32,640
DISCOVERED THESE GLYCAN-MEDIATED

4072
03:16:32,640 --> 03:16:34,080
INTERACTIONS EVER ORAL BACTERIA

4073
03:16:34,080 --> 03:16:37,240
WHEN WE LOOKED AT THE BINDING TO

4074
03:16:37,240 --> 03:16:39,640
SALIVARY GLYCOPROTEINS, WHAT YOU

4075
03:16:39,640 --> 03:16:48,200
SEE ON THE LEFT-HAND SIDE IS A

4076
03:16:48,200 --> 03:16:50,360
DOT PLOT, DEFINED GLYCAN

4077
03:16:50,360 --> 03:16:51,240
SEQUENCES.

4078
03:16:51,240 --> 03:16:58,560
WE HAVE OVERLAID THIS WITH 

4079
03:16:58,560 --> 03:17:00,800
STRING OF STREPTOCOCCUS GORDONII

4080
03:17:00,800 --> 03:17:06,040
1 FLUORESCENTLY LABELED.

4081
03:17:06,040 --> 03:17:07,480
THESE BIND TO FETUIN, THAT

4082
03:17:07,480 --> 03:17:14,200
CARRIES A LOT OF FATTY ACID, BUT

4083
03:17:14,200 --> 03:17:18,080
NOT ISIALO-FETUIN AND BIND ONLY

4084
03:17:18,080 --> 03:17:22,520
TO ALPHA2-3 AS SHOWN HERE. 

4085
03:17:22,520 --> 03:17:24,240
BUT NOT TO ALPHA2-6 LINK

4086
03:17:24,240 --> 03:17:24,600
GLYCOPROTEINS.

4087
03:17:24,600 --> 03:17:29,800
THEY DO NOT BIND TO THE

4088
03:17:29,800 --> 03:17:30,560
UNDERLYING GLYCAN.

4089
03:17:30,560 --> 03:17:34,040
SO THIS SHOWS SOME SPECIFICITY,

4090
03:17:34,040 --> 03:17:38,240
AND THIS SPECIFICITY BECOMES

4091
03:17:38,240 --> 03:17:40,920
MORE INTERESTING.

4092
03:17:40,920 --> 03:17:46,400
HERE ARE SECRETIONS OF PAROTID

4093
03:17:46,400 --> 03:17:52,080
GLAND SALIVA, SUBLINGUAL, 

4094
03:17:52,080 --> 03:18:02,360
S UBMANDIBULA, WE SEE A BAND I 

4095
03:18:02,360 --> 03:18:05,880
HAVES ILLIN SUBMANDIBLE, THIS

4096
03:18:05,880 --> 03:18:07,360
REPRESENTS THE SALIVARY MUC7,

4097
03:18:07,360 --> 03:18:09,160
THIS DISAPPEARED IF TREATED

4098
03:18:09,160 --> 03:18:11,840
PRIOR TO OVERLAY WITH THE

4099
03:18:11,840 --> 03:18:12,120
BACTERIA.

4100
03:18:12,120 --> 03:18:14,120
BINDING ALSO DOES NOT TAKE PLACE

4101
03:18:14,120 --> 03:18:17,560
WITH A MUTANT OF THE

4102
03:18:17,560 --> 03:18:20,080
STREPTOCOCCUS THAT LOST ITS

4103
03:18:20,080 --> 03:18:22,560
SIALIC BINDING ADHESION.

4104
03:18:22,560 --> 03:18:26,360
WITH THIS SPECIFICITY IN MIND,

4105
03:18:26,360 --> 03:18:29,080
IT WAS INTERESTING WHICH ARE

4106
03:18:29,080 --> 03:18:31,240
THESE ADHESINS ON THE SURFACE OF

4107
03:18:31,240 --> 03:18:33,000
BACTERIA THAT ARE RESPONSIBLE

4108
03:18:33,000 --> 03:18:34,840
FOR BINDING TO SIALIC ACIDS.

4109
03:18:34,840 --> 03:18:36,480
IT TURNED OUT, THIS WAS MOSTLY

4110
03:18:36,480 --> 03:18:41,640
THE WORK FROM PAUL SULLAM AT

4111
03:18:41,640 --> 03:18:53,560
UCSF, THAT THOSE ARE SYRIN-RICH,

4112
03:18:53,560 --> 03:18:56,720
EXTENDING FROM THE CELL WALL AND

4113
03:18:56,720 --> 03:18:59,000
CONTAIN A NON-REPEAT BINDING

4114
03:18:59,000 --> 03:19:06,840
REGION HERE..

4115
03:19:06,840 --> 03:19:09,480
THIS CONTAINS A UNIQUE DOMAIN

4116
03:19:09,480 --> 03:19:11,400
THAT BOTH ARE RESPONSIBLE FOR

4117
03:19:11,400 --> 03:19:12,720
BINDING TO SIALIC ACID.

4118
03:19:12,720 --> 03:19:17,960
YOU HAVE TO IMAGINE BACTERIA 

4119
03:19:17,960 --> 03:19:20,440
BEING COVERED WITH FUR-LIKE

4120
03:19:20,440 --> 03:19:25,280
COVER OF MANY, MANY ADHESINS,

4121
03:19:25,280 --> 03:19:28,240
THAT MULTIVALENTLY BIND TO

4122
03:19:28,240 --> 03:19:31,000
CLUSTERED GLYCAN RECEPTORS ON

4123
03:19:31,000 --> 03:19:32,040
THE BACTERIA SURFACE,

4124
03:19:32,040 --> 03:19:35,800
VELCRO-LIKE PROCESS THAT I

4125
03:19:35,800 --> 03:19:37,040
COMPARE TO BURS STICKING TO YOUR

4126
03:19:37,040 --> 03:19:39,040
SWEATER OR MAYBE IF YOU HAVE A

4127
03:19:39,040 --> 03:19:40,840
DOG YOU KNOW HOW DIFFICULT THEY

4128
03:19:40,840 --> 03:19:42,200
ARE TO REMOVE, ONCE ATTACHED

4129
03:19:42,200 --> 03:19:45,640
THEY ARE DIFFICULT TO REMOVE.

4130
03:19:45,640 --> 03:19:49,280
HERE IS AFTER SCANNING ELECTRON

4131
03:19:49,280 --> 03:19:53,040
MICROSCOPIC IMAGE OF

4132
03:19:53,040 --> 03:19:54,080
STREPTOCOCCUS EARLY COLONIZING

4133
03:19:54,080 --> 03:19:56,080
TOOTH SURFACE, SPREAD OUT LIKE A

4134
03:19:56,080 --> 03:20:06,800
MONOLAYER, LATER ON PILE UP AND 

4135
03:20:06,800 --> 03:20:07,520
FORM BIOFILMS.

4136
03:20:07,520 --> 03:20:09,960
ONE GLYCAN THAT IS A PREFERRED

4137
03:20:09,960 --> 03:20:12,320
RECEPTOR IS SIALIC ACID BECAUSE

4138
03:20:12,320 --> 03:20:17,960
IT IS ON MAMMALIAN GLYCANS THE

4139
03:20:17,960 --> 03:20:22,960
OUTER MOST, FIRST ENCOUNTERED BY

4140
03:20:22,960 --> 03:20:23,440
MICROBES.

4141
03:20:23,440 --> 03:20:32,200
SIALIC ACID IN  NATURE, OCCURS

4142
03:20:32,200 --> 03:20:35,120
IN 50 SUBTYPES, DEPENDING ON THE

4143
03:20:35,120 --> 03:20:46,520
SUGAR RING OF SIALIC ACID.

4144
03:20:46,520 --> 03:20:50,560
A GREAT STEP FORWARD WAS THE

4145
03:20:50,560 --> 03:20:51,840
AVAILABILITY OF ARRAYS, SO OUR

4146
03:20:51,840 --> 03:20:54,240
GROUP AND ALSO GROUP OF PAUL

4147
03:20:54,240 --> 03:20:59,200
SULLAM FORTUNATE TO BE ABLE TO

4148
03:20:59,200 --> 03:21:02,600
COLLABORATE WITH THE LAB THAT

4149
03:21:02,600 --> 03:21:06,200
DEVELOPED AN ARRAY CARRYING 

4150
03:21:06,200 --> 03:21:09,800
DIFFERENT SIALIC ACID SUBTYPES. 

4151
03:21:09,800 --> 03:21:14,880
WHEN WE EXPOSEED RECOMBINANT 

4152
03:21:14,880 --> 03:21:16,640
SIALIC ACID BINDING PROTEIN, AND

4153
03:21:16,640 --> 03:21:20,440
ALSO WHOLE BACTERIA TO THESE

4154
03:21:20,440 --> 03:21:22,480
GLYCAN-BINDING ARRAYS WE FOUND

4155
03:21:22,480 --> 03:21:24,480
DIFFERENT SPECTRA OF GLYCANS

4156
03:21:24,480 --> 03:21:26,360
BEING BOUND.

4157
03:21:26,360 --> 03:21:31,720
SO THERE ARE -- THERE'S

4158
03:21:31,720 --> 03:21:33,600
ADHESIN-A THAT BINDS TO GLYCANS,

4159
03:21:33,600 --> 03:21:38,600
ALSO HAVE 2, 3 LINKED TO

4160
03:21:38,600 --> 03:21:40,200
UNDERLYING GLYCAN BACKBONE.

4161
03:21:40,200 --> 03:21:44,600
OTHERS HAVE A MORE DEFINED

4162
03:21:44,600 --> 03:21:45,880
SMALLER SPECTRUM.

4163
03:21:45,880 --> 03:21:47,640
THERE'S SPECIFICITY.

4164
03:21:47,640 --> 03:21:50,560
WE'RE WONDERING NOW WHETHER THIS

4165
03:21:50,560 --> 03:21:53,200
IS SPECIFICITY MEDIATES HOST

4166
03:21:53,200 --> 03:21:53,840
TROPISM.

4167
03:21:53,840 --> 03:21:56,360
AND THERE IS ONE NATURAL ANIMAL

4168
03:21:56,360 --> 03:21:59,240
MODEL THAT ONE COULD EXPLORE

4169
03:21:59,240 --> 03:22:00,600
NAMELY DIFFERENCE BETWEEN HUMANS

4170
03:22:00,600 --> 03:22:08,320
AND GREAT APES. 

4171
03:22:08,320 --> 03:22:13,840
AND THAT GREAT APES EXPRESS 

4172
03:22:13,840 --> 03:22:15,280
SHOWN HERE, IN ADDITION.

4173
03:22:15,280 --> 03:22:19,040
HUMANS HAVE LOST THIS TYPE OF

4174
03:22:19,040 --> 03:22:19,400
GLYCAN.

4175
03:22:19,400 --> 03:22:38,240
THIS IS DUE TO AN ENZYMATIC 

4176
03:22:38,240 --> 03:22:39,080
DEACTIVATION AN ENZYME

4177
03:22:39,080 --> 03:22:40,280
CONVERTING.

4178
03:22:40,280 --> 03:22:41,040
THE LOSS IN HUMANS HAS BEEN

4179
03:22:41,040 --> 03:22:41,280
DESCRIBED.

4180
03:22:41,280 --> 03:22:44,400
THIS IS THE WORK OF SEVERAL

4181
03:22:44,400 --> 03:22:50,400
YEARS OF MY STUDENT NINA

4182
03:22:50,400 --> 03:23:06,640
THAMADILOK, WE ISOLATED

4183
03:23:06,640 --> 03:23:07,840
STREPTOCOCCI.

4184
03:23:07,840 --> 03:23:12,800
OUR HYPOTHESIS WAS THAT WE MIGHT

4185
03:23:12,800 --> 03:23:18,360
FIND BACTERIA THAT  BIND IN THE

4186
03:23:18,360 --> 03:23:19,240
GREAT APES BECAUSE THEY ARE

4187
03:23:19,240 --> 03:23:21,160
STILL ABLE TO PRODUCE THIS,

4188
03:23:21,160 --> 03:23:23,720
ABSENT IN HUMANS.

4189
03:23:23,720 --> 03:23:24,920
SURPRISINGLY, JUST THE OPPOSITE

4190
03:23:24,920 --> 03:23:30,840
WAS THE CASE. 

4191
03:23:30,840 --> 03:23:33,840
WE FOUND STREPTOCOCCUS BINDING

4192
03:23:33,840 --> 03:23:37,080
IN THE HUMORAL CAVITY, ABSENT OR

4193
03:23:37,080 --> 03:23:39,840
ALMOST ABSENT IN CHIMPANZEES AND

4194
03:23:39,840 --> 03:23:40,440
GORILLAS.

4195
03:23:40,440 --> 03:23:43,320
WHEREAS OTHER TYPES OF SIALIC

4196
03:23:43,320 --> 03:23:46,640
ACIDS WERE STILL BOUND, IN THE

4197
03:23:46,640 --> 03:23:47,240
CHIMPANZEES AND GORILLAS.

4198
03:23:47,240 --> 03:23:50,720
THIS IS A WHOLE STORY IN ITSELF.

4199
03:23:50,720 --> 03:23:54,360
WE USED A SCREENING ASSAY FOR

4200
03:23:54,360 --> 03:23:58,240
THAT, LOOKING AT THE

4201
03:23:58,240 --> 03:24:01,840
DIFFERENTIAL HEMAGGLUTINATION OF

4202
03:24:01,840 --> 03:24:02,480
HUMAN VERSE CHIMPANZEE, STILL

4203
03:24:02,480 --> 03:24:06,080
HAVE ACID ON THE SURFACE, HUMAN

4204
03:24:06,080 --> 03:24:08,360
DEVOID OF IT.

4205
03:24:08,360 --> 03:24:12,720
WE WERE LOOKING FOR THIS 

4206
03:24:12,720 --> 03:24:16,040
PHENOTYPE OF HEMAGGLUTINATION,

4207
03:24:16,040 --> 03:24:19,640
SHOWN BY A PANCAKE-LIKE

4208
03:24:19,640 --> 03:24:21,360
APPEARANCE IN THE MICROTITER

4209
03:24:21,360 --> 03:24:27,560
PLATE AND NOT OTHER

4210
03:24:27,560 --> 03:24:29,240
ERYTHROSITES.

4211
03:24:29,240 --> 03:24:33,800
WE HAD A THOUSAND STRAINS WHERE

4212
03:24:33,800 --> 03:24:37,480
WE KNEW SPECIFICITY, A POSTDOC

4213
03:24:37,480 --> 03:24:40,160
USED A FEW EXAMPLES FROM THESE

4214
03:24:40,160 --> 03:24:46,240
DIFFERENT BINDING SPECIFICITIES,

4215
03:24:46,240 --> 03:24:47,840
DIFFERENT PHENOTYPES, WHOLE

4216
03:24:47,840 --> 03:24:49,440
GENOME SEQUENCING, WITH THE

4217
03:24:49,440 --> 03:24:51,160
UNIVERSITY OF MARYLAND, PICKED A

4218
03:24:51,160 --> 03:24:56,840
FEW STRAINS FROM EACH PHYLO

4219
03:24:56,840 --> 03:25:08,080
GENETIC CLADE. 

4220
03:25:08,080 --> 03:25:09,720
THIS SORTS BACTERIA ACCORDING TO

4221
03:25:09,720 --> 03:25:11,840
SPECIES AFFILIATION.

4222
03:25:11,840 --> 03:25:17,640
IF WE CONCENTRATE ON THE  CYCLIC

4223
03:25:17,640 --> 03:25:20,320
DOMAIN WE SEE THE TREE, BRANCHES

4224
03:25:20,320 --> 03:25:32,920
OF THE TREE ARE DIVIDED TO THE 

4225
03:25:32,920 --> 03:25:34,320
SIALIC ACID SPECIFICITY.

4226
03:25:34,320 --> 03:25:36,760
STRAINS EXCLUSIVELY PRESENT IN

4227
03:25:36,760 --> 03:25:38,960
ORAL CAVITY OF HUMANS CLUSTER IN

4228
03:25:38,960 --> 03:25:40,200
ONE BRANCH.

4229
03:25:40,200 --> 03:25:47,640
WE ALSO FOUND THAT AN IMPORTANT

4230
03:25:47,640 --> 03:25:48,960
MOTIF BECOMES MODIFIED,

4231
03:25:48,960 --> 03:25:55,640
DEPENDING ON SPECIFICITY SO THAT

4232
03:25:55,640 --> 03:25:59,280
FOR THE BINDING DOMAINS FTRT OR

4233
03:25:59,280 --> 03:26:06,520
YTRT PLODIFICATION OF THIS

4234
03:26:06,520 --> 03:26:07,000
CANONICAL MOTIF.

4235
03:26:07,000 --> 03:26:14,240
BEN RECOMBINANT EXPRESSED SOME

4236
03:26:14,240 --> 03:26:16,640
OF THIS SILGEC SUBDOMAINS AND WE

4237
03:26:16,640 --> 03:26:26,800
USED THEM AS PROBES, TESTED

4238
03:26:26,800 --> 03:26:27,440
THEM.

4239
03:26:27,440 --> 03:26:33,480
I SHOWED TWO EXAMPLES OF MONEY. 

4240
03:26:33,480 --> 03:26:42,560
ONE IS A STREPTOCOCCUS ST01 THAT

4241
03:26:42,560 --> 03:26:44,440
BLINDS, GLYCOARRAY CONFIRMS,

4242
03:26:44,440 --> 03:26:50,920
BINDING  TOOL.

4243
03:26:50,920 --> 03:26:53,600
OTHER SIALIC ACID SUBSTITUTIONS

4244
03:26:53,600 --> 03:26:54,720
ARE BOUND WITH MUCH LESS

4245
03:26:54,720 --> 03:26:58,520
AFFINITY.

4246
03:26:58,520 --> 03:27:03,440
HERE IS ANOTHER STRAIN.

4247
03:27:03,440 --> 03:27:06,040
BR3.

4248
03:27:06,040 --> 03:27:07,040
EXCUSE ME.

4249
03:27:07,040 --> 03:27:08,000
THIS IS MA6.

4250
03:27:08,000 --> 03:27:14,400
THAT HAS A VERY DIFFERENT 

4251
03:27:14,400 --> 03:27:17,640
BINDING SPECTRUM, BINDS TO A 50

4252
03:27:17,640 --> 03:27:20,880
ACETYLATED FORM, SO IT'S A MUCH

4253
03:27:20,880 --> 03:27:25,440
MORE NARROW SPECIFICITY OF 

4254
03:27:25,440 --> 03:27:26,800
SIALIC ACID BINDING SHOWING

4255
03:27:26,800 --> 03:27:28,160
BACTERIAL LECTINS HAVE DIFFERENT

4256
03:27:28,160 --> 03:27:30,560
AND VERY, VERY SPECIFIC

4257
03:27:30,560 --> 03:27:32,040
AFFINITIES.

4258
03:27:32,040 --> 03:27:38,440
 

4259
03:27:38,440 --> 03:27:40,240
 

4260
03:27:40,240 --> 03:27:42,560
 

4261
03:27:42,560 --> 03:27:44,920
SO, NEXT STEP WAS TO LOOK AT THE

4262
03:27:44,920 --> 03:27:48,800
3D STRUCTURE AND THIS WAS DONE 

4263
03:27:48,800 --> 03:27:52,960
WITH TINA IVERSON AT VANDERBILT

4264
03:27:52,960 --> 03:27:53,240
UNIVERSITY.

4265
03:27:53,240 --> 03:27:54,440
AND THREE STRUCTURES WERE

4266
03:27:54,440 --> 03:28:00,560
DETERMINED IN COLLABORATION WITH

4267
03:28:00,560 --> 03:28:08,560
PAUL SULLAM'S LAB, AND WE ADDED

4268
03:28:08,560 --> 03:28:11,320
SY10, CR29 AND ST01,

4269
03:28:11,320 --> 03:28:13,280
EXPERIMENTAL STRUCTURES

4270
03:28:13,280 --> 03:28:15,840
DETERMINED FOR ST 701 AND SY 10,

4271
03:28:15,840 --> 03:28:20,160
CR 29 STRUCTURE IS ALMOST DONE.

4272
03:28:20,160 --> 03:28:20,760
THESE STRUCTURES ALL RESEMBLE

4273
03:28:20,760 --> 03:28:24,000
EACH OTHER BUT THERE ARE FINE

4274
03:28:24,000 --> 03:28:25,600
DIFFERENCES TINA FOUND THAT MAY

4275
03:28:25,600 --> 03:28:27,760
ACCOUNT FOR THE DIFFERENCES IN

4276
03:28:27,760 --> 03:28:29,880
SPECIFICITY.

4277
03:28:29,880 --> 03:28:39,640
 

4278
03:28:39,640 --> 03:28:39,800
 

4279
03:28:39,800 --> 03:28:44,440
WHAT BEN ALSO DID WAS BASED ON

4280
03:28:44,440 --> 03:28:48,240
THE INSIGHTS GAINED FROM TINA'S

4281
03:28:48,240 --> 03:28:50,320
3D STUDIES WE KNEW WHICH AMINO

4282
03:28:50,320 --> 03:28:53,240
ACIDS ARE ESSENTIAL FOR HOLDING

4283
03:28:53,240 --> 03:28:56,240
SIALIC ACID MOLECULE IN THE

4284
03:28:56,240 --> 03:28:57,840
BINDING POCKET AND WHEN MUTATED

4285
03:28:57,840 --> 03:29:01,960
AMINO ACIDS -- HE DID SINGLE

4286
03:29:01,960 --> 03:29:06,520
AMINO ACID SUBSTITUTION MUTANTS,

4287
03:29:06,520 --> 03:29:20,560
BY SUBSTITUTING ARGININE WITH

4288
03:29:20,560 --> 03:29:22,080
GLUTAMIC ACID.

4289
03:29:22,080 --> 03:29:23,640
BINDING WAS ABOLISHED.

4290
03:29:23,640 --> 03:29:26,320
WE HAD PROBES AND CONTROLS

4291
03:29:26,320 --> 03:29:27,480
IDENTICAL JUST AS THE DIFFERENCE

4292
03:29:27,480 --> 03:29:29,600
THAT ONE AMINO ACID HAS BEEN

4293
03:29:29,600 --> 03:29:30,440
EXCHANGED.

4294
03:29:30,440 --> 03:29:35,520
AND THIS IS AN IDEAL TOOL  SET

4295
03:29:35,520 --> 03:29:38,760
TO EXPLORE, TO USE THESE

4296
03:29:38,760 --> 03:29:41,440
GLYCAN-BINDING PROTEINS IN

4297
03:29:41,440 --> 03:29:42,560
VARIOUS DIFFERENT SETTINGS.

4298
03:29:42,560 --> 03:29:45,440
WE HAVE USED THEM IN FLOW

4299
03:29:45,440 --> 03:29:48,120
CYTOMETRY LOOKING AT BINDING TO

4300
03:29:48,120 --> 03:29:49,880
HUMAN NEUTROPHILS, THIS IS

4301
03:29:49,880 --> 03:29:52,440
BINDING OF HSA, YOU CAN SEE IT

4302
03:29:52,440 --> 03:29:55,400
BIND TO NEUTROPHILS AND SIALIC

4303
03:29:55,400 --> 03:29:57,400
ACID IS BEING REMOVED, BINDING

4304
03:29:57,400 --> 03:29:58,640
IS REDUCED.

4305
03:29:58,640 --> 03:30:02,440
THIS IN COLLABORATION WITH NISSI

4306
03:30:02,440 --> 03:30:05,840
VARK USED THESE PROBES IN LECTIN

4307
03:30:05,840 --> 03:30:07,240
HISTOCHEMISTRY LOOKING AT TISSUE

4308
03:30:07,240 --> 03:30:07,440
SLIDES.

4309
03:30:07,440 --> 03:30:13,000
AND WE HAVE USED THEM ALSO IN

4310
03:30:13,000 --> 03:30:16,520
FAR-WESTERN BLOTS, SERUM

4311
03:30:16,520 --> 03:30:18,240
PROTEINS AND ALSO LOOKING AT

4312
03:30:18,240 --> 03:30:22,120
HUMAN SALIVA AND MORE RECENTLY

4313
03:30:22,120 --> 03:30:30,400
ALSO AT MURINE SALIVA, USING A 

4314
03:30:30,400 --> 03:30:34,520
KNOCKOUT MOUSE SYSTEM DEFICIENT

4315
03:30:34,520 --> 03:30:41,760
IN IN N GLYCOAMINNIC ACID, 

4316
03:30:41,760 --> 03:30:43,920
SHOWS CLEAR DIFFERENCE, IT BINDS

4317
03:30:43,920 --> 03:30:47,920
TO WILDTYPE BUT NOT KNOCKOUT

4318
03:30:47,920 --> 03:30:49,120
MOUSE PROTEIN.

4319
03:30:49,120 --> 03:30:51,520
MORE RECENTLY MY LAB IS ALSO

4320
03:30:51,520 --> 03:31:01,040
TRYING TO USE THESE PROTEINS IN 

4321
03:31:01,040 --> 03:31:05,440
BIOFILMS, AND WE TRY TO LOOK AT

4322
03:31:05,440 --> 03:31:07,240
BACTERIAL CO-ADHESION, DONE BY

4323
03:31:07,240 --> 03:31:14,720
CHRISTIAN AHERN IN MY LAB. 

4324
03:31:14,720 --> 03:31:18,080
GOING BEYOND THIS TOOLBOX, WE

4325
03:31:18,080 --> 03:31:20,320
HAVE ALSO DONE IN SILICO

4326
03:31:20,320 --> 03:31:21,640
ANALYSIS IN COLLABORATION WITH

4327
03:31:21,640 --> 03:31:24,640
UNIVERSITY OF MARYLAND, WHAT YOU

4328
03:31:24,640 --> 03:31:32,840
SEE HERE IS A PHYLO GENETIC TREE

4329
03:31:32,840 --> 03:31:33,720
OF STREPTOCOCCUS, REPRESENTING

4330
03:31:33,720 --> 03:31:40,280
ALL THE SPECIES AND STRAINS THAT

4331
03:31:40,280 --> 03:31:42,800
HAVE BEEN SEQUENCED.

4332
03:31:42,800 --> 03:31:46,960
THE GRAY STICKING OUT REPRESENTS

4333
03:31:46,960 --> 03:31:51,200
SUCH STRAINS THAT CARRY A SERINE

4334
03:31:51,200 --> 03:31:54,080
REPEAT PROTEIN.

4335
03:31:54,080 --> 03:31:56,400
SEVERAL STREPTOCOCCAL SPECIES

4336
03:31:56,400 --> 03:32:01,960
HAVE REPEAT PROTEINS BUT ONLY

4337
03:32:01,960 --> 03:32:06,520
THESE HIGHLIGHTED HERE HAVE

4338
03:32:06,520 --> 03:32:08,840
PROPANES CONTAINS AS CYCLIC,

4339
03:32:08,840 --> 03:32:10,480
HIGHLIGHTED IN RED, THE LONG

4340
03:32:10,480 --> 03:32:11,240
STICKS HERE.

4341
03:32:11,240 --> 03:32:15,120
THE SURPRISING RESULT WAS THAT

4342
03:32:15,120 --> 03:32:17,280
THE REPEAT PROTEINS THAT CARRY

4343
03:32:17,280 --> 03:32:19,040
CYCLIC DOMAINS CLUSTER IN ONE

4344
03:32:19,040 --> 03:32:23,560
REGION OF THE PHYLO GENETIC TREE

4345
03:32:23,560 --> 03:32:27,480
AND ALL SPECIES THAT ARE

4346
03:32:27,480 --> 03:32:29,480
POSITIVE HERE ARE INHABITANTS OF

4347
03:32:29,480 --> 03:32:38,560
THE ORAL CAVITY. 

4348
03:32:38,560 --> 03:32:52,400
AT LEAST INHABITANTS OF MUCOSAL

4349
03:32:52,400 --> 03:32:54,840
SURFACES.

4350
03:32:54,840 --> 03:32:58,080
BUT WHAT WE DID FURTHER WAS WE

4351
03:32:58,080 --> 03:33:03,040
TOOK NOW THESE RED HIGHLIGHTED

4352
03:33:03,040 --> 03:33:07,840
REPEAT PROTEINS AND ONLY ALIGNED

4353
03:33:07,840 --> 03:33:09,400
THEIR CYCLIC AND UNIQUE DOMAINS.

4354
03:33:09,400 --> 03:33:13,240
HERE ONLY THE CYCLIC AND UNIQUE

4355
03:33:13,240 --> 03:33:21,480
DOMAINS ARE ALIGNED, AND 

4356
03:33:21,480 --> 03:33:24,440
ALIGNMENT NOW DOES NOT REPRESENT

4357
03:33:24,440 --> 03:33:26,440
THE DIFFERENT SPECIES ANYMORE,

4358
03:33:26,440 --> 03:33:28,360
DOESN'T CLUSTER SPECIES, IT

4359
03:33:28,360 --> 03:33:32,840
CLUSTERS PHENOTYPIC ACTIVITY OF

4360
03:33:32,840 --> 03:33:33,200
SIALIC.

4361
03:33:33,200 --> 03:33:35,680
AND FOR US IT WAS VERY

4362
03:33:35,680 --> 03:33:40,880
INTERESTING THAT THIS THESE 

4363
03:33:40,880 --> 03:33:42,520
BACTERIA WE FOUND BIND, CLUSTER

4364
03:33:42,520 --> 03:33:45,640
IN ONE BRANCH OF THE

4365
03:33:45,640 --> 03:33:49,720
PHYLOGENETIC TREE, BELONGING TO

4366
03:33:49,720 --> 03:33:50,440
THE STREPTOCOCCUS

4367
03:33:50,440 --> 03:33:51,760
[AUDIO DISTORTION]

4368
03:33:51,760 --> 03:33:57,160
SO WE PREDICT THAT OTHER BRANCH

4369
03:33:57,160 --> 03:34:00,640
OF THE PHYLOGENETIC TREE MIGHT

4370
03:34:00,640 --> 03:34:04,040
REPRESENT SPECIFICITIES FOR

4371
03:34:04,040 --> 03:34:06,280
OTHER SIALIC ACIDS.

4372
03:34:06,280 --> 03:34:12,440
SO, THESE BINDING LECTINS, WE

4373
03:34:12,440 --> 03:34:14,520
ENVISION AS HELPFUL IN DIAGNOSIS

4374
03:34:14,520 --> 03:34:18,960
OF ORAL DISEASE AND PERHAPS

4375
03:34:18,960 --> 03:34:22,120
EVENTUALLY ALSO AS THERAPEUTIC

4376
03:34:22,120 --> 03:34:25,400
WAY OF INHIBITING BACTERIAL OR

4377
03:34:25,400 --> 03:34:28,680
STREPTOCOCCAL ADHESION TO SIALIC

4378
03:34:28,680 --> 03:34:31,080
ACID COUNTER RECEPTORS IN THE

4379
03:34:31,080 --> 03:34:31,920
HOST.

4380
03:34:31,920 --> 03:34:34,840
WITH THIS  THANK YOU FOR

4381
03:34:34,840 --> 03:34:35,560
ATTENTION.

4382
03:34:35,560 --> 03:34:40,520
THIS IS MY LAB IN TIMES OF THE

4383
03:34:40,520 --> 03:34:41,320
PANDEMIC.

4384
03:34:41,320 --> 03:34:44,200
HERE ARE THE COLLABORATORS WHO

4385
03:34:44,200 --> 03:34:47,800
CONTRIBUTED TO VARIOUS ASPECTS

4386
03:34:47,800 --> 03:34:49,040
OF OUR PROJECT.

4387
03:34:49,040 --> 03:34:50,840
WE COULDN'T HAVE DONE THIS

4388
03:34:50,840 --> 03:34:54,560
WITHOUT THE SUPPORT BY NIH AND

4389
03:34:54,560 --> 03:34:57,840
NIDCR. 

4390
03:34:57,840 --> 03:34:58,480
THANK YOU VERY MUCH.

4391
03:34:58,480 --> 03:35:02,240
>> WE HAVE A QUESTION IN THE

4392
03:35:02,240 --> 03:35:10,360
CHAT.

4393
03:35:10,360 --> 03:35:15,880
IN ADDITION TO ATTACHMENT SITE,

4394
03:35:15,880 --> 03:35:18,480
IS THERE KNOWN PREFERENCE?

4395
03:35:18,480 --> 03:35:22,520
I GOT TRIPPED UP.

4396
03:35:22,520 --> 03:35:24,000
>> SO, THE METABOLIC PREFERENCE,

4397
03:35:24,000 --> 03:35:27,600
IT IS LIKELY THAT THEY MIGHT

4398
03:35:27,600 --> 03:35:28,960
HAVE METABOLIC PREFERENCE FOR

4399
03:35:28,960 --> 03:35:31,200
SIALIC ACIDS AND THAT'S ANOTHER

4400
03:35:31,200 --> 03:35:34,600
INTERESTING QUESTION WHICH WE

4401
03:35:34,600 --> 03:35:44,360
ARE ABOUT TO INVESTIGATE.

4402
03:35:44,360 --> 03:35:46,400
[AUDIO DISTORTION]

4403
03:35:46,400 --> 03:35:49,680
IT IS KNOWN THAT SOME

4404
03:35:49,680 --> 03:35:51,200
STREPTOCOCCUS CAN PRODUCE

4405
03:35:51,200 --> 03:35:52,640
SIALIDASE, SOME CANNOT, THERE'S

4406
03:35:52,640 --> 03:35:54,800
ALREADY KNOWLEDGE IN THE

4407
03:35:54,800 --> 03:35:57,720
LITERATURE BUT WE HAVE CONDUCTED

4408
03:35:57,720 --> 03:36:00,160
IN SILICO SEARCH FOR PRESENCE

4409
03:36:00,160 --> 03:36:03,480
AND ABSENCE OF SIALIDASE IN THE

4410
03:36:03,480 --> 03:36:10,880
GENUS STREPTOCOCCUS, I DIDN'T

4411
03:36:10,880 --> 03:36:14,200
BRING THIS DATA BUT MAYBE NEXT

4412
03:36:14,200 --> 03:36:14,440
TIME.

4413
03:36:14,440 --> 03:36:16,080
I'M SURE THERE'S SPECIFICITY IN

4414
03:36:16,080 --> 03:36:18,520
TERMS OF DIETARY REQUIREMENTS.

4415
03:36:18,520 --> 03:36:23,960
>> ANOTHER QUESTION, DO YOU

4416
03:36:23,960 --> 03:36:25,400
THINK BINDING MICROBES MIGHT

4417
03:36:25,400 --> 03:36:32,880
ORIGINATE FROM RED MEAT DIET OF

4418
03:36:32,880 --> 03:36:33,600
HUMANS?

4419
03:36:33,600 --> 03:36:34,840
>> AN INTERESTING QUESTION.

4420
03:36:34,840 --> 03:36:38,000
OF COURSE WE WERE VERY PUZZLED

4421
03:36:38,000 --> 03:36:42,840
BY THE FINDING THAT WE FIND

4422
03:36:42,840 --> 03:36:49,160
BACTERIA THAT BIND TO GLYCAN.

4423
03:36:49,160 --> 03:36:51,760
THAT HUMANS CAN NORMALLY NOT

4424
03:36:51,760 --> 03:36:52,000
PRODUCE.

4425
03:36:52,000 --> 03:36:54,400
[AUDIO DISTORTION] 

4426
03:36:54,400 --> 03:36:56,760
SO THE MOST LOGICAL EXPLANATION

4427
03:36:56,760 --> 03:36:59,960
THROUGH DIETARY INTAKE, SO IT

4428
03:36:59,960 --> 03:37:04,200
COULD EITHER BE THAT THE ACID

4429
03:37:04,200 --> 03:37:10,000
BECOMES INCORPORATED INTO HOST

4430
03:37:10,000 --> 03:37:11,120
OWN GLYCANS.

4431
03:37:11,120 --> 03:37:16,200
HOWEVER WHEN WE LOOK AT SALIVA,

4432
03:37:16,200 --> 03:37:19,600
WE NEVER FOUND ANY TRACES OF

4433
03:37:19,600 --> 03:37:23,680
5GC, MORE LIKELY THROUGH THE

4434
03:37:23,680 --> 03:37:25,440
INTAKE OF ANIMAL FOOD, THIS

4435
03:37:25,440 --> 03:37:30,840
COULD BE MEAT, COULD ALSO BE

4436
03:37:30,840 --> 03:37:33,240
DAIRY PRODUCTS, N GLYCOMINI ACID

4437
03:37:33,240 --> 03:37:34,720
CAN GET INTO THE ORAL MICROBIOME

4438
03:37:34,720 --> 03:37:41,920
AND CERTAIN MIKE ROAMS  --

4439
03:37:41,920 --> 03:37:45,680
MICROBES CAN EXPRESS ON THE

4440
03:37:45,680 --> 03:37:48,040
SURFACE, IT'S VERY POSSIBLE THAT

4441
03:37:48,040 --> 03:37:57,880
THOSE ARE THE NATURAL COUNTER 

4442
03:37:57,880 --> 03:37:58,520
RECEPTORS FOR THOSE BINDING

4443
03:37:58,520 --> 03:38:03,040
STREPTOCOCCI WE HEAR IN THE ORAL

4444
03:38:03,040 --> 03:38:03,440
CAVITY.

4445
03:38:03,440 --> 03:38:06,560
>> THANK YOU FOR YOUR SEMINAR.

4446
03:38:06,560 --> 03:38:09,600
VERY INTERESTING. 

4447
03:38:09,600 --> 03:38:10,640
TWO QUESTIONS.

4448
03:38:10,640 --> 03:38:21,240
FIRST IS IS THERE ANYTHING KNOWN

4449
03:38:21,240 --> 03:38:23,640
ABOUT PATHOGENETICTY OF

4450
03:38:23,640 --> 03:38:26,000
STREPTOCOCCUS BINDING TO SIALIC

4451
03:38:26,000 --> 03:38:32,160
ACID AND VARIATIONS BETWEEN

4452
03:38:32,160 --> 03:38:34,080
SPECIES COULD THAT BE USED TO

4453
03:38:34,080 --> 03:38:36,240
IMPROVE THE TOOL IF SOMETHING

4454
03:38:36,240 --> 03:38:37,000
BINDS MORE TIGHTLY FROM ONE

4455
03:38:37,000 --> 03:38:40,360
SPECIES HAVE YOU LOOKED AT

4456
03:38:40,360 --> 03:38:42,200
BINDING AFFINITY IS THE MAIN

4457
03:38:42,200 --> 03:38:43,160
POINT OF MY QUESTION.

4458
03:38:43,160 --> 03:38:44,520
>> THANK YOU FOR THIS

4459
03:38:44,520 --> 03:38:45,840
INTERESTING QUESTION.

4460
03:38:45,840 --> 03:38:50,440
TO ANSWER THE FIRST PART, DOES

4461
03:38:50,440 --> 03:38:53,040
THIS DIFFERENCE IN SIALIC ACID

4462
03:38:53,040 --> 03:38:56,960
SPECIFICITY PLAY A ROLE IN

4463
03:38:56,960 --> 03:38:58,520
PATHOLOGY, SO WE KNOW AND THIS

4464
03:38:58,520 --> 03:39:07,760
HAS BEEN SHOWN BY OTHERS THAT

4465
03:39:07,760 --> 03:39:10,800
BINDING TO SIALIC PLAYS A ROLE,

4466
03:39:10,800 --> 03:39:13,280
PARTICULARLY MEDIATED BY BINDING

4467
03:39:13,280 --> 03:39:18,240
TO PLATELETS IN BLOOD THAT THEN

4468
03:39:18,240 --> 03:39:22,360
ARE ACCUMULATE ON THE HEART

4469
03:39:22,360 --> 03:39:24,800
VALVE AND BACTERIAL VEGETATIONS

4470
03:39:24,800 --> 03:39:29,240
CAN FORM THERE. 

4471
03:39:29,240 --> 03:39:31,440
WHETHER THE DIFFERENCE PLAYS A

4472
03:39:31,440 --> 03:39:33,400
DIFFERENCE IN THAT REGARD IS A

4473
03:39:33,400 --> 03:39:34,440
VERY INTERESTING QUESTION.

4474
03:39:34,440 --> 03:39:38,440
BECAUSE IT HAS BEEN SHOWN IN

4475
03:39:38,440 --> 03:39:40,840
SOME STUDIES THROUGH DIETARY

4476
03:39:40,840 --> 03:39:42,040
INTAKE, IT CAN BE EXPRESSED ON

4477
03:39:42,040 --> 03:39:43,000
THE HEART VALVE.

4478
03:39:43,000 --> 03:39:46,880
OUR LAB HAS NOT BEEN ABLE YET TO

4479
03:39:46,880 --> 03:39:49,200
DO ANY EXPERIMENTS SUPPORTING

4480
03:39:49,200 --> 03:39:50,280
THIS HYPOTHESIS, THIS

4481
03:39:50,280 --> 03:39:52,360
DIFFERENCE, THAT ONE OF THESE

4482
03:39:52,360 --> 03:39:56,440
BACTERIA MAY BE MORE PATHOGENIC

4483
03:39:56,440 --> 03:39:57,480
THAN THE OTHER.

4484
03:39:57,480 --> 03:40:04,040
THIS WOULD BE AN INTERESTING 

4485
03:40:04,040 --> 03:40:13,320
NEXT STEP TO DO.

4486
03:40:13,320 --> 03:40:37,680
THE 

4487
03:40:37,680 --> 03:40:40,640
>> THEY ARE DIFFERENT FOR

4488
03:40:40,640 --> 03:40:44,400
DIFFERENT SIALIC ACID BUT WE

4489
03:40:44,400 --> 03:40:44,760
HAVEN'T TESTED

4490
03:40:44,760 --> 03:40:45,800
[AUDIO DISTORTION]

4491
03:40:45,800 --> 03:40:49,320
TO DO THAT WOULD NEED TO GO TOP

4492
03:40:49,320 --> 03:40:52,200
SUBSTRATES AND THIS WOULD BE AN

4493
03:40:52,200 --> 03:41:02,640
INTERESTING NEXT STEP, TO USE

4494
03:41:02,640 --> 03:41:05,920
GLYCAN ARRAY.

4495
03:41:05,920 --> 03:41:09,400
WE'RE PLANNING TO DO THAT USING

4496
03:41:09,400 --> 03:41:10,480
SALIVA GLYCOPROTEINS, RELEASE

4497
03:41:10,480 --> 03:41:13,520
THE GLYCANS AND EXPRESS THEM ON

4498
03:41:13,520 --> 03:41:14,200
AN ARRAY.

4499
03:41:14,200 --> 03:41:19,440
AND THAT WOULD TELL THE 

4500
03:41:19,440 --> 03:41:21,200
DIFFERENCE.

4501
03:41:21,200 --> 03:41:22,040
THANK YOU.

4502
03:41:22,040 --> 03:41:29,960
>> WE'LL MOVE TO THE NEXT

4503
03:41:29,960 --> 03:41:35,000
SPEAKER.

4504
03:41:35,000 --> 03:41:37,480
DR. MICHAEL FISCHBACH FROM

4505
03:41:37,480 --> 03:41:37,920
STANFORD UNIVERSITY.

4506
03:41:37,920 --> 03:41:38,800
>> THANK YOU.

4507
03:41:38,800 --> 03:41:42,400
THANKS TO THE ORGANIZERS FOR

4508
03:41:42,400 --> 03:41:43,480
INVITING ME.

4509
03:41:43,480 --> 03:41:46,280
A DIFFERENT TOPIC THAN I

4510
03:41:46,280 --> 03:41:48,240
ANTICIPATED, A NEW STORY WE'RE

4511
03:41:48,240 --> 03:41:49,440
EXCITED ABOUT, I'M LOOKING

4512
03:41:49,440 --> 03:41:51,480
FORWARD TO SHARING.

4513
03:41:51,480 --> 03:41:55,320
THIS IS ALL WORK LED BY AN

4514
03:41:55,320 --> 03:41:56,240
EXTRAORDINARY

4515
03:41:56,240 --> 03:41:57,240
PHYSICIAN-SCIENTIST IN THE LAB,

4516
03:41:57,240 --> 03:42:09,040
ERIN CHEN, A BIG ASSIST FROM

4517
03:42:09,040 --> 03:42:10,720
YASMINE BELKAID.

4518
03:42:10,720 --> 03:42:11,680
THE BROAD OVERARCHING QUESTION

4519
03:42:11,680 --> 03:42:15,560
THAT WE WERE TRYING TO ADDRESS

4520
03:42:15,560 --> 03:42:17,680
IN SOME PART WAS WHAT THE

4521
03:42:17,680 --> 03:42:21,040
IMMUNE -- HOW THE IMMUNE SYSTEM

4522
03:42:21,040 --> 03:42:22,440
SEES A COMMENSAL, WHETHER --

4523
03:42:22,440 --> 03:42:24,120
WE'RE ALL FAMILIAR WITH HOW THE

4524
03:42:24,120 --> 03:42:26,480
IMMUNE SYSTEM HANDLES AN ACTIVE

4525
03:42:26,480 --> 03:42:29,720
INFECTION BUT THE QUESTION IS

4526
03:42:29,720 --> 03:42:32,880
FOR COLONIZING BARRIER SURFACE, 

4527
03:42:32,880 --> 03:42:34,840
SKIN AND GUT MAINLY, WHAT IS THE

4528
03:42:34,840 --> 03:42:36,320
IMMUNE SYSTEM SEEING OR DOING

4529
03:42:36,320 --> 03:42:37,160
THAT IT'S COMPLETELY IGNORING

4530
03:42:37,160 --> 03:42:38,200
THEM BECAUSE THEY ARE ON THE

4531
03:42:38,200 --> 03:42:39,040
OPPOSITE SIDE OF THE BARRIER OR

4532
03:42:39,040 --> 03:42:42,120
IS IT SOMETHING ELSE?

4533
03:42:42,120 --> 03:42:44,400
SO THIS BROAD QUESTION IS WHAT

4534
03:42:44,400 --> 03:42:48,040
GOT US INTERESTED IN THIS.

4535
03:42:48,040 --> 03:42:50,440
THERE'S A BUNCH OF WORK DONE

4536
03:42:50,440 --> 03:42:53,520
PRIOR, SUMMARIZING HERE WITH

4537
03:42:53,520 --> 03:42:56,040
THREE LESSONS FOR IMMUNE

4538
03:42:56,040 --> 03:42:57,720
MODULATION BY THE MICROBIOME,

4539
03:42:57,720 --> 03:42:59,120
IMPORTANT BECAUSE THEY SHAPE THE

4540
03:42:59,120 --> 03:43:00,040
NARRATIVE AND SPECIFIC FORM OF

4541
03:43:00,040 --> 03:43:03,840
THE QUESTION WE WANT TO ADDRESS.

4542
03:43:03,840 --> 03:43:06,480
HERE I'M GOING US TO ADAPTIVE

4543
03:43:06,480 --> 03:43:07,880
IMMUNE RESPONSE, ON THE T-CELL

4544
03:43:07,880 --> 03:43:08,840
RESPONSE THERE'S BEEN A LOT OF

4545
03:43:08,840 --> 03:43:11,120
WORK IN THAT AREA MORE THAN ANY

4546
03:43:11,120 --> 03:43:12,200
OTHER AREA AND THE FIRST LESSON

4547
03:43:12,200 --> 03:43:15,920
OF THE THREE IS THAT WHICH BUG

4548
03:43:15,920 --> 03:43:16,920
YOU'RE TALKING ABOUT DETERMINES

4549
03:43:16,920 --> 03:43:19,560
WHAT KIND OF T CELL COMES OUT ON

4550
03:43:19,560 --> 03:43:22,360
THE OTHER EN.

4551
03:43:22,360 --> 03:43:27,200
IF YOU COLONIZE MICE WITH STAPH

4552
03:43:27,200 --> 03:43:33,400
EPIDERMIDIS, YOU GET A BURST.

4553
03:43:33,400 --> 03:43:37,800
SAME WITH SFB EXCEPT T CELLS ARE

4554
03:43:37,800 --> 03:43:39,120
TH 27 AND WITH WITH THIS YOU GET

4555
03:43:39,120 --> 03:43:41,600
A BURST ON THE OTHER SIDE BUT

4556
03:43:41,600 --> 03:43:43,040
THEY ARE REGULATORY T CELLS, SO

4557
03:43:43,040 --> 03:43:46,000
THE NATURE OF THE BUG APPEARS TO

4558
03:43:46,000 --> 03:43:47,960
WHAT DETERMINE WHAT KINDS OF T

4559
03:43:47,960 --> 03:43:49,360
CELL IS INDUCED.

4560
03:43:49,360 --> 03:43:51,160
I SHOULD SAY THIS STORY I'M

4561
03:43:51,160 --> 03:44:09,200
GOING TO TELL IS ABOUT STAPH

4562
03:44:09,200 --> 03:44:09,520
EPIDEHMIDIS.

4563
03:44:09,520 --> 03:44:11,880
IT IS CONSERVED IN NON-HUMAN

4564
03:44:11,880 --> 03:44:17,200
PRIMATE, NOT SOMETHING PECULIAR

4565
03:44:17,200 --> 03:44:19,840
TO THE MOUSE.

4566
03:44:19,840 --> 03:44:22,000
T CELLS THAT RESULT EXPRESS

4567
03:44:22,000 --> 03:44:26,640
T-CELL RECEPTOR LOOKING FOR A 

4568
03:44:26,640 --> 03:44:28,840
PEPTIDE THAT DERIVES, THIS

4569
03:44:28,840 --> 03:44:29,880
DEGREE OF SPECIFICITY YOU WOULD

4570
03:44:29,880 --> 03:44:32,400
ASSOCIATE WITH RESPONSE TO

4571
03:44:32,400 --> 03:44:33,520
INFECTION, ALSO PRETTY

4572
03:44:33,520 --> 03:44:34,680
INTERESTING FROM A UTILITY

4573
03:44:34,680 --> 03:44:35,840
PERSPECTIVE BECAUSE AS WE ALL

4574
03:44:35,840 --> 03:44:38,320
KNOW PEOPLE ARE GOING TO GREAT

4575
03:44:38,320 --> 03:44:39,280
LENGTHS TO ENGINEER ANTIGEN

4576
03:44:39,280 --> 03:44:41,200
SPECIFIC T CELLS BECAUSE THEY

4577
03:44:41,200 --> 03:44:43,200
ARE SO USEFUL.

4578
03:44:43,200 --> 03:44:45,280
ANTIGEN-SPECIFIC CD8 T CELLS ARE

4579
03:44:45,280 --> 03:44:48,800
HELPFUL IN ONCOLOGY, ALSO THE

4580
03:44:48,800 --> 03:44:49,480
AGENT OF KILLING FOR INFECTIOUS

4581
03:44:49,480 --> 03:44:52,560
DISEASE, T CELL COMPONENT OF

4582
03:44:52,560 --> 03:44:53,320
THAT, AND ANTIGEN-SPECIFIC

4583
03:44:53,320 --> 03:44:56,040
REGULATORY T CELLS HAVE BECOME

4584
03:44:56,040 --> 03:44:57,640
GREAT IF FOR AUTOIMMUNE DISEASE,

4585
03:44:57,640 --> 03:44:59,360
THE DEGREE OF SPECIFICITY HAS

4586
03:44:59,360 --> 03:44:59,920
CAUGHT OUR ATTENTION AND

4587
03:44:59,920 --> 03:45:02,200
ATTENTION OF OTHER PEOPLE IN THE

4588
03:45:02,200 --> 03:45:02,640
FIELD.

4589
03:45:02,640 --> 03:45:06,240
THE THIRD LESSON IS PERHAPS THE

4590
03:45:06,240 --> 03:45:08,840
MOST PROFOUND, THAT ALL THE THIS

4591
03:45:08,840 --> 03:45:10,880
HAPPENS WITHOUT A BREACH IN

4592
03:45:10,880 --> 03:45:11,200
BARRIER.

4593
03:45:11,200 --> 03:45:12,160
TEXT BOOK IMMUNOLOGY TELLS YOU

4594
03:45:12,160 --> 03:45:19,640
IN ORDER TO GET ADAPTIVE IMMUNE

4595
03:45:19,640 --> 03:45:20,800
RESPONSE YOU NEED INFECTION OR

4596
03:45:20,800 --> 03:45:22,720
VACCINATION, NEEDS TO BE

4597
03:45:22,720 --> 03:45:24,760
INFILTRATION OF INNATE IMMUNE

4598
03:45:24,760 --> 03:45:26,920
CELLS, SWELLING, A FIVE ALARM

4599
03:45:26,920 --> 03:45:30,640
FIRE, WHAT RESULTS FROM THAT ARE

4600
03:45:30,640 --> 03:45:33,440
ANTIGEN-SPECIFIC T AND B CELLS,

4601
03:45:33,440 --> 03:45:34,440
CANONICAL IMMUNOLOGY.

4602
03:45:34,440 --> 03:45:38,080
THIS IS THE BIG PIECE OF

4603
03:45:38,080 --> 03:45:39,920
CURIOSITY, THAT WHEN YOU

4604
03:45:39,920 --> 03:45:41,080
COLONIZE ANIMALS WITH CERTAIN

4605
03:45:41,080 --> 03:45:42,680
BUGS FROM THE MICROBIOME, YOU

4606
03:45:42,680 --> 03:45:45,080
GET TO THE SAME ENDPOINT,

4607
03:45:45,080 --> 03:45:52,040
ANTIGEN-SPECIFIC T AND B CELLS

4608
03:45:52,040 --> 03:45:54,200
AND IMMUNE MEMORY, BUT NO

4609
03:45:54,200 --> 03:45:54,840
INFECTION.

4610
03:45:54,840 --> 03:45:59,720
THIS IS THE PUZZLE WE'RE TRYING

4611
03:45:59,720 --> 03:46:00,680
TO FIGURE OUT.

4612
03:46:00,680 --> 03:46:02,120
TWO BIG QUESTIONS ABOUT IMMUNE

4613
03:46:02,120 --> 03:46:03,040
MODULATION WE AND OTHERS ARE

4614
03:46:03,040 --> 03:46:03,800
INTERESTED IN.

4615
03:46:03,800 --> 03:46:05,280
ONE IS HOW DOES IT WORK?

4616
03:46:05,280 --> 03:46:07,840
SECOND IS WHY DOES IT HAPPEN?

4617
03:46:07,840 --> 03:46:08,880
HOW AND WHY.

4618
03:46:08,880 --> 03:46:12,560
WE VERY MUCH STARTED OUT ON THE

4619
03:46:12,560 --> 03:46:17,840
HOW, AND BY HITTING A POINT OF

4620
03:46:17,840 --> 03:46:18,320
FRUSTRATION BECAME MORE

4621
03:46:18,320 --> 03:46:19,320
INTERESTED IN THE WHY.

4622
03:46:19,320 --> 03:46:21,040
WHY IS HOST DEVELOPING WHAT

4623
03:46:21,040 --> 03:46:23,040
APPEARS TO BE PREEMPTIVE

4624
03:46:23,040 --> 03:46:25,360
ADAPTIVE IMMUNE RESPONSE AGAINST

4625
03:46:25,360 --> 03:46:25,920
COLONISTS?

4626
03:46:25,920 --> 03:46:27,840
WHAT DO THESE CELLS FUNCTIONALLY

4627
03:46:27,840 --> 03:46:30,640
CAPABLE OF DOING, WHAT IS THEIR

4628
03:46:30,640 --> 03:46:33,040
ROLE IN LIFE?

4629
03:46:33,040 --> 03:46:35,320
OUR APPROACH WAS

4630
03:46:35,320 --> 03:46:36,160
COUNTERINTUITIVE.

4631
03:46:36,160 --> 03:46:39,120
I SHOULD TELL YOU ERIN'S POINT

4632
03:46:39,120 --> 03:46:47,200
OF ENVY TO DEVELOP A SYSTEM TO

4633
03:46:47,200 --> 03:46:53,080
MANIPULATE STAFF EPIDERMIDIS.

4634
03:46:53,080 --> 03:46:56,080
VERY FEW MUTANTS WERE MADE.

4635
03:46:56,080 --> 03:47:02,480
ERIN DEVELOPED A WAY TO

4636
03:47:02,480 --> 03:47:10,200
MANIPULATE GENOME OF STAPH

4637
03:47:10,200 --> 03:47:11,640
EPIDERMIDIS.

4638
03:47:11,640 --> 03:47:14,280
THIS REMAINS A PAUSED STORY,

4639
03:47:14,280 --> 03:47:16,560
INSTEAD OF TRYING TO FIGURE OUT

4640
03:47:16,560 --> 03:47:18,880
MECHANISM, WE'RE TRYING TO

4641
03:47:18,880 --> 03:47:20,840
FIGURE OUT WHAT FUNCTIONAL THESE

4642
03:47:20,840 --> 03:47:22,240
DO.

4643
03:47:22,240 --> 03:47:24,760
WE DID SOMETHING THAT'S

4644
03:47:24,760 --> 03:47:25,200
COUNTERINTUITIVE BUT

4645
03:47:25,200 --> 03:47:25,480
INTERESTING.

4646
03:47:25,480 --> 03:47:26,960
I TOLD YOU IN AN EARLIER SLIDE

4647
03:47:26,960 --> 03:47:31,280
THAT THE T CELLS THAT RESULT

4648
03:47:31,280 --> 03:47:32,200
FROM STAPH EPIDERMIDIS

4649
03:47:32,200 --> 03:47:37,560
COLONIZING A MOUSE HAVE A T-CELL

4650
03:47:37,560 --> 03:47:38,440
RECEPTOR, HAVE A PEPTIDE ANTIGEN

4651
03:47:38,440 --> 03:47:39,520
THEY ARE LOOKING FOR.

4652
03:47:39,520 --> 03:47:42,640
WE DECIDED TO TRICK THIS PROCESS

4653
03:47:42,640 --> 03:47:45,840
AND REDIRECT BY EXPRESSING TUMOR

4654
03:47:45,840 --> 03:47:46,600
ANTIGEN INSIDE.

4655
03:47:46,600 --> 03:47:48,760
WHAT WE HOPED WOULD HAPPEN IS

4656
03:47:48,760 --> 03:47:52,760
THAT THROUGH THE SAME PROCESS OF

4657
03:47:52,760 --> 03:47:53,800
COLONIZATION AND PRESENTATION

4658
03:47:53,800 --> 03:47:54,920
COULD GET CD8 T CELLS SPECIFIC

4659
03:47:54,920 --> 03:47:59,200
FOR THE BUG BUT SPECIFIC FOR

4660
03:47:59,200 --> 03:47:59,760
NON-NATIVE ANTIGEN, TUMOR

4661
03:47:59,760 --> 03:48:03,280
ANTIGEN, WOULD BE LICENSED BY

4662
03:48:03,280 --> 03:48:07,280
THE SAME IMMUNE PROCESS THAT

4663
03:48:07,280 --> 03:48:08,440
RESPONDS TO COLONIST BUT

4664
03:48:08,440 --> 03:48:09,200
SPECIFICITY FOR TUMOR IN MOUSE,

4665
03:48:09,200 --> 03:48:10,680
SEND THEM OFF TO SEE WHAT THEY

4666
03:48:10,680 --> 03:48:12,920
ARE CAPABLE OF DOING.

4667
03:48:12,920 --> 03:48:18,560
THERE WERE TWO KIND OF OPPOSITE

4668
03:48:18,560 --> 03:48:19,520
HYPOTHESIS.

4669
03:48:19,520 --> 03:48:22,120
ONE WAS THAT THESE CD8 T CELLS

4670
03:48:22,120 --> 03:48:27,520
WERE UNLIKE OTHER CD8 T CELLS IN

4671
03:48:27,520 --> 03:48:28,040
IMMUNOLOGY, MORE COLONIST

4672
03:48:28,040 --> 03:48:29,120
INTERACTIVE AND CALM AND WOULD

4673
03:48:29,120 --> 03:48:31,280
REMAIN IN THE TISSUE THAT WAS

4674
03:48:31,280 --> 03:48:32,920
COLONIZED, NOT DO MUCH OF

4675
03:48:32,920 --> 03:48:34,360
ANYTHING, A PEACE-KEEPING ROLE.

4676
03:48:34,360 --> 03:48:36,880
WHEREAS THE OTHER POLAR OPPOSITE

4677
03:48:36,880 --> 03:48:39,480
HYPOTHESIS, THEY ARE LIKE CD8 T

4678
03:48:39,480 --> 03:48:41,040
CELLS ELSEWHERE IN IMMUNOLOGY,

4679
03:48:41,040 --> 03:48:42,920
WILLING TO TRAVEL SYSTEMICALLY

4680
03:48:42,920 --> 03:48:43,560
THROUGHOUT THE ANIMAL, LICENSED

4681
03:48:43,560 --> 03:48:44,520
TO KILL.

4682
03:48:44,520 --> 03:48:46,640
WE WERE TRYING TO DIFFERENTIATE

4683
03:48:46,640 --> 03:48:49,120
BETWEEN THESE TWO POSSIBILITIES.

4684
03:48:49,120 --> 03:48:58,560
ERIN CONSTRUCTED A SERIES OF

4685
03:48:58,560 --> 03:49:00,760
STAPH EPIDERMIDIS MUTANTS, USING

4686
03:49:00,760 --> 03:49:03,440
PEPTIDES USED AS AN ANTIGEN IN

4687
03:49:03,440 --> 03:49:05,040
IMMUNOLOGY, LOTS OF TOOLS EXIST

4688
03:49:05,040 --> 03:49:07,040
TO DETECT.

4689
03:49:07,040 --> 03:49:11,560
WE DIDN'T KNOW WHERE TO EXPRESS

4690
03:49:11,560 --> 03:49:14,480
THIS TO ELICIT RESPONSE ERIN

4691
03:49:14,480 --> 03:49:18,320
TRIED  CYTOPLASM OR ATTACHED TO

4692
03:49:18,320 --> 03:49:19,880
THE WALL OR SMALL EPITOPE ON THE

4693
03:49:19,880 --> 03:49:22,200
WALL AND SO ON INCLUDING

4694
03:49:22,200 --> 03:49:23,360
SECRETED CONSTRUCTS.

4695
03:49:23,360 --> 03:49:25,080
IT TURNS OUT THROUGH SOME IN

4696
03:49:25,080 --> 03:49:27,680
VITRO WORK THAT WE DID, WE FOUND

4697
03:49:27,680 --> 03:49:35,120
COMBINATION OF WALL ATTACHED AND

4698
03:49:35,120 --> 03:49:38,120
SECRETED EPITOPES WOULD BE

4699
03:49:38,120 --> 03:49:39,000
USEFUL.

4700
03:49:39,000 --> 03:49:41,640
WE TESTED THIS HYPOTHESIS, IN

4701
03:49:41,640 --> 03:49:44,480
RETROSPECT NOT THE RIGHT MODEL,

4702
03:49:44,480 --> 03:49:48,280
DIFFICULT TUMOR MODEL, WE TAKE

4703
03:49:48,280 --> 03:49:50,280
CONVENTIONALLY COLONIZED BLACK 6

4704
03:49:50,280 --> 03:49:53,280
MICE, NOT GERM FREE OR

4705
03:49:53,280 --> 03:49:54,280
PRE-TREATED, NOT SCRUBBED OR

4706
03:49:54,280 --> 03:49:55,200
ANTIBIOTIC TREATED OR SHAVED,

4707
03:49:55,200 --> 03:50:00,760
RIGHT OUT OF THE SHIPPING

4708
03:50:00,760 --> 03:50:03,640
CONTAINER FROM TAKONIK, INJECT

4709
03:50:03,640 --> 03:50:07,840
TUMOR CELLS B 16 MELANOMA FROM

4710
03:50:07,840 --> 03:50:11,640
THE BLACK 6 MICE, YOU CAN INJECT

4711
03:50:11,640 --> 03:50:13,440
IT, IMMUNE COMPETENT, NOTHING

4712
03:50:13,440 --> 03:50:15,400
HAS CHANGED, YOU CAN STUDY

4713
03:50:15,400 --> 03:50:20,440
IMMUNE RESPONSE TO TUMOR IN ITS

4714
03:50:20,440 --> 03:50:22,760
FULL GLORY.

4715
03:50:22,760 --> 03:50:25,800
B 16 MELANOMA CELLS DON'T

4716
03:50:25,800 --> 03:50:27,640
RESPOND WELL TO IMMUNE-DIRECTED

4717
03:50:27,640 --> 03:50:30,360
THERAPIES, THE TUMOR KEEPS

4718
03:50:30,360 --> 03:50:31,400
IMMUNE CELLS OUT EFFICIENTLY.

4719
03:50:31,400 --> 03:50:33,040
THIS TURNS OUT TO HAVE BEEN A

4720
03:50:33,040 --> 03:50:38,120
HIGH  BAR TO SET.

4721
03:50:38,120 --> 03:50:45,640
THE BUG IS THE ONLY THING ADDED,

4722
03:50:45,640 --> 03:50:47,240
RUBBED GENTLY ON THE HEAD OF THE

4723
03:50:47,240 --> 03:50:49,640
MOUSE, THAT'S THE TREATMENT.

4724
03:50:49,640 --> 03:50:51,880
SO HERE WE'RE COMPARING APPLYING

4725
03:50:51,880 --> 03:50:55,080
NOTHING TO THE MICE VERSUS

4726
03:50:55,080 --> 03:51:02,440
APPLYING THE CONTROL STRAIN OF 

4727
03:51:02,440 --> 03:51:05,120
STAPH EPIDERMIDIS WITH EMPTY

4728
03:51:05,120 --> 03:51:07,800
PLASMID VERSUS A WALL EXPRESSED

4729
03:51:07,800 --> 03:51:20,440
EPITOPE AND OTHER SECRETED

4730
03:51:20,440 --> 03:51:22,520
OVALBUMUNIN CONSTRUCT, THE

4731
03:51:22,520 --> 03:51:24,320
OVALBUMUNIN WITH LIGHTER AND

4732
03:51:24,320 --> 03:51:25,880
SMALLER TUMORS, JUMPING OUT AT

4733
03:51:25,880 --> 03:51:26,440
US.

4734
03:51:26,440 --> 03:51:29,600
THIS IS WHAT WE WERE HOPING TO

4735
03:51:29,600 --> 03:51:31,840
SEE BUT SURPRISED BY MAGNITUDE

4736
03:51:31,840 --> 03:51:34,560
GIVEN HOW AGGRESSIVE TUMORS ARE

4737
03:51:34,560 --> 03:51:35,040
WHEN THEY GROW.

4738
03:51:35,040 --> 03:51:37,120
ERIN WAS STRUCK BY THE FACT THE

4739
03:51:37,120 --> 03:51:39,920
TUMOR CELLS ARE INJECTED INTO

4740
03:51:39,920 --> 03:51:42,200
THE FLANK OF THE MOUSE, HIP,

4741
03:51:42,200 --> 03:51:43,200
GENTLY APPLYING THE BUG TO THE

4742
03:51:43,200 --> 03:51:45,880
HEAD OF THE MOUSE, IN A WAY

4743
03:51:45,880 --> 03:51:47,800
THAT'S ACTION AT A DISTANCE,

4744
03:51:47,800 --> 03:51:49,440
SEEING A VERY STRONG EFFECT ON

4745
03:51:49,440 --> 03:51:50,760
PRIMARY TUMOR SITE IN THE FLANK

4746
03:51:50,760 --> 03:51:52,440
OF THE MOUSE FROM A GENTLE

4747
03:51:52,440 --> 03:51:54,160
APPLICATION OF BUG TO THE HEAD

4748
03:51:54,160 --> 03:51:55,880
AND SO WE OF COURSE WERE

4749
03:51:55,880 --> 03:51:57,240
IMMEDIATELY INTRIGUED.

4750
03:51:57,240 --> 03:51:58,600
THERE ARE A COUPLE THINGS I NEED

4751
03:51:58,600 --> 03:52:00,200
TO TELL YOU ABOUT THAT ARE

4752
03:52:00,200 --> 03:52:01,840
IMPORTANT FOR UNDERSTANDING.

4753
03:52:01,840 --> 03:52:03,520
FIRST IS THAT IF SHE DOES

4754
03:52:03,520 --> 03:52:05,200
EXACTLY THE SAME THING BUT

4755
03:52:05,200 --> 03:52:06,880
APPLIES BUG THAT'S BEEN HEAT

4756
03:52:06,880 --> 03:52:09,280
KILLED WE SEE NO RESPONSE.

4757
03:52:09,280 --> 03:52:12,120
THIS IS NOT SIMPLY THE IMMUNE

4758
03:52:12,120 --> 03:52:19,280
SYSTEM RESPONDING TO WHAT WOULD 

4759
03:52:19,280 --> 03:52:22,320
AMOUNT TO AN INERT ANTIGEN PLUS

4760
03:52:22,320 --> 03:52:23,760
ADJUVANT, THIS REQUIRES THE BUG

4761
03:52:23,760 --> 03:52:25,000
TO BE ALIVE.

4762
03:52:25,000 --> 03:52:27,960
THAT'S POINT ONE.

4763
03:52:27,960 --> 03:52:32,520
SECOND POINT, WE DID THE

4764
03:52:32,520 --> 03:52:33,720
EXPERIMENT DIFFERENT USING

4765
03:52:33,720 --> 03:52:35,200
METASTATIC TUMOR TO ANSWER THE

4766
03:52:35,200 --> 03:52:36,640
QUESTION, I TOLD YOU THAT THIS

4767
03:52:36,640 --> 03:52:40,640
SEEMS LIKE ACTION AT A DISTANCE,

4768
03:52:40,640 --> 03:52:41,640
COLONIZE HEAD, SEE TUMOR IN THE

4769
03:52:41,640 --> 03:52:44,040
FLANK GO DOWN IN SIZE.

4770
03:52:44,040 --> 03:52:46,240
PROBLEM WAS THAT MICE GROOM EACH

4771
03:52:46,240 --> 03:52:48,640
OTHER AND THEMSELVES SO WE

4772
03:52:48,640 --> 03:52:49,560
FIGURED THEY WERE SPREADING THE

4773
03:52:49,560 --> 03:52:52,120
BUG ALL OVER THEIR SKIN, MAKING

4774
03:52:52,120 --> 03:52:53,280
IT POSSIBLE THERE WAS BUG

4775
03:52:53,280 --> 03:52:55,200
GROWING ON THE SURFACE OF THE

4776
03:52:55,200 --> 03:52:56,840
SKIN NEAR WHERE THE SUBCUTANEOUS

4777
03:52:56,840 --> 03:52:58,520
SITE OF THE TUMOR WAS AND WANTED

4778
03:52:58,520 --> 03:52:59,880
TO FIGURE OUT DOES THE BUG NEED

4779
03:52:59,880 --> 03:53:01,840
TO BE NEAR THE TUMOR TO ACT.

4780
03:53:01,840 --> 03:53:03,880
SO IN ORDER TO ANSWER THAT

4781
03:53:03,880 --> 03:53:08,440
QUESTION INSTEAD OF INJECTING

4782
03:53:08,440 --> 03:53:10,520
TUMOR CELLS SUBCUTANEOUSLY

4783
03:53:10,520 --> 03:53:13,120
INJECTED INTRAVENOUSLY IN THE

4784
03:53:13,120 --> 03:53:18,240
TAIL VEIN, THEY DEVELOP RAMPANT

4785
03:53:18,240 --> 03:53:20,800
METASTASES MAINLY IN THE LUNG,

4786
03:53:20,800 --> 03:53:23,040
FAR FROM THE SITE.

4787
03:53:23,040 --> 03:53:27,920
DOES THE BUG NEED TO BE NEAR THE

4788
03:53:27,920 --> 03:53:28,240
TUMOR?

4789
03:53:28,240 --> 03:53:33,760
IT DOES NOT, VERY STRONG 

4790
03:53:33,760 --> 03:53:35,720
EFFECT, SO THIS WAS ACTION AT A

4791
03:53:35,720 --> 03:53:36,600
DISTANCE.

4792
03:53:36,600 --> 03:53:39,320
A PIECE OF DATA I'M NOT SHOWING,

4793
03:53:39,320 --> 03:53:41,600
ERIN WAS ABLE TO SEE LONG

4794
03:53:41,600 --> 03:53:43,520
INDUCED T CELLS TRAVEL FROM THE

4795
03:53:43,520 --> 03:53:45,400
SKIN DRAINING LYMPH NODE TO THE

4796
03:53:45,400 --> 03:53:49,440
TUMOR, SEES THEM IN BOTH PLACES,

4797
03:53:49,440 --> 03:53:50,160
WE DO THINK OF THE IMMUNE

4798
03:53:50,160 --> 03:53:53,600
TRAINING HAPPENS IN THE SKIN AND

4799
03:53:53,600 --> 03:53:58,200
T CELLS LEAVE THE SKIN AND 

4800
03:53:58,200 --> 03:54:02,040
TRAVEL TO THE TUMOR.

4801
03:54:02,040 --> 03:54:04,840
THEY GENERALIZES IN IMPORTANT

4802
03:54:04,840 --> 03:54:05,400
WAYS.

4803
03:54:05,400 --> 03:54:06,640
WE'VE BEEN USING OVALBUMUNIN AS

4804
03:54:06,640 --> 03:54:12,480
A MODEL BECAUSE IT'S USEFUL AND

4805
03:54:12,480 --> 03:54:13,200
HIGHLY IMMUNOGENIC, WE WONDERED

4806
03:54:13,200 --> 03:54:15,920
WHETHER THIS WOULD WORK WITH A

4807
03:54:15,920 --> 03:54:19,640
REAL WORLD ANTIGEN, NOT ONE

4808
03:54:19,640 --> 03:54:20,920
OPTIMIZED IMMUNOLOGICALLY.

4809
03:54:20,920 --> 03:54:23,040
INSTEAD WE USED NATURALLY

4810
03:54:23,040 --> 03:54:25,280
OCCURRING MUTATED PEPTIDES FROM

4811
03:54:25,280 --> 03:54:27,240
THE TUMOR, NEOANTIGENS, TO SEE

4812
03:54:27,240 --> 03:54:28,440
WHETHER THIS WOULD WORK IN

4813
03:54:28,440 --> 03:54:30,520
ANYTHING LIKE THE SAME WAY.

4814
03:54:30,520 --> 03:54:32,520
IT DOES.

4815
03:54:32,520 --> 03:54:34,560
ANTI-TUMOR EFFECT IS COMPARABLY

4816
03:54:34,560 --> 03:54:37,240
STRONG IF YOU COLONIZE MICE WITH

4817
03:54:37,240 --> 03:54:39,760
STAPH EPIDERMIDIS THAT EXPRESS

4818
03:54:39,760 --> 03:54:44,840
NEOANTIGENS INSTEAD OF 

4819
03:54:44,840 --> 03:54:49,640
OVALBUMUNIN, NOT A PECULIARARITY

4820
03:54:49,640 --> 03:54:51,760
CAUSED BY OVALBUMUNIN.

4821
03:54:51,760 --> 03:54:52,640
FOR HISTORICAL REASONS, THIS IS

4822
03:54:52,640 --> 03:54:55,720
THE WAY WE SET IT UP AT THE

4823
03:54:55,720 --> 03:54:57,520
BEGINNING, MOST EXPERIMENTS THAT

4824
03:54:57,520 --> 03:54:58,560
SHOWN BEFORE NOW, I'LL CLICK

4825
03:54:58,560 --> 03:55:00,440
BACK TO THE PREVIOUS SITE SO YOU

4826
03:55:00,440 --> 03:55:02,480
CAN SEE, INVOLVE A TIME LINE

4827
03:55:02,480 --> 03:55:05,080
WHERE MICE ARE COLONIZED BY

4828
03:55:05,080 --> 03:55:06,520
STAPH EPIDERMIDIS AHEAD OF TIME

4829
03:55:06,520 --> 03:55:19,360
AND TUMOR CELLS ARE INJECTED 

4830
03:55:19,360 --> 03:55:21,880
SUBCUTANEOUSLY OR I.V

4831
03:55:21,880 --> 03:55:24,480
B 16 MELANOMA GROWS SO FAST IF

4832
03:55:24,480 --> 03:55:27,160
YOU WAIT THEY GET OUT OF

4833
03:55:27,160 --> 03:55:27,440
CONTROL.

4834
03:55:27,440 --> 03:55:29,240
THE IMMUNE RESPONSE TO A

4835
03:55:29,240 --> 03:55:34,200
COLONIST, TO ANYTHING IF YOU'RE

4836
03:55:34,200 --> 03:55:35,280
LOOKING FOR ADAPTIVE T-CELL

4837
03:55:35,280 --> 03:55:36,680
RESPONSE, TAKES 7 TO 10 DAYS,

4838
03:55:36,680 --> 03:55:42,760
THE WINDOW OF TIME IS NARROW,

4839
03:55:42,760 --> 03:55:45,880
WITH THIS TUMOR MODEL.

4840
03:55:45,880 --> 03:55:50,480
IF FIRST INJECT I.V. MELANOMA 

4841
03:55:50,480 --> 03:55:53,640
CELLS AND COLONIZE WITH STAFF

4842
03:55:53,640 --> 03:55:55,440
YOU GET A STRONG EFFECT.

4843
03:55:55,440 --> 03:55:58,560
WE DO THINK THAT IN PRINCIPLE

4844
03:55:58,560 --> 03:56:00,360
THIS COULD WORK, IN TREATMENT

4845
03:56:00,360 --> 03:56:03,120
MODE, NOT JUST IN PROPHYLAXIS

4846
03:56:03,120 --> 03:56:03,320
MODE.

4847
03:56:03,320 --> 03:56:08,480
I'LL END BY SHOWING TWO

4848
03:56:08,480 --> 03:56:11,560
EXPERIMENTS THAT SPEAK TO

4849
03:56:11,560 --> 03:56:11,920
TRANSLATABILITY.

4850
03:56:11,920 --> 03:56:13,320
WE NOTICED THE T CELLS INDUCED

4851
03:56:13,320 --> 03:56:16,720
BY STAPH EPIDERMIDIS AND END UP

4852
03:56:16,720 --> 03:56:20,480
IN TUMOR LOOK PARTIALLY --

4853
03:56:20,480 --> 03:56:22,200
EXPRESSING MARKER P1 INDICATING

4854
03:56:22,200 --> 03:56:25,160
THAT THEY COULD BE DEREPRESSED

4855
03:56:25,160 --> 03:56:30,120
FURTHER BY GIVING MICE

4856
03:56:30,120 --> 03:56:33,080
CHECKPOINT INHIBITORS, SO WE

4857
03:56:33,080 --> 03:56:38,360
TRIED A COMBINATION, SMALL DOSE,

4858
03:56:38,360 --> 03:56:39,640
AND ADDED THE BUG.

4859
03:56:39,640 --> 03:56:41,840
THE QUESTION WAS WHETHER THE

4860
03:56:41,840 --> 03:56:44,440
COMBINATION OF THE TWO WOULD BE

4861
03:56:44,440 --> 03:56:45,920
SYNERGISTIC.

4862
03:56:45,920 --> 03:56:49,040
AND THE ANSWER STRIKINGLY, THEY

4863
03:56:49,040 --> 03:56:50,200
ARE SYNERGISTIC, THE MICE NOT

4864
03:56:50,200 --> 03:56:53,520
ONLY IS THE SIZE OF THE TUMOR

4865
03:56:53,520 --> 03:56:57,360
SMALLER BUT THE TUMORS ARE IN

4866
03:56:57,360 --> 03:56:58,360
MOST MICE CLEARED ENTIRELY.

4867
03:56:58,360 --> 03:57:01,440
A 

4868
03:57:01,440 --> 03:57:03,200
AFTER TWO WEEKS THE BUG IS GONE,

4869
03:57:03,200 --> 03:57:05,440
NOT A GOOD COLONIST.

4870
03:57:05,440 --> 03:57:07,240
FROM A SMALL EXPOSURE TO THIS

4871
03:57:07,240 --> 03:57:09,960
BUG MICE ARE CLEARING TUMORS

4872
03:57:09,960 --> 03:57:11,400
ENTIRELY WHICH LEADS TO A STRONG

4873
03:57:11,400 --> 03:57:12,960
GAIN IN SURVIVAL, ALL THE

4874
03:57:12,960 --> 03:57:15,400
UNTREATED MICE WILL END UP

4875
03:57:15,400 --> 03:57:17,320
DYING, ALL THE TREATED MICE WILL

4876
03:57:17,320 --> 03:57:18,680
END UP LIVING.

4877
03:57:18,680 --> 03:57:20,200
MOREOVER IF YOU TAKE THE SAME

4878
03:57:20,200 --> 03:57:22,440
MICE THAT CLEARED THEIR TUMOR

4879
03:57:22,440 --> 03:57:24,280
NOW THEY HAVE LONG SINCE STOPPED

4880
03:57:24,280 --> 03:57:26,480
SEEING BUG, THE BUG HAS GONE

4881
03:57:26,480 --> 03:57:28,160
AWAY, YOU RECHALLENGE WITH TUMOR

4882
03:57:28,160 --> 03:57:36,080
CELLS, TUMOR CELLS DON'T GROW.

4883
03:57:36,080 --> 03:57:37,400
THIS TRANSIENT EXPOSURE YIELDED

4884
03:57:37,400 --> 03:57:38,440
LASTING IMMUNE MEMORY, AT LEAST

4885
03:57:38,440 --> 03:57:40,760
LASTING ON THE TIME SCALE OF

4886
03:57:40,760 --> 03:57:41,280
THIS EXPERIMENT.

4887
03:57:41,280 --> 03:57:42,600
THIS IS PRETTY EXCITING,

4888
03:57:42,600 --> 03:57:46,560
SOMETHING THAT WE THINK SUPPORTS

4889
03:57:46,560 --> 03:57:46,960
TRANSLATABILITY.

4890
03:57:46,960 --> 03:57:49,640
FINALLY IF YOU COMBINE THE

4891
03:57:49,640 --> 03:57:53,040
TREATMENT WITH BUG IN TREATMENT

4892
03:57:53,040 --> 03:57:55,520
MODE, AFTER TUMOR CELLS HAVE

4893
03:57:55,520 --> 03:57:57,760
BEEN INJECTED, YOU GET A STRONG

4894
03:57:57,760 --> 03:57:58,600
RESPONSE.

4895
03:57:58,600 --> 03:58:00,800
SO AGAIN THIS IS SOMETHING WE

4896
03:58:00,800 --> 03:58:02,440
WERE SURPRISED TO SEE BECAUSE

4897
03:58:02,440 --> 03:58:08,560
THE THINGS YOU HAVE TO ADD TO

4898
03:58:08,560 --> 03:58:15,920
ANTI-PD-1 AND ANTI-CTLA-4 ARE

4899
03:58:15,920 --> 03:58:16,640
AGGRESSIVE.

4900
03:58:16,640 --> 03:58:18,040
VERSUS TREATMENT HERE, VERY

4901
03:58:18,040 --> 03:58:21,560
MILD, COLONIZING THE SKIN GENTLY

4902
03:58:21,560 --> 03:58:23,440
WITH Q-TIP WITH A BUG THAT

4903
03:58:23,440 --> 03:58:24,960
DOESN'T CAUSE OTHER SIDE

4904
03:58:24,960 --> 03:58:25,360
EFFECTS.

4905
03:58:25,360 --> 03:58:27,600
SO THERE'S SOMETHING INTERESTING

4906
03:58:27,600 --> 03:58:28,720
GOING ON HERE, JUST THAT

4907
03:58:28,720 --> 03:58:30,240
COMBINATION OF TREATMENTS IS

4908
03:58:30,240 --> 03:58:32,560
YELLING A STRONG ANTI-TUMOR

4909
03:58:32,560 --> 03:58:32,840
RESPONSE.

4910
03:58:32,840 --> 03:58:35,960
AND WE'RE REALLY EXCITED BY IT.

4911
03:58:35,960 --> 03:58:37,200
WE DON'T KNOW EVERYTHING ABOUT

4912
03:58:37,200 --> 03:58:38,680
HOW THIS WORKS, WE KNOW VERY

4913
03:58:38,680 --> 03:58:40,400
LITTLE ABOUT THE MECHANISM BUT

4914
03:58:40,400 --> 03:58:42,840
OUR MODEL TO DATE WE THINK THAT

4915
03:58:42,840 --> 03:58:52,240
IN THE SKIN COLONIZATION IS

4916
03:58:52,240 --> 03:58:54,120
YIELDING A RESPONSE, I OF WE

4917
03:58:54,120 --> 03:58:55,280
THINK THE COMBINATION OF THESE

4918
03:58:55,280 --> 03:58:56,480
TWO IS REQUIRED.

4919
03:58:56,480 --> 03:58:57,800
THEY THEN TRAVEL TO THE TUMOR.

4920
03:58:57,800 --> 03:59:01,440
I'M NOT SURE WHETHER THROUGH THE

4921
03:59:01,440 --> 03:59:02,960
BLOODSTREAM OR LYMPHATICS BUT

4922
03:59:02,960 --> 03:59:04,640
END UP THERE AND KILL TUMOR

4923
03:59:04,640 --> 03:59:05,040
CELLS.

4924
03:59:05,040 --> 03:59:07,320
LET ME COMPARE WHAT WE'VE

4925
03:59:07,320 --> 03:59:09,760
LEARNED ABOUT THIS COLONIST

4926
03:59:09,760 --> 03:59:11,640
RESPONSE TO THE MORE COMMON

4927
03:59:11,640 --> 03:59:12,400
INFECTION PROGRAM.

4928
03:59:12,400 --> 03:59:14,400
WE KNEW THE PURPOSE OF THE T

4929
03:59:14,400 --> 03:59:21,080
CELL COMPONENT OF ADAPTIVE

4930
03:59:21,080 --> 03:59:24,680
IMMUNITY IS TO KILL CELLS.

4931
03:59:24,680 --> 03:59:27,200
WE HADN'T REALIZED THESE ARE

4932
03:59:27,200 --> 03:59:28,640
ALSO LICENSED TO KILL,

4933
03:59:28,640 --> 03:59:29,200
PREVIOUSLY BEEN THOUGHT THEY

4934
03:59:29,200 --> 03:59:32,600
PLAYED ROLES THAT WERE MORE

4935
03:59:32,600 --> 03:59:33,960
HOMEOSTATIC AND TISSUE REPAIR

4936
03:59:33,960 --> 03:59:35,440
AND KEEPING THE PEACE IN THE

4937
03:59:35,440 --> 03:59:36,880
COLONIZED TISSUE, SO THIS WAS A

4938
03:59:36,880 --> 03:59:38,040
NEW FINDING.

4939
03:59:38,040 --> 03:59:39,240
WE LEARNED T CELLS ARE WILLING

4940
03:59:39,240 --> 03:59:41,880
TO TRAVEL TO OTHER PARTS OF THE

4941
03:59:41,880 --> 03:59:44,520
BODY AND ACT AGGRESSIVELY.

4942
03:59:44,520 --> 03:59:46,560
WHAT WE THINK THIS SUGGESTS IS

4943
03:59:46,560 --> 03:59:48,200
THAT WHAT THE HOST NEEDS TO DO

4944
03:59:48,200 --> 03:59:53,480
IN THE PRESENCE OF A COLONIST IS

4945
03:59:53,480 --> 03:59:54,920
SEEK OUT COLONIST PREEMPTIVELY

4946
03:59:54,920 --> 03:59:56,280
AND DEVELOP IMMUNE RESPONSE

4947
03:59:56,280 --> 03:59:57,360
BEFORE INFECTION HAPPENS.

4948
03:59:57,360 --> 04:00:00,320
THIS IS NEW.

4949
04:00:00,320 --> 04:00:03,080
THE HOST IS SURVEILLING BARRIER

4950
04:00:03,080 --> 04:00:06,840
SURFACES  PRESUMABLY IT'S

4951
04:00:06,840 --> 04:00:08,520
INEVITABLE YOU'LL GET NICKS AND

4952
04:00:08,520 --> 04:00:10,840
CUTS AND SCRAPES AND BECOME

4953
04:00:10,840 --> 04:00:12,400
BACTEREMIC, AND SO WHAT THE HOST

4954
04:00:12,400 --> 04:00:16,280
IS TRYING TO DO HERE IS TO

4955
04:00:16,280 --> 04:00:17,000
PREEMPT ACTIVELY DEVELOP

4956
04:00:17,000 --> 04:00:19,320
ADAPTIVE IMMUNITY SO WHEN YOU

4957
04:00:19,320 --> 04:00:23,040
BECOME INFECTED, YOU WON'T DIE.

4958
04:00:23,040 --> 04:00:36,720
DEATH FROM STAPH EPIDERMIDIS IS

4959
04:00:36,720 --> 04:00:37,360
EXCEEDINGLY RARE.

4960
04:00:37,360 --> 04:00:38,760
WE THINK THIS IS PREVENTING YOU

4961
04:00:38,760 --> 04:00:39,320
FROM DYING.

4962
04:00:39,320 --> 04:00:41,880
IF WE TRICK THE HOST INTO

4963
04:00:41,880 --> 04:00:43,120
THINKING THE TUMOR IS INFECTED,

4964
04:00:43,120 --> 04:00:44,760
THEN THE HOST DIRECTS A VERY

4965
04:00:44,760 --> 04:00:45,440
AGGRESSIVE IMMUNE RESPONSE

4966
04:00:45,440 --> 04:00:46,440
AGAINST THE TUMOR AND THAT'S

4967
04:00:46,440 --> 04:00:48,440
WHAT WE THINK IS HAPPENING HERE.

4968
04:00:48,440 --> 04:00:49,360
THANK YOU FOR LISTENING.

4969
04:00:49,360 --> 04:00:51,360
I WANT TO THANK OUR FUNDERS AND

4970
04:00:51,360 --> 04:00:56,280
FOLKS IN THE LAB. 

4971
04:00:56,280 --> 04:00:58,480
HAPPY TO TAKE QUESTIONS.

4972
04:00:58,480 --> 04:00:59,640
>> I DON'T SEE QUESTIONS IN THE

4973
04:00:59,640 --> 04:01:00,320
CHAT.

4974
04:01:00,320 --> 04:01:04,400
I HAVE A QUESTION. 

4975
04:01:04,400 --> 04:01:07,560
THERE'S TWO STAFF VARIATIONS,

4976
04:01:07,560 --> 04:01:11,600
ONE TETHERED TO SURFACE, ONE

4977
04:01:11,600 --> 04:01:11,880
SECRETING.

4978
04:01:11,880 --> 04:01:16,160
IF YOU JUST HAVE SECRETION

4979
04:01:16,160 --> 04:01:19,720
VERSION, YOU CAN MIX WITH STAPH

4980
04:01:19,720 --> 04:01:21,240
IS IT HAVING STAPH PRESENT ABLE

4981
04:01:21,240 --> 04:01:27,200
TO TAKE UP STAPH IN THAT

4982
04:01:27,200 --> 04:01:30,560
ENVIRONMENT, IS IS THAT

4983
04:01:30,560 --> 04:01:34,320
SUFFICIENT OR DOES IT HAVE TO BE

4984
04:01:34,320 --> 04:01:37,120
TETHERED TO SEE IF IT'S CAPABLE

4985
04:01:37,120 --> 04:01:38,600
OF ELIMINATING THE MELANOMA

4986
04:01:38,600 --> 04:01:39,240
MODEL?

4987
04:01:39,240 --> 04:01:51,680
>> WE TRIED TO ADD ANTIGEN NOT

4988
04:01:51,680 --> 04:01:54,200
COVALENTLY TETHERED, THAT

4989
04:01:54,200 --> 04:01:55,160
DOESN'T WORK.

4990
04:01:55,160 --> 04:01:57,920
WE HAVEN'T NAILED WHAT THE

4991
04:01:57,920 --> 04:02:00,520
ANTIGEN REQUIREMENTS ARE BUT

4992
04:02:00,520 --> 04:02:05,000
THINK YOU NEED MINIMALLY CD8 AND

4993
04:02:05,000 --> 04:02:06,840
CD4 EPITOPE FOR B 16 MELANOMA AT

4994
04:02:06,840 --> 04:02:11,280
LEAST, MAYBE DIFFERENT FOR

4995
04:02:11,280 --> 04:02:19,480
OTHERS BUT IN THIS CASE YOU NEED

4996
04:02:19,480 --> 04:02:20,480
BOTH.

4997
04:02:20,480 --> 04:02:22,680
SOMETHING PEOPLE HAVE SEEN WITH

4998
04:02:22,680 --> 04:02:29,440
CAR T CELLS, I DON'T KNOW THE

4999
04:02:29,440 --> 04:02:30,040
MINIMAL ANTIGEN REQUIREMENTS.

5000
04:02:30,040 --> 04:02:44,520
>> THERE'S A FEW QUESTIONS IN 

5001
04:02:44,520 --> 04:02:44,800
THE CHAT.

5002
04:02:44,800 --> 04:02:46,640
WHAT'S YOUR BEST GUESS HOW IT

5003
04:02:46,640 --> 04:02:48,640
WORKS AT A DISTANCE ACROSS THE

5004
04:02:48,640 --> 04:02:49,080
BARRIER?

5005
04:02:49,080 --> 04:02:50,080
>> THAT'S A GREAT QUESTION.

5006
04:02:50,080 --> 04:02:54,520
WE DON'T KNOW AND WOULD LOVE TO

5007
04:02:54,520 --> 04:02:56,160
KNOW.

5008
04:02:56,160 --> 04:02:58,520
THE WAY I RESTATE, BEGGING

5009
04:02:58,520 --> 04:02:59,960
FORGIVENESS, WHAT IS THE

5010
04:02:59,960 --> 04:03:01,760
MECHANISM OF SURVEILLANCE, HOW

5011
04:03:01,760 --> 04:03:04,720
DOES THE IMMUNE SYSTEM SEE?

5012
04:03:04,720 --> 04:03:08,040
THE ANSWER IS I DON'T KNOW.

5013
04:03:08,040 --> 04:03:11,280
SOMEHOW, IT COULD BE THROUGH

5014
04:03:11,280 --> 04:03:13,960
DENDRITIC CELL OR ANTIGEN

5015
04:03:13,960 --> 04:03:15,840
PRESENTING CELL, REACHING

5016
04:03:15,840 --> 04:03:18,600
THROUGH THE EPITHELIUM INTO A

5017
04:03:18,600 --> 04:03:21,320
FOLLICLE AND GRABBING CELLULAR

5018
04:03:21,320 --> 04:03:23,720
MATERIAL BUT THERE'S A SPECIAL

5019
04:03:23,720 --> 04:03:27,040
QUESTION HERE, CD8 T CELLS, HOW

5020
04:03:27,040 --> 04:03:28,360
THEY ARE INDUCED.

5021
04:03:28,360 --> 04:03:30,560
THOSE USUALLY ONLY RESULT FROM

5022
04:03:30,560 --> 04:03:35,640
INFECTION INSIDE THE CYTOPLASM,

5023
04:03:35,640 --> 04:03:40,960
LIKE LISTERIA OR A VIRUS, SO IT

5024
04:03:40,960 --> 04:03:43,000
IS ATTRACTIVE TO SPECULATE THIS

5025
04:03:43,000 --> 04:03:44,440
BUG ENDS UP SOMEHOW STUCK INSIDE

5026
04:03:44,440 --> 04:03:45,760
OF A CELL.

5027
04:03:45,760 --> 04:03:48,000
YOU DON'T THINK OF YOUR COLONIST

5028
04:03:48,000 --> 04:03:49,800
ACTING ON THE OTHER SIDE OF THE

5029
04:03:49,800 --> 04:03:51,040
BARRIER WALL ALIVE BUT WE THINK

5030
04:03:51,040 --> 04:03:54,240
THAT MAY BE HAPPENING HERE AND

5031
04:03:54,240 --> 04:03:58,440
THE BUG MAYBE ENDS UP STALLED IN

5032
04:03:58,440 --> 04:03:58,680
ENDOSOME.

5033
04:03:58,680 --> 04:04:01,000
I THINK THE NICHE MAY BE CLOSER

5034
04:04:01,000 --> 04:04:08,480
TO HOME THAN WE INITIALLY

5035
04:04:08,480 --> 04:04:08,720
THOUGHT.

5036
04:04:08,720 --> 04:04:14,440
SETH, DO YOU HAVE A QUESTION?

5037
04:04:14,440 --> 04:04:19,680
 

5038
04:04:19,680 --> 04:04:23,960
>> GREAT WORK.

5039
04:04:23,960 --> 04:04:24,880
SO IMPORTANT.

5040
04:04:24,880 --> 04:04:28,440
I THINK YOU'RE WORK -- TWO

5041
04:04:28,440 --> 04:04:29,760
QUESTIONS.

5042
04:04:29,760 --> 04:04:34,600
HOW MUCH OF A LOCAL -- HOW MUCH

5043
04:04:34,600 --> 04:04:35,520
LOCAL INFORMATION AND/OR TISSUE

5044
04:04:35,520 --> 04:04:40,440
DAMAGE DO YOU THINK THE TUMOR IS

5045
04:04:40,440 --> 04:04:43,320
DOING, LEADING TO RECRUITMENT OF

5046
04:04:43,320 --> 04:04:46,400
THE ANTI-TUMOR T CELLS?

5047
04:04:46,400 --> 04:04:51,000
TWO, RELATED TO HYPOTHESIS OF

5048
04:04:51,000 --> 04:04:52,040
SENSING PREDICTIVE SENSING FOR

5049
04:04:52,040 --> 04:04:54,080
FUTURE RESPONSES DO YOU THINK

5050
04:04:54,080 --> 04:04:56,320
THAT SIMILAR THINGS ARE

5051
04:04:56,320 --> 04:05:02,480
HAPPENING IN THE GUT FOR

5052
04:05:02,480 --> 04:05:06,240
ANAEROBES MAY NOT BE HAPPENING

5053
04:05:06,240 --> 04:05:08,080
FOR PREDICTIVE RESPONSES TO

5054
04:05:08,080 --> 04:05:08,640
POTENTIAL PATHOGENS?

5055
04:05:08,640 --> 04:05:10,440
>> GREAT QUESTIONS.

5056
04:05:10,440 --> 04:05:11,720
FIRST QUESTION IS REALLY

5057
04:05:11,720 --> 04:05:12,040
INTERESTING.

5058
04:05:12,040 --> 04:05:14,080
I'VE NEVER BEEN ASKED THAT

5059
04:05:14,080 --> 04:05:14,600
BEFORE.

5060
04:05:14,600 --> 04:05:16,640
I DON'T KNOW -- IT'S AN

5061
04:05:16,640 --> 04:05:31,160
ARTIFICIAL PROCESS WHEN YOU GIVE

5062
04:05:31,160 --> 04:05:34,920
A SYNGENEIC TUMOR CELLS, IT'S

5063
04:05:34,920 --> 04:05:37,360
DIFFERENT IN HOW THE TUMOR

5064
04:05:37,360 --> 04:05:39,480
GROSS, MICROENVIRONMENTS ARE

5065
04:05:39,480 --> 04:05:41,240
DISTINCT.

5066
04:05:41,240 --> 04:05:44,040
FOR THE INTRAVENOUS MODEL,

5067
04:05:44,040 --> 04:05:45,080
METASTASES IN LUNG, I WORRY

5068
04:05:45,080 --> 04:05:48,400
LESS, I THINK THE PROCESS OF B

5069
04:05:48,400 --> 04:05:50,160
16 CELLS SETTING UP SHOP IN THE

5070
04:05:50,160 --> 04:05:52,360
LUNG IS DAMAGING TO THE TISSUE,

5071
04:05:52,360 --> 04:05:53,640
IT'S A REALLY INTERESTING

5072
04:05:53,640 --> 04:05:54,880
QUESTION AND IT STANDS LIKE WHAT

5073
04:05:54,880 --> 04:05:57,680
ROLE DOES THAT PLAY IN IMMUNE

5074
04:05:57,680 --> 04:05:58,080
CELL RECRUITMENT?

5075
04:05:58,080 --> 04:06:00,840
THE OTHER QUESTION YOU ASKED,

5076
04:06:00,840 --> 04:06:01,880
WHICH IS TO WHAT EXTENT WE THINK

5077
04:06:01,880 --> 04:06:04,240
THIS IS HAPPENING IN THE GUT, I

5078
04:06:04,240 --> 04:06:05,840
THINK IT'S HAPPENING A LOT

5079
04:06:05,840 --> 04:06:06,960
THROUGH ANOTHER PROJECT JUST

5080
04:06:06,960 --> 04:06:09,040
WRAPPING UP IN THE LAB, I

5081
04:06:09,040 --> 04:06:10,560
SUSPECT THERE'S A LOT OF -- A

5082
04:06:10,560 --> 04:06:16,360
LOT OF WHAT WE'RE SEEING FROM

5083
04:06:16,360 --> 04:06:21,960
HELICOBACTER AND OTHERS IS THE

5084
04:06:21,960 --> 04:06:23,920
SAME THING, PREEMPTIVE,

5085
04:06:23,920 --> 04:06:24,720
IMMUNITY, HOW THE HOST DEALS

5086
04:06:24,720 --> 04:06:28,960
WITH DIVERSITY OF BUGS AND

5087
04:06:28,960 --> 04:06:29,720
CHOOSES WHICH TO DEVELOP

5088
04:06:29,720 --> 04:06:32,000
ADAPTIVE IMMUNE RESPONSE TO IS

5089
04:06:32,000 --> 04:06:38,280
THE BIG QUESTION..

5090
04:06:38,280 --> 04:06:42,000
>> TO ADD TO THAT WHAT IS A

5091
04:06:42,000 --> 04:06:45,040
COMMENSAL, WHAT IS A PATHOGEN,

5092
04:06:45,040 --> 04:06:47,040
AND ARE BUGS ATTACHING WITH

5093
04:06:47,040 --> 04:06:49,600
PATHOGENIC FEATURES, HOW MUCH

5094
04:06:49,600 --> 04:06:50,440
ARE PROGRAMMING.

5095
04:06:50,440 --> 04:06:51,200
>> FANTASTIC QUESTION.

5096
04:06:51,200 --> 04:06:55,440
I DON'T THINK THE HOST HAS LIKE

5097
04:06:55,440 --> 04:06:57,280
A SEQUENCER, OR LIKE THERE'S NO

5098
04:06:57,280 --> 04:07:00,040
VOICE SAYING THIS ONE IS A

5099
04:07:00,040 --> 04:07:04,080
PATHOGEN, BETTER WATCH OUT.

5100
04:07:04,080 --> 04:07:05,120
>> ATTACHMENT RECOGNITION

5101
04:07:05,120 --> 04:07:05,600
SYSTEMS.

5102
04:07:05,600 --> 04:07:06,880
>> THAT'S TOTALLY IT.

5103
04:07:06,880 --> 04:07:08,720
THE HOST JUST SAYS WHOEVER YOU

5104
04:07:08,720 --> 04:07:10,560
ARE, WHATEVER YOU ARE, IF YOU

5105
04:07:10,560 --> 04:07:12,240
SHOW UP IN THIS NICHE YOU'RE

5106
04:07:12,240 --> 04:07:14,240
CLOSE ENOUGH TO TROUBLE THAT I'M

5107
04:07:14,240 --> 04:07:17,600
GOING TO SURVEIL AND DOING THAT.

5108
04:07:17,600 --> 04:07:18,960
THAT'S NICHE DEPENDENT.

5109
04:07:18,960 --> 04:07:22,040
IF YOU'RE IN THAT PLACE AT THAT

5110
04:07:22,040 --> 04:07:24,640
TIME, EVERYTHING IS QUIET, WE'LL

5111
04:07:24,640 --> 04:07:29,280
DEVELOP A CALM  PROPHYLACTIC

5112
04:07:29,280 --> 04:07:30,440
RESPONSE.

5113
04:07:30,440 --> 04:07:32,200
IF IT'S NOT QUIET, BREACH IN

5114
04:07:32,200 --> 04:07:32,840
BARRIER, IMMUNE SYSTEM

5115
04:07:32,840 --> 04:07:34,480
RESPONDING TO A BREACH IN

5116
04:07:34,480 --> 04:07:37,040
BARRIER COULD GIVE YOU SOMETHING

5117
04:07:37,040 --> 04:07:37,800
LIKE CHRONIC INFLAMMATION.

5118
04:07:37,800 --> 04:07:45,640
>> THANK YOU SO MUCH FOR THAT

5119
04:07:45,640 --> 04:07:45,840
TALK.

5120
04:07:45,840 --> 04:07:47,720
WE'RE BEHIND BUT ON TIME ALMOST

5121
04:07:47,720 --> 04:07:48,800
FOR 1:00 TALK.

5122
04:07:48,800 --> 04:07:51,120
I'M GOING TO TURN THIS OVER TO

5123
04:07:51,120 --> 04:07:51,560
KATHERINE.

5124
04:07:51,560 --> 04:07:52,960
THESE WILL BE RECORDED SO IF YOU

5125
04:07:52,960 --> 04:07:55,400
NEED TO TAKE A BREAK, AS I DO,

5126
04:07:55,400 --> 04:07:57,360
GRAB LUNCH, I ENCOURAGE YOU TO

5127
04:07:57,360 --> 04:07:59,040
DO SO.

5128
04:07:59,040 --> 04:08:00,640
AND WE CAN ONCE AGAIN PROVIDE

5129
04:08:00,640 --> 04:08:04,840
LINKS AND SO FORTH SO EVERYONE

5130
04:08:04,840 --> 04:08:09,520
CAN WATCH THE TALK LATER ON.

5131
04:08:09,520 --> 04:08:12,280
I'LL TURN THIS OVER TO

5132
04:08:12,280 --> 04:08:13,400
CATHERINE.

5133
04:08:13,400 --> 04:08:14,880
>> WE'RE ON TIME.

5134
04:08:14,880 --> 04:08:19,240
WE PLANNED THAT LUNCH BREAK

5135
04:08:19,240 --> 04:08:19,840
PERFECTLY.

5136
04:08:19,840 --> 04:08:21,800
FOR THE QUESTIONS ASKING ON THE

5137
04:08:21,800 --> 04:08:25,320
ONLINE CHAT PLEASE KEEP THEM

5138
04:08:25,320 --> 04:08:25,520
GOING.

5139
04:08:25,520 --> 04:08:26,240
PRESENTERS ARE GETTING COPIES OF

5140
04:08:26,240 --> 04:08:28,840
THE QUESTIONS AND THEY WILL

5141
04:08:28,840 --> 04:08:29,680
RESPOND VIA E-MAIL.

5142
04:08:29,680 --> 04:08:32,600
AN OPPORTUNITY TO ENGAGE WITH

5143
04:08:32,600 --> 04:08:33,440
THE PRESENTER ONLINE THROUGH

5144
04:08:33,440 --> 04:08:35,040
E-MAIL AS WELL WILL FOLLOW.

5145
04:08:35,040 --> 04:08:36,840
PLEASE KEEP THE QUESTIONS

5146
04:08:36,840 --> 04:08:37,320
COMING.

5147
04:08:37,320 --> 04:08:38,360
WE APPRECIATE THE VIRTUAL

5148
04:08:38,360 --> 04:08:39,600
QUESTIONS COMING IN AS WELL.

5149
04:08:39,600 --> 04:08:41,120
THANK YOU SO MUCH.

5150
04:08:41,120 --> 04:08:50,320
NOW I'M GOING TO INTRODUCE OUR 

5151
04:08:50,320 --> 04:08:57,440
NEXT SPEAKER, RICHARD CUMMINGS, 

5152
04:08:57,440 --> 04:08:59,000
INTERRELATIONSHIPS OF INTESTINAL

5153
04:08:59,000 --> 04:08:59,240
GLYCOME.

5154
04:08:59,240 --> 04:09:02,040
HOPEFULLY YOU KNOW HOW TO SHARE

5155
04:09:02,040 --> 04:09:02,360
A SCREEN.

5156
04:09:02,360 --> 04:09:05,040
PERFECT.

5157
04:09:05,040 --> 04:09:10,080
 

5158
04:09:10,080 --> 04:09:14,480
 

5159
04:09:14,480 --> 04:09:16,120
>> THANK YOU FOR THE

5160
04:09:16,120 --> 04:09:16,520
OPPORTUNITY.

5161
04:09:16,520 --> 04:09:20,560
I'M EXCITED ABOUT THIS. 

5162
04:09:20,560 --> 04:09:24,320
HEARD FANTASTIC TALKS TODAY.

5163
04:09:24,320 --> 04:09:28,880
I WANT TO FOCUS ON AN ISSUE NOT

5164
04:09:28,880 --> 04:09:31,600
DEALT WITH YET, THE RELATIONSHIP

5165
04:09:31,600 --> 04:09:35,040
BETWEEN HOST GLYCOME, MICROBIAL

5166
04:09:35,040 --> 04:09:36,760
GLYCOME, INTESTINAL CELLS,

5167
04:09:36,760 --> 04:09:39,040
INNATE AND ADAPTIVE IMMUNE

5168
04:09:39,040 --> 04:09:40,840
SYSTEM, OTHER GLYCAN BINDING

5169
04:09:40,840 --> 04:09:44,960
PROTEINS EXPRESSED BY US AND THE

5170
04:09:44,960 --> 04:09:45,440
MICROBES.

5171
04:09:45,440 --> 04:09:49,360
SO, IN THAT REGARD I WANT TO

5172
04:09:49,360 --> 04:09:51,360
FIRST ACKNOWLEDGE SOME REALLY

5173
04:09:51,360 --> 04:09:54,600
GREAT COLLABORATORS ON THIS

5174
04:09:54,600 --> 04:09:57,360
PROJECT, I'LL JUST MENTION THEIR

5175
04:09:57,360 --> 04:10:06,600
NAMES HERE. 

5176
04:10:06,600 --> 04:10:07,760
 

5177
04:10:07,760 --> 04:10:09,560
 

5178
04:10:09,560 --> 04:10:11,520
THESE ARE THE COLLABORATORS I'VE

5179
04:10:11,520 --> 04:10:13,040
BEEN WORKING WITH OVER THE YEARS

5180
04:10:13,040 --> 04:10:18,760
LOOKING AT THESE ISSUES ABOUT

5181
04:10:18,760 --> 04:10:20,760
THESE RELATIONSHIPS.

5182
04:10:20,760 --> 04:10:23,840
A MUCIN IS HEAVILY GLYCOSYLATED

5183
04:10:23,840 --> 04:10:25,800
AND MAY HAVE A VARIETY OF

5184
04:10:25,800 --> 04:10:29,720
GLYCANS, HUNDREDS IF NOT

5185
04:10:29,720 --> 04:10:31,320
THOUSANDS OF GLYCANS.

5186
04:10:31,320 --> 04:10:32,400
WHEN THERE'S DEFICIENCY IN

5187
04:10:32,400 --> 04:10:35,400
GLYCOSYLATION OF PROTEIN, A

5188
04:10:35,400 --> 04:10:37,560
MUCIN, IT CAN RESULT IN

5189
04:10:37,560 --> 04:10:39,480
TREMENDOUS COLLAPSE OF LARGE

5190
04:10:39,480 --> 04:10:43,360
NUMBER OF GLYCANS, LOSS OF KEY

5191
04:10:43,360 --> 04:10:44,480
MONO SACCHARIDES, KEY CHANGES,

5192
04:10:44,480 --> 04:10:51,840
NOT JUST IN STRUCTURE BUT 

5193
04:10:51,840 --> 04:11:00,160
STABILITY OF THE PROTEIN.

5194
04:11:00,160 --> 04:11:01,240
DEFICIENCIES OF GLYCOSYLATION

5195
04:11:01,240 --> 04:11:01,880
ARE ASSOCIATED WITH PATHOLOGY,

5196
04:11:01,880 --> 04:11:10,200
WE NEED TO KEEP THAT IN MIND AS

5197
04:11:10,200 --> 04:11:14,040
WE GO FORWARD.

5198
04:11:14,040 --> 04:11:18,880
I WANT TO FOCUS ON THE OLD

5199
04:11:18,880 --> 04:11:21,960
GLYCOSYLATION. 

5200
04:11:21,960 --> 04:11:24,040
BASICALLY IN THE GOLGI, SINGLE

5201
04:11:24,040 --> 04:11:32,520
MONO SACCHARIDE, THERE'S ONLY 

5202
04:11:32,520 --> 04:11:36,680
ONE ENZYME THAT INITIATES CORE 

5203
04:11:36,680 --> 04:11:38,840
DERIVED O-GLYCANS, THAT ENZYME

5204
04:11:38,840 --> 04:11:44,040
IS REGULATED BY A CHAPERONE,

5205
04:11:44,040 --> 04:11:46,880
COSMC. 

5206
04:11:46,880 --> 04:11:50,160
THE COSMC IS ENCODED ON X

5207
04:11:50,160 --> 04:11:52,440
CHROMOSOME, THIS FUNCTION IS AS

5208
04:11:52,440 --> 04:11:53,400
A KEY MOLECULAR CHAPERONE FOR

5209
04:11:53,400 --> 04:11:53,960
ONE PROTEIN.

5210
04:11:53,960 --> 04:11:55,640
THIS IS GOING TO COME UP LATER

5211
04:11:55,640 --> 04:11:58,800
AS I TALK ABOUT CHILDREN WITH A

5212
04:11:58,800 --> 04:12:01,640
MUTATION IN THIS GENE ENCODING

5213
04:12:01,640 --> 04:12:03,440
COSMC, IMPORTANT TO UNDERSTAND

5214
04:12:03,440 --> 04:12:04,840
HOW THE GLYCOME IS REGULATED

5215
04:12:04,840 --> 04:12:08,880
THROUGH THE SIMPLE INTERACTION

5216
04:12:08,880 --> 04:12:10,840
IN THE E.R.

5217
04:12:10,840 --> 04:12:12,840
PRODUCTION IS REGULATED BY

5218
04:12:12,840 --> 04:12:19,720
PROTEIN COSMC, IF NOT FUNCTION

5219
04:12:19,720 --> 04:12:22,240
YAM P SYNTHASE WILL DEGRADE,

5220
04:12:22,240 --> 04:12:25,960
GLYCOPROTEINS WILL BE SUFFICIENT

5221
04:12:25,960 --> 04:12:26,640
IN TERMINAL STRUCTURES, THE

5222
04:12:26,640 --> 04:12:28,440
LARGE TABLE I SHOWED YOU.

5223
04:12:28,440 --> 04:12:30,880
THERE'S A COLLAPSE OF THE O

5224
04:12:30,880 --> 04:12:31,200
GLYCOME.

5225
04:12:31,200 --> 04:12:33,920
I'D LIKE TO FOCUS ON WHAT

5226
04:12:33,920 --> 04:12:36,200
HAPPENS WHEN YOU LOSE THE O

5227
04:12:36,200 --> 04:12:42,840
GLYCAN, CALL THEM THE EXTENDED

5228
04:12:42,840 --> 04:12:43,200
O-GLYCANS.

5229
04:12:43,200 --> 04:12:45,240
WE TALKED ABOUT THE PRODUCTION

5230
04:12:45,240 --> 04:12:49,640
OF THE TN ANTIGEN IN TUMORS, AND

5231
04:12:49,640 --> 04:12:51,120
THAT'S A SPECIAL EPITOPE

5232
04:12:51,120 --> 04:12:58,440
EXPRESSED MOST  CARCINOMAS.

5233
04:12:58,440 --> 04:13:00,520
IT'S NOT A BIOMARKER, IT'S A

5234
04:13:00,520 --> 04:13:08,440
DRIVER OF TUMORIGENESIS.

5235
04:13:08,440 --> 04:13:13,440
THE REALITY WHEN COSMC AND T

5236
04:13:13,440 --> 04:13:17,840
SYNTHASE IS COMPROMISED THERE'S

5237
04:13:17,840 --> 04:13:18,840
LOSS OF O-GLYCANS.

5238
04:13:18,840 --> 04:13:24,040
THERE ARE CORE 3 AND CORE 4

5239
04:13:24,040 --> 04:13:24,960
STRUCTURES WHICH HAVE BEEN

5240
04:13:24,960 --> 04:13:28,360
STUDIED AND THEY CAN ALSO BE

5241
04:13:28,360 --> 04:13:32,520
EXPRESSED IN THE INTESTINE.

5242
04:13:32,520 --> 04:13:35,840
CORE 1, 2, 3, 4 AND OTHERS IN

5243
04:13:35,840 --> 04:13:37,880
HUMANS VERSUS MICE, WE HAVE TO

5244
04:13:37,880 --> 04:13:40,280
ACKNOWLEDGE UNDERSTANDING OF THE

5245
04:13:40,280 --> 04:13:42,080
MOUSE GLYCOME IS PARTIALLY

5246
04:13:42,080 --> 04:13:47,040
REFLECTIVE OF THE HUMAN GLYCOME.

5247
04:13:47,040 --> 04:13:49,000
COSMC IS ON THE X CHROMOSOME,

5248
04:13:49,000 --> 04:13:51,440
THERE ARE MANY IMPORTANT GENES

5249
04:13:51,440 --> 04:13:52,760
REGULATING GLYCOSYLATION THAT

5250
04:13:52,760 --> 04:13:55,040
HAVE BEEN IDENTIFIED ON THE X

5251
04:13:55,040 --> 04:13:55,400
CHROMOSOME.

5252
04:13:55,400 --> 04:13:56,800
THAT'S ALSO VERY INTERESTING

5253
04:13:56,800 --> 04:13:59,040
AREA OF BIOLOGY, SO KEEP THAT IN

5254
04:13:59,040 --> 04:13:59,680
MIND.

5255
04:13:59,680 --> 04:14:05,240
THE GENES HAVE BEEN FOUND TO BE

5256
04:14:05,240 --> 04:14:06,560
ALTERED IN HEMATOPOIETIC CELLS

5257
04:14:06,560 --> 04:14:07,640
OCCURRING IN HEMATOPOIETIC STEM

5258
04:14:07,640 --> 04:14:11,840
CELLS MORE SO THAN ALMOST ANY 

5259
04:14:11,840 --> 04:14:15,040
OTHER STEM CELL POPULATION.

5260
04:14:15,040 --> 04:14:17,440
A FEW YEARS AGO A WONDERFUL

5261
04:14:17,440 --> 04:14:20,280
REVIEW WAS PUT TOGETHER,

5262
04:14:20,280 --> 04:14:21,160
DESCRIBING THE PROTEIN

5263
04:14:21,160 --> 04:14:26,520
GLYCOSYLATION OF MUCINS AND

5264
04:14:26,520 --> 04:14:30,600
GLYCOPROTEINS THAT REGULATE

5265
04:14:30,600 --> 04:14:34,240
HOMEOSTASIS AND GUT MICROBIOTA,

5266
04:14:34,240 --> 04:14:36,200
EXPRESS OF COSMC PROTEIN OR LOSS

5267
04:14:36,200 --> 04:14:40,720
OF EXPRESS LEADING TO CHANGE IN

5268
04:14:40,720 --> 04:14:41,440
MICROBIOME.

5269
04:14:41,440 --> 04:14:44,040
WE CREATED A MOUSE WITH A

5270
04:14:44,040 --> 04:14:48,120
KNOCKOUT IN THE INTESTINAL 

5271
04:14:48,120 --> 04:14:51,480
EPITHELIAL CELLS DRIVEN BY THE

5272
04:14:51,480 --> 04:14:53,160
BILLEN PROMOTER, EXPRESSES TN

5273
04:14:53,160 --> 04:14:54,040
ANTIGEN, MALES EXPRESS

5274
04:14:54,040 --> 04:14:56,560
EXTENSIVELY SHOWN IN THE MIDDLE

5275
04:14:56,560 --> 04:14:57,200
PANEL HERE.

5276
04:14:57,200 --> 04:15:00,000
IN THE COLORECTAL REGION AND

5277
04:15:00,000 --> 04:15:02,560
SMALL INTESTINE, THE FEMALES 

5278
04:15:02,560 --> 04:15:08,920
BECAUSE OF THE X-LINKAGE ARE

5279
04:15:08,920 --> 04:15:10,120
MOSAIC, YOU CAN SEE EXPRESSION

5280
04:15:10,120 --> 04:15:12,920
VERY INTERESTING IN THE FEMALES.

5281
04:15:12,920 --> 04:15:16,720
IF YOU DO A SWISS ROLL YOU CAN

5282
04:15:16,720 --> 04:15:23,920
SEE IN WILDTYPE VERSUS KNOCKOUT 

5283
04:15:23,920 --> 04:15:26,240
MICE, THERE'S TREMENDOUS

5284
04:15:26,240 --> 04:15:27,640
THICKENING OF THE CLONIC WALL,

5285
04:15:27,640 --> 04:15:29,400
DIFFERENT BETWEEN THE WILDTYPE

5286
04:15:29,400 --> 04:15:31,440
AND COSMC KNOCKOUT, SO THAT

5287
04:15:31,440 --> 04:15:33,720
SINGLE MUTATION LEADING TO A

5288
04:15:33,720 --> 04:15:36,640
LOSS OF THESE O-GLYCANS HAS LED

5289
04:15:36,640 --> 04:15:38,520
TO A MASSIVE CHANGE IN THE

5290
04:15:38,520 --> 04:15:48,480
MORPHOLOGY OF THE ORGAN ITSELF.

5291
04:15:48,480 --> 04:15:50,000
EXPRESSION OF FUCOSE, AN

5292
04:15:50,000 --> 04:15:52,000
INTERESTING SUGAR A LOT OF

5293
04:15:52,000 --> 04:15:54,280
LABORATORIES ARE STUDYING IN THE

5294
04:15:54,280 --> 04:15:59,400
INTESTINAL SUGAR, IF WE TAKE THE

5295
04:15:59,400 --> 04:16:01,200
LECTIN THAT STAINS, WE SEE

5296
04:16:01,200 --> 04:16:03,560
FUCOSE IS EXPRESSED IN SMALL AND

5297
04:16:03,560 --> 04:16:07,520
LARGE INTESTINE BUT IN THE COSMC

5298
04:16:07,520 --> 04:16:09,840
KNOCKOUT CELLS IT'S MOSTLY LOST

5299
04:16:09,840 --> 04:16:16,000
IN THE COLON, MOSTLY THEREFORE

5300
04:16:16,000 --> 04:16:19,840
MOST O-GLYCANS, MOST FUCOSE ON N

5301
04:16:19,840 --> 04:16:22,520
GLYCANS IN THE INTESTINE,

5302
04:16:22,520 --> 04:16:24,960
DIFFERENTIAL EXPRESSION OF

5303
04:16:24,960 --> 04:16:26,240
SIMPLE EPITOPES WITHIN THE

5304
04:16:26,240 --> 04:16:28,360
DISTRIBUTION IN THE INTESTINE,

5305
04:16:28,360 --> 04:16:30,040
THIS IS NOT WELL UNDERSTOOD,

5306
04:16:30,040 --> 04:16:32,360
IT'S POORLY UNDERSTOOD IN REGARD

5307
04:16:32,360 --> 04:16:34,280
TO SPATIAL AND TEMPORAL

5308
04:16:34,280 --> 04:16:36,520
REGULATION OF GLYCOSYLATION AND

5309
04:16:36,520 --> 04:16:38,920
THIS SIMPLE EXPERIMENT

5310
04:16:38,920 --> 04:16:39,840
ILLUSTRATES THAT.

5311
04:16:39,840 --> 04:16:46,800
YOU CAN SEE MANY CELLS DO NOT 

5312
04:16:46,800 --> 04:16:48,840
EXPRESS FUCOSE DETECTABLE,

5313
04:16:48,840 --> 04:16:54,080
DETECTABLE FUCOSE  EPITOPES.

5314
04:16:54,080 --> 04:16:55,800
IF YOU ELIMINATE EXTENDED O

5315
04:16:55,800 --> 04:17:00,840
GLYCAN YOU CHANGE THE STRUCTURE

5316
04:17:00,840 --> 04:17:05,040
OF MICROVILLI, THIS IS IS

5317
04:17:05,040 --> 04:17:06,640
FANTASTIC WORK.

5318
04:17:06,640 --> 04:17:08,520
THE ANIMALS DEVELOP A LOT OF

5319
04:17:08,520 --> 04:17:10,760
INFLAMMATION AS A RESULT.

5320
04:17:10,760 --> 04:17:15,080
SO THE  GLYCOME IS REGULATED TO

5321
04:17:15,080 --> 04:17:22,200
SOME EXTENT BY THE PRODUCTION OF

5322
04:17:22,200 --> 04:17:23,000
THE O-GLYCANS.

5323
04:17:23,000 --> 04:17:25,640
THE LOSS OF INTEGRITY OF THE

5324
04:17:25,640 --> 04:17:27,600
O-GLYCANS AND MUCINS IN THE

5325
04:17:27,600 --> 04:17:29,800
COSMC KNOCKOUT CELLS LEADS TO A

5326
04:17:29,800 --> 04:17:32,120
LOSS OF BARRIER FUNCTION BETWEEN

5327
04:17:32,120 --> 04:17:33,600
THE LUMINAL CONTENTS AND

5328
04:17:33,600 --> 04:17:34,040
EPITHELIAL CELL LAYER.

5329
04:17:34,040 --> 04:17:36,160
THIS IS NOT A MUTATION OF THE

5330
04:17:36,160 --> 04:17:38,200
MUCINS BY THE WAY.

5331
04:17:38,200 --> 04:17:39,840
THE MUCINS ARE STILL EXPRESSED.

5332
04:17:39,840 --> 04:17:43,640
THIS IS A LOSS OF THE 

5333
04:17:43,640 --> 04:17:44,520
GLYCOSYLATION OF THE MUCINS.

5334
04:17:44,520 --> 04:17:46,760
THEY ARE STILL AROUND BUT NO

5335
04:17:46,760 --> 04:17:49,640
LONGER FUNCTIONING IN A BARRIER

5336
04:17:49,640 --> 04:17:50,400
WAY.

5337
04:17:50,400 --> 04:17:50,960
THIS IS POORLY UNDERSTOOD IN

5338
04:17:50,960 --> 04:17:56,480
TERMS OF HOW A PROTEIN CAN BE

5339
04:17:56,480 --> 04:18:02,480
THERE, NOT A BARRIER, STILL HAS

5340
04:18:02,480 --> 04:18:02,840
SUGARS ON IT.

5341
04:18:02,840 --> 04:18:05,200
THIS IS A SPECIFIC LOSS NOT OF

5342
04:18:05,200 --> 04:18:07,880
GLYCANS, IT'S A CHANGE IN

5343
04:18:07,880 --> 04:18:09,640
STRUCTURE OF GLYCANS AND LOSS OF

5344
04:18:09,640 --> 04:18:13,040
EXTENDED GLYCANS LEADING TO

5345
04:18:13,040 --> 04:18:15,400
CHANGE IN THE BARRIER FUNCTION

5346
04:18:15,400 --> 04:18:16,960
EPITHELIAL CELL LAYER.

5347
04:18:16,960 --> 04:18:20,720
LOOK AT THE POPULATION OF THE

5348
04:18:20,720 --> 04:18:27,080
COLON BY BACTERIA, CLONIC MUCOSA

5349
04:18:27,080 --> 04:18:34,560
CHANGED TREMENDOUSLY, THERE'S

5350
04:18:34,560 --> 04:18:36,280
LOSS OF BACTEROIDES.

5351
04:18:36,280 --> 04:18:44,200
THIS DID NOT CHANGE HOWEVER IN 

5352
04:18:44,200 --> 04:18:45,800
THE ILIUM MUCOSA.

5353
04:18:45,800 --> 04:18:47,640
THERE WERE SOME CHANGES, THEY

5354
04:18:47,640 --> 04:18:48,960
WERE MUCH LESS.

5355
04:18:48,960 --> 04:18:51,440
LUMINAL CONTENTS DID NOT CHANGE

5356
04:18:51,440 --> 04:18:53,040
AT ALL SIGNIFICANTLY.

5357
04:18:53,040 --> 04:19:01,520
THERE ARE DIFFERENTIAL EFFECTS.

5358
04:19:01,520 --> 04:19:20,360
THERE'S A CHANGE IN HOST GENES, 

5359
04:19:20,360 --> 04:19:23,520
IMPORTANT IN MICROBIOTA. 

5360
04:19:23,520 --> 04:19:29,360
THE CONSEQUENCE OF ALTERING THE

5361
04:19:29,360 --> 04:19:31,200
SINGLE GENE, OVERALL THE

5362
04:19:31,200 --> 04:19:32,440
REGULATED FUNCTION OF THE

5363
04:19:32,440 --> 04:19:35,480
O-GLYCANS IS TO CONTROL THE

5364
04:19:35,480 --> 04:19:42,600
RELATIONSHIPS OF INFLAMMATION, 

5365
04:19:42,600 --> 04:19:43,800
UNFOLDED PROTEIN RESPONSES,

5366
04:19:43,800 --> 04:19:46,360
MICROBIOME, TUMORIGENESIS AND SO

5367
04:19:46,360 --> 04:19:47,200
FORTH, ACCENTUATED WHEN ONE

5368
04:19:47,200 --> 04:19:52,000
CHANGES THE GLYCOME OF THE

5369
04:19:52,000 --> 04:19:52,240
INTESTINE.

5370
04:19:52,240 --> 04:19:54,280
WORK WITH SETH'S GROUP AND

5371
04:19:54,280 --> 04:19:58,320
STEPHEN SEGAL LOOKING AT 

5372
04:19:58,320 --> 04:20:00,040
GLYCOME OF THE INTESTINE OF THE

5373
04:20:00,040 --> 04:20:00,400
MOUSE.

5374
04:20:00,400 --> 04:20:09,280
WE'RE NOT GROWING TO GO OVER IT

5375
04:20:09,280 --> 04:20:10,120
EXTENSIVELY.

5376
04:20:10,120 --> 04:20:14,480
THERE ARE BIG CHANGES IN THE 

5377
04:20:14,480 --> 04:20:16,960
FUCOSLYATED AND SIALYATED

5378
04:20:16,960 --> 04:20:17,840
O-GLYCANS.

5379
04:20:17,840 --> 04:20:20,160
THE REPERTOIRE IS SUBJECT TO

5380
04:20:20,160 --> 04:20:24,400
CHANGE, TO BE MODIFIED BY THE

5381
04:20:24,400 --> 04:20:25,200
INFLAMMATORY REACTION, ALSO MAY

5382
04:20:25,200 --> 04:20:28,160
BE SUBJECT TO CHANGE BY THE

5383
04:20:28,160 --> 04:20:29,320
MICROBIOME.

5384
04:20:29,320 --> 04:20:31,040
THAT WILL BE STORIES THAT ARE

5385
04:20:31,040 --> 04:20:42,560
COMING OUT LATER FROM SETH'S

5386
04:20:42,560 --> 04:20:47,240
LAB. 

5387
04:20:47,240 --> 04:20:50,480
GENERALS THAT REGULATE

5388
04:20:50,480 --> 04:20:54,480
GLYCOSYLATION HAVE BEEN

5389
04:20:54,480 --> 04:20:56,360
IMPLICATED IN INTESTINAL BOWEL

5390
04:20:56,360 --> 04:20:59,440
DISEASES, NOT WELL EXPLORED IN 

5391
04:20:59,440 --> 04:21:06,120
THE BIG PICTURE OF IBD AND

5392
04:21:06,120 --> 04:21:06,360
CROHN'S.

5393
04:21:06,360 --> 04:21:08,960
WE COULD SAY P53 GENE, GUARDIAN

5394
04:21:08,960 --> 04:21:10,880
OF THE GENOME, WE ACCEPT THAT.

5395
04:21:10,880 --> 04:21:13,840
IT'S IMPORTANT IN REGULATING

5396
04:21:13,840 --> 04:21:15,160
GENOMIC STABILITY, PREVENTING

5397
04:21:15,160 --> 04:21:15,960
APOPTOSIS, EXHIBITING TO

5398
04:21:15,960 --> 04:21:17,120
ANGIOGENESIS, ET CETERA.

5399
04:21:17,120 --> 04:21:21,480
BUT WE CAN THINK OF O AND

5400
04:21:21,480 --> 04:21:22,840
N-GLYCANS, GENES THAT REGULATE

5401
04:21:22,840 --> 04:21:24,640
STRUCTURES AS GUARDIANS OF THE

5402
04:21:24,640 --> 04:21:26,680
CELL BECAUSE THEY ARE

5403
04:21:26,680 --> 04:21:28,440
ALTERATIONS LEAD TO TREMENDOUS

5404
04:21:28,440 --> 04:21:34,200
PATHOLOGY, CHANGES IN CELL

5405
04:21:34,200 --> 04:21:35,200
ADHESIONS SIGNALING

5406
04:21:35,200 --> 04:21:35,600
LYMPHANGIOGENESIS.

5407
04:21:35,600 --> 04:21:37,200
WE MUST IDENTIFY THE INDIVIDUAL

5408
04:21:37,200 --> 04:21:38,760
FUNCTIONS OF GLYCANS OF COURSE

5409
04:21:38,760 --> 04:21:39,680
AND INDIVIDUAL FUNCTIONS OF

5410
04:21:39,680 --> 04:21:42,440
GENES BUT THINK THE STORY IS

5411
04:21:42,440 --> 04:21:44,480
VERY CLEAR.

5412
04:21:44,480 --> 04:21:51,360
THE HOST GLYCOME IS IMPORTANT IN

5413
04:21:51,360 --> 04:21:53,200
MAINTAINING NORMAL HOMEOSTASIS.

5414
04:21:53,200 --> 04:21:54,160
WE'VE IDENTIFIED SEVERAL

5415
04:21:54,160 --> 04:21:56,160
CHILDREN WITH A MUTATION IN THE

5416
04:21:56,160 --> 04:21:56,960
COSMC GENE.

5417
04:21:56,960 --> 04:22:02,680
THIS WAS DONE WITH OUR

5418
04:22:02,680 --> 04:22:04,560
TREMENDOUS COLLABORATORS IN

5419
04:22:04,560 --> 04:22:06,760
COLOGNE, IDENTIFIED A FAMILY

5420
04:22:06,760 --> 04:22:10,560
THAT INCLUDES TWO CHILDREN, TWO

5421
04:22:10,560 --> 04:22:16,200
BROTHERS, THAT HAVE A HEMIZYGOUS

5422
04:22:16,200 --> 04:22:17,600
GERMLINE MUTATION, THAT CHANGES

5423
04:22:17,600 --> 04:22:22,160
THE STRUCTURE OF THE

5424
04:22:22,160 --> 04:22:23,280
TRANSMEMBRANE DOMAIN ABOUT THE

5425
04:22:23,280 --> 04:22:26,440
COSMC PROTEIN.

5426
04:22:26,440 --> 04:22:29,960
THE BOYS PRESENTED WITH

5427
04:22:29,960 --> 04:22:31,520
DEVELOPMENTAL DAY, SHORT

5428
04:22:31,520 --> 04:22:32,520
STATURE, SEVERE

5429
04:22:32,520 --> 04:22:34,320
IMMUNODEFICIENCY, BOTH HAVE

5430
04:22:34,320 --> 04:22:44,560
ACUTE KIDNEY FAILURE, TREATABLE 

5431
04:22:44,560 --> 04:22:49,080
WITH ECULIDUMAB, THIS PATHWAY

5432
04:22:49,080 --> 04:22:52,080
CRITICAL FOR IgA NEPHROPATHY,

5433
04:22:52,080 --> 04:22:56,560
ASSOCIATED WITH INSUFFICIENT

5434
04:22:56,560 --> 04:22:57,920
GLYCOSYLATION OF IgA 1.

5435
04:22:57,920 --> 04:23:02,520
ONE HAS BEEN  HOSPITALIZED

5436
04:23:02,520 --> 04:23:04,840
REPEATED LIE.

5437
04:23:04,840 --> 04:23:08,280
MANY PATIENTS WITH CONGENITAL

5438
04:23:08,280 --> 04:23:11,840
DISORDERS OF GLYCOSYLATION HAVE

5439
04:23:11,840 --> 04:23:12,840
GASTROINTESTINAL COMPLICATIONS

5440
04:23:12,840 --> 04:23:13,800
INCLUDING DIARRHEA AND RECURRENT

5441
04:23:13,800 --> 04:23:16,040
INFECTION, BY THE WAY.

5442
04:23:16,040 --> 04:23:18,480
THIS SHOWS THE PEDIGREE OF THE

5443
04:23:18,480 --> 04:23:19,720
FAMILY, BOTH FEMALES AND

5444
04:23:19,720 --> 04:23:21,920
GRANDMOTHER AND MOTHER ARE

5445
04:23:21,920 --> 04:23:23,800
CARRIERS OF THIS MUTANT BUT THEY

5446
04:23:23,800 --> 04:23:27,040
ARE ALSO AFFECTED BECAUSE

5447
04:23:27,040 --> 04:23:29,320
THERE'S X SKEWING.

5448
04:23:29,320 --> 04:23:30,920
THEY WOULD BE A 50-50 MOSAIC,

5449
04:23:30,920 --> 04:23:32,560
IT'S NOT LIKE THAT.

5450
04:23:32,560 --> 04:23:34,480
THEY ARE SKEWED TOWARD UTILIZING

5451
04:23:34,480 --> 04:23:35,800
MUTATED X CHROMOSOME WHICH FROM

5452
04:23:35,800 --> 04:23:38,360
A BIOLOGICAL POINT OF VIEW IS

5453
04:23:38,360 --> 04:23:39,760
VERY INTERESTING HOW DOES X

5454
04:23:39,760 --> 04:23:42,680
SKEWING HAPPEN AND IS THERE A

5455
04:23:42,680 --> 04:23:44,400
PRIVILEGE BY HAVING THE

5456
04:23:44,400 --> 04:23:50,600
EXPRESSION OF THE TN ANTIGEN IN

5457
04:23:50,600 --> 04:23:50,800
CELLS.

5458
04:23:50,800 --> 04:23:53,360
THIS MUTATION RULEDDED IN CHAIN

5459
04:23:53,360 --> 04:23:57,040
OF ALANINE RESIDUE AT C 20,

5460
04:23:57,040 --> 04:24:02,520
LEADS TO A LOSS OF FUNCTION OF

5461
04:24:02,520 --> 04:24:03,760
COSMC, CHANGE IN STABILITY,

5462
04:24:03,760 --> 04:24:06,480
LEADS TO DECREASE OF THE TOTAL

5463
04:24:06,480 --> 04:24:09,440
PROTEIN AND THE T SYNTHASE IS 2

5464
04:24:09,440 --> 04:24:12,040
TO 3% OF NORMAL ACTIVITY.

5465
04:24:12,040 --> 04:24:20,760
THAT 2 TO 3% ALLOWS  90% OF O

5466
04:24:20,760 --> 04:24:22,280
GLYCANS, THAT'S ON YOU THEY

5467
04:24:22,280 --> 04:24:23,040
SURVIVED, MAJORITY ARE NORMAL

5468
04:24:23,040 --> 04:24:26,200
BECAUSE OF THE SMALL AMOUNT OF

5469
04:24:26,200 --> 04:24:26,720
ACTIVITY.

5470
04:24:26,720 --> 04:24:29,520
WE ARE HOPEFUL AND RAJ IS

5471
04:24:29,520 --> 04:24:39,400
PURSUING THIS MIGHT BE TREATABLE

5472
04:24:39,400 --> 04:24:40,480
BY MONO SACCHARIDE THERAPY.

5473
04:24:40,480 --> 04:24:43,560
THE LAST THING I WANT TO TALK

5474
04:24:43,560 --> 04:24:54,080
ABOUT IS FLY  -- GLYCOME, WE

5475
04:24:54,080 --> 04:24:59,760
HAVEN'T ABOUT IMMUNOGLOBULIN, A 

5476
04:24:59,760 --> 04:25:01,240
MAJOR COMPONENT.

5477
04:25:01,240 --> 04:25:03,440
IgA IS PROMINENT IN THE GUT

5478
04:25:03,440 --> 04:25:11,280
LUMEN, FUNCTIONS IN HOST

5479
04:25:11,280 --> 04:25:13,280
COMMENSAL SYMBIOSIS, DEFICIENT

5480
04:25:13,280 --> 04:25:22,640
MICE AND HUMANS ARE SUBJECT TO 

5481
04:25:22,640 --> 04:25:23,840
GI INFECTION AND IBDs.

5482
04:25:23,840 --> 04:25:26,960
WE'VE LOOKED AT PRESENCE OF

5483
04:25:26,960 --> 04:25:32,320
IgA 1, IgA 2, RECOGNITION OF

5484
04:25:32,320 --> 04:25:32,560
GLYCANS.

5485
04:25:32,560 --> 04:25:38,760
WE EXAMINED A LOT OF SPECIFICITY

5486
04:25:38,760 --> 04:25:40,240
OF IgA 1, BROADLY SPEAKING

5487
04:25:40,240 --> 04:25:42,200
MANY OF THE ANTIBODIES

5488
04:25:42,200 --> 04:25:53,120
RECOGNIZED FEATURES OF GLYCANS,

5489
04:25:53,120 --> 04:25:59,320
WITH TERMINAL N GLUCOSAMINE, BUT

5490
04:25:59,320 --> 04:26:01,560
THEY HAVE MANY DIFFERENCES IN

5491
04:26:01,560 --> 04:26:09,440
RECOGNITION OF GLYCANS, ONLY 15

5492
04:26:09,440 --> 04:26:10,960
GLYCANS WERE CO-TARGETED.

5493
04:26:10,960 --> 04:26:14,640
MANY GLYCANS ARE KNOWN TO BE

5494
04:26:14,640 --> 04:26:16,600
ATTACHMENT SITES FOR BACTERIA,

5495
04:26:16,600 --> 04:26:17,800
THEY ARE PREDICTED TO BE.

5496
04:26:17,800 --> 04:26:19,440
THAT'S INTERESTING BECAUSE THE

5497
04:26:19,440 --> 04:26:22,520
IgA MAY ALSO BE INTERACTING

5498
04:26:22,520 --> 04:26:26,040
WITH HOST GLYCANS, AND AFFECTING

5499
04:26:26,040 --> 04:26:30,080
COLONIZATION AND STABILITY OF

5500
04:26:30,080 --> 04:26:31,120
THE MICROBIOME ITSELF.

5501
04:26:31,120 --> 04:26:33,840
MOST OF THE BACTERIA WE COULD

5502
04:26:33,840 --> 04:26:36,280
IDENTIFY WERE ASSOCIATED WITH

5503
04:26:36,280 --> 04:26:38,720
SURFACE-BOUND IgA.

5504
04:26:38,720 --> 04:26:42,400
WE CAN DEVELOP MONOCLONAL

5505
04:26:42,400 --> 04:26:46,200
ANTIBODY, CELLS PRODUCING 

5506
04:26:46,200 --> 04:26:49,000
DIFFERENT MONOCLONAL ANTIBODY

5507
04:26:49,000 --> 04:26:53,640
IgA 2, ALL WERE IgA 2 BY THE

5508
04:26:53,640 --> 04:26:56,560
WAY, THIS SHOWS A PATTERN ON A

5509
04:26:56,560 --> 04:27:05,240
MICROARRAY, RECOGNIZING A SET OF

5510
04:27:05,240 --> 04:27:07,040
GLYCANS WITH OVERLAP, VERY

5511
04:27:07,040 --> 04:27:08,600
INTERESTING BECAUSE MOST

5512
04:27:08,600 --> 04:27:10,040
IgGs HAVE SPECIFIC BINDING,

5513
04:27:10,040 --> 04:27:18,200
IgAs SEEM TO BE MORE PATTERN

5514
04:27:18,200 --> 04:27:20,920
RECOGNITION MOLECULES.

5515
04:27:20,920 --> 04:27:22,040
SECRETORY COMPONENT, REQUIRED

5516
04:27:22,040 --> 04:27:26,040
FOR THE TRANSFER OF IgA INTO

5517
04:27:26,040 --> 04:27:27,320
THE LUMEN, SECRETORY COMPONENT

5518
04:27:27,320 --> 04:27:28,920
IS ABLE TO BIND CARBOHYDRATES.

5519
04:27:28,920 --> 04:27:31,560
BEFORE THIS WORK I NEVER THOUGHT

5520
04:27:31,560 --> 04:27:34,440
MUCH ABOUT IT BUT IT'S A

5521
04:27:34,440 --> 04:27:44,400
PROTEOLYTIC CLEAVAGE PROJECT OF 

5522
04:27:44,400 --> 04:27:48,120
THE IMMUNOGLOBULIN RECEPTOR

5523
04:27:48,120 --> 04:27:48,720
SUGGESTING SECRETORY COMPONENT

5524
04:27:48,720 --> 04:27:52,600
HAS ABILITY TO BIND SELECTIVE

5525
04:27:52,600 --> 04:27:53,040
GLYCANS.

5526
04:27:53,040 --> 04:27:54,640
IT DOES RECOGNIZE A PATTERN.

5527
04:27:54,640 --> 04:27:56,280
THIS IS SOMETHING WE WANT TO

5528
04:27:56,280 --> 04:27:58,800
PURSUE IN THE FUTURE, WHAT IS

5529
04:27:58,800 --> 04:28:01,800
THE OVERALL REPERTOIRE OF IgA

5530
04:28:01,800 --> 04:28:02,920
ANTIBODIES IN THE INTESTINE,

5531
04:28:02,920 --> 04:28:05,040
WHAT DO THEY RECOGNIZE AND WHAT

5532
04:28:05,040 --> 04:28:09,920
IS THEIR PATTERNS OR SPECIFIC

5533
04:28:09,920 --> 04:28:11,120
LIGANDS THEY BIND TO.

5534
04:28:11,120 --> 04:28:12,760
I WANT TO MENTION SOME BEAUTIFUL

5535
04:28:12,760 --> 04:28:15,840
WORK THAT WE'RE GOING TO HEAR

5536
04:28:15,840 --> 04:28:17,240
ABOUT LATER FROM KATERINA, WE'VE

5537
04:28:17,240 --> 04:28:19,160
BEEN FORTUNATE TO WORK WITH HER

5538
04:28:19,160 --> 04:28:27,080
IN JUST LOOKING AT SOME ROLES OF

5539
04:28:27,080 --> 04:28:30,040
MUCIN GLYCANS ON THE ROLES OF

5540
04:28:30,040 --> 04:28:31,760
GLYCANS RECOGNIZED BY BACTERIA.

5541
04:28:31,760 --> 04:28:34,240
WE THOUGHT ABOUT BACTERIA THAT

5542
04:28:34,240 --> 04:28:36,440
ADHERE TO MUCINS, BUT KATERINA

5543
04:28:36,440 --> 04:28:39,560
HAS BEEN LOOKING BEYOND IN A AT

5544
04:28:39,560 --> 04:28:41,600
THE INTERACTIONS OF BACTERIA

5545
04:28:41,600 --> 04:28:43,160
WITH OLIGOSACCHARIDES OF MUCINS

5546
04:28:43,160 --> 04:28:52,800
AND THEY FUNCTION AS A SIGNALING

5547
04:28:52,800 --> 04:28:54,560
WAY.

5548
04:28:54,560 --> 04:28:58,440
THIS IS THE ONLY SLIDE I'LL

5549
04:28:58,440 --> 04:29:01,280
SHOW, THE HOST GLYCOME IS

5550
04:29:01,280 --> 04:29:03,200
BIOACTIVE NOT JUST AS ADHESION

5551
04:29:03,200 --> 04:29:06,120
AND BARRIER FUNCTION BUT

5552
04:29:06,120 --> 04:29:06,800
REGULATORY FUNCTION.

5553
04:29:06,800 --> 04:29:08,720
I'LL END BY SAYING WE HEARD

5554
04:29:08,720 --> 04:29:10,560
ABOUT THE CROSSROADS BUT THE

5555
04:29:10,560 --> 04:29:11,240
ROADS CROSS.

5556
04:29:11,240 --> 04:29:14,640
ALL OF THESE INTERACTIONS ARE

5557
04:29:14,640 --> 04:29:15,200
OCCURRING SIMULTANEOUSLY, AND

5558
04:29:15,200 --> 04:29:16,960
IT'S HARD TO WRAP YOUR HEAD

5559
04:29:16,960 --> 04:29:19,320
AROUND ALL THE INTERACTIONS

5560
04:29:19,320 --> 04:29:20,400
GOING ON, I'M JUST TALKING ABOUT

5561
04:29:20,400 --> 04:29:21,480
A FEW.

5562
04:29:21,480 --> 04:29:23,760
WE'VE HEARD ABOUT OTHER

5563
04:29:23,760 --> 04:29:27,000
ADHESIONS AND GLYCAN SENSORS AND

5564
04:29:27,000 --> 04:29:33,600
LECTINS THAT ARE INVOLVED.

5565
04:29:33,600 --> 04:29:35,400
THAT'S THE STORY.

5566
04:29:35,400 --> 04:29:36,640
WE HAVEN'T TALKED ABOUT DIETARY

5567
04:29:36,640 --> 04:29:38,080
GLYCANS WHICH WILL BE

5568
04:29:38,080 --> 04:29:40,040
INFLUENTIAL IN MANY AFFECTS

5569
04:29:40,040 --> 04:29:40,760
ALSO.

5570
04:29:40,760 --> 04:29:41,800
I'D LIKE TO ACKNOWLEDGE ALL THE

5571
04:29:41,800 --> 04:29:49,200
WONDERFUL PEOPLE IN MY LAB. 

5572
04:29:49,200 --> 04:29:50,320
THANK YOU FOR LISTENING.

5573
04:29:50,320 --> 04:29:51,960
>> BEAUTIFUL WORK AS ALWAYS,

5574
04:29:51,960 --> 04:29:52,960
RICK.

5575
04:29:52,960 --> 04:29:57,880
THANK YOU FOR REMINDING US THEY

5576
04:29:57,880 --> 04:29:58,400
INTERSECT.

5577
04:29:58,400 --> 04:30:03,000
I'LL BE MONITORING THE CHAT SO 

5578
04:30:03,000 --> 04:30:05,120
PLEASE GET THOSE IN.

5579
04:30:05,120 --> 04:30:08,920
>> I WAS CURIOUS WHETHER OR NOT

5580
04:30:08,920 --> 04:30:11,920
YOU THINK THAT MAYBE LOSS OF THE

5581
04:30:11,920 --> 04:30:13,280
CHAPERONE MIGHT ALSO CHANGE WHAT

5582
04:30:13,280 --> 04:30:16,040
SOME OF OUR HOST LECTINS

5583
04:30:16,040 --> 04:30:19,560
RECOGNIZE, THAT MIGHT BE ALSO

5584
04:30:19,560 --> 04:30:20,520
PROBLEMATIC TO THE HOST.

5585
04:30:20,520 --> 04:30:23,600
>> I THINK YOU'RE EXACTLY RIGHT.

5586
04:30:23,600 --> 04:30:26,720
I WOULD PREDICT IT CHANGES IgA

5587
04:30:26,720 --> 04:30:28,440
BINDING, LECTIN BINDING, A LOT

5588
04:30:28,440 --> 04:30:31,240
OF THE HOST ADAPTIVE AND PERHAPS

5589
04:30:31,240 --> 04:30:33,160
INNATE IMMUNE RECEPTORS THAT

5590
04:30:33,160 --> 04:30:35,480
PROBABLY INTERACT WITH ALL THOSE

5591
04:30:35,480 --> 04:30:36,400
GLYCANS.

5592
04:30:36,400 --> 04:30:37,480
THINK IT'S ESPECIALLY

5593
04:30:37,480 --> 04:30:40,200
INTERESTING IN CDGs, BY THE

5594
04:30:40,200 --> 04:30:45,200
WAY, IN GENERAL WHERE THE 

5595
04:30:45,200 --> 04:30:48,680
DIFFERENT N AND O-GLYCANS HAVE

5596
04:30:48,680 --> 04:30:50,120
BEEN CHANGED IN EXPRESSION,

5597
04:30:50,120 --> 04:30:51,120
ASSOCIATED WITH GUT HOMEOSTASIS,

5598
04:30:51,120 --> 04:30:52,800
SO THE CLUES ARE THERE.

5599
04:30:52,800 --> 04:30:55,240
I WOULD SAY THE CLUES ARE THERE.

5600
04:30:55,240 --> 04:30:57,400
SPECIFICITY IS NOT SO CLEAR BUT

5601
04:30:57,400 --> 04:30:59,640
THE CLUES ARE STRONG THAT YOU'RE

5602
04:30:59,640 --> 04:31:00,080
ABSOLUTELY RIGHT.

5603
04:31:00,080 --> 04:31:11,120
A CHANGE IN HOST   GLYCOME WILL

5604
04:31:11,120 --> 04:31:13,440
CHANGE THE MICROBIOME ITSELF.

5605
04:31:13,440 --> 04:31:14,960
>> I WAS THINKING ABOUT IT

5606
04:31:14,960 --> 04:31:17,840
BECAUSE MBL HAS ALL THOSE ROLES

5607
04:31:17,840 --> 04:31:19,560
IN COMPLEMENT, YOU MENTIONED

5608
04:31:19,560 --> 04:31:19,920
THAT.

5609
04:31:19,920 --> 04:31:22,520
THERE ARE A NUMBER OF LECTINS

5610
04:31:22,520 --> 04:31:26,040
THAT CAN CONTRIBUTE TO THE

5611
04:31:26,040 --> 04:31:27,840
PATHWAY, USEFUL TO LOOK

5612
04:31:27,840 --> 04:31:33,720
INCISIVELY AT WHAT MIGHT BE IN

5613
04:31:33,720 --> 04:31:33,920
THERE.

5614
04:31:33,920 --> 04:31:35,720
>> YOU'RE ABSOLUTELY RIGHT.

5615
04:31:35,720 --> 04:31:37,240
THERE'S A WHOLE ASPECT OF

5616
04:31:37,240 --> 04:31:38,840
COMPLEMENT INVOLVEMENT IN SOME

5617
04:31:38,840 --> 04:31:42,560
OF THE CDGs THAT HAVE NOT BEEN

5618
04:31:42,560 --> 04:31:43,720
WELL STUDIED.

5619
04:31:43,720 --> 04:31:44,920
THANK YOU.

5620
04:31:44,920 --> 04:31:45,760
>> GREAT WORK.

5621
04:31:45,760 --> 04:31:49,040
IN THE INTEREST OF TIME WE'LL

5622
04:31:49,040 --> 04:31:52,640
MOVE ON TO OUR NEXT SPEAKERS.

5623
04:31:52,640 --> 04:31:55,400
WITH ALL THE SPEAKERS, I'M

5624
04:31:55,400 --> 04:31:58,360
E-MAILING THE QUESTIONS.

5625
04:31:58,360 --> 04:31:59,880
PLEASE ASK A QUESTION.

5626
04:31:59,880 --> 04:32:05,640
I'M GOING TO INTRODUCE THE NEXT

5627
04:32:05,640 --> 04:32:18,480
SPEAKER, NEXT SPEAKER WILL TALK 

5628
04:32:18,480 --> 04:32:21,040
ABOUT DISRUPTION OF MICROBIOTA.

5629
04:32:21,040 --> 04:32:26,960
>> CAN YOU HEAR ME?

5630
04:32:26,960 --> 04:32:28,040
>> YES.

5631
04:32:28,040 --> 04:32:33,000
>> THANK YOU FOR THE INVITATION 

5632
04:32:33,000 --> 04:32:34,280
TO PRESENT MY WORK.

5633
04:32:34,280 --> 04:32:36,480
I'M GOING TO TALK ABOUT

5634
04:32:36,480 --> 04:32:44,200
INTERACTION TO PROTECT HOST AND 

5635
04:32:44,200 --> 04:32:45,480
SOMETIMES TO CAUSE DISEASE.

5636
04:32:45,480 --> 04:32:50,280
A BROAD VIEW OF MY LAB, HOST AND

5637
04:32:50,280 --> 04:32:51,040
MICROBIOTA ARE TALKING TO

5638
04:32:51,040 --> 04:32:54,000
PROMOTE HEALTH.

5639
04:32:54,000 --> 04:32:55,840
WHAT HAPPENS WHEN BENEFICIAL

5640
04:32:55,840 --> 04:32:56,760
INTERACTION GETS DISRUPTED AND

5641
04:32:56,760 --> 04:32:59,040
MAY LEAD TO HUMAN DISEASE.

5642
04:32:59,040 --> 04:33:03,640
WHAT WE KNOW IS THAT DISRUPTION

5643
04:33:03,640 --> 04:33:05,640
OF THE GUT MICROBIOTA HAS BEEN

5644
04:33:05,640 --> 04:33:10,280
ASSOCIATED WITH A LOT OF HUMAN

5645
04:33:10,280 --> 04:33:14,080
DISEASES FROM NECROTIZING

5646
04:33:14,080 --> 04:33:17,960
INTERCOLITIS IN INFANTS, IBS,

5647
04:33:17,960 --> 04:33:22,520
IBD, THE LIST GOES ON.

5648
04:33:22,520 --> 04:33:26,040
ONE PARTICULAR ASPECT OF

5649
04:33:26,040 --> 04:33:29,320
DYSBIOSIS, IMBALANCE, THAT IS

5650
04:33:29,320 --> 04:33:31,320
ASSOCIATED WITH DISEASE IS THAT

5651
04:33:31,320 --> 04:33:33,040
THIS -- I'M TALKING SPECIFICALLY

5652
04:33:33,040 --> 04:33:35,200
FOR THE LARGE BOWEL.

5653
04:33:35,200 --> 04:33:46,560
WHAT WE SEE IS THAT MICROBIC 

5654
04:33:46,560 --> 04:33:50,000
COMMUNITY STARTS TO SEE

5655
04:33:50,000 --> 04:33:50,800
EXTENSIONEN ANAEROBIC BACTERIA,

5656
04:33:50,800 --> 04:33:56,040
WHAT MY LAB IS INTERESTED IN.

5657
04:33:56,040 --> 04:33:57,440
WE'RE INTERESTED IN

5658
04:33:57,440 --> 04:34:05,920
PROTEOBACTERIA BECAUSE THEY

5659
04:34:05,920 --> 04:34:06,840
BEHAVE DIFFERENTLY.

5660
04:34:06,840 --> 04:34:09,840
THEY ARE NOT ABLE TO DIGEST

5661
04:34:09,840 --> 04:34:16,720
FIBER THE SAME WAY A LOT OF

5662
04:34:16,720 --> 04:34:20,200
MICROBES ARE, SOME ARE

5663
04:34:20,200 --> 04:34:20,840
PATHOGENIC.

5664
04:34:20,840 --> 04:34:22,520
I'M GOING TO REFER TODAY MOSTLY

5665
04:34:22,520 --> 04:34:26,840
TO E. COLI STRAINS.

5666
04:34:26,840 --> 04:34:30,960
WHAT IS INTERESTING, THEY HAVE A

5667
04:34:30,960 --> 04:34:33,760
DIFFERENT METABOLISM THAN

5668
04:34:33,760 --> 04:34:38,160
ANAEROBIC BACTERIA.

5669
04:34:38,160 --> 04:34:39,840
THEY CAN RESPIRE OXYGEN, BUT

5670
04:34:39,840 --> 04:34:42,960
THEY CAN ALSO PERFORM ANAEROBIC

5671
04:34:42,960 --> 04:34:48,160
RESPIRATION, IN THE ABSENCE OF

5672
04:34:48,160 --> 04:34:49,960
OXYGEN, ANAEROBIC ENVIRONMENT

5673
04:34:49,960 --> 04:34:52,440
CAN USE OTHER IONS TO RESPIRE

5674
04:34:52,440 --> 04:34:55,160
AND GROW.

5675
04:34:55,160 --> 04:34:57,880
WHAT'S INTERESTING, THEY PREFER

5676
04:34:57,880 --> 04:34:59,520
OXYGEN FOR RESPIRATION BUT RIGHT

5677
04:34:59,520 --> 04:35:02,520
BELOW THERE'S TWO OTHER

5678
04:35:02,520 --> 04:35:08,440
RECEPTORS THEY LIKE,  AND WE

5679
04:35:08,440 --> 04:35:15,560
KNOW BY WORK FROM OUR GROUP AND

5680
04:35:15,560 --> 04:35:19,080
OTHERS THAT NITRATES AND

5681
04:35:19,080 --> 04:35:35,280
NITRITES ARE PRESENT IN THE GUT.

5682
04:35:35,280 --> 04:35:38,360
OUR GROUP HAS PROPOSED A

5683
04:35:38,360 --> 04:35:40,120
MICROBIAL SIGNATURE OF

5684
04:35:40,120 --> 04:35:40,400
DYSBIOSIS.

5685
04:35:40,400 --> 04:35:41,800
WHAT WE WANTED TO DO FOR MY WORK

5686
04:35:41,800 --> 04:35:44,040
AS A POSTDOC BEFORE I STARTED MY

5687
04:35:44,040 --> 04:35:48,320
LAB TO USE SOME OF OUR KNOWLEDGE

5688
04:35:48,320 --> 04:35:50,520
TO TRY TO UNDERSTAND WHY.

5689
04:35:50,520 --> 04:35:52,200
THIS IS PUBLISHED WORK.

5690
04:35:52,200 --> 04:35:55,640
WHAT WE FOUND USING A MODEL OF

5691
04:35:55,640 --> 04:35:56,440
ANTIBIOTICS IN THE HEALTHY GUT

5692
04:35:56,440 --> 04:36:03,520
ON THE LEFT WHAT HAPPENS IS THAT

5693
04:36:03,520 --> 04:36:08,160
THE HEALTHY MICROBIOTA PROTECTS

5694
04:36:08,160 --> 04:36:14,080
THE HOST, BUTYRATE INCREASES

5695
04:36:14,080 --> 04:36:17,280
OXIDATIVE METABOLISM OF THE

5696
04:36:17,280 --> 04:36:25,040
INTESTINE EPITHELIUM, THROUGH 

5697
04:36:25,040 --> 04:36:39,680
ACTIVATION OF NUCLEAR RECEPTOR.

5698
04:36:39,680 --> 04:36:47,560
ANTIBIOTICS KILL THESE,

5699
04:36:47,560 --> 04:36:50,840
INCREASING INFLAMMATORY CONTENT,

5700
04:36:50,840 --> 04:36:52,840
ALSO DECREASES OXIDATIVE

5701
04:36:52,840 --> 04:36:55,840
METABOLISM LEADING TO INCREASED 

5702
04:36:55,840 --> 04:36:58,480
OXYGENATION OF THE GUT, AND

5703
04:36:58,480 --> 04:37:14,000
USING THIS OXYGEN TO GROW.

5704
04:37:14,000 --> 04:37:18,000
MAYBE 

5705
04:37:18,000 --> 04:37:24,640
THIS COULD BE A SIGNATURE,

5706
04:37:24,640 --> 04:37:25,880
EPITHELIUM NOT FUNCTIONING

5707
04:37:25,880 --> 04:37:26,440
PROPERLY.

5708
04:37:26,440 --> 04:37:28,280
THERE'S A LOT OF DISEASES WE

5709
04:37:28,280 --> 04:37:29,720
COULD HAVE FOCUSED ON BUT

5710
04:37:29,720 --> 04:37:32,880
DECIDED TO FOCUS ON ONE SPECIFIC

5711
04:37:32,880 --> 04:37:37,280
DISEASE, METABOLIC SYNDROME, 

5712
04:37:37,280 --> 04:37:42,080
SPECIFICALLY DIET INDUCED

5713
04:37:42,080 --> 04:37:42,320
OBESITY.

5714
04:37:42,320 --> 04:37:44,640
BEFORE COVID, WE KNOW OBESITY

5715
04:37:44,640 --> 04:37:49,360
WAS THE EPIDEMIC OF THE 21ST

5716
04:37:49,360 --> 04:37:49,840
CENTURY.

5717
04:37:49,840 --> 04:37:52,320
IN THE 2000, 20 TO 30% OF WEST

5718
04:37:52,320 --> 04:37:56,000
POPULATION WAS CONSIDERED OBESE.

5719
04:37:56,000 --> 04:37:59,440
NOW 2019 UP TO 40%.

5720
04:37:59,440 --> 04:38:02,360
PREDICTION IS BY 2030 ABOUT 50

5721
04:38:02,360 --> 04:38:13,120
TO 60% OF OUR POPULATION WILL BE

5722
04:38:13,120 --> 04:38:17,400
OBESE, AFFECTING THE GUT

5723
04:38:17,400 --> 04:38:17,920
MICROBIOTA.

5724
04:38:17,920 --> 04:38:19,040
TO MIMIC DIET INDUCED OBESITY

5725
04:38:19,040 --> 04:38:22,440
DECIDED TO USE A MOUSE MODEL.

5726
04:38:22,440 --> 04:38:25,840
CHRONICALLY FEED MICE 10% DIET,

5727
04:38:25,840 --> 04:38:27,800
LOW FAT DIET, MATCHING DIET

5728
04:38:27,800 --> 04:38:34,000
EXCEPT FOR THE FAT CONTENT TO

5729
04:38:34,000 --> 04:38:34,440
60% FAT.

5730
04:38:34,440 --> 04:38:38,320
WE CAN SEE MICE WITH HIGH FAT

5731
04:38:38,320 --> 04:38:43,160
DIET HAVE INCREASE THE

5732
04:38:43,160 --> 04:38:45,000
ANTIBIOTICOSITY IN THE

5733
04:38:45,000 --> 04:38:45,400
MICROBIOTA.

5734
04:38:45,400 --> 04:38:48,040
100 FOLD MORE IN THEIR GUT THAN

5735
04:38:48,040 --> 04:38:58,960
THE MICE WITH LOW FAT DIET.

5736
04:38:58,960 --> 04:39:02,960
I LIKE TO TAKE A MOMENT TO

5737
04:39:02,960 --> 04:39:08,480
EXPLAIN THE ASSAY, A MODEL WE

5738
04:39:08,480 --> 04:39:13,520
USE TO DETERMINE IF SPECIFIC

5739
04:39:13,520 --> 04:39:17,240
NUTRIENTS ARE IMPORTANT FOR

5740
04:39:17,240 --> 04:39:19,960
MICROBIAL SURVIVAL.

5741
04:39:19,960 --> 04:39:22,880
1:1 RATIO OF WILDTYPE AND MUTANT

5742
04:39:22,880 --> 04:39:24,840
STRAIN FOR A PARTICULAR NUTRIENT

5743
04:39:24,840 --> 04:39:28,360
AND SEE OUTPUT IN THE FECES.

5744
04:39:28,360 --> 04:39:34,640
IF THE NUTRIENT IS ABSENT, WILD

5745
04:39:34,640 --> 04:39:43,320
TYPE AND MUTANT STRAIN SHOULD

5746
04:39:43,320 --> 04:39:43,680
RECOVER.

5747
04:39:43,680 --> 04:39:47,640
IF THE NUTRIENT IS PRESENT,

5748
04:39:47,640 --> 04:39:49,800
INDEX ABOVE 1, SO FIRST WE

5749
04:39:49,800 --> 04:39:53,280
WANTED TO SEE IF AS WE SEE IN

5750
04:39:53,280 --> 04:39:58,800
ANTIBIOTIC MODELS HIGH FAT DIET

5751
04:39:58,800 --> 04:40:01,840
E. COLI, USING OXYGEN, WE DID

5752
04:40:01,840 --> 04:40:02,520
THIS COMPETITIVE INFECTION USING

5753
04:40:02,520 --> 04:40:07,000
E. COLI STRAIN THAT CANNOT

5754
04:40:07,000 --> 04:40:09,200
PERFORM AEROBIC RESTORATION.

5755
04:40:09,200 --> 04:40:13,840
YOU CAN SEE ABOUT ONLY THE MICE

5756
04:40:13,840 --> 04:40:15,440
WITH HIGH FAT DIET E. COLI

5757
04:40:15,440 --> 04:40:17,200
EXPANDS BY USING OXYGEN,

5758
04:40:17,200 --> 04:40:20,560
AVAILABLE FOR BACTERIA TO USE.

5759
04:40:20,560 --> 04:40:24,840
IN THIS CASE WE WANTED TO SEEK

5760
04:40:24,840 --> 04:40:27,200
NITRATE BECOMES AVAILABLE TO

5761
04:40:27,200 --> 04:40:28,720
HOST RESPONSE, PROMOTING E. COLI

5762
04:40:28,720 --> 04:40:31,360
GROWTH DURING HIGH FAT DIET,

5763
04:40:31,360 --> 04:40:33,640
WHAT WE SEE IS THAT SIMILAR TO

5764
04:40:33,640 --> 04:40:36,280
OXYGEN, ONLY HIGH FAT DIET FED

5765
04:40:36,280 --> 04:40:38,920
MICE E. COLI IS USING NITRATES

5766
04:40:38,920 --> 04:40:39,680
FOR GROWTH.

5767
04:40:39,680 --> 04:40:48,160
THE QUESTION HERE THEN IS HOW IS

5768
04:40:48,160 --> 04:40:53,560
THIS BECOMING AVAILABLE.

5769
04:40:53,560 --> 04:40:58,480
TO REMIND YOU, ANTIBIOTICS

5770
04:40:58,480 --> 04:41:00,160
MODEL, ELECTRON ACCEPTORS BECOME

5771
04:41:00,160 --> 04:41:04,720
AVAILABLE,  METABOLITES ARE

5772
04:41:04,720 --> 04:41:11,480
DEPLETED WITH ANTIBIOTICS SUCH

5773
04:41:11,480 --> 04:41:13,760
AS BUTYRATES.

5774
04:41:13,760 --> 04:41:19,920
WITH SLIGHT DECREASE, NOT THE

5775
04:41:19,920 --> 04:41:22,000
SAME REASON WHY ACCEPTORS BECAME

5776
04:41:22,000 --> 04:41:23,760
ABLE, CHRONIC EXPOSURE DAMAGES

5777
04:41:23,760 --> 04:41:26,520
THE GUT EPITHELIUM.

5778
04:41:26,520 --> 04:41:31,400
IT'S ABOUT -- YOU CAN SEE BOTTOM

5779
04:41:31,400 --> 04:41:37,800
PANEL THERE'S A LOSS OF CELLS,

5780
04:41:37,800 --> 04:41:38,960
INCREASE THE PROLIFERATION,

5781
04:41:38,960 --> 04:41:44,200
SUGGESTING MAYBE THE DIET

5782
04:41:44,200 --> 04:41:46,520
ITSELF, IT'S IMPORTANT TO SAY WE

5783
04:41:46,520 --> 04:41:47,800
SAW THE SAME CHANGES IN

5784
04:41:47,800 --> 04:41:51,520
GERM-FREE MICE SUGGESTING THE

5785
04:41:51,520 --> 04:41:56,480
DIET MAY BE AFFECTING EPITHELIAL

5786
04:41:56,480 --> 04:41:57,040
FUNCTION.

5787
04:41:57,040 --> 04:41:59,160
TO CONFIRM, WE USED CELL LINE

5788
04:41:59,160 --> 04:42:00,640
EXPOSING CELLS TO INCREASE THE

5789
04:42:00,640 --> 04:42:04,960
LEVELS OF FAT TO MIMIC WHAT WE

5790
04:42:04,960 --> 04:42:09,480
SAW IN A HIGH FAT DIET AND

5791
04:42:09,480 --> 04:42:10,680
LOOKED FOR MITOCHONDRIAL

5792
04:42:10,680 --> 04:42:11,440
FUNCTION.

5793
04:42:11,440 --> 04:42:14,840
YOU CAN APPRECIATE HERE IS AS

5794
04:42:14,840 --> 04:42:16,920
INCREASED EXPOSURE TO FAT

5795
04:42:16,920 --> 04:42:20,520
THERE'S A DECREASE IN CAPACITY

5796
04:42:20,520 --> 04:42:25,680
AND DECREASE IN ATP COMING FROM 

5797
04:42:25,680 --> 04:42:26,520
MITOCHONDRIA, SUGGESTING

5798
04:42:26,520 --> 04:42:27,920
MITOCHONDRIA IS NOT FUNCTIONING

5799
04:42:27,920 --> 04:42:33,280
PROPERLY NOT BECAUSE CELLS WERE

5800
04:42:33,280 --> 04:42:33,520
DYING.

5801
04:42:33,520 --> 04:42:36,880
WE ALSO SAW INCREASE LEVEL OF

5802
04:42:36,880 --> 04:42:40,280
REACTIVE OXYGEN SPECIES COMING

5803
04:42:40,280 --> 04:42:43,480
FROM MITOCHONDRIA, WHEN EXPOSURE

5804
04:42:43,480 --> 04:42:49,840
TO PALMITATE, SUGGESTING HIGH

5805
04:42:49,840 --> 04:42:51,280
FAT DIET DAMAGING MITOCHONDRIA.

5806
04:42:51,280 --> 04:42:55,240
SO WE THINK IT'S HAPPENING IN

5807
04:42:55,240 --> 04:42:59,800
HIGH FAT DIET, THAT WHILE IN LOW

5808
04:42:59,800 --> 04:43:04,600
FAT HEALTHY DIET, MITOCHONDRIA

5809
04:43:04,600 --> 04:43:06,560
FUNCTION PROPERLY, PREVENTING

5810
04:43:06,560 --> 04:43:13,560
ELECTRON  ACCEPTORS TO BE

5811
04:43:13,560 --> 04:43:14,480
AVAILABLE.

5812
04:43:14,480 --> 04:43:17,600
HIGH FAT DIET IS DAMAGING, A

5813
04:43:17,600 --> 04:43:22,920
CONSEQUENCE IS OXYGEN BECOMES 

5814
04:43:22,920 --> 04:43:28,000
AVAILABLE AND STARTS TO PRODUCE

5815
04:43:28,000 --> 04:43:28,600
NITRATES, ACCEPTORS BECOME

5816
04:43:28,600 --> 04:43:31,920
AVAILABLE, TO EXPAND IN THE GUT,

5817
04:43:31,920 --> 04:43:38,760
ALSO FEED THE RESIDENT

5818
04:43:38,760 --> 04:43:39,040
MICROBIOTA.

5819
04:43:39,040 --> 04:43:44,200
SO WHAT, RIGHT? 

5820
04:43:44,200 --> 04:43:46,520
WHAT IS RELEVANCE OF

5821
04:43:46,520 --> 04:43:48,640
ENTEROBACTERIA, WHAT IS THE

5822
04:43:48,640 --> 04:43:49,800
CONSEQUENCE?

5823
04:43:49,800 --> 04:43:53,160
OUR LAB IS INVESTIGATING BUT ONE

5824
04:43:53,160 --> 04:43:55,920
THING I WANT TO PRESENT,

5825
04:43:55,920 --> 04:43:57,680
SOMETHING RELATED TO INCREASED

5826
04:43:57,680 --> 04:43:58,360
RISK FOR CARDIOVASCULAR DISEASE,

5827
04:43:58,360 --> 04:44:01,240
AGAIN A NUMBER ONE KILLER IN OUR

5828
04:44:01,240 --> 04:44:04,560
COUNTRY IN A WORLD WITHOUT

5829
04:44:04,560 --> 04:44:04,880
COVID.

5830
04:44:04,880 --> 04:44:14,080
OUR LAB IN PARTICULAR  BECAME

5831
04:44:14,080 --> 04:44:17,600
INTERESTED IN CARDIOVASCULAR

5832
04:44:17,600 --> 04:44:19,120
DISEASE, THE MICROBIOME CAN

5833
04:44:19,120 --> 04:44:23,800
METABOLIZE ENZYMES THAT BREAK

5834
04:44:23,800 --> 04:44:29,040
DOWN COMPONENTS, TMA, OXIDIZED

5835
04:44:29,040 --> 04:44:31,400
INTO TMAO, METABOLIZED, PLAYING

5836
04:44:31,400 --> 04:44:36,560
A ROLE IN METABOLIC SYNDROME AND

5837
04:44:36,560 --> 04:44:36,880
HEART DISEASE.

5838
04:44:36,880 --> 04:44:38,840
AN INTERESTING STUDY TO SEE WHAT

5839
04:44:38,840 --> 04:44:45,240
MEMBERS ARE ABLE TO METABOLIZE

5840
04:44:45,240 --> 04:44:49,200
SPECIFICALLY CHOLINE, YOU SEE 

5841
04:44:49,200 --> 04:44:51,440
LARGE NUMBER OF MICROBES ARE

5842
04:44:51,440 --> 04:44:53,680
ENTEROBACTERIA.

5843
04:44:53,680 --> 04:44:55,640
WE KNEW HIGH CAPACITY TO

5844
04:44:55,640 --> 04:44:56,040
METABOLIZE CHOLINE.

5845
04:44:56,040 --> 04:45:01,080
THE WEIGH THEY MA  METABOLIZE IS

5846
04:45:01,080 --> 04:45:01,720
CREATING MICROCOMPARTMENT THAT

5847
04:45:01,720 --> 04:45:06,520
ENABLES BACTERIA TO BREAK DOWN

5848
04:45:06,520 --> 04:45:10,520
CHOLINE, INTO ENERGY, AND PMAs

5849
04:45:10,520 --> 04:45:15,480
INTO THIS METABOLIC PATHWAY. 

5850
04:45:15,480 --> 04:45:17,960
WHAT DECIDED TO SEE IN VITRO IF

5851
04:45:17,960 --> 04:45:19,040
CONDITIONS THAT MIMIC CONDITIONS

5852
04:45:19,040 --> 04:45:24,000
IN THE HIGH FAT DIET, OXYGEN IS

5853
04:45:24,000 --> 04:45:26,040
AVAILABLE, NITRATE IS AVAILABLE,

5854
04:45:26,040 --> 04:45:34,800
WHETHER E. COLI WOULD BE ABLE TO

5855
04:45:34,800 --> 04:45:35,960
METABOLIZE CHOLINE.

5856
04:45:35,960 --> 04:45:38,440
WE GAVE OXYGEN AND NITRATE, ONLY

5857
04:45:38,440 --> 04:45:41,720
UNDER THOSE CONDITIONS E. COLI

5858
04:45:41,720 --> 04:45:45,760
IS BREAKING DOWN CHOLINE AND

5859
04:45:45,760 --> 04:45:46,720
GROWING USING CHOLINE, MUTANT

5860
04:45:46,720 --> 04:45:48,960
STRAIN CANNOT DO THE SAME THING.

5861
04:45:48,960 --> 04:45:50,840
THIS IS INTERESTING TO US, WE

5862
04:45:50,840 --> 04:45:52,880
WANTED TO SEE IF THIS IS

5863
04:45:52,880 --> 04:45:53,800
RELEVANT IN VIVO, WENT BACK TO

5864
04:45:53,800 --> 04:45:56,200
THE MOUSE MODEL AND WE DID HAVE

5865
04:45:56,200 --> 04:45:58,200
TO SUPPLEMENT CHOLINE BECAUSE

5866
04:45:58,200 --> 04:46:01,160
TURNS OUT MOUSE DIET DOESN'T

5867
04:46:01,160 --> 04:46:07,880
HAVE A LOT OF CHOLINE, BACK TO

5868
04:46:07,880 --> 04:46:09,560
THE ASSAY.

5869
04:46:09,560 --> 04:46:12,440
WE SAW ONLY MICE FED HIGH FAT

5870
04:46:12,440 --> 04:46:17,200
DIET, WILDTYPE STRAIN OF E

5871
04:46:17,200 --> 04:46:18,920
CO-COULD OUTCOMPETE SUGGESTING

5872
04:46:18,920 --> 04:46:21,440
ONLY HIGH FAT DIET E. COLI WAS

5873
04:46:21,440 --> 04:46:22,880
USING CHOLINE FOR GROWTH.

5874
04:46:22,880 --> 04:46:27,200
IT WAS REALLY BECAUSE THE 

5875
04:46:27,200 --> 04:46:30,600
BACTERIA WAS RESPIRING USING

5876
04:46:30,600 --> 04:46:34,080
CHOLINE, IN REPEATED EXPERIMENTS

5877
04:46:34,080 --> 04:46:38,400
USING STRAINS COULD NOT PERFORM

5878
04:46:38,400 --> 04:46:40,840
RESPIRATION, WILD TYPE COULD NOT

5879
04:46:40,840 --> 04:46:41,640
OUTPERFORM, IF THEY CAN'T

5880
04:46:41,640 --> 04:46:43,840
RESPIRE THEY CAN'T USE CHOLINE

5881
04:46:43,840 --> 04:46:46,040
IN THE INTESTINAL LUMEN.

5882
04:46:46,040 --> 04:46:47,040
TO REMIND UP WHAT WAS

5883
04:46:47,040 --> 04:46:52,400
INTERESTING ABOUT THE STORY IS

5884
04:46:52,400 --> 04:46:53,360
THAT CHOLINE, METABOLISM OF

5885
04:46:53,360 --> 04:46:55,480
CHOLINE LEADS TO PRODUCTION OF

5886
04:46:55,480 --> 04:46:58,520
METABOLITES HARMFUL TO THE HOST.

5887
04:46:58,520 --> 04:47:04,080
SO WE WANTED TO SEE WHAT HAPPENS

5888
04:47:04,080 --> 04:47:07,760
IF WE MEASURE IN THE MOUSE FED

5889
04:47:07,760 --> 04:47:10,560
LOW FAT OR HIGH FAT DIET,

5890
04:47:10,560 --> 04:47:13,800
DIFFERENT E. COLI.

5891
04:47:13,800 --> 04:47:16,240
WE CAN SEE THAT HIGH FAT MED

5892
04:47:16,240 --> 04:47:25,080
MICE WITH E. COLI ABLE TO

5893
04:47:25,080 --> 04:47:26,840
METABOLIZE CHOLINE IN

5894
04:47:26,840 --> 04:47:29,440
MICROBIOTA, INCREASE CIRCULATING

5895
04:47:29,440 --> 04:47:30,520
TMAO.

5896
04:47:30,520 --> 04:47:31,760
IF WE COLONIZE DO NOT

5897
04:47:31,760 --> 04:47:33,160
METABOLIZE, DOES IT GO AWAY, THE

5898
04:47:33,160 --> 04:47:35,640
SAME IS TRUE IF WE COLONIZE MICE

5899
04:47:35,640 --> 04:47:40,520
WITH STRAIN OF E. COLI THAT

5900
04:47:40,520 --> 04:47:41,560
CANNOT RESPIRE CONFIRMING

5901
04:47:41,560 --> 04:47:44,360
RESPIRATION IS WHAT IS LEADING

5902
04:47:44,360 --> 04:47:47,720
TO INCREASED LEVELS OF TMAO IN

5903
04:47:47,720 --> 04:47:49,480
THE BLOOD CIRCULATION.

5904
04:47:49,480 --> 04:47:52,480
THE LAST QUESTION HERE, THIS WAS

5905
04:47:52,480 --> 04:47:57,280
INTERESTING TO US, BUT IF THIS 

5906
04:47:57,280 --> 04:48:00,840
INTERACTION BETWEEN INTESTINE

5907
04:48:00,840 --> 04:48:03,000
EPITHELIUM AND MICROBIOTA IS

5908
04:48:03,000 --> 04:48:07,520
DRIVING PRODUCTION, COULD IT

5909
04:48:07,520 --> 04:48:08,160
PREVENT PRODUCTION?

5910
04:48:08,160 --> 04:48:16,120
TO DO THAT WE CHOSE TO USE A

5911
04:48:16,120 --> 04:48:20,240
DRUG WHICH IS USED, FDA APPROVED

5912
04:48:20,240 --> 04:48:26,400
USED FOR IBD TREATMENT.

5913
04:48:26,400 --> 04:48:29,840
WE'VE SHOWN 5-ASA TARGETS --

5914
04:48:29,840 --> 04:48:31,200
RESTORES METABOLISM OF INTESTINE

5915
04:48:31,200 --> 04:48:31,840
EPITHELIUM.

5916
04:48:31,840 --> 04:48:37,800
WHAT WE DID HERE, WE TREATED

5917
04:48:37,800 --> 04:48:41,040
MICE ARE 5-ASA AND LOOKED INTO

5918
04:48:41,040 --> 04:48:43,880
FUNCTION AND SAW THAT HERE CELLS

5919
04:48:43,880 --> 04:48:49,000
IN RED ARE CELLS PERFORMING

5920
04:48:49,000 --> 04:48:49,760
OXIDATIVE METABOLISM.

5921
04:48:49,760 --> 04:48:54,160
WE CAN APPRECIATE HERE THAT IN

5922
04:48:54,160 --> 04:48:56,560
UNTREATED MICE, HIGH FAT DIET,

5923
04:48:56,560 --> 04:48:58,560
METABOLISM OF INTESTINES GOES

5924
04:48:58,560 --> 04:49:02,000
AWAY, CAN RESTORE THIS BY GIVING

5925
04:49:02,000 --> 04:49:04,280
THIS DRUG TO THE MICE.

5926
04:49:04,280 --> 04:49:06,640
NOT ONLY THAT 5-ASA WAS ABLE TO

5927
04:49:06,640 --> 04:49:15,280
INHIBIT GROWTH OF E. COLI IN THE

5928
04:49:15,280 --> 04:49:17,480
GUT, BY USING CHOLINE.

5929
04:49:17,480 --> 04:49:20,120
THAT ACTUALLY LED TO DECREASED

5930
04:49:20,120 --> 04:49:22,480
LEVELS OF BLOOD CIRCULATING TMAO

5931
04:49:22,480 --> 04:49:25,200
IF YOU RESTORE FUNCTION IN MICE

5932
04:49:25,200 --> 04:49:26,600
WITH HIGH FAT DIET.

5933
04:49:26,600 --> 04:49:29,960
SO WHAT I SHOWED YOU HERE TODAY

5934
04:49:29,960 --> 04:49:33,840
DURING HIGH FAT DIET WE THINK

5935
04:49:33,840 --> 04:49:43,120
THERE'S DYSFUNCTION OF INTESTINE

5936
04:49:43,120 --> 04:49:48,840
EPITHELIUM, MAY NOT BE HARMFUL

5937
04:49:48,840 --> 04:49:52,680
BUT IF IT CAN METABOLIZE CHOLINE

5938
04:49:52,680 --> 04:50:04,120
INTO TMA PATHWAYS TURNS ON AND

5939
04:50:04,120 --> 04:50:06,760
CAN CAUSE HARM.

5940
04:50:06,760 --> 04:50:08,080
WE'RE SHOWING MICROBIAL

5941
04:50:08,080 --> 04:50:09,600
METABOLISM IS CONTEXT DEPENDENT,

5942
04:50:09,600 --> 04:50:13,640
NOT JUST MICROBES HAVE GENE OR

5943
04:50:13,640 --> 04:50:14,240
CAPACITY TO PERFORM METABOLIC

5944
04:50:14,240 --> 04:50:15,280
PATHWAY, THEY ARE GOING TO BE

5945
04:50:15,280 --> 04:50:18,560
DOING THIS ALL THE TIME.

5946
04:50:18,560 --> 04:50:21,320
THE CONTEXT AROUND THIS MICROBES

5947
04:50:21,320 --> 04:50:23,680
HOW IMPORTANT TO TURN ON AND

5948
04:50:23,680 --> 04:50:25,240
REALLY EXPLAIN WHAT PARTICULAR

5949
04:50:25,240 --> 04:50:26,360
METABOLISM IS HAPPENING IN THE

5950
04:50:26,360 --> 04:50:29,240
CONTEXT OF HEALTH AND DISEASE,

5951
04:50:29,240 --> 04:50:31,040
AND SHOULD KEEP THAT IN MIND TO

5952
04:50:31,040 --> 04:50:32,160
UNDERSTAND WHAT MICROBES ARE

5953
04:50:32,160 --> 04:50:34,320
DOING IN THE GUT IN OUR MODELS

5954
04:50:34,320 --> 04:50:35,800
OF DISEASE.

5955
04:50:35,800 --> 04:50:38,480
SO WITH THAT, I CAN THANK THE

5956
04:50:38,480 --> 04:50:41,320
PEOPLE THAT HAVE DONE THE WORK,

5957
04:50:41,320 --> 04:50:52,680
MY POSTDOC, AND OUR FUNDING

5958
04:50:52,680 --> 04:50:53,240
SOURCES.

5959
04:50:53,240 --> 04:50:55,840
>> ANY QUESTIONS FROM ANYONE IN

5960
04:50:55,840 --> 04:50:57,080
THE AUDIENCE, ZOOM, OR VIRTUAL?

5961
04:50:57,080 --> 04:51:01,640
I BELIEVE YOU GOT A QUESTION 

5962
04:51:01,640 --> 04:51:03,520
EARLY IN THE CHAT, A LOGISTICAL

5963
04:51:03,520 --> 04:51:06,040
QUESTION, WHAT TYPE OF HIGH FAT

5964
04:51:06,040 --> 04:51:06,600
DIET WAS USED?

5965
04:51:06,600 --> 04:51:09,040
>> YEAH, I GET THAT QUESTION A

5966
04:51:09,040 --> 04:51:09,520
LOT.

5967
04:51:09,520 --> 04:51:12,240
THIS IS NOT A KETOGENIC DIET.

5968
04:51:12,240 --> 04:51:15,640
WE'VE NOT DONE WORK WITH THAT

5969
04:51:15,640 --> 04:51:17,800
KIND OF DIET.

5970
04:51:17,800 --> 04:51:21,880
WE USE TYPICAL RESEARCH DIET.

5971
04:51:21,880 --> 04:51:24,360
WHICH IS FAT COMES FROM LARD

5972
04:51:24,360 --> 04:51:24,640
USUALLY.

5973
04:51:24,640 --> 04:51:27,400
IT'S NOT A SPECIFIC TYPE OF FAT.

5974
04:51:27,400 --> 04:51:30,520
>> DO YOU THINK AGE IS A FACTOR,

5975
04:51:30,520 --> 04:51:32,360
OF THE ANIMALS YOU USE, OR NO?

5976
04:51:32,360 --> 04:51:34,520
>> YES, WHEN I FIRST STARTED THE

5977
04:51:34,520 --> 04:51:38,560
PROJECT I DID A COUPLE PILOT

5978
04:51:38,560 --> 04:51:38,840
EXPERIMENTS.

5979
04:51:38,840 --> 04:51:40,800
THESE 16, 17 WEEKS OF AGE WHEN

5980
04:51:40,800 --> 04:51:42,520
DOING EXPERIMENTS.

5981
04:51:42,520 --> 04:51:45,080
I'VE DONE EXPERIMENTS WITH MICE

5982
04:51:45,080 --> 04:51:48,440
AT 23, 24 WEEKS, LIKE OLDER,

5983
04:51:48,440 --> 04:51:49,680
MOST DIFFERENCES STARTED TO GO

5984
04:51:49,680 --> 04:51:52,240
AWAY, IT WAS BECAUSE OUR LOW FAT

5985
04:51:52,240 --> 04:52:04,160
MICE STARTED TO BE MORE

5986
04:52:04,160 --> 04:52:04,440
SUSCEPTIBLE.

5987
04:52:04,440 --> 04:52:05,600
HIGH FAT DIET ACCELERATING

5988
04:52:05,600 --> 04:52:07,400
MITOCHONDRIA DYSFUNCTION

5989
04:52:07,400 --> 04:52:09,360
ASSOCIATED WITH AGE AND MICE ARE

5990
04:52:09,360 --> 04:52:12,040
OLDER YOU LOSE THAT PHENOTYPE

5991
04:52:12,040 --> 04:52:14,600
BECAUSE OLDER MICE MAY START TO

5992
04:52:14,600 --> 04:52:15,880
HAVE DYSFUNCTION.

5993
04:52:15,880 --> 04:52:19,040
>> LIKE AN ADDITIVE THING TOO,

5994
04:52:19,040 --> 04:52:22,240
AGE AND COMPOUNDING OF HIGH FAT

5995
04:52:22,240 --> 04:52:22,440
DIET.

5996
04:52:22,440 --> 04:52:26,480
>> WOULD BE, YES.

5997
04:52:26,480 --> 04:52:28,160
>> THANK YOU FOR SHARING YOUR

5998
04:52:28,160 --> 04:52:28,440
WORK.

5999
04:52:28,440 --> 04:52:34,840
WE'LL MOVE ON IN THE INTEREST OF

6000
04:52:34,840 --> 04:52:35,240
TIME.

6001
04:52:35,240 --> 04:52:38,840
NEXT SPEAKER IS DR. CHRIS STEIN

6002
04:52:38,840 --> 04:52:42,040
SZYMANSKI FROM UNIVERSITY OF

6003
04:52:42,040 --> 04:52:45,960
GEORGIA, NEW PARADIGMS FOR

6004
04:52:45,960 --> 04:52:47,720
CAMPYLOBACTER JEJUNI IN THE GUT.

6005
04:52:47,720 --> 04:52:50,240
PERFECT, YOU'RE ON TOP OF IT.

6006
04:52:50,240 --> 04:52:53,240
I APPRECIATE YOU BEING HERE, SO

6007
04:52:53,240 --> 04:52:53,920
SUFFICIENT.

6008
04:52:53,920 --> 04:52:56,040
LOOKING FORWARD TO YOUR WORK.

6009
04:52:56,040 --> 04:52:58,640
>> THANK YOU, CATHERINE AND ALL

6010
04:52:58,640 --> 04:53:00,520
THE ORGANIZERS FOR INVITING ME.

6011
04:53:00,520 --> 04:53:06,000
IT'S BEEN AN EXCITING DAY. 

6012
04:53:06,000 --> 04:53:10,640
I'M GOING TO TELL YOU ABOUT MY

6013
04:53:10,640 --> 04:53:16,640
FAVORITE GUT MICRO,

6014
04:53:16,640 --> 04:53:17,560
CAMPYLOBACTER JEJUNI.

6015
04:53:17,560 --> 04:53:21,280
IT'S A LEADING CAUSE OF FOOD 

6016
04:53:21,280 --> 04:53:23,440
BORNE ILLNESS IN HUMANS.

6017
04:53:23,440 --> 04:53:25,840
CAMPYLOBACTER CAUSES DIARRHEA

6018
04:53:25,840 --> 04:53:28,040
BUT CAN ALSO CAUSE PARALYSIS AND

6019
04:53:28,040 --> 04:53:32,640
THE WAY THE PARALYSIS IS FORMED

6020
04:53:32,640 --> 04:53:34,560
IS THROUGH THESE GANGLIOSIDE

6021
04:53:34,560 --> 04:53:38,880
MIMICKING STRUCTURES ON THE

6022
04:53:38,880 --> 04:53:40,720
SURFACE, IN SOME CASES PEOPLE

6023
04:53:40,720 --> 04:53:43,920
WILL CREATE ANTIBODIES AGAINST

6024
04:53:43,920 --> 04:53:48,680
THESE GANGLIOSIDE AND

6025
04:53:48,680 --> 04:53:49,920
CROSS-REACT WITH OUR OWN

6026
04:53:49,920 --> 04:53:59,800
NEURONS, LEADING TO   PARALYSIS.

6027
04:53:59,800 --> 04:54:01,840
A SHOUT OUT TOP A PROJECT FUNDED

6028
04:54:01,840 --> 04:54:06,600
BY THE DoD TO LOOK AFTER

6029
04:54:06,600 --> 04:54:13,280
PATIENT SERA ON GLYCAN ARRAYS HE

6030
04:54:13,280 --> 04:54:14,040
SYNTHESIZED WITH CAMPYLOBACTER

6031
04:54:14,040 --> 04:54:15,000
LOS TYPE SUGARS.

6032
04:54:15,000 --> 04:54:18,360
WHAT I'M GOING TO FOCUS ON TODAY

6033
04:54:18,360 --> 04:54:22,320
IS ANOTHER CONSEQUENCE OF 

6034
04:54:22,320 --> 04:54:22,960
CAMPYLOBACTER INFECTION, THAT'S

6035
04:54:22,960 --> 04:54:24,160
IN LOW- AND MIDDLE-INCOME

6036
04:54:24,160 --> 04:54:26,080
COUNTRIES, CAMPYLOBACTER IS A

6037
04:54:26,080 --> 04:54:27,280
HUGE COURSE OF GROWTH STUNTING.

6038
04:54:27,280 --> 04:54:32,520
THE REASON FOR THIS IS BECAUSE

6039
04:54:32,520 --> 04:54:33,840
THE MICROBE DISPLACES BENEFICIAL

6040
04:54:33,840 --> 04:54:36,040
MICROBES EARLY IN LIFE, WHICH IS

6041
04:54:36,040 --> 04:54:37,840
VERY IMPORTANT FOR DEVELOPMENT,

6042
04:54:37,840 --> 04:54:40,760
NOT JUST OF GUT HEALTH BUT

6043
04:54:40,760 --> 04:54:42,840
NORMAL HUMAN DEVELOPMENT BUT

6044
04:54:42,840 --> 04:54:44,160
ALSO CAUSES SIGNIFICANT

6045
04:54:44,160 --> 04:54:48,880
INFLAMMATION AND THAT ALSO LEADS

6046
04:54:48,880 --> 04:54:50,560
TO NUTRIENT MALABSORPTION.

6047
04:54:50,560 --> 04:54:53,120
IN THIS STUDY FUNDED BY THE BILL

6048
04:54:53,120 --> 04:54:54,040
AND MELINDA GATES FOUNDATION

6049
04:54:54,040 --> 04:54:57,880
THEY FOUND CHILDREN UP TO 85% OF

6050
04:54:57,880 --> 04:54:58,800
CHILDREN WERE INFECTED WITH

6051
04:54:58,800 --> 04:55:01,920
CAMPYLOBACTER BY THE AGE OF 1.

6052
04:55:01,920 --> 04:55:04,960
AND SO WE'VE KNOWN FOR A LONG

6053
04:55:04,960 --> 04:55:06,440
TIME THAT CAMPYLOBACTER COULD

6054
04:55:06,440 --> 04:55:09,240
ADHERE TO FUCOSLYATED 

6055
04:55:09,240 --> 04:55:12,280
FUCOSLYATED SUGARS, AND WE HEARD

6056
04:55:12,280 --> 04:55:14,400
A TALK BY RICK CUMMINGS, HOW

6057
04:55:14,400 --> 04:55:16,640
IMPORTANT FUCOSE IS IN THE GUT.

6058
04:55:16,640 --> 04:55:18,480
WE DIDN'T KNOW IT COULD

6059
04:55:18,480 --> 04:55:24,440
METABOLIZE SHOULD GO ASHES,  --

6060
04:55:24,440 --> 04:55:27,640
SUGARS, IT WAS PREVIOUSLY

6061
04:55:27,640 --> 04:55:42,360
THOUGHT THAT CAMPYLOBACTER WAS

6062
04:55:42,360 --> 04:55:42,800
ASACHROLYTIC.

6063
04:55:42,800 --> 04:55:44,320
WHAT WE DISCOVERED WAS SOME

6064
04:55:44,320 --> 04:55:45,920
CAMPYLOBACTERS DIDN'T ONLY

6065
04:55:45,920 --> 04:55:48,080
SURVIVE ON PROTEIN SHAKES BUT

6066
04:55:48,080 --> 04:55:50,440
THAT THEY ACTUALLY COULD

6067
04:55:50,440 --> 04:55:50,840
METABOLIZE FUCOSE.

6068
04:55:50,840 --> 04:55:52,280
AND THESE ARE THE PEOPLE

6069
04:55:52,280 --> 04:55:54,520
INSTRUMENTAL IN THE STUDIES IN

6070
04:55:54,520 --> 04:55:57,520
MY LAB, LOOKING AT THIS FUCOSE

6071
04:55:57,520 --> 04:56:00,880
PATHWAY IN CAMPYLOBACTER WHICH

6072
04:56:00,880 --> 04:56:09,920
EXISTS AS A SINGLE OPERON. 

6073
04:56:09,920 --> 04:56:11,240
STRAINS CAN METABOLIZE,

6074
04:56:11,240 --> 04:56:12,120
INDICATED AS GREEN, SHOWING

6075
04:56:12,120 --> 04:56:19,440
GROWTH ADVANTAGE IN THE PRESENCE

6076
04:56:19,440 --> 04:56:22,280
OF FUCOSE, STRAINS DO WHICH DO

6077
04:56:22,280 --> 04:56:24,800
NOT SHOW GROWTH ADVANTAGE IN

6078
04:56:24,800 --> 04:56:28,560
PRESENCE OF FUCOSE, DENOTED AS 

6079
04:56:28,560 --> 04:56:28,720
RED.

6080
04:56:28,720 --> 04:56:31,920
TOGETHER WE LOOKED AT ALL THE

6081
04:56:31,920 --> 04:56:34,080
SEQUENCED CAMPYLOBACTER GENOMES

6082
04:56:34,080 --> 04:56:36,640
AND DISCOVERED A SIGNIFICANT

6083
04:56:36,640 --> 04:56:49,200
PROPORTION OF CAMPYLOBACTER

6084
04:56:49,200 --> 04:57:01,560
ISOLATES, THESE IN RED HAVE THE

6085
04:57:01,560 --> 04:57:01,960
OPERON.

6086
04:57:01,960 --> 04:57:07,320
JOLENE LOOKED  AT PATHWAY SHOWN

6087
04:57:07,320 --> 04:57:10,800
HERE, BROKEN DOWN INTO PYRUVATE,

6088
04:57:10,800 --> 04:57:17,080
STUDIED THAT  ARABINOS IS

6089
04:57:17,080 --> 04:57:17,640
METABOLIZED.

6090
04:57:17,640 --> 04:57:25,360
I WANTED TO FOCUS ON FOR THIS

6091
04:57:25,360 --> 04:57:42,240
TALK   A DEHYDROGENASE.

6092
04:57:42,240 --> 04:57:49,560
STUDIES WERE DONE SHOWING

6093
04:57:49,560 --> 04:57:52,920
WITHOUT FUCOSE, WILDTYPE 

6094
04:57:52,920 --> 04:57:54,360
CAMPYLOBACTER FORMS REBUST

6095
04:57:54,360 --> 04:57:56,240
BIOFILMS BUT IN PRESENCE WILL

6096
04:57:56,240 --> 04:57:59,720
DISPERSE AND SWIM TOWARDS THIS

6097
04:57:59,720 --> 04:58:00,680
SUGAR STRUCTURE, WE DEVELOPED

6098
04:58:00,680 --> 04:58:05,800
THIS ASSAY TO UNDERSTAND THE

6099
04:58:05,800 --> 04:58:07,840
SWIMMING BEHAVIOR, CAMPYLOBACTER

6100
04:58:07,840 --> 04:58:16,240
AT THE BOTTOM, A FILTER DISC AT 

6101
04:58:16,240 --> 04:58:17,520
THE TOP WITH REREPELLANT, GAUGE

6102
04:58:17,520 --> 04:58:28,840
WHETHER IT  SWAM TO THE TOP,

6103
04:58:28,840 --> 04:58:29,800
MEASURING RESPIRATION.

6104
04:58:29,800 --> 04:58:32,600
IT CAN SWIM TO FEW DOSE.

6105
04:58:32,600 --> 04:58:34,320
RED LINE.

6106
04:58:34,320 --> 04:58:37,480
THE FUCOSE CAN'T ENTER THE

6107
04:58:37,480 --> 04:58:38,520
CYTOPLASM, IT'S STILL ABLE TO

6108
04:58:38,520 --> 04:58:44,240
SWIM TO IT BUT WHEN YOU KNOCK

6109
04:58:44,240 --> 04:58:47,240
OUT THE DEHYDROGENASE ENZYME CAN

6110
04:58:47,240 --> 04:58:50,200
NO LONGER SWIM TO FUCOSE, WHEN I

6111
04:58:50,200 --> 04:58:53,880
PUT IT BACK IT RESTORES SWIMMING

6112
04:58:53,880 --> 04:58:54,160
BEHAVIOR.

6113
04:58:54,160 --> 04:58:55,880
IF YOU TAKE A STRAIN THAT

6114
04:58:55,880 --> 04:58:57,440
DOESN'T HAVE PATHWAY, CAN SWIM

6115
04:58:57,440 --> 04:59:04,000
TO FUCOSE, GIVE IT THAT FUCOSE 

6116
04:59:04,000 --> 04:59:06,240
OPERON, IT CAN SWIM.

6117
04:59:06,240 --> 04:59:07,360
IF YOU DIVERSITY JUST

6118
04:59:07,360 --> 04:59:08,240
DEHYDROGENASE WITHOUT ENZYMES

6119
04:59:08,240 --> 04:59:10,560
IT'S STILL ABLE TO SWIM TO

6120
04:59:10,560 --> 04:59:10,840
FUCOSE.

6121
04:59:10,840 --> 04:59:13,080
SO WHAT THAT TELLS US IS THAT

6122
04:59:13,080 --> 04:59:17,640
FUCOSE DOESN'T NEED TO ENTER THE

6123
04:59:17,640 --> 04:59:20,520
CYTOPLASM TO TRIGGER CHEMOTAXIS

6124
04:59:20,520 --> 04:59:26,600
AND THIS DEHYDROGENASE PLAYS A 

6125
04:59:26,600 --> 04:59:36,680
KEY ROLE IN CHEMOTAXI.

6126
04:59:36,680 --> 04:59:39,000
IT BINDS AND CONVERTS.

6127
04:59:39,000 --> 04:59:49,600
WHAT WE THOUGHT WAS SINCE WHEN

6128
04:59:49,600 --> 04:59:52,120
WE CRYSTALLIZED NADP CAN BIND

6129
04:59:52,120 --> 04:59:53,600
WITHOUT FUCOSE, AND MAY BE

6130
04:59:53,600 --> 04:59:57,000
IMPORTANT IN SENSING WHETHER TO

6131
04:59:57,000 --> 04:59:58,440
SWIM OR NOT.

6132
04:59:58,440 --> 05:00:00,880
WE DID THIS EXPERIMENT HERE,

6133
05:00:00,880 --> 05:00:05,640
SUBJECTED THE BACTERIA TO 

6134
05:00:05,640 --> 05:00:07,560
OXIDATIVE STRESS, HYDROGEN

6135
05:00:07,560 --> 05:00:09,920
PEROXIDE, REMOVED CATALASE

6136
05:00:09,920 --> 05:00:11,000
ENZYME, PRIMARY MECHANISM FOR

6137
05:00:11,000 --> 05:00:12,960
RELIEVING STRESS TO FORCE THE

6138
05:00:12,960 --> 05:00:16,440
MICROBE TO USE THE SECONDARY

6139
05:00:16,440 --> 05:00:20,840
PATHWAY THAT WOULD USE NADP.

6140
05:00:20,840 --> 05:00:24,840
YOU SEE SWIMMING WHEN HYDROGEN

6141
05:00:24,840 --> 05:00:25,880
PEROXIDE IS PRESENT, WHEN

6142
05:00:25,880 --> 05:00:28,240
CATALASE IS KNOCKED OUT BUT NO

6143
05:00:28,240 --> 05:00:30,680
LONGER SWIMMING TO FUCOSE WHEN

6144
05:00:30,680 --> 05:00:32,880
BOTH ARE THERE.

6145
05:00:32,880 --> 05:00:40,920
THAT'S TELLING US NEDPH IS THE

6146
05:00:40,920 --> 05:00:48,200
SIGNAL, TO CONFIRM USED A GLO

6147
05:00:48,200 --> 05:00:50,520
ASSAYS. 

6148
05:00:50,520 --> 05:00:53,200
WHEN ENZYME IS PRESENT SEE

6149
05:00:53,200 --> 05:00:54,480
DROPPED IN THAT LEVEL, WHAT I

6150
05:00:54,480 --> 05:00:58,400
SHOULD POINT OUT IS THIS IS A

6151
05:00:58,400 --> 05:00:58,960
LOG SCALE HERE.

6152
05:00:58,960 --> 05:01:02,440
ONE OF THE THINGS QUITE UNUSUAL

6153
05:01:02,440 --> 05:01:06,880
IS CAMPYLOBACTER AND ITS RELATED

6154
05:01:06,880 --> 05:01:10,480
PROTEOBACTERIA HELICOBACTER HAVE

6155
05:01:10,480 --> 05:01:16,480
A FLIPPED RATIO OF NADP/NADPH TO

6156
05:01:16,480 --> 05:01:17,720
 E. COLI.

6157
05:01:17,720 --> 05:01:22,720
WE SHOWED THESE RATIOS WERE

6158
05:01:22,720 --> 05:01:25,640
ACTUALLY TRUE USING NMR.

6159
05:01:25,640 --> 05:01:31,960
I'LL SAY PHOEBE IN THE LAND  --

6160
05:01:31,960 --> 05:01:33,400
LAB HAS DETERMINED WHICH

6161
05:01:33,400 --> 05:01:35,040
COMPONENTS ARE INVOLVED IN

6162
05:01:35,040 --> 05:01:40,480
SENSING, AND SHE'S NARROWED DOWN

6163
05:01:40,480 --> 05:01:42,240
TO THESE THREE PROTEINS.

6164
05:01:42,240 --> 05:01:47,400
WHICH ARE INVOLVED IN ENERGY

6165
05:01:47,400 --> 05:01:49,960
TAXIS IN CAMPYLOBACTER.

6166
05:01:49,960 --> 05:01:52,040
WHAT FUCOSE OR NADP IS SIGNALING

6167
05:01:52,040 --> 05:01:54,280
ENERGY STATUS TO THE MICROBE, IT

6168
05:01:54,280 --> 05:02:00,360
WILL DETERMINE ITS FLAGELLA

6169
05:02:00,360 --> 05:02:02,480
ROTATION BASED ON NADP LEVELS.

6170
05:02:02,480 --> 05:02:05,640
WHAT WE THINK IS HAPPENING BASED

6171
05:02:05,640 --> 05:02:08,440
ON RESULTS IS THAT NADP PH

6172
05:02:08,440 --> 05:02:11,080
LEVELS CHANGE IN THE MICROBE,

6173
05:02:11,080 --> 05:02:15,160
AND NADPH WILL COME AND REDUCE F

6174
05:02:15,160 --> 05:02:17,920
OF FAD CO-FACTOR OF SET B AND C

6175
05:02:17,920 --> 05:02:21,640
WHICH ACTIVATES SET A WHICH THEN

6176
05:02:21,640 --> 05:02:23,600
INTERACTS WITH CHEMOTAXIS

6177
05:02:23,600 --> 05:02:27,560
PROTEIN WHICH INFLUENCES

6178
05:02:27,560 --> 05:02:28,040
FLAGELLA ROTATION.

6179
05:02:28,040 --> 05:02:31,800
I TOLD YOU ABOUT THE MONO

6180
05:02:31,800 --> 05:02:32,280
SACCHARIDE FUCOSE.

6181
05:02:32,280 --> 05:02:33,640
YOU KNOW THAT FUCOSE DOESN'T

6182
05:02:33,640 --> 05:02:35,800
EXIST AS A MONO SACCHARIDE

6183
05:02:35,800 --> 05:02:36,080
TYPICALLY.

6184
05:02:36,080 --> 05:02:41,680
IT EXISTS AS PART OF MORE 

6185
05:02:41,680 --> 05:02:44,640
COMPLEX OLIGOSACCHARIDES SO 

6186
05:02:44,640 --> 05:02:45,840
YOU'RE WONDERING HOW DOES

6187
05:02:45,840 --> 05:02:47,240
CAMPYLOBACTER GET FUCOSE?

6188
05:02:47,240 --> 05:02:50,360
WE THOUGHT THAT QUESTION TOO.

6189
05:02:50,360 --> 05:02:54,440
MARIO ALLUDED TO THIS EARLIER

6190
05:02:54,440 --> 05:02:58,520
THIS MORNING THAT PATHOGENS

6191
05:02:58,520 --> 05:03:02,080
SOMETIMES ARE LAZY AND DON'T

6192
05:03:02,080 --> 05:03:03,760
HAVE REPERTOIRE AND WILL

6193
05:03:03,760 --> 05:03:10,520
SCAVENGE FROM MICROBES READY IN

6194
05:03:10,520 --> 05:03:12,080
OUR GUT LIKE BACTEROIDES,

6195
05:03:12,080 --> 05:03:14,560
CAPABLE OF RELEASING FUCOSE.

6196
05:03:14,560 --> 05:03:18,520
CAMPYLOBACTER CANNOT RELEASE

6197
05:03:18,520 --> 05:03:32,160
FUCOSE BUT USED  BACTEROIDES

6198
05:03:32,160 --> 05:03:35,520
VULGATUS, WE SEE ENHANCED

6199
05:03:35,520 --> 05:03:38,120
GROWTH, THAT'S FUCOSE PATHWAY

6200
05:03:38,120 --> 05:03:38,400
DEPENDENT.

6201
05:03:38,400 --> 05:03:42,000
WHAT THIS TELLS US IS THAT

6202
05:03:42,000 --> 05:03:46,160
CAMPYLOBACTER FUCOSE PATHWAY

6203
05:03:46,160 --> 05:03:51,320
BECOMES UPREGULATED WHEN 

6204
05:03:51,320 --> 05:03:59,120
BACTEROIDES IS SUPPLYING FUCOSE.

6205
05:03:59,120 --> 05:04:00,240
WE USED MARIO'S PROTOCOL,

6206
05:04:00,240 --> 05:04:03,160
INCUBATED WITH MUCIN, SHOWING WE

6207
05:04:03,160 --> 05:04:07,280
COULD GET RELEASE OF FREE FUCOSE

6208
05:04:07,280 --> 05:04:08,440
FROM THIS MEDIA.

6209
05:04:08,440 --> 05:04:15,240
AND SO WE THEN WONDERED IS

6210
05:04:15,240 --> 05:04:17,800
FUCOSE BENEFICIAL TO

6211
05:04:17,800 --> 05:04:18,120
CAMPYLOBACTER?

6212
05:04:18,120 --> 05:04:21,720
WORK SHOWED WILDTYPE STRAIN

6213
05:04:21,720 --> 05:04:22,280
COULD OUTCOMPETE FUCOSE

6214
05:04:22,280 --> 05:04:26,520
METABOLIZING DEFICIENT STRAIN IN

6215
05:04:26,520 --> 05:04:30,480
THE PIGLET DIARRHEAL MODEL AND

6216
05:04:30,480 --> 05:04:32,560
WANTED TO INVESTIGATE IN

6217
05:04:32,560 --> 05:04:34,360
BREASTFEEDING AND HUMAN MILK

6218
05:04:34,360 --> 05:04:34,760
OLIGOSACCHARIDES.

6219
05:04:34,760 --> 05:04:38,080
AND SO WHAT WE WANTED TO FEMALE

6220
05:04:38,080 --> 05:04:40,040
FOLLOW UP ON REALLY ELEGANT

6221
05:04:40,040 --> 05:04:47,040
PIONEERING WORK THAT DAVID

6222
05:04:47,040 --> 05:04:47,680
NEWBERG'S GROUP PUBLISHED,

6223
05:04:47,680 --> 05:04:51,240
SHOWING IT BINDS AND THEY ACT AS

6224
05:04:51,240 --> 05:04:52,760
DECOYS TO REMOVE CAMPYLOBACTER

6225
05:04:52,760 --> 05:04:54,240
TO INTESTINAL TRACT.

6226
05:04:54,240 --> 05:05:02,280
AT THAT TIME, WE WEREN'T AWARE

6227
05:05:02,280 --> 05:05:12,560
IT COULD METABOLIZE FOE COAST --

6228
05:05:12,560 --> 05:05:12,800
FUCOSE.

6229
05:05:12,800 --> 05:05:15,840
WE'RE SEEING SO MUCH INFECTION

6230
05:05:15,840 --> 05:05:21,960
IN INFANTS, OR ARE THEY ACTING' 

6231
05:05:21,960 --> 05:05:23,920
DECOYS AND PROTECTING CHILDREN

6232
05:05:23,920 --> 05:05:25,440
AND WE'RE SEEING OTHER

6233
05:05:25,440 --> 05:05:26,840
CAMPYLOBACTERS THRIVING?

6234
05:05:26,840 --> 05:05:37,080
THIS WAS THE QUESTION XIAOMIN G

6235
05:05:37,080 --> 05:05:42,240
WANTED TO ANSWER, PIGGYBACKING

6236
05:05:42,240 --> 05:05:49,560
OFF GEMS  STUDY, ISOLATES FROM

6237
05:05:49,560 --> 05:05:50,400
BREAST FEDS AND NON-BREASTFED

6238
05:05:50,400 --> 05:05:54,120
INFANTS LESS THAN ONE YEAR OF

6239
05:05:54,120 --> 05:05:56,520
AGE, ALSO FECAL SAMPLES AND DNA

6240
05:05:56,520 --> 05:05:58,600
TO LOOK AT LEVEL OF

6241
05:05:58,600 --> 05:05:59,720
CAMPYLOBACTER IN THESE CHILDREN.

6242
05:05:59,720 --> 05:06:02,560
AND WHAT WE FOUND WAS ACTUALLY

6243
05:06:02,560 --> 05:06:03,760
QUITE SURPRISING.

6244
05:06:03,760 --> 05:06:07,240
NOT ONLY WERE THEY ALL COLONIZED

6245
05:06:07,240 --> 05:06:10,440
WITH CAMPYLOBACTER BUT WE SAW

6246
05:06:10,440 --> 05:06:11,280
SIGNIFICANTLY HIGHER PROPORTIONS

6247
05:06:11,280 --> 05:06:14,080
OF CAMPYLOBACTER IN KIDS THAT

6248
05:06:14,080 --> 05:06:16,320
WERE BREASTFED, SO THERE'S

6249
05:06:16,320 --> 05:06:18,240
ACTUALLY MORE CAMPYLOBACTER IN

6250
05:06:18,240 --> 05:06:20,480
THE BREAST-FED CHILDREN THAT HAD

6251
05:06:20,480 --> 05:06:23,440
DIARRHEA THAN CHILDREN THAT HAD

6252
05:06:23,440 --> 05:06:24,800
CAMPYLOBACTER DIARRHEA THAT

6253
05:06:24,800 --> 05:06:25,720
WEREN'T BREASTFED.

6254
05:06:25,720 --> 05:06:30,040
WE WANTED TO FOLLOW UP ON THAT,

6255
05:06:30,040 --> 05:06:34,440
DO OLIGO  OLIGOSACCHARIDES ACT

6256
05:06:34,440 --> 05:06:38,640
AS DECOYS OR PROVIDING NUTRIENTS

6257
05:06:38,640 --> 05:06:40,200
FOR SUCCESSFUL COLONIZATION?

6258
05:06:40,200 --> 05:06:42,040
AND SO THIS IS SUMMARY OF

6259
05:06:42,040 --> 05:06:43,880
LOOKING AT ALL OF THOSE ISOLATES

6260
05:06:43,880 --> 05:06:45,720
WE OBTAINED FROM THE GEM STUDY

6261
05:06:45,720 --> 05:06:50,720
SO WE FIRST LOOKED FOR PRESENCE

6262
05:06:50,720 --> 05:06:54,560
OF FUC PG, CONFIRMED PATHWAY WAS

6263
05:06:54,560 --> 05:06:57,080
ACTIVE BY DOING GROWTH ANALYSIS

6264
05:06:57,080 --> 05:06:59,200
OF EACH STRAIN AND I SHOULD

6265
05:06:59,200 --> 05:07:02,840
POINT OUT FOR EVERY CHILD ONLY

6266
05:07:02,840 --> 05:07:04,200
ONE STRAIN WAS ISOLATED.

6267
05:07:04,200 --> 05:07:09,000
SO THEN WHAT WE LOOKED AT IS THE

6268
05:07:09,000 --> 05:07:15,720
PROPORTION OF FUCOSE 

6269
05:07:15,720 --> 05:07:17,000
METABOLIZING VERSUS

6270
05:07:17,000 --> 05:07:17,640
NON-METABOLIZING CAMPYLOBACTERS.

6271
05:07:17,640 --> 05:07:24,760
IF NOT BREASTFED YOU SAW EQUAL

6272
05:07:24,760 --> 05:07:26,680
NUMBERS IN THEIR FECAL SAMPLES

6273
05:07:26,680 --> 05:07:30,520
BUT IF THE CHILDREN WERE

6274
05:07:30,520 --> 05:07:35,800
BREASTFED THEN YOU ACTUALLY SAW

6275
05:07:35,800 --> 05:07:37,920
SIGNIFICANTLY LESS

6276
05:07:37,920 --> 05:07:39,760
CAMPYLOBACTERS THAT WERE FUCOSE

6277
05:07:39,760 --> 05:07:45,800
METABOLIZING, SO THIS DOES 

6278
05:07:45,800 --> 05:07:47,600
SUPPORT DAVID NEWBERG'S THEORY,

6279
05:07:47,600 --> 05:07:49,320
PROBABLY SENSING MONO SACCHARIDE

6280
05:07:49,320 --> 05:07:54,520
AND WILL SWIM TOWARD IT AND BE

6281
05:07:54,520 --> 05:07:56,120
RELEASED FROM INTESTINAL TRACT

6282
05:07:56,120 --> 05:07:59,600
WHEREAS THEN WHAT'S LEFT BEHIND

6283
05:07:59,600 --> 05:08:02,200
ARE THE CAMPYLOBACTERS THAT DO

6284
05:08:02,200 --> 05:08:04,240
NOT METABOLIZE FUCOSE AND

6285
05:08:04,240 --> 05:08:05,640
PROBABLY DO HAVE A COMPETITIVE

6286
05:08:05,640 --> 05:08:07,480
ADVANTAGE BECAUSE THEY ARE WITH

6287
05:08:07,480 --> 05:08:09,040
ALL OF THESE CARBOHYDRATE

6288
05:08:09,040 --> 05:08:11,400
METABOLIZERS IN THE GUT AND THEY

6289
05:08:11,400 --> 05:08:17,760
HAVE THIS EXPANDED REPERTOIRE OF

6290
05:08:17,760 --> 05:08:20,240
METABOLIZING TCA CYCLIN AND

6291
05:08:20,240 --> 05:08:20,560
AMINO ACIDS.

6292
05:08:20,560 --> 05:08:24,760
TO INVESTIGATE WHETHER THIS IS

6293
05:08:24,760 --> 05:08:30,600
TRUE, PHOEBE WITH JOLENE HAS

6294
05:08:30,600 --> 05:08:32,280
DONE RNAseq EXPERIMENTS,

6295
05:08:32,280 --> 05:08:35,240
PATHWAY NOT INDUCED IN BREAST

6296
05:08:35,240 --> 05:08:36,520
MILK, PATHWAYS ARE BEING

6297
05:08:36,520 --> 05:08:38,520
EXPRESSED, AND TO DETERMINE

6298
05:08:38,520 --> 05:08:39,600
WHICH ONES ARE THE MOST

6299
05:08:39,600 --> 05:08:45,560
IMPORTANT FIB  -- PHOEBE DID

6300
05:08:45,560 --> 05:08:46,600
EVOLUTION STUDIES, WHEN

6301
05:08:46,600 --> 05:08:48,400
CAMPYLOBACTER IS GROWN DIRECTLY

6302
05:08:48,400 --> 05:08:50,120
WITH MILK IT IS ACTUALLY TOXIC

6303
05:08:50,120 --> 05:08:50,880
TO THE MICROBE.

6304
05:08:50,880 --> 05:08:53,440
AND SO YOU CAN SEE HERE WHETHER

6305
05:08:53,440 --> 05:08:56,840
IT HAS THE FUCOSE PATHWAY OR NOT

6306
05:08:56,840 --> 05:08:57,840
CAMPYLOBACTER WILL NOT BE ABLE

6307
05:08:57,840 --> 05:09:02,400
TO GROW IN MILK ON ITS DOWN

6308
05:09:02,400 --> 05:09:04,040
WITHOUT BENEFICIAL MICROS IN THE

6309
05:09:04,040 --> 05:09:06,840
GUT TO BREAK DOWN CERTAIN

6310
05:09:06,840 --> 05:09:07,120
COMPONENTS.

6311
05:09:07,120 --> 05:09:15,040
SHE HAD TO EVOLVE STRAINS TO

6312
05:09:15,040 --> 05:09:16,440
GROW IN MILK AND GENOME SEQUENCE

6313
05:09:16,440 --> 05:09:18,560
FOG SEE WHAT HAS CHANGED IN

6314
05:09:18,560 --> 05:09:21,360
CAMPYLOBACTER STRAINS AND WE'VE

6315
05:09:21,360 --> 05:09:22,400
ACTUALLY DISCOVERED THAT

6316
05:09:22,400 --> 05:09:24,640
ATTENTION SPECIFIC CHANGES IN

6317
05:09:24,640 --> 05:09:26,800
TRANSPORTERS THAT ARE INVOLVED

6318
05:09:26,800 --> 05:09:27,640
IN NUTRIENT ACQUISITION.

6319
05:09:27,640 --> 05:09:30,240
SO THAT'S WHAT WE'RE FOLLOWING

6320
05:09:30,240 --> 05:09:33,040
UP ON NOW.

6321
05:09:33,040 --> 05:09:45,400
IN CONCLUSION WE'VE DESCRIBED

6322
05:09:45,400 --> 05:09:50,120
PATHWAYS, FUCX IS NECESSARY FOR

6323
05:09:50,120 --> 05:09:52,600
CHEMOTAXIS.

6324
05:09:52,600 --> 05:09:58,560
IT DEPENDS ON COMMENSAL MICROBES

6325
05:09:58,560 --> 05:10:00,320
LIKE VULGATUS.

6326
05:10:00,320 --> 05:10:04,240
CO-CULTURE STUDIES SHOW ENHANCE

6327
05:10:04,240 --> 05:10:08,560
GROWTH WITH MUCIN AND VULGATUS,

6328
05:10:08,560 --> 05:10:10,480
AND MASS SPECTROMETRY SHOWED

6329
05:10:10,480 --> 05:10:24,160
EVIDENCE OF FUCOSE RELEASE FROM 

6330
05:10:24,160 --> 05:10:26,760
MUCINS BY BACTEROIDES VULGATUS.

6331
05:10:26,760 --> 05:10:32,560
 

6332
05:10:32,560 --> 05:10:33,600
BREASTFED INFANTS IN

6333
05:10:33,600 --> 05:10:36,480
LOW-RESOURCE SETTINGS HAVE

6334
05:10:36,480 --> 05:10:39,080
HIGHER PROPORTIONS OF

6335
05:10:39,080 --> 05:10:39,640
CAMPYLOBACTERS WITHIN FECAL

6336
05:10:39,640 --> 05:10:41,560
MICROBIOTA, THIS COULD BE

6337
05:10:41,560 --> 05:10:44,000
RELATED TO A SELECTION FOR

6338
05:10:44,000 --> 05:10:47,080
STRAINS WITH ENHANCED AMINO ACID

6339
05:10:47,080 --> 05:10:47,640
METABOLISM.

6340
05:10:47,640 --> 05:10:50,200
FINALLY, I'VE ALSO TOLD YOU

6341
05:10:50,200 --> 05:10:54,840
HUMAN MILK IS TOXIC TO

6342
05:10:54,840 --> 05:10:57,320
CAMPYLOBACTER BACKUP MICROBE CAN

6343
05:10:57,320 --> 05:10:57,960
EVOLVE TO RESIST TOXICITY.

6344
05:10:57,960 --> 05:10:59,400
I'D LIKE TO ACKNOWLEDGE A LOT OF

6345
05:10:59,400 --> 05:11:08,440
THE PEOPLE THAT HAVE BEEN 

6346
05:11:08,440 --> 05:11:17,560
INVOLVED IN THESE STUDIES.

6347
05:11:17,560 --> 05:11:19,240
I'M NOT MOVING LIKE SOME OTHER

6348
05:11:19,240 --> 05:11:21,280
SPEAKERS BUT I'M INVOLVED IN

6349
05:11:21,280 --> 05:11:22,480
SEVERAL COMMITTEES, AMBASSADOR

6350
05:11:22,480 --> 05:11:24,040
FOR THE AMERICAN SOCIETY OF

6351
05:11:24,040 --> 05:11:26,240
MICROBIOLOGY SO I'LL THROW UP

6352
05:11:26,240 --> 05:11:28,040
THIS ADVERTISEMENT, AND ALSO

6353
05:11:28,040 --> 05:11:31,400
CONTRIBUTOR TO THE ESSENTIALS OF

6354
05:11:31,400 --> 05:11:32,440
GLYCOBIOLOGY, I WANTED TO

6355
05:11:32,440 --> 05:11:34,560
HIGHLIGHT THIS BOOK AS WELL.

6356
05:11:34,560 --> 05:11:38,120
THANK YOU FOR YOUR ATTENTION.

6357
05:11:38,120 --> 05:11:39,560
>> THANK YOU FOR A FANTASTIC

6358
05:11:39,560 --> 05:11:40,840
TALK AND SERVICE WORK.

6359
05:11:40,840 --> 05:11:41,240
REALLY IMPORTANT.

6360
05:11:41,240 --> 05:11:43,600
THANK YOU SO MUCH.

6361
05:11:43,600 --> 05:11:47,640
WE HAVE A QUESTION, JUST ONE,

6362
05:11:47,640 --> 05:11:50,840
I'LL USE ONLINE TO ENCOURAGE

6363
05:11:50,840 --> 05:11:52,600
PEOPLE TO COMMUNICATE.

6364
05:11:52,600 --> 05:11:55,120
GRACE HENRY SAYS DID YOU LOOK AT

6365
05:11:55,120 --> 05:11:57,800
HMO COMPETITION OF THE WOMAN WHO

6366
05:11:57,800 --> 05:12:01,040
BREASTFED WHERE MAYBE IF THEY

6367
05:12:01,040 --> 05:12:04,640
WERE OR NOT SECRETORS, DID YOU

6368
05:12:04,640 --> 05:12:05,680
NOTICE ANY TRENDS?

6369
05:12:05,680 --> 05:12:09,640
>> IN OUR STUDIES WITH EVOLUTION

6370
05:12:09,640 --> 05:12:13,120
AND WITH RNAseq, WE USED TWO

6371
05:12:13,120 --> 05:12:14,560
DIFFERENT DONORS.

6372
05:12:14,560 --> 05:12:16,520
AND IN BOTH CASES THEY ARE

6373
05:12:16,520 --> 05:12:19,800
SECRETERS BUT THERE WAS ANOTHER

6374
05:12:19,800 --> 05:12:21,840
STUDY PUBLISHED NOT LONG AGO

6375
05:12:21,840 --> 05:12:24,120
SHOWING THERE ISN'T A

6376
05:12:24,120 --> 05:12:24,720
CORRELATION BETWEEN SECRETERS

6377
05:12:24,720 --> 05:12:26,600
AND NON-SECRETERS, IF I REMEMBER

6378
05:12:26,600 --> 05:12:30,240
CORRECTLY.

6379
05:12:30,240 --> 05:12:30,640
>> THANK YOU.

6380
05:12:30,640 --> 05:12:33,120
IN THE INTEREST OF TIME WE HAVE

6381
05:12:33,120 --> 05:12:36,000
A 20-MINUTE BUFFER TO 5:00 SO

6382
05:12:36,000 --> 05:12:40,840
WE'LL TRY GET THIS MEETING

6383
05:12:40,840 --> 05:12:43,240
FINISHED BY FIVE.

6384
05:12:43,240 --> 05:12:48,920
SWITCHING SPEAKERS, THANK YOU

6385
05:12:48,920 --> 05:12:52,320
FOR THE TALK.

6386
05:12:52,320 --> 05:12:55,040
NEXT SPEAKER IS AMANDA LEWIS,

6387
05:12:55,040 --> 05:12:58,560
FROM UNIVERSITY OF SAN DIEGO IN

6388
05:12:58,560 --> 05:13:00,640
CALIFORNIA, TALKING ABOUT

6389
05:13:00,640 --> 05:13:03,480
RESIDENT MICROBES WHICH SHAPE

6390
05:13:03,480 --> 05:13:04,240
VAGINAL EPITHELIAL GLYCAN

6391
05:13:04,240 --> 05:13:05,280
LANDSCAPE.

6392
05:13:05,280 --> 05:13:06,600
I HOPE YOU SEE INTERSECTION AS

6393
05:13:06,600 --> 05:13:09,160
WORK IS BUILDING ON EACH OTHER.

6394
05:13:09,160 --> 05:13:10,520
IF YOU HAVEN'T MET PEOPLE YOU'RE

6395
05:13:10,520 --> 05:13:11,760
MEETING IN THIS COMMUNITY AND

6396
05:13:11,760 --> 05:13:13,280
ABLE TO USE THE CHAT FEATURE

6397
05:13:13,280 --> 05:13:14,240
WITHIN THE ZOOM.

6398
05:13:14,240 --> 05:13:20,560
IT'S AVAILABLE FOR YOU TO TALK

6399
05:13:20,560 --> 05:13:21,960
TO EACH OTHER.

6400
05:13:21,960 --> 05:13:22,440
THANK YOU.

6401
05:13:22,440 --> 05:13:23,480
>> GOOD AFTERNOON.

6402
05:13:23,480 --> 05:13:26,320
TODAY WE'LL TALK MORE ABOUT THE

6403
05:13:26,320 --> 05:13:27,640
VAGINA, IT'S NICE TO NOT BE THE

6404
05:13:27,640 --> 05:13:31,400
ONLY PERSON IN THE ROOM TALKING

6405
05:13:31,400 --> 05:13:37,160
ABOUT VAGINAS, SO THANKS TO

6406
05:13:37,160 --> 05:13:38,360
EMILY BYNDLOSS WHO INTRODUCED

6407
05:13:38,360 --> 05:13:39,520
THE TOPIC EARLIER.

6408
05:13:39,520 --> 05:13:48,040
I WANTED TO START WITH

6409
05:13:48,040 --> 05:13:49,440
ACKNOWLEDGMENTS, KAVITA IS THE

6410
05:13:49,440 --> 05:13:51,480
FIRST AUTHOR, AND WARREN LEWIS

6411
05:13:51,480 --> 05:13:54,320
IS THE LAST AUTHOR ON THIS.

6412
05:13:54,320 --> 05:13:57,560
A LOT OF GOOD WORK.

6413
05:13:57,560 --> 05:14:04,000
WE'LL START WITH A BRIEF

6414
05:14:04,000 --> 05:14:04,840
INTRODUCTION.

6415
05:14:04,840 --> 05:14:07,280
MANY WOMEN HAVE MICROBIOTA

6416
05:14:07,280 --> 05:14:11,240
DOMINATED BY LACTOBACILLUS, A 

6417
05:14:11,240 --> 05:14:17,920
LOT OF OTHER WOMEN HAVE OTHER 

6418
05:14:17,920 --> 05:14:23,160
ORGANISMS THAT CAN OVERVIEW,

6419
05:14:23,160 --> 05:14:26,440
GARDNER VAGINALUS IS ONE.

6420
05:14:26,440 --> 05:14:30,040
IT'S A DYSBIOSIS WITH HEALTH

6421
05:14:30,040 --> 05:14:31,400
COMPLICATIONS INCLUDING SEXUALLY

6422
05:14:31,400 --> 05:14:33,480
TRANSMITTED INFECTIONS, URINARY

6423
05:14:33,480 --> 05:14:34,480
TRACT INFECTIONS, ASCENDING

6424
05:14:34,480 --> 05:14:38,240
INFECTIONS AT THE UTERUS,

6425
05:14:38,240 --> 05:14:40,680
PRE-TERM BIRTH, PELVIC

6426
05:14:40,680 --> 05:14:42,600
INFLAMMATORY DISEASE,

6427
05:14:42,600 --> 05:14:43,680
INFERTILITY, AMONG OTHER

6428
05:14:43,680 --> 05:14:44,080
OUTCOMES.

6429
05:14:44,080 --> 05:14:47,080
IT'S RARE FOR ME TO HAVE ONE

6430
05:14:47,080 --> 05:14:50,240
SLIDE THAT TALKS ABOUT MOUSE

6431
05:14:50,240 --> 05:14:56,600
WORK, I'M GOING TO GIVE A BRIEF

6432
05:14:56,600 --> 05:14:58,680
OVERVIEW WHY WE BELIEVE

6433
05:14:58,680 --> 05:15:02,120
GARDNERELLA IS POTENTIAL LIP A

6434
05:15:02,120 --> 05:15:03,960
CAUSAL FACTOR, FROM OUR WORK NOT

6435
05:15:03,960 --> 05:15:10,520
IN HUMAN STUDIES BUT RATHER IN

6436
05:15:10,520 --> 05:15:11,000
MICE.

6437
05:15:11,000 --> 05:15:12,800
WE KNOW GARDNERELLA ON ITS OWN

6438
05:15:12,800 --> 05:15:21,800
WHEN INTRODUCED INTO THE HAVE 

6439
05:15:21,800 --> 05:15:25,360
THE VAGINA OF MICE CAN TRIGGER

6440
05:15:25,360 --> 05:15:25,640
VAGINOSIS.

6441
05:15:25,640 --> 05:15:30,200
I WON'T SHARE ALL THAT TODAY.

6442
05:15:30,200 --> 05:15:32,840
IN THE BLADDER WHICH WE HAPPENS

6443
05:15:32,840 --> 05:15:40,200
WITH HYGIENIC AND SEXUALLY 

6444
05:15:40,200 --> 05:15:42,440
ACTIVITIES, EXPOSURE, CAUSES

6445
05:15:42,440 --> 05:15:43,760
BLADDER APOPTOSIS OF EPITHELIAL

6446
05:15:43,760 --> 05:15:47,640
CELLS AND WITH SMALL  EXPOSURE

6447
05:15:47,640 --> 05:15:50,600
TO KIDNEY CAN CAUSE IL-1

6448
05:15:50,600 --> 05:15:53,840
DEPENDENT KIDNEY INJURY, ENABLES

6449
05:15:53,840 --> 05:15:55,200
COLONIZATION BY OTHER ORGANISMS,

6450
05:15:55,200 --> 05:15:59,600
MOUSE MODELS WHERE WE'RE DOING 

6451
05:15:59,600 --> 05:16:01,440
SINGLE OR CO-INFECTIONS AND

6452
05:16:01,440 --> 05:16:02,640
COMPARING OUTCOMES, IN RECURRENT

6453
05:16:02,640 --> 05:16:05,240
UTI MODEL IF WE EXPOSE MICE IN A

6454
05:16:05,240 --> 05:16:08,240
ALREADY HAVE E. COLI RESERVOIRS

6455
05:16:08,240 --> 05:16:09,880
INSIDE THEIR BLADDER EPITHELIAL

6456
05:16:09,880 --> 05:16:11,000
CELLS IT TRIGGERS RECURRENT UTI

6457
05:16:11,000 --> 05:16:13,200
WHICH CAN ALSO GO UP INTO THE

6458
05:16:13,200 --> 05:16:15,760
KIDNEYS TO CAUSE KIDNEY

6459
05:16:15,760 --> 05:16:16,040
INFECTION.

6460
05:16:16,040 --> 05:16:18,120
WE'VE SHOWN IN CO-INFECTIONS

6461
05:16:18,120 --> 05:16:22,200
WITH PREVOTELLA, ANOTHER 

6462
05:16:22,200 --> 05:16:23,000
ORGANIZATION ASSOCIATED WITH

6463
05:16:23,000 --> 05:16:25,160
BACTERIAL VAGINOSIS WHEN IT'S

6464
05:16:25,160 --> 05:16:29,280
TOGETHER IT CAUSES MUCH WORSE

6465
05:16:29,280 --> 05:16:30,600
ASCENDING INTRAUTERINE

6466
05:16:30,600 --> 05:16:30,880
INFECTIONS.

6467
05:16:30,880 --> 05:16:34,640
IN PREGNANCY MODELS WE'VE SHOWN

6468
05:16:34,640 --> 05:16:36,920
THAT GROUP B STREPTOCOCCUS IS

6469
05:16:36,920 --> 05:16:42,760
MORE LIKELY TO COLONIZE IN WOMEN

6470
05:16:42,760 --> 05:16:46,920
WITH BV, FINE DISTINCTION, IN 

6471
05:16:46,920 --> 05:16:48,880
THE PRESENCE OF GARDNERELLA,

6472
05:16:48,880 --> 05:16:49,800
MORE LIKELY TO COLONIZE

6473
05:16:49,800 --> 05:16:52,000
VAGINALLY BUT ALSO MORE LIKELY

6474
05:16:52,000 --> 05:16:53,720
TO CAUSE ASCENDING INFECTIONS

6475
05:16:53,720 --> 05:16:55,680
AND I'M SHOWING ON THE RIGHT A

6476
05:16:55,680 --> 05:16:59,320
PICTURE OF GROUP B STREP WITHIN

6477
05:16:59,320 --> 05:17:00,160
THE PLACENTAL TISSUE.

6478
05:17:00,160 --> 05:17:03,400
WE'VE ALSO SHOWN IT LIBERATES

6479
05:17:03,400 --> 05:17:03,960
CARBOHYDRATE RESOURCES THAT

6480
05:17:03,960 --> 05:17:18,080
ENABLES  GROWTH OF  OTHER

6481
05:17:18,080 --> 05:17:18,360
ORGANISMS.

6482
05:17:18,360 --> 05:17:22,560
NOW WHAT I WANT TO DO IS TALK

6483
05:17:22,560 --> 05:17:23,280
ABOUT GLYCOBIOLOGY.

6484
05:17:23,280 --> 05:17:27,160
WE BECAME INTERESTED IN THIS

6485
05:17:27,160 --> 05:17:27,680
LARGELY BECAUSE SIALIDASE

6486
05:17:27,680 --> 05:17:29,520
ACTIVITY HAS BEEN KNOWN FOR

6487
05:17:29,520 --> 05:17:32,480
QUITE SOME TIME, DECADES, TO BE

6488
05:17:32,480 --> 05:17:33,600
ASSOCIATED WITH BACTERIAL

6489
05:17:33,600 --> 05:17:34,880
VAGINOSIS, FOUND IN THE VAGINAL

6490
05:17:34,880 --> 05:17:36,840
FLUIDS OF WOMEN WITH BACTERIAL

6491
05:17:36,840 --> 05:17:40,520
VAGINOSIS BUT NOT WITHOUT THIS

6492
05:17:40,520 --> 05:17:41,840
CONDITION.

6493
05:17:41,840 --> 05:17:43,480
SO WE HAVE DONE WORK IN THIS

6494
05:17:43,480 --> 05:17:49,160
REGARD AND HAVE BEEN ABLE TO 

6495
05:17:49,160 --> 05:17:52,400
SHOW THAT GARDNERELLA VAGINALIS

6496
05:17:52,400 --> 05:17:54,400
PRODUCED SIALIDASE, ABLE TO

6497
05:17:54,400 --> 05:18:01,240
CLEAVE IN CONTEXTS INCLUDING 

6498
05:18:01,240 --> 05:18:02,800
FROM MUCINS, SECRETEORY IgA,

6499
05:18:02,800 --> 05:18:04,640
DEPLETING FROM MUCOSA, IN BOTH

6500
05:18:04,640 --> 05:18:06,200
HUMANS AS WELL AS MICE WHEN WE

6501
05:18:06,200 --> 05:18:09,120
JUST LOOK AT SORT OF THE WHOLE

6502
05:18:09,120 --> 05:18:10,240
VAGINAL SAMPLE.

6503
05:18:10,240 --> 05:18:12,840
AND WE'VE BEEN ABLE TO IDENTIFY

6504
05:18:12,840 --> 05:18:14,040
THE SIALIDASES THAT ARE

6505
05:18:14,040 --> 05:18:15,760
RESPONSIBLE FOR THIS ACTIVITY,

6506
05:18:15,760 --> 05:18:19,920
AND SHOW THAT BOTH THE

6507
05:18:19,920 --> 05:18:21,120
RECOMBINANT AND SIALIDASES THAT

6508
05:18:21,120 --> 05:18:23,920
ARE PRESENT WITHIN CLINICAL

6509
05:18:23,920 --> 05:18:26,600
SPECIMENS ARE ABLE TO CLEAVE OFF

6510
05:18:26,600 --> 05:18:30,640
SIALIC ACIDS IN VIRTUALLY ALL

6511
05:18:30,640 --> 05:18:31,840
CONTEXTS WE'VE TESTED.

6512
05:18:31,840 --> 05:18:33,640
GOING FURTHER THAN THAT WE KNOW

6513
05:18:33,640 --> 05:18:45,080
THAT   GARDNERELLA IS ABLE TO

6514
05:18:45,080 --> 05:18:46,040
CATABOLIZE, NOT JUST CLEAVE.

6515
05:18:46,040 --> 05:18:48,200
YOU'RE HEARD A THEME THROUGHOUT

6516
05:18:48,200 --> 05:18:52,040
A FEW TIMES THAT SOME ORGANISMS

6517
05:18:52,040 --> 05:18:53,440
CAN PRODUCE HYDROLASES, SOME CAN

6518
05:18:53,440 --> 05:18:54,560
TAKE ADVANTAGE.

6519
05:18:54,560 --> 05:18:58,560
THIS IS ALSO HAPPENING IN THE

6520
05:18:58,560 --> 05:19:02,000
VAGINA WHERE WE HAVE ADDITIONAL

6521
05:19:02,000 --> 05:19:03,360
SPECTRA OF BACTERIA IN THIS

6522
05:19:03,360 --> 05:19:05,520
CONTEXT UP HERE ABLE TO EAT THE

6523
05:19:05,520 --> 05:19:08,640
SIALIC ACIDS BUT DON'T

6524
05:19:08,640 --> 05:19:09,720
THEMSELVES PRODUCE SIALIDASES.

6525
05:19:09,720 --> 05:19:10,360
ALL RIGHT.

6526
05:19:10,360 --> 05:19:12,800
BUT WHAT I REALLY WANT TO TALK

6527
05:19:12,800 --> 05:19:17,840
TO YOU ABOUT TODAY GOES FURTHER 

6528
05:19:17,840 --> 05:19:24,800
THAN JUSTS SO MOLECULES, IF THEY

6529
05:19:24,800 --> 05:19:36,960
ARE ACTING  ON THE EPITHELIAL 

6530
05:19:36,960 --> 05:19:37,240
GLYCOCALYX.

6531
05:19:37,240 --> 05:19:40,000
YOU CAN SEE THIS COVERED IN

6532
05:19:40,000 --> 05:19:40,320
BACTERIA.

6533
05:19:40,320 --> 05:19:41,680
THESE BACTERIA ARE LIVING RIGHT

6534
05:19:41,680 --> 05:19:51,240
ON THE SURFACE OF THE EPITHELIAL

6535
05:19:51,240 --> 05:19:52,640
CELLS.

6536
05:19:52,640 --> 05:19:57,240
WE CAN DO TRADITIONAL STAINING,

6537
05:19:57,240 --> 05:20:01,560
NEGATIVE STAINING WITH RED.

6538
05:20:01,560 --> 05:20:05,400
 

6539
05:20:05,400 --> 05:20:06,640
AND PETRONIUM OXIDE.

6540
05:20:06,640 --> 05:20:09,560
I'VE GOT THAT WRONG.

6541
05:20:09,560 --> 05:20:12,240
WE USED LECTINS TO PROBE

6542
05:20:12,240 --> 05:20:17,040
EPITHELIAL CELLS AND SHOWED

6543
05:20:17,040 --> 05:20:24,360
MAL-II IS ABLE TO BIND VERY WELL

6544
05:20:24,360 --> 05:20:26,800
TO NO BV CELLS, AS YOU CAN SEE

6545
05:20:26,800 --> 05:20:29,040
WHEN YOU INCREASE LEVEL OF

6546
05:20:29,040 --> 05:20:32,600
SIALIDASE ACTIVITY PRESENT IN

6547
05:20:32,600 --> 05:20:35,040
THE SAMPLE, WITH ONE EXCEPTION

6548
05:20:35,040 --> 05:20:37,280
HERE YOU HAVE FEWER OF THESE

6549
05:20:37,280 --> 05:20:42,080
CELLS LIGHTING UP THAT ARE

6550
05:20:42,080 --> 05:20:44,280
STAINING FOR 2, 3 LINK SIALIC

6551
05:20:44,280 --> 05:20:47,080
ACID, THE FIRST EVIDENCE THEY

6552
05:20:47,080 --> 05:20:48,520
MAY BE DEPLETED.

6553
05:20:48,520 --> 05:20:50,680
SO TAKING THIS A STEP FURTHER

6554
05:20:50,680 --> 05:20:52,920
AND USING THESE PRIMARY HUMAN

6555
05:20:52,920 --> 05:20:54,520
VAGINAL EPITHELIAL CELLS

6556
05:20:54,520 --> 05:20:58,120
ISOLATED FROM VAGINAL SWABS, WE

6557
05:20:58,120 --> 05:21:00,840
DID GLYCAN ANALYSIS WITH A SCORE

6558
05:21:00,840 --> 05:21:04,800
AT UCSD AND WERE ABLE TO SHOW A

6559
05:21:04,800 --> 05:21:16,000
STARK LOW LEVEL OF SIALYTATED N

6560
05:21:16,000 --> 05:21:16,880
AND O.

6561
05:21:16,880 --> 05:21:19,440
IF DEPLETED IT MIGHT BE THAT WE

6562
05:21:19,440 --> 05:21:21,360
SHOULD BE ABLE TO SEE REVEALING

6563
05:21:21,360 --> 05:21:33,720
OF  CARBOHYDRATE RESIDUES, USING

6564
05:21:33,720 --> 05:21:36,840
PEANUT AGGLUTININ, RECOGNIZING

6565
05:21:36,840 --> 05:21:41,080
UNDERLYING GALACTOSE RESIDUE,

6566
05:21:41,080 --> 05:21:46,360
SHOWING BY FLOW CYTOMETRY, YOU

6567
05:21:46,360 --> 05:21:50,080
SEE LOTS OF STAINING WITH PNA

6568
05:21:50,080 --> 05:21:56,160
BUT ONLY WHEN UP ADD EXOGENOUS

6569
05:21:56,160 --> 05:21:56,440
SIALIDASE.

6570
05:21:56,440 --> 05:21:58,840
YOU SEE YOU CAN'T REVEAL ANY

6571
05:21:58,840 --> 05:22:00,640
MORE PNA STAINING, IT'S ALREADY

6572
05:22:00,640 --> 05:22:02,600
HIGHLY STAINED AND CAN'T REVEAL

6573
05:22:02,600 --> 05:22:05,760
ANY MORE BY ADDING EXOGENOUS

6574
05:22:05,760 --> 05:22:07,760
SIALIDASE SUGGESTING THESE ARE

6575
05:22:07,760 --> 05:22:10,520
REMOVED AND THIS UNDERLYING

6576
05:22:10,520 --> 05:22:11,640
LIGAND IS COMPLETELY UNCAPPED.

6577
05:22:11,640 --> 05:22:14,040
AND SO HERE YOU CAN SEE IN OF IF

6578
05:22:14,040 --> 05:22:16,480
YOU DO THIS OVER A NUMBER OF

6579
05:22:16,480 --> 05:22:18,520
SAMPLES, WE HAD 15 IN EACH

6580
05:22:18,520 --> 05:22:21,680
GROUP, YOU CAN SEE A VERY HIGHLY

6581
05:22:21,680 --> 05:22:23,120
STATISTICALLY SIGNIFICANT

6582
05:22:23,120 --> 05:22:26,240
DIFFERENCE BETWEEN THIS BINDING

6583
05:22:26,240 --> 05:22:31,160
OF PNA TO THE EPITHELIAL CELLS

6584
05:22:31,160 --> 05:22:35,760
IN BV.

6585
05:22:35,760 --> 05:22:39,240
GOING FURTHER TO LOOK AT N AND

6586
05:22:39,240 --> 05:22:42,520
O-GLYCANS WE'VE DONE ANALYSIS

6587
05:22:42,520 --> 05:22:45,880
WITH GLYCOANALYTIC SCORE AT

6588
05:22:45,880 --> 05:22:46,080
UCSD.

6589
05:22:46,080 --> 05:22:51,360
I'M SHOWING TO SHOW PROFILES OF

6590
05:22:51,360 --> 05:22:54,040
N-GLYCANS RELEASED FROM

6591
05:22:54,040 --> 05:22:55,440
EPITHELIAL CELL LYSATES.

6592
05:22:55,440 --> 05:22:58,760
WHEN WE SEPARATE YOU CAN SEE

6593
05:22:58,760 --> 05:23:00,440
HIGH MANNOSE GLYCANS BUT IF YOU

6594
05:23:00,440 --> 05:23:03,320
LOOK IN WOMEN WITHOUT BV YOU'LL

6595
05:23:03,320 --> 05:23:22,960
SEE QUITE A LOT OF PEAKS THAT 

6596
05:23:22,960 --> 05:23:25,960
ARE SIALYTED.

6597
05:23:25,960 --> 05:23:29,360
PREPARING FOR MASS SPENDING WE

6598
05:23:29,360 --> 05:23:30,360
DID FOLLOW-UP FLOW CYTOMETRY TO

6599
05:23:30,360 --> 05:23:31,680
LOOK AT STRUCTURES.

6600
05:23:31,680 --> 05:23:34,480
WE CAN SEE IN WOMEN WITHOUT BV,

6601
05:23:34,480 --> 05:23:40,760
WE SEE A LOT OF CORE 2

6602
05:23:40,760 --> 05:23:43,800
O-GLYCANS, SOME CORE 1 AS WELL.

6603
05:23:43,800 --> 05:23:53,080
THE MOST PROMINENT ONE, HIGHEST

6604
05:23:53,080 --> 05:23:53,720
SENSETY, CONTAINING POTENTIAL

6605
05:23:53,720 --> 05:23:58,920
LEWIS X, IF WE TOOK THOSE 

6606
05:23:58,920 --> 05:24:02,600
EPITHELIAL CELLS AND TREATED

6607
05:24:02,600 --> 05:24:04,680
WITH A COMMERCIAL SIALIDASE,

6608
05:24:04,680 --> 05:24:06,120
USED ANTIBODY AGAINST LEWIS X

6609
05:24:06,120 --> 05:24:08,320
ABLE TO SHOW THAT WE CAN SHOW

6610
05:24:08,320 --> 05:24:12,840
THAT LEWIS X IS THERE BY FLOW

6611
05:24:12,840 --> 05:24:13,120
CYTOMETRY.

6612
05:24:13,120 --> 05:24:15,960
ALSO POINTING TO THIS GLYCAN

6613
05:24:15,960 --> 05:24:22,560
HERE, WHEN WE FRAGMENT AND WERE 

6614
05:24:22,560 --> 05:24:24,240
ABLE TO SEE SIALYATED ANTIGEN

6615
05:24:24,240 --> 05:24:25,840
CONFIRMING THAT WHAT WE WERE

6616
05:24:25,840 --> 05:24:30,280
SEEING EARLIER WITH PNA WHEN WE

6617
05:24:30,280 --> 05:24:32,680
RELEASE THE SIALIC ACID WE SEE

6618
05:24:32,680 --> 05:24:33,520
THAT UNDERLYING ANTIGEN.

6619
05:24:33,520 --> 05:24:36,640
IN CONTRAST WHEN YOU LOOK AT

6620
05:24:36,640 --> 05:24:38,480
WOMEN WITHOUT -- WITH BV, WE SEE

6621
05:24:38,480 --> 05:24:45,320
THERE'S A LOT OF HYPO SIALYATED

6622
05:24:45,320 --> 05:24:45,640
STRUCTURES.

6623
05:24:45,640 --> 05:24:49,200
SENT OF THE 1878 PEAK YOU SEE

6624
05:24:49,200 --> 05:24:50,280
LOW INTENSITY, AND INSTEAD

6625
05:24:50,280 --> 05:24:52,880
HIGHER INTENSITY PEAK OF WHAT

6626
05:24:52,880 --> 05:24:58,480
WOULD BE UNDERLYING GLYCAN 

6627
05:24:58,480 --> 05:24:58,760
STRUCTURE.

6628
05:24:58,760 --> 05:25:01,920
SO MOVING BACK TO, YOU KNOW,

6629
05:25:01,920 --> 05:25:03,520
10,000-FOOT VIEW HERE, WE'RE

6630
05:25:03,520 --> 05:25:05,240
GOING BACK TO TRANSMISSION

6631
05:25:05,240 --> 05:25:07,000
ELECTRON MICROSCOPY TO LOOK AT

6632
05:25:07,000 --> 05:25:13,920
THE SURFACE OF THE CELL AND LOOK

6633
05:25:13,920 --> 05:25:16,440
AT THE GLYCOCALIX, YOU CAN OFTEN

6634
05:25:16,440 --> 05:25:18,120
SEE A LOT OF BACTERIA HERE.

6635
05:25:18,120 --> 05:25:20,840
WE DID MORE THAN JUST TAKE A

6636
05:25:20,840 --> 05:25:24,560
COUPLE PICTURES AND CALL THEM

6637
05:25:24,560 --> 05:25:24,920
REPRESENTATIVE.

6638
05:25:24,920 --> 05:25:26,640
WE TOOK VAGINAL EPITHELIAL CELLS

6639
05:25:26,640 --> 05:25:28,880
AND WE DID A SCORING PROCEDURE

6640
05:25:28,880 --> 05:25:31,480
IN WHICH WE HAD THREE OBSERVERS,

6641
05:25:31,480 --> 05:25:34,200
THE PERSON WHO TOOK ALL OF THE

6642
05:25:34,200 --> 05:25:37,880
IMAGES WAS BLINDED TO THE

6643
05:25:37,880 --> 05:25:38,760
CLINICAL STATUS OF THOSE

6644
05:25:38,760 --> 05:25:40,560
SAMPLES, AND ALL PEOPLE WHO

6645
05:25:40,560 --> 05:25:41,920
SCORED THE SAMPLES WERE BLINDED

6646
05:25:41,920 --> 05:25:43,440
TO THE STATUS OF THE SAMPLES.

6647
05:25:43,440 --> 05:25:45,080
AND SO WHAT WE CAN SEE IS THAT

6648
05:25:45,080 --> 05:26:02,520
IN THE CONTEXT OF WOMEN WITHOUT 

6649
05:26:02,520 --> 05:26:04,320
BV YOU SEE GLYCOCALYX, IN MORE

6650
05:26:04,320 --> 05:26:13,960
THAN HALF ALL THREE SAID THERE 

6651
05:26:13,960 --> 05:26:15,640
WAS ZERO GLYCOCALIX PRESENT.

6652
05:26:15,640 --> 05:26:19,520
WE'VE BEEN ABLE TO STUDY IN

6653
05:26:19,520 --> 05:26:23,440
VITRO, WE HAVE RECOMBINANT FROM

6654
05:26:23,440 --> 05:26:24,360
GARDNERELLA, DECIDED TO TAKE

6655
05:26:24,360 --> 05:26:27,320
NORMAL CELLS AND TREAT WITH

6656
05:26:27,320 --> 05:26:29,080
SIALIDASE TO DETERMINE WHETHER

6657
05:26:29,080 --> 05:26:32,480
WE'RE STILL SEEING THIS WHOLE

6658
05:26:32,480 --> 05:26:35,280
PHENOTYPE, WERE SIALIC ACID

6659
05:26:35,280 --> 05:26:36,240
REMOVAL IS RESPONSIBLE OR MORE

6660
05:26:36,240 --> 05:26:38,160
MIGHT BE GOING ON.

6661
05:26:38,160 --> 05:26:45,720
WE CAN SEE THIS SIALIDASE 

6662
05:26:45,720 --> 05:26:47,240
TREATMENT WITH GARDNERELLA

6663
05:26:47,240 --> 05:26:49,960
REDUCED APPEARANCE AND TO

6664
05:26:49,960 --> 05:26:52,600
PHENOCOPY WHAT WE'RE SEEING IN

6665
05:26:52,600 --> 05:26:53,280
BACTERIAL VAGINOSIS.

6666
05:26:53,280 --> 05:26:54,960
KIND OF TAKING THIS BACK TO,

6667
05:26:54,960 --> 05:26:57,200
OKAY, WHAT DO WE THINK IS

6668
05:26:57,200 --> 05:26:58,400
HAPPENING, WHY IS THIS

6669
05:26:58,400 --> 05:27:02,400
IMPORTANT, IF YOU ARE DOING A

6670
05:27:02,400 --> 05:27:03,640
WHOLE SCALE REMOVAL THIS COULD

6671
05:27:03,640 --> 05:27:06,120
HAVE A LOT OF DOWNSTREAM

6672
05:27:06,120 --> 05:27:08,280
EFFECTS, AS I'M SURE THIS

6673
05:27:08,280 --> 05:27:09,480
AUDIENCE CAN APPRECIATE.

6674
05:27:09,480 --> 05:27:12,640
AND SO SOME OF THE EXPERIMENTS

6675
05:27:12,640 --> 05:27:13,640
THAT WE'VE DONE, WE HAVE

6676
05:27:13,640 --> 05:27:15,400
DIFFERENT AVENUES TO FOLLOW, BUT

6677
05:27:15,400 --> 05:27:17,640
SOME EXPERIMENTS THAT WE'VE DONE

6678
05:27:17,640 --> 05:27:20,000
INVOLVE LOOKING AT WHETHER THE

6679
05:27:20,000 --> 05:27:22,520
CHANGES TO THE GLYCANS ON THE

6680
05:27:22,520 --> 05:27:24,320
CELL SURFACE MAY INFLUENCE

6681
05:27:24,320 --> 05:27:26,640
ABILITY OF EITHER GARDNERELLA OR

6682
05:27:26,640 --> 05:27:28,440
OTHER BACTERIA TO BIND TO

6683
05:27:28,440 --> 05:27:32,640
EPITHELIAL CELLS AND COLONIZE

6684
05:27:32,640 --> 05:27:33,520
THE VAGINA, MAYBE HAS SOMETHING

6685
05:27:33,520 --> 05:27:35,760
TO DO WITH HOW YOU DEVELOP

6686
05:27:35,760 --> 05:27:37,480
COLONIZATION AND OVERGROWTH YOU

6687
05:27:37,480 --> 05:27:39,000
SEE IN BV.

6688
05:27:39,000 --> 05:27:40,360
THESE ARE NOT WITH EPITHELIAL

6689
05:27:40,360 --> 05:27:40,560
CELLS.

6690
05:27:40,560 --> 05:27:42,960
THIS HAPPENS A LITTLE BIT

6691
05:27:42,960 --> 05:27:44,560
EARLIER IN THE PROCESS OF THE

6692
05:27:44,560 --> 05:27:46,560
LAB.

6693
05:27:46,560 --> 05:27:47,840
BUT INSTEAD WE'RE USING

6694
05:27:47,840 --> 05:27:53,120
HEMAGGLUTINATION TO LOOK AT 

6695
05:27:53,120 --> 05:27:53,840
BINDING OF GARDNERELLA VAGINALIS

6696
05:27:53,840 --> 05:27:55,760
AND EVALUATE IMPACT OF GLYCANS.

6697
05:27:55,760 --> 05:27:58,560
FIRST I'M GOING TO TELL YOU THAT

6698
05:27:58,560 --> 05:28:03,120
WE WERE ABLE TO OBSERVE THAT

6699
05:28:03,120 --> 05:28:05,120
SIALIDASE TREATMENT IMPROVED

6700
05:28:05,120 --> 05:28:05,760
HEMAGGLUTINATION TO SHEEP

6701
05:28:05,760 --> 05:28:09,240
RBCs, AND THEN WE COULD

6702
05:28:09,240 --> 05:28:10,560
ACTUALLY OUTCOMPETE THAT WITH

6703
05:28:10,560 --> 05:28:12,120
GALACTOSE OR LACTOSE.

6704
05:28:12,120 --> 05:28:15,040
BUT NOT WITH THESE OTHER SUGARS.

6705
05:28:15,040 --> 05:28:17,040
WE THINK THIS IS GOOD EVIDENCE

6706
05:28:17,040 --> 05:28:20,000
IN RELATION TO THIS MODEL WITH

6707
05:28:20,000 --> 05:28:24,280
RBCs THAT GARDNERELLA CAN BIND

6708
05:28:24,280 --> 05:28:26,640
TO GALACTOSE RESIDUES UNDERLYING

6709
05:28:26,640 --> 05:28:30,640
SIALIC ACID, MAY BE RELEVANT TO

6710
05:28:30,640 --> 05:28:32,080
EPITHELIUM.

6711
05:28:32,080 --> 05:28:34,600
TO ASK DOES IT REALLY IMPACT

6712
05:28:34,600 --> 05:28:37,120
BINDING, I WANTED TO SHARE ONE

6713
05:28:37,120 --> 05:28:38,520
MORE EXPERIMENT WITH YOU GUYS.

6714
05:28:38,520 --> 05:28:41,800
THIS IS A LITTLE BIT MORE

6715
05:28:41,800 --> 05:28:42,080
PRELIMINARY.

6716
05:28:42,080 --> 05:28:46,640
WE STILL NEED TO FOLLOW UP.

6717
05:28:46,640 --> 05:28:50,480
THIS IS MORE RELEVANT TO HUMAN

6718
05:28:50,480 --> 05:28:52,000
CONTEXT USING CELLS ISOLATED

6719
05:28:52,000 --> 05:28:52,560
FROM VAGINAL SWABS.

6720
05:28:52,560 --> 05:28:55,200
IN THIS CASE WE'RE USING

6721
05:28:55,200 --> 05:28:57,960
EPITHELIAL CELLS FROM NORMAL

6722
05:28:57,960 --> 05:29:00,840
WOMEN WITHOUT BV.

6723
05:29:00,840 --> 05:29:03,520
AND THEN WE HAVE ALSO DEVELOPED

6724
05:29:03,520 --> 05:29:04,880
THIS RESOURCE WHETHER WE'VE

6725
05:29:04,880 --> 05:29:09,480
BROUGHT VAGINAL SWABS TO THE LAB

6726
05:29:09,480 --> 05:29:15,400
UNDER ANAEROBIC CONDITIONS AND,

6727
05:29:15,400 --> 05:29:18,000
WELL, CAN FREEZE THEM DOWN,

6728
05:29:18,000 --> 05:29:19,760
REMOVED THEM FROM FREEZERS AND

6729
05:29:19,760 --> 05:29:20,520
CULTIVATE.

6730
05:29:20,520 --> 05:29:22,280
THIS IS FROM A COMPLETELY

6731
05:29:22,280 --> 05:29:23,800
DIFFERENT COHORT, THAT DOESN'T

6732
05:29:23,800 --> 05:29:25,160
MATTER, BUT THE EXPERIMENT IS

6733
05:29:25,160 --> 05:29:29,280
ULTIMATELY TO TAKE THESE PRIMARY

6734
05:29:29,280 --> 05:29:31,720
EPITHELIAL CELLS, TREAT THEM

6735
05:29:31,720 --> 05:29:33,280
WITH OR WITHOUT SIALIDASE, TAKE

6736
05:29:33,280 --> 05:29:36,840
THESE COMMUNITIES THAT WE'RE

6737
05:29:36,840 --> 05:29:40,000
ABLE TO GROW IN VITRO, INCUBATE

6738
05:29:40,000 --> 05:29:43,040
WITH CELLS, DO FLOW CYTOMETRY TO

6739
05:29:43,040 --> 05:29:46,440
EVALUATE BINDING.

6740
05:29:46,440 --> 05:29:48,840
WHAT WE CAN SEE WITH A COUPLE

6741
05:29:48,840 --> 05:29:52,160
DIFFERENT POOLS FROM THE WOMEN

6742
05:29:52,160 --> 05:29:52,720
WITHOUT BACTERIAL VAGINOSIS

6743
05:29:52,720 --> 05:29:55,160
WE'RE ABLE TO SEE THAT IN THE

6744
05:29:55,160 --> 05:29:57,440
CONTEXT OF SIALIDASE MUCH BETTER

6745
05:29:57,440 --> 05:29:59,560
INTERACTION OF THIS COMMUNITY

6746
05:29:59,560 --> 05:30:00,040
WITH THE CELLS.

6747
05:30:00,040 --> 05:30:02,640
SO THIS IS SORT OF SOME

6748
05:30:02,640 --> 05:30:04,720
PRELIMINARY TEASER EVIDENCE THAT

6749
05:30:04,720 --> 05:30:06,560
WE THINK SIALIDASE MAY BE

6750
05:30:06,560 --> 05:30:10,000
INVOLVED IN HELPING SOME OTHER

6751
05:30:10,000 --> 05:30:14,560
BACTERIA ATTACH TO THE HOST AND

6752
05:30:14,560 --> 05:30:16,440
THEREFORE COLONIZE AND

6753
05:30:16,440 --> 05:30:18,440
POTENTIALLY CAUSE BV.

6754
05:30:18,440 --> 05:30:20,160
A TINY BIT FURTHER, THIS IS

6755
05:30:20,160 --> 05:30:23,120
OLDER DATA BUT I WANTED TO SHARE

6756
05:30:23,120 --> 05:30:24,760
IT BECAUSE IT'S RELEVANT.

6757
05:30:24,760 --> 05:30:28,920
IN SOME EARLIER STUDIES WE WERE

6758
05:30:28,920 --> 05:30:32,960
LOOKING AT ABILITY OF

6759
05:30:32,960 --> 05:30:34,480
GARDNERELLA AND THE GLYCOSYLASES

6760
05:30:34,480 --> 05:30:46,360
PRESENT IN THE CONTEXT TO 

6761
05:30:46,360 --> 05:30:47,440
DEGRADE SUBSTRATE, PROVIDING

6762
05:30:47,440 --> 05:30:49,040
IgA, HIGHLY GLYCOSYLATED,

6763
05:30:49,040 --> 05:30:53,320
LABELED TO OBSERVE ON THE GEL.

6764
05:30:53,320 --> 05:30:59,520
WHEN WE INCUBATE THIS SIGA-FITC

6765
05:30:59,520 --> 05:31:01,320
OF WOMEN WITH OR WITHOUT

6766
05:31:01,320 --> 05:31:02,720
BACTERIAL VAGINOSIS CAN SEE

6767
05:31:02,720 --> 05:31:05,240
ANALOGOUS TO EARLIER STUDIES

6768
05:31:05,240 --> 05:31:05,840
WITH IMMUNOFLUORESCENCE, EXCEPT

6769
05:31:05,840 --> 05:31:10,440
THIS TIME LOOKING AT SNA, 2, 6

6770
05:31:10,440 --> 05:31:13,000
LINKED, TOP IS SECRETORY

6771
05:31:13,000 --> 05:31:15,440
COMPONENT, BOTTOM IS HEAVY

6772
05:31:15,440 --> 05:31:20,640
CHAIN, LABELING FROM FIT-C, IN

6773
05:31:20,640 --> 05:31:24,480
THE CONTEXT OF THE BV STATUS YOU

6774
05:31:24,480 --> 05:31:25,640
SEE THAT THERE'S, SORRY, THIS

6775
05:31:25,640 --> 05:31:32,240
ONE IS NOT COMING FROM FIT-C, 

6776
05:31:32,240 --> 05:31:33,800
FROM SNA, EARLIER.

6777
05:31:33,800 --> 05:31:35,440
YOU SEE VERY LITTLE STAINING,

6778
05:31:35,440 --> 05:31:36,960
YOU DO SEE THAT AS YOU WOULD

6779
05:31:36,960 --> 05:31:42,280
EXPECT ON OF THE IgA OF THE

6780
05:31:42,280 --> 05:31:44,560
WOMEN, SAMPLES FROM WOMEN

6781
05:31:44,560 --> 05:31:46,400
WITHOUT BV BEING TREEDED HERE.

6782
05:31:46,400 --> 05:31:50,560
IF YOU TAKE THAT A STEP FURTHER

6783
05:31:50,560 --> 05:31:55,920
WE WANT TO KNOW IS THERE

6784
05:31:55,920 --> 05:31:57,240
PROCESSIVE DEGLYCOSYLATION.

6785
05:31:57,240 --> 05:32:04,000
WE TESTED TO SEE IF WE COULD SEE

6786
05:32:04,000 --> 05:32:06,480
REVEALING OF CON-A BINDING

6787
05:32:06,480 --> 05:32:06,960
SITES.

6788
05:32:06,960 --> 05:32:09,240
IN FACT EXPERIMENTS CAN BE

6789
05:32:09,240 --> 05:32:13,640
MESSY, BUT WHEN YOU LOOK HERE,

6790
05:32:13,640 --> 05:32:16,240
WHEN THE SUBSTRATE WAS ADDED TO

6791
05:32:16,240 --> 05:32:18,160
SAMPLES OF WOMEN WITHOUT

6792
05:32:18,160 --> 05:32:19,520
BACTERIAL VAGINOSIS YOU SEE MORE

6793
05:32:19,520 --> 05:32:21,040
CLEAN BANDS HERE AND HERE AND

6794
05:32:21,040 --> 05:32:21,240
HERE.

6795
05:32:21,240 --> 05:32:23,120
THIS IS THE CONTROL WHETHER

6796
05:32:23,120 --> 05:32:24,400
WE'RE TAKING COMMERCIAL ENZYMES

6797
05:32:24,400 --> 05:32:27,320
AND TREATING SO YOU CAN SEE HOW

6798
05:32:27,320 --> 05:32:30,600
IT SMEARS DOWNWARDS, AND IN THE

6799
05:32:30,600 --> 05:32:31,960
CONTEXT OF BACTERIAL VAGINOSIS

6800
05:32:31,960 --> 05:32:36,640
YOU SEE A SIMILAR PHENOTYPE,

6801
05:32:36,640 --> 05:32:37,440
SMEARING DOWNWARDS OF CON-A

6802
05:32:37,440 --> 05:32:40,080
BINDING SITES, HERE AND HERE.

6803
05:32:40,080 --> 05:32:42,880
THIS IS THE QUANTITATION OF

6804
05:32:42,880 --> 05:32:44,320
THOSE BANDS.

6805
05:32:44,320 --> 05:32:46,560
AND SO JUST COMING BACK TO THE

6806
05:32:46,560 --> 05:32:48,080
BEGINNING I HOPE THAT I HAVE

6807
05:32:48,080 --> 05:32:51,960
CONVINCED YOU THAT RESIDENT

6808
05:32:51,960 --> 05:32:53,280
MICROBES IN VAGINA SHAPE THE

6809
05:32:53,280 --> 05:32:56,600
EPITHELIAL LANDSCAPE AND MAY BE

6810
05:32:56,600 --> 05:33:00,080
RELEVANT FOR THE BEEN OF

6811
05:33:00,080 --> 05:33:01,040
BACTERIAL VAGINOSIS, AND KAVEETA

6812
05:33:01,040 --> 05:33:04,440
IS THE FIRST AUTHOR, SHE'S ON

6813
05:33:04,440 --> 05:33:07,160
THE JOB MARKET IF YOU'RE

6814
05:33:07,160 --> 05:33:07,880
INTERESTED.

6815
05:33:07,880 --> 05:33:09,120
THANKS TO THE COLLABORATORS AND

6816
05:33:09,120 --> 05:33:10,440
PATIENTS WHO MADE THIS WORK

6817
05:33:10,440 --> 05:33:10,720
POSSIBLE.

6818
05:33:10,720 --> 05:33:14,520
I'LL TAKE ANY QUESTIONS.

6819
05:33:14,520 --> 05:33:15,040
>> SUPER TALK.

6820
05:33:15,040 --> 05:33:16,640
DO WE HAVE QUESTIONS FROM ANYONE

6821
05:33:16,640 --> 05:33:19,440
LISTENING ON THE ZOOM?

6822
05:33:19,440 --> 05:33:20,760
YOU CAN USE YOUR MICROPHONES OR

6823
05:33:20,760 --> 05:33:23,600
I'LL MONITOR THE CHAT.

6824
05:33:23,600 --> 05:33:29,880
 

6825
05:33:29,880 --> 05:33:37,080
I'LL LET YOU CAN, LAURA.

6826
05:33:37,080 --> 05:33:38,040
>> I WAS CURIOUS, I'LL SOUND

6827
05:33:38,040 --> 05:33:39,640
LIKE A BROKEN RECORD ASKING THE

6828
05:33:39,640 --> 05:33:42,680
SAME KIND OF QUESTION OVER AND

6829
05:33:42,680 --> 05:33:43,040
OVER.

6830
05:33:43,040 --> 05:33:45,240
SEEMS LIKE THE LOSS OF SIALIC

6831
05:33:45,240 --> 05:33:48,160
ACID COULD OPEN SITES FOR

6832
05:33:48,160 --> 05:33:51,440
GALECTINS, WONDERING IF YOU'VE

6833
05:33:51,440 --> 05:33:54,480
EVER LOOKED TO SEE IF YOU SEE AN

6834
05:33:54,480 --> 05:33:56,640
INCREASE IN GALECTINS, MAYBE

6835
05:33:56,640 --> 05:33:58,320
BEING RECRUITED TO THE MUCOUS OR

6836
05:33:58,320 --> 05:33:59,920
SORTS OF LAYERS AND BRINGING

6837
05:33:59,920 --> 05:34:03,240
THAT UP BECAUSE SEAN MIGHT BE

6838
05:34:03,240 --> 05:34:03,560
INTERESTED.

6839
05:34:03,560 --> 05:34:05,200
>> YEAH, WE HAVEN'T LOOKED AT

6840
05:34:05,200 --> 05:34:07,160
THAT YET BUT I THINK IT'S VERY

6841
05:34:07,160 --> 05:34:10,240
INTERESTING AND SINCE WE KNOW WE

6842
05:34:10,240 --> 05:34:14,400
HAVE AN EXFOLIATION PHENOTYPE IN

6843
05:34:14,400 --> 05:34:15,800
BACTERIAL VAGINOSIS AND IT'S

6844
05:34:15,800 --> 05:34:18,320
ALSO SHOWN THAT THOSE CELLS ARE

6845
05:34:18,320 --> 05:34:21,840
UNDERGOING APOPTOSIS AS THEY ARE

6846
05:34:21,840 --> 05:34:26,040
 EXFOLIATING AND COULD BE

6847
05:34:26,040 --> 05:34:30,480
REVEALING GALACTOSE EPITOPES

6848
05:34:30,480 --> 05:34:32,800
CAUSES GALECTIN 1 OR OTHERS TO

6849
05:34:32,800 --> 05:34:33,880
ACT IN THAT CONTEXT.

6850
05:34:33,880 --> 05:34:35,120
>> THERE ARE SOME, I DON'T KNOW

6851
05:34:35,120 --> 05:34:36,280
WHICH ONES, BUT I THINK IT WOULD

6852
05:34:36,280 --> 05:34:41,040
BE INTERESTING TO LOOK AT.

6853
05:34:41,040 --> 05:34:41,960
>> COMPLETELY AGREE.

6854
05:34:41,960 --> 05:34:46,240
I WON'T COMMENT FOR TIME BUT 

6855
05:34:46,240 --> 05:34:50,520
THIS IS BEAUTIFUL WORK.

6856
05:34:50,520 --> 05:34:52,480
>> THANK YOU FOR A GREAT TALK.

6857
05:34:52,480 --> 05:34:53,000
REALLY NICE.

6858
05:34:53,000 --> 05:34:54,600
IN THE INTEREST OF TIME WE'LL

6859
05:34:54,600 --> 05:34:58,200
MOVE ON BECAUSE WE DO WANT TO

6860
05:34:58,200 --> 05:34:58,960
WRAP BY FIVE.

6861
05:34:58,960 --> 05:35:05,200
THE FAIL-SAFE SHY OF  -- IS I

6862
05:35:05,200 --> 05:35:11,120
WON'T GIVE MY TALK.

6863
05:35:11,120 --> 05:35:15,960
NEXT IS MOHAMMED ABDEL FROM THE

6864
05:35:15,960 --> 05:35:22,000
WISTAR INSTITUTE, FLY COMBIC 

6865
05:35:22,000 --> 05:35:26,040
MODULATION OF THE GUT

6866
05:35:26,040 --> 05:35:28,400
MICROBIOME.

6867
05:35:28,400 --> 05:35:31,760
>> MY PRESENTATION WILL FOCUS ON

6868
05:35:31,760 --> 05:35:32,120
VIRAL INFECTION.

6869
05:35:32,120 --> 05:35:35,960
IN PARTICULAR I WANT TO

6870
05:35:35,960 --> 05:35:38,000
HIGHLIGHT IMPORTANCE OF GLYCANS

6871
05:35:38,000 --> 05:35:40,120
IN REGULATING RELATIONSHIP

6872
05:35:40,120 --> 05:35:41,600
BETWEEN THE MICROBIOME AND

6873
05:35:41,600 --> 05:35:42,160
IMMUNITY DURING VIRAL

6874
05:35:42,160 --> 05:35:42,600
INFECTIONS.

6875
05:35:42,600 --> 05:35:44,080
BECAUSE OF THAT I WANT TO GIVE

6876
05:35:44,080 --> 05:35:44,920
TWO EXAMPLES.

6877
05:35:44,920 --> 05:35:50,480
FIRST EXAMPLE I WILL FOCUS ON

6878
05:35:50,480 --> 05:35:52,640
HOST, IN PARTICULAR GUT

6879
05:35:52,640 --> 05:35:53,880
GLYCOSYLATION AND REGULATING

6880
05:35:53,880 --> 05:35:54,520
RELATIONSHIP BETWEEN MICROBIOME

6881
05:35:54,520 --> 05:35:56,640
AND IMMUNITY AND I WILL USE HIV

6882
05:35:56,640 --> 05:35:58,600
AS AN EXAMPLE.

6883
05:35:58,600 --> 05:36:02,560
AND IN THE SECOND EXAMPLE I WANT

6884
05:36:02,560 --> 05:36:05,440
TO MOVE FROM HOST TO HOST

6885
05:36:05,440 --> 05:36:07,160
GLYCANS IN MICROBIOME AND HOW DO

6886
05:36:07,160 --> 05:36:12,120
GLYCANS IN BACTERIA AND FUNGUS

6887
05:36:12,120 --> 05:36:13,680
IN OUR MICROBIOME IMPACT THE

6888
05:36:13,680 --> 05:36:14,880
RELATIONSHIP BETWEEN HOST AND

6889
05:36:14,880 --> 05:36:16,000
IMMUNITY IN SARS-COV-2.

6890
05:36:16,000 --> 05:36:17,480
STARTING WITH THE FIRST EXAMPLE

6891
05:36:17,480 --> 05:36:19,560
IN HIV INFECTION I WANT TO START

6892
05:36:19,560 --> 05:36:22,440
BY HIGHLIGHTING WHY THE GUT IS A

6893
05:36:22,440 --> 05:36:26,240
MAJOR SITE FOR HIV PATHOGENESIS.

6894
05:36:26,240 --> 05:36:32,920
SO HIV CAUSES  SYSTEMIC

6895
05:36:32,920 --> 05:36:34,280
INFLAMMATION THROUGH CYTOKINE

6896
05:36:34,280 --> 05:36:40,000
STORM, SOME CAN INJURY THE GUT,

6897
05:36:40,000 --> 05:36:41,680
CAUSING PERMEABILITY, LEAKY GUT,

6898
05:36:41,680 --> 05:36:43,360
MEANING IT ALLOWS MICROBES AND

6899
05:36:43,360 --> 05:36:45,040
BYPRODUCTS TO TRANSLOCATE FROM

6900
05:36:45,040 --> 05:36:47,800
THE GUT TO THE BLOOD BEING

6901
05:36:47,800 --> 05:36:49,240
RECOGNIZED BY SYSTEMIC IMMUNE

6902
05:36:49,240 --> 05:36:52,720
SYSTEM CAUSING EVEN FURTHER

6903
05:36:52,720 --> 05:36:54,040
INFLAMMATION, FURTHER CYTOKINE

6904
05:36:54,040 --> 05:36:55,680
RELEASE, WHICH HAPPENS TO BE THE

6905
05:36:55,680 --> 05:36:57,520
THING HIV NEEDS TO EVEN INFECT

6906
05:36:57,520 --> 05:36:59,760
MORE CELLS.

6907
05:36:59,760 --> 05:37:00,400
HIV CAN ALSO DIRECTLY INFECT T

6908
05:37:00,400 --> 05:37:04,360
CELLS IN THE GUT TO EVEN FURTHER

6909
05:37:04,360 --> 05:37:10,720
FEED THE CYCLE, EVENTUALLY THIS 

6910
05:37:10,720 --> 05:37:14,720
VICIOUS CYCLE CONTRIBUTES TO THE

6911
05:37:14,720 --> 05:37:15,600
DEVELOPMENT OF SEVERAL

6912
05:37:15,600 --> 05:37:16,640
INFLAMMATION-ASSOCIATED DISEASES

6913
05:37:16,640 --> 05:37:18,640
IN PEOPLE LIVING WITH HIV

6914
05:37:18,640 --> 05:37:19,840
INCLUDING NEUROLOGICAL

6915
05:37:19,840 --> 05:37:20,520
IMPAIRMENTS, CARDIOVASCULAR

6916
05:37:20,520 --> 05:37:24,600
DISEASES, SEVERAL KIND OF

6917
05:37:24,600 --> 05:37:24,840
CANCERS.

6918
05:37:24,840 --> 05:37:28,080
EVEN IF PEOPLE LIVING WITH HIV

6919
05:37:28,080 --> 05:37:32,720
ARE ON SUPPRESSIVE THERAPY,

6920
05:37:32,720 --> 05:37:35,240
VIRUS IS SUPPRESSED, THIS CYCLE

6921
05:37:35,240 --> 05:37:36,280
NEVER COMPLETELY RECOVERS AND

6922
05:37:36,280 --> 05:37:37,720
NEVER COMPLETELY STOPS,

6923
05:37:37,720 --> 05:37:40,320
CONTINUES CAUSING CHRONIC

6924
05:37:40,320 --> 05:37:43,600
INFLAMMATION IN PEOPLE WITH HIV

6925
05:37:43,600 --> 05:37:51,560
EVEN AFTER LONG-TERM THEY 

6926
05:37:51,560 --> 05:37:52,040
LONG-TERM -- THERAPY.

6927
05:37:52,040 --> 05:37:53,240
THERE'S A LOT OF INTEREST IN

6928
05:37:53,240 --> 05:37:55,760
FINDING A WAY OR WAYS TO BREAK

6929
05:37:55,760 --> 05:37:59,080
THIS CYCLE AND PREVENT THIS

6930
05:37:59,080 --> 05:38:01,640
INFLAMMATION AND PREVENT THESE

6931
05:38:01,640 --> 05:38:02,320
COMORBIDITIES.

6932
05:38:02,320 --> 05:38:03,680
NOW AS MENTIONED EARLIER TODAY

6933
05:38:03,680 --> 05:38:07,600
IN MULTIPLE TALKS, IN THE LAST

6934
05:38:07,600 --> 05:38:11,880
COUPLE YEARS IT'S BECOME CLEAR 

6935
05:38:11,880 --> 05:38:14,160
GUT GLYCANS PLAY A ROLE IN

6936
05:38:14,160 --> 05:38:16,600
REGULATING GUT AND MICROBIOME.

6937
05:38:16,600 --> 05:38:18,520
THERE'S SEVERAL BACTERIA THAT

6938
05:38:18,520 --> 05:38:21,000
CAN RELEASE HIGH LEVEL OF GLYCAN

6939
05:38:21,000 --> 05:38:21,640
DEGRADING ENZYMES BECAUSE

6940
05:38:21,640 --> 05:38:24,240
BACTERIA IS TRYING TO USE THIS

6941
05:38:24,240 --> 05:38:27,120
SUGARS AS FOOD SOURCE.

6942
05:38:27,120 --> 05:38:31,240
GUT MICROBIOME CAN IMPACT THE

6943
05:38:31,240 --> 05:38:31,920
GLYCOME.

6944
05:38:31,920 --> 05:38:36,920
THE GUT GLYCOME IS FOOD

6945
05:38:36,920 --> 05:38:37,920
SOURCEING SITE.

6946
05:38:37,920 --> 05:38:54,320
WHEN BACTERIA CONSUMES    SUGAR

6947
05:38:54,320 --> 05:38:56,080
IMPACTION VIRULENCE.

6948
05:38:56,080 --> 05:38:58,560
THIS IS EXPRESSED BY EPITHELIAL

6949
05:38:58,560 --> 05:39:08,840
CELLS IN THE GUT, WHEN CONSUMED 

6950
05:39:08,840 --> 05:39:11,640
CAN REPRESS VIRULENT GENES.

6951
05:39:11,640 --> 05:39:14,960
AN INDIVIDUAL WHO DOES NOT HAVE

6952
05:39:14,960 --> 05:39:17,320
ABILITY TO SUPPRESS MORE PRONE

6953
05:39:17,320 --> 05:39:19,000
FOR GUT INFLAMMATION IN

6954
05:39:19,000 --> 05:39:20,400
INFLAMMATORY BOWEL DISEASES.

6955
05:39:20,400 --> 05:39:23,160
WE WANT TO ASK THE QUESTION DOES

6956
05:39:23,160 --> 05:39:37,000
HIV INFECTION EVEN AFTER LONG

6957
05:39:37,000 --> 05:39:43,760
TERM SUPPRESSIVE THERAPY

6958
05:39:43,760 --> 05:39:44,120
RELATED?

6959
05:39:44,120 --> 05:39:48,320
WE ISOLATED CELL MEMBRANE

6960
05:39:48,320 --> 05:39:50,520
PROTEINS FROM EPITHELIAL CELLS,

6961
05:39:50,520 --> 05:39:52,280
APPLIED TO LECTIN ARRAY, AN

6962
05:39:52,280 --> 05:40:04,760
ARRAY WITH IMMOBILIZED LECTINS,

6963
05:40:04,760 --> 05:40:06,560
HIGHER BINDING TO INDICATE

6964
05:40:06,560 --> 05:40:08,520
HIGHER EXPRESSION OF SUGAR.

6965
05:40:08,520 --> 05:40:12,240
IN THIS HEAT MAP AN EXAMPLE FROM

6966
05:40:12,240 --> 05:40:14,040
THE ILIUM, SIMILAR FROM THE

6967
05:40:14,040 --> 05:40:15,160
COLON.

6968
05:40:15,160 --> 05:40:20,640
RED IS HIGHER EXHIBITION, BLUE

6969
05:40:20,640 --> 05:40:21,960
IS LOWER EXPRESSION.

6970
05:40:21,960 --> 05:40:23,640
GUT GLYCOME SHOWING SEVERAL

6971
05:40:23,640 --> 05:40:25,920
DIFFERENCES COMPARED TO GUT

6972
05:40:25,920 --> 05:40:29,760
GLYCOME FROM CONTROL.

6973
05:40:29,760 --> 05:40:33,360
NOTABLY, A LOWER LEVEL OF THIS

6974
05:40:33,360 --> 05:40:34,560
PROTECTIVE FUCOSE AS INDICATED

6975
05:40:34,560 --> 05:40:38,560
BY LOWER BINDING TO SEVERAL

6976
05:40:38,560 --> 05:40:44,640
LECTINS IS SPECIFIC FOR ALPHA.

6977
05:40:44,640 --> 05:40:47,640
WE CAN CONFIRM USING

6978
05:40:47,640 --> 05:40:48,280
IMMUNOHISTOCHEMISTRY, HERE AN

6979
05:40:48,280 --> 05:40:53,840
EXAMPLE OF SLIDES FROM SAME

6980
05:40:53,840 --> 05:40:54,080
DONORS.

6981
05:40:54,080 --> 05:40:57,200
LEFT HAVING THE LOWEST SIGNAL

6982
05:40:57,200 --> 05:40:58,960
FROM LECTIN ARRAY, ONE ON THE

6983
05:40:58,960 --> 05:41:00,680
RIGHT SHOWING HIGHEST SIGNAL BY

6984
05:41:00,680 --> 05:41:04,000
LECTIN ARRAY, AND ALSO YOU CAN

6985
05:41:04,000 --> 05:41:09,360
SEE FROM LEFT TO RIGHT A HIGHER

6986
05:41:09,360 --> 05:41:10,320
LEVEL BY IMMUNOHISTOCHEMISTRY

6987
05:41:10,320 --> 05:41:12,400
USING THIS LECTIN.

6988
05:41:12,400 --> 05:41:21,280
WE CAN SEE NICE BURST OF 

6989
05:41:21,280 --> 05:41:22,960
CORRELATION MEASURED BY

6990
05:41:22,960 --> 05:41:24,720
IMMUNOHISTOCHEMISTRY.

6991
05:41:24,720 --> 05:41:26,200
WE THINK HIV INFECTION EVEN

6992
05:41:26,200 --> 05:41:33,400
AFTER LONG-TERM THEY WERE

6993
05:41:33,400 --> 05:41:35,240
ASSOCIATED WITH FUCOSLYATED

6994
05:41:35,240 --> 05:41:35,440
GLYCANS.

6995
05:41:35,440 --> 05:41:37,240
NEXT WE WANT TO EXAMINE

6996
05:41:37,240 --> 05:41:40,840
CORRELATION BETWEEN LEVEL OF

6997
05:41:40,840 --> 05:41:42,560
THESE BRANCHES, FUCOSLYATED

6998
05:41:42,560 --> 05:41:44,640
GLYCANS, INFLAMMATION, FEATURES

6999
05:41:44,640 --> 05:41:46,240
OF THE MICROBIOME.

7000
05:41:46,240 --> 05:41:50,520
IN THIS PLOT, RED IS INDICATING

7001
05:41:50,520 --> 05:41:55,880
SIGNIFICANT  BURST OF

7002
05:41:55,880 --> 05:41:56,440
CORRELATION.

7003
05:41:56,440 --> 05:42:00,840
I WANT TO SHOW CORRELATION

7004
05:42:00,840 --> 05:42:01,640
BETWEEN MICROBIOTA AND

7005
05:42:01,640 --> 05:42:02,000
INFLAMMATION.

7006
05:42:02,000 --> 05:42:05,800
THIS MARKER IS USED AS MARKER,

7007
05:42:05,800 --> 05:42:07,600
THE MORE DIVERSE THE MICROBIOTA,

7008
05:42:07,600 --> 05:42:10,240
THE MORE HEALTHY THE GUT.

7009
05:42:10,240 --> 05:42:14,040
AS EXPECTED, THERE'S A NEGATIVE

7010
05:42:14,040 --> 05:42:18,840
CORRELATION BETWEEN IT, AND

7011
05:42:18,840 --> 05:42:19,640
PRO-INFLAMMATORY MARKERS,

7012
05:42:19,640 --> 05:42:20,640
EXPRESSED HIV INFECTION.

7013
05:42:20,640 --> 05:42:22,480
WHEN WE LOOK AT THE MICROBIOME

7014
05:42:22,480 --> 05:42:27,840
WE FOUND IT IS THE LEVEL OF THIS

7015
05:42:27,840 --> 05:42:29,720
PARTICULAR BACTERIAL SPECIES

7016
05:42:29,720 --> 05:42:38,600
MEASURED IN ILIUM, RIGHT COLON, 

7017
05:42:38,600 --> 05:42:39,720
SIGMOID COLON, CORRELATION IN

7018
05:42:39,720 --> 05:42:41,840
THE GUT DURING HIV INFECTION,

7019
05:42:41,840 --> 05:42:56,280
QUITE INTERESTING BECAUSE AS I 

7020
05:42:56,280 --> 05:42:57,520
MENTIONED EARLIER, BACTERIA

7021
05:42:57,520 --> 05:42:58,280
VULGARIS, HIGHER LEVEL OF THIS

7022
05:42:58,280 --> 05:43:05,440
BACK TEAR YEA  -- BACTERIA,

7023
05:43:05,440 --> 05:43:06,760
CONSISTENT WITH

7024
05:43:06,760 --> 05:43:08,840
ANTI-INFLAMMATORY PROPERTIES OF

7025
05:43:08,840 --> 05:43:10,640
THIS BRANCH OF FUCOSE WITHOUT

7026
05:43:10,640 --> 05:43:21,240
FOUND ITS LEVEL EXHIBIT A BURST

7027
05:43:21,240 --> 05:43:24,480
OF INFLAMMATION, AND CORRELATION

7028
05:43:24,480 --> 05:43:30,040
WITH IL-10, ANTI-INFLAMMATORY

7029
05:43:30,040 --> 05:43:30,280
MARKERS.

7030
05:43:30,280 --> 05:43:32,160
OBVIOUSLY THE LOWER LEVEL OF GUT

7031
05:43:32,160 --> 05:43:34,800
FUCOSYLATION WE SEE IN HIV

7032
05:43:34,800 --> 05:43:39,840
INFECTION IS ASSOCIATED WITH 

7033
05:43:39,840 --> 05:43:42,400
LOWER MICROBIAL DIVERSITY.

7034
05:43:42,400 --> 05:43:46,560
WE WANTED TO EXPLORE POTENTIAL

7035
05:43:46,560 --> 05:43:48,960
MECHANISM WHY LOWER FUCOSE

7036
05:43:48,960 --> 05:43:49,240
CORRELATES.

7037
05:43:49,240 --> 05:43:53,600
WE DID RNA SEQUENCING AND

7038
05:43:53,600 --> 05:43:59,680
FOCUSED ON THE GENES, EXHIBITING

7039
05:43:59,680 --> 05:44:00,640
 BURST OF CORRELATION WITH

7040
05:44:00,640 --> 05:44:04,160
INFLAMMATION, OR WITH LEVEL OF 

7041
05:44:04,160 --> 05:44:10,160
HIV IN THE GUT.

7042
05:44:10,160 --> 05:44:11,360
FUCOSE IS ANTI-INFLAMMATORY, BY

7043
05:44:11,360 --> 05:44:13,280
DEFAULT NEGATIVE CORRELATION

7044
05:44:13,280 --> 05:44:14,760
WITH FUCOSE.

7045
05:44:14,760 --> 05:44:16,920
WHEN WE DID ANALYSIS WE FOUND

7046
05:44:16,920 --> 05:44:20,840
LOWER LEVEL OF FUCOSE DURING HIV

7047
05:44:20,840 --> 05:44:22,160
INFECTION ASSOCIATED WITH

7048
05:44:22,160 --> 05:44:26,240
ACTIVATION OF THESE SIGNALING

7049
05:44:26,240 --> 05:44:28,400
PATHWAYS, A SIGNALING PATHWAY

7050
05:44:28,400 --> 05:44:36,080
KNOWN TO ACTIVATE THE GUT 

7051
05:44:36,080 --> 05:44:38,240
INFLAMMASOME, WE THINK MAYBE THE

7052
05:44:38,240 --> 05:44:39,880
RELATIONSHIP BETWEEN LOWER

7053
05:44:39,880 --> 05:44:41,000
FUCOSE AND HIGHER INFLAMMATION

7054
05:44:41,000 --> 05:44:42,840
DURING HIV INFECTION MAY BE

7055
05:44:42,840 --> 05:44:47,920
RELATED TO THE ACTIVATION OF THE

7056
05:44:47,920 --> 05:44:49,600
GUT INFLAMMASOME MEDIATOR.

7057
05:44:49,600 --> 05:44:53,400
WE DID THIS ANIMAL STUDY USING

7058
05:44:53,400 --> 05:44:55,840
HUMANIZED MICE OF HIV INFECTION,

7059
05:44:55,840 --> 05:44:58,440
IT CANNOT INFECT REGULAR MICE,

7060
05:44:58,440 --> 05:45:00,120
INFECTED WITH HIV, WE TREATED

7061
05:45:00,120 --> 05:45:05,640
THEM OR NOT WITH GLYCOMIC 

7062
05:45:05,640 --> 05:45:06,840
MODULATOR INCLUDING L FUCOSE AND

7063
05:45:06,840 --> 05:45:10,240
AS YOU CAN SEE THE MICE, TREATED

7064
05:45:10,240 --> 05:45:13,840
MICE IN RED, SHOWED LOWER LEVEL

7065
05:45:13,840 --> 05:45:16,480
OF IMMUNE ACTIVATION, IN THE

7066
05:45:16,480 --> 05:45:18,560
BLOOD AND GUT COMPARED TO

7067
05:45:18,560 --> 05:45:22,160
UNTREATED MICE IN GRAY BARS.

7068
05:45:22,160 --> 05:45:26,600
SOME DATA HAS BEEN PUBLISHED,

7069
05:45:26,600 --> 05:45:30,040
YOU CAN READ MORE.

7070
05:45:30,040 --> 05:45:32,240
ON THE HOST GLYCANS, IMPORTANCE

7071
05:45:32,240 --> 05:45:38,000
IN VIRAL INFECTION, LOWER LEVEL

7072
05:45:38,000 --> 05:45:38,960
OF ANTI-INFLAMMATORY FUCOSLYATED

7073
05:45:38,960 --> 05:45:46,640
GLYCAN ASSOCIATED WITH HIGHER

7074
05:45:46,640 --> 05:45:49,320
ABUNDANCE, IN PARTICULAR

7075
05:45:49,320 --> 05:45:51,640
BACTERIA VULGARDIS, HIGHER LEVEL

7076
05:45:51,640 --> 05:45:54,240
OF INFLAMMATION AND THESE

7077
05:45:54,240 --> 05:45:56,640
FINDINGS WERE CORRELATED, OR

7078
05:45:56,640 --> 05:46:03,920
ASSOCIATED WITH ACTIVATION OF 

7079
05:46:03,920 --> 05:46:04,840
INFLAMMASOME TO SIGNALING

7080
05:46:04,840 --> 05:46:05,640
MESSENGER LEVEL.

7081
05:46:05,640 --> 05:46:08,600
THEY WERE ONE OF THE FEW

7082
05:46:08,600 --> 05:46:20,600
EVIDENCE THAT EXIST PREVIOUSLY

7083
05:46:20,600 --> 05:46:22,120
UNAPPRECIATED FACTOR IN

7084
05:46:22,120 --> 05:46:22,400
VIROLOGY.

7085
05:46:22,400 --> 05:46:26,720
I SHOWED AN EXAMPLE OF HIV BUT

7086
05:46:26,720 --> 05:46:29,640
THIS COULD BE TRUE FOR SEVERAL

7087
05:46:29,640 --> 05:46:31,440
VIRAL INFECTIONS WHERE GUT

7088
05:46:31,440 --> 05:46:36,840
MICROBIOME AND GUT ARE

7089
05:46:36,840 --> 05:46:37,120
IMPLICATED.

7090
05:46:37,120 --> 05:46:42,240
FOCUSING IN THE GUT 

7091
05:46:42,240 --> 05:46:44,680
GLYCOSYLATION I'LL MOVE TO

7092
05:46:44,680 --> 05:46:46,760
SECOND EXAMPLE, THE OTHER

7093
05:46:46,760 --> 05:46:48,560
MEMBER, THE MICROBIOME, THE

7094
05:46:48,560 --> 05:46:51,840
FUNGUS AND BACTERIA IN THE GUT

7095
05:46:51,840 --> 05:46:53,640
HEAVILY COVERED WITH GLYCANS AND

7096
05:46:53,640 --> 05:46:57,920
SHOWING AN EXAMPLE HOW GLYCANS,

7097
05:46:57,920 --> 05:46:59,880
BACTERIA AND FUNGUS MAY PLAY

7098
05:46:59,880 --> 05:47:00,760
IMPORTANT ROLE REGULATING

7099
05:47:00,760 --> 05:47:02,480
RELATIONSHIP BETWEEN HOST AND

7100
05:47:02,480 --> 05:47:06,280
IMMUNITY BUT NOW DURING

7101
05:47:06,280 --> 05:47:07,320
SARS-COV-2 INFECTION.

7102
05:47:07,320 --> 05:47:10,480
BEFORE THE SARS-COV-2 PANDEMIC

7103
05:47:10,480 --> 05:47:14,080
THERE WERE SEVERAL EVIDENCE OF

7104
05:47:14,080 --> 05:47:15,520
THIS EMERGING CONCEPT, GUT-LUNG

7105
05:47:15,520 --> 05:47:17,560
AXIS, IN THE LUNG INFECTION

7106
05:47:17,560 --> 05:47:21,080
OTHER DAMAGE THAT IT CAN CAUSE

7107
05:47:21,080 --> 05:47:23,960
SYSTEMIC INFLATION, RELEASE OF

7108
05:47:23,960 --> 05:47:25,840
HIGH LEVEL OF CYTOKINES, CAN

7109
05:47:25,840 --> 05:47:27,920
INDIRECTLY ALSO LEAD TO HIGHER

7110
05:47:27,920 --> 05:47:30,520
INTESTINAL PERMEABILITY AND HIGH

7111
05:47:30,520 --> 05:47:32,640
LEVEL OF MICROBIAL

7112
05:47:32,640 --> 05:47:34,320
TRANSLOCATION, THIS CAN CAUSE

7113
05:47:34,320 --> 05:47:35,640
FUEL THIS SYSTEMIC INFLAMMATION

7114
05:47:35,640 --> 05:47:39,760
OF CYTOKINE IN A MATTER THAT CAN

7115
05:47:39,760 --> 05:47:40,560
WORSEN ORIGINAL LUNG INFECTION

7116
05:47:40,560 --> 05:47:41,440
OR DAMAGE.

7117
05:47:41,440 --> 05:47:44,040
IN SARS-COV-2 WE KNOW IT'S ALSO

7118
05:47:44,040 --> 05:47:45,440
SARS-COV-2 CAN DIRECTLY INFECT

7119
05:47:45,440 --> 05:47:48,600
INTERIOR SITE IN THE GUT TO

7120
05:47:48,600 --> 05:47:50,240
MAYBE FEEDING THE CYCLE.

7121
05:47:50,240 --> 05:47:56,040
WE ASKED THE QUESTION IS THERE

7122
05:47:56,040 --> 05:47:57,000
LINK BETWEEN LUNG INFLAMMATION

7123
05:47:57,000 --> 05:47:58,000
AND GUT IN COVID-19?

7124
05:47:58,000 --> 05:47:59,840
THAT WAS NOT THE FOCUS OF MIGHT

7125
05:47:59,840 --> 05:48:01,240
HAVE EXAMPLE TODAY.

7126
05:48:01,240 --> 05:48:09,440
WE EXAMINED THE PLASMA SAMPLE OF

7127
05:48:09,440 --> 05:48:11,840
SARS-COV-2 NEGATIVE AND POSITIVE

7128
05:48:11,840 --> 05:48:16,880
INDIVIDUAL WITH DIFFERENT 

7129
05:48:16,880 --> 05:48:18,120
DISEASE SEVERITY, MILD,

7130
05:48:18,120 --> 05:48:18,880
MODERATE, SEVERE.

7131
05:48:18,880 --> 05:48:22,800
AS YOU CAN SEE INDEED WE FOUND

7132
05:48:22,800 --> 05:48:25,280
HIGHER LEVEL OF MARKERS AND

7133
05:48:25,280 --> 05:48:27,040
DRIVER OF TIGHT JUNCTION

7134
05:48:27,040 --> 05:48:30,040
PERMEABILITY IN PLASMA OF

7135
05:48:30,040 --> 05:48:34,320
INDIVIDUALS  WITH SEVERE

7136
05:48:34,320 --> 05:48:36,760
COVID-19 COMPARED TO CONTROL,

7137
05:48:36,760 --> 05:48:39,240
ALLOWING MICROBES AND BY-PRODUCT

7138
05:48:39,240 --> 05:48:43,600
TO TRANSLATE TO THE BLOOD USING

7139
05:48:43,600 --> 05:48:50,080
MARKERS TO MEASURE, OR MARKER OF

7140
05:48:50,080 --> 05:48:52,640
FUNGAL TRANSLOCATION, A GLYCAN

7141
05:48:52,640 --> 05:48:56,680
COVERING SURFACE OF FUNGUS.

7142
05:48:56,680 --> 05:49:02,120
IN BOTH CASE THERE'S EVIDENCE OF

7143
05:49:02,120 --> 05:49:03,640
BACTERIA AND FUNGUS CAN

7144
05:49:03,640 --> 05:49:06,080
STIMULATE IMMUNE SYSTEM, IN THIS

7145
05:49:06,080 --> 05:49:22,240
EXAMPLE YOU CAN SEE STRONG BURST

7146
05:49:22,240 --> 05:49:23,200
OF CORRELATION.

7147
05:49:23,200 --> 05:49:27,880
THERE WAS ROBUST BODY OF

7148
05:49:27,880 --> 05:49:29,720
LITERATURE USING STOOL SAMPLE

7149
05:49:29,720 --> 05:49:34,600
SHOWING COVID-19 IS ASSOCIATED

7150
05:49:34,600 --> 05:49:36,320
WITH STATE OF GET MICROBIAL

7151
05:49:36,320 --> 05:49:37,880
DYSBIOSIS, IN A MANNER

7152
05:49:37,880 --> 05:49:39,960
ASSOCIATED WITH HIGH

7153
05:49:39,960 --> 05:49:41,800
INFLAMMATION AND HIGH -- WORSE

7154
05:49:41,800 --> 05:49:43,080
DISEASE SEVERITY.

7155
05:49:43,080 --> 05:49:45,080
MY EXAMPLE TODAY WILL FOCUS ON

7156
05:49:45,080 --> 05:49:46,800
WHAT HAPPENED AFTER RECOVERY

7157
05:49:46,800 --> 05:49:48,200
FROM ACUTE COVID-19.

7158
05:49:48,200 --> 05:49:49,880
AND WE NOW KNOW THERE'S AT LEAST

7159
05:49:49,880 --> 05:49:55,120
10 TO 30% OF PEOPLE WHO RECOVER

7160
05:49:55,120 --> 05:49:56,360
FROM ACUTE COVID-19 CAN

7161
05:49:56,360 --> 05:50:04,720
EXPERIENCE WIDE VARIETY OF

7162
05:50:04,720 --> 05:50:05,320
SYMPTOMS, EITHER PERSISTENCE,

7163
05:50:05,320 --> 05:50:06,600
COVID-ATTRIBUTED SYMPTOMS FOR

7164
05:50:06,600 --> 05:50:09,640
THREE TO FOUR MONTHS FOLLOWING

7165
05:50:09,640 --> 05:50:12,480
ACUTE COVID-19, LONG COVID,

7166
05:50:12,480 --> 05:50:13,960
POST-ACUTE SEQUELAE OF COVID-19.

7167
05:50:13,960 --> 05:50:15,400
THIS PHENOMENON IS VERY

7168
05:50:15,400 --> 05:50:16,960
IMPORTANT, CAN IMPACT LIFE OF

7169
05:50:16,960 --> 05:50:19,480
MILLIONS OF PEOPLE RECOVERED AND

7170
05:50:19,480 --> 05:50:20,040
RECOVERING FROM COVID-19.

7171
05:50:20,040 --> 05:50:30,240
THERE'S A LOT OF INTEREST IN

7172
05:50:30,240 --> 05:50:34,440
UNDERSTANDING MECHANISM DRIVING 

7173
05:50:34,440 --> 05:50:37,480
THIS, ASSOCIATED WITH SUSTAINED

7174
05:50:37,480 --> 05:50:38,560
LEVEL OF INFLAMMATION,

7175
05:50:38,560 --> 05:50:41,400
MULTI-FACTORIAL IN NATURE BUT IN

7176
05:50:41,400 --> 05:50:43,760
OUR CASE WANTED TO EXAMINE DOES

7177
05:50:43,760 --> 05:50:45,160
MICROBIAL TRANSLOCATION

7178
05:50:45,160 --> 05:50:51,280
BACTERIAL OR FUNGAL RESIST AFTER

7179
05:50:51,280 --> 05:50:52,440
CONVALESCENS.

7180
05:50:52,440 --> 05:50:56,520
WE ASKED SAMPLES FROM UCSF

7181
05:50:56,520 --> 05:50:57,480
COHORT, FROM INDIVIDUALS THREE

7182
05:50:57,480 --> 05:51:00,360
TO FOUR MONTHS AFTER RECOVERY IN

7183
05:51:00,360 --> 05:51:02,040
ACUTE COVID-19.

7184
05:51:02,040 --> 05:51:08,000
THAT WERE EITHER STILL SUFFERING

7185
05:51:08,000 --> 05:51:10,440
FROM SOME SYMPTOMS, PASC, OR

7186
05:51:10,440 --> 05:51:10,600
NOT.

7187
05:51:10,600 --> 05:51:12,520
WE LOOKED AT MARKERS.

7188
05:51:12,520 --> 05:51:15,600
YOU CAN SEE IN BLUE INDIVIDUALS

7189
05:51:15,600 --> 05:51:17,320
STILL SUFFERING FROM PASC HAVING

7190
05:51:17,320 --> 05:51:20,240
HIGHER LEVEL OF MARKER OF TIGHT

7191
05:51:20,240 --> 05:51:21,240
JUNCTION PERMEABILITY, THAT

7192
05:51:21,240 --> 05:51:23,840
COULD BE IN THE GUT OR LUNG.

7193
05:51:23,840 --> 05:51:27,480
AND INDEED WHEN WE LOOK AT

7194
05:51:27,480 --> 05:51:31,440
MARKER OF FUNGAL TRANSLOCATION,

7195
05:51:31,440 --> 05:51:33,040
THIS IS POLYSACCHARIDE, SUGAR,

7196
05:51:33,040 --> 05:51:41,800
WE FIND HIGH LEVEL OF FUNGAL,

7197
05:51:41,800 --> 05:51:48,920
YOU MIGHT NOTE WE DRAW A LINE AT

7198
05:51:48,920 --> 05:51:50,520
40, A CLINICAL CUT OFF,

7199
05:51:50,520 --> 05:51:53,040
DIFFERENTIALING INDIVIDUAL WHO

7200
05:51:53,040 --> 05:51:53,720
WILL HAVE FUNGAL TRANSLOCATION

7201
05:51:53,720 --> 05:51:56,120
IN A MANNER LEADING TO CLINICAL

7202
05:51:56,120 --> 05:51:59,000
OUTCOME AND WORSE INFLAMMATION,

7203
05:51:59,000 --> 05:52:02,800
INDEED YOU CAN SEE INDIVIDUAL

7204
05:52:02,800 --> 05:52:05,520
WITH NO PASC, THERE ARE SEVERAL

7205
05:52:05,520 --> 05:52:08,760
INDIVIDUALS WITH PASC WITH

7206
05:52:08,760 --> 05:52:18,560
HIGHER THAN 40-MICROGRAM PER M 

7207
05:52:18,560 --> 05:52:21,240
MIL CUTOFF OF BETA GROUP CAN.

7208
05:52:21,240 --> 05:52:23,960
EVEN 18 SYMPTOMS IN SOME

7209
05:52:23,960 --> 05:52:24,600
INDIVIDUALS, ALSO CORRELATING

7210
05:52:24,600 --> 05:52:26,600
NEGATIVELY WITH QUALITY OF LIFE

7211
05:52:26,600 --> 05:52:30,000
THAT IS REPORTED BY THOSE

7212
05:52:30,000 --> 05:52:31,240
INDIVIDUALS OR PATIENTS.

7213
05:52:31,240 --> 05:52:37,480
WHEN WE DIVIDE INDIVIDUALS WHO 

7214
05:52:37,480 --> 05:52:39,440
ARE SUFFERING FROM PASC,

7215
05:52:39,440 --> 05:52:41,560
INCLUDING G.I.-RELATED SYMPTOMS,

7216
05:52:41,560 --> 05:52:46,480
YOU CAN SEE INDIVIDUALS WHO HAVE

7217
05:52:46,480 --> 05:52:48,000
PASC WITH G.I.-RELATED SYMPTOMS

7218
05:52:48,000 --> 05:52:50,840
HAVE HIGH LEVEL OF BETA GLUCAN

7219
05:52:50,840 --> 05:52:52,400
COMPARED TO INDIVIDUALS WITHOUT

7220
05:52:52,400 --> 05:52:55,640
G.I.-RELATED SYMPTOMS OR NO

7221
05:52:55,640 --> 05:52:56,400
PASC, HIGHLIGHTING POTENTIAL

7222
05:52:56,400 --> 05:53:05,120
ROLE OF GUT IN THIS PHENOMENA.

7223
05:53:05,120 --> 05:53:15,680
WE SEE TREND TOWARD HIGH LEVEL 

7224
05:53:15,680 --> 05:53:16,280
TRANSLOCATION

7225
05:53:16,280 --> 05:53:17,200
WHY FUNCTIONAL TRANSLOCATION

7226
05:53:17,200 --> 05:53:27,760
WILL BE ELEVATED, AND WE KNOW 

7227
05:53:27,760 --> 05:53:28,400
THESE POLYSACCHARIDES BETA

7228
05:53:28,400 --> 05:53:30,920
GLUCAN CAN DRIVE ON SURFACE OF

7229
05:53:30,920 --> 05:53:35,240
MYELOID CELLS, THE BINDING CAN

7230
05:53:35,240 --> 05:53:37,920
ACTIVATE SYK SIGNALING LINKED TO

7231
05:53:37,920 --> 05:53:39,600
NF-kappaB ACTIVATION, LEADING

7232
05:53:39,600 --> 05:53:42,560
TO MYELOID INFLAMMASOME.

7233
05:53:42,560 --> 05:53:50,560
ONE COULD HIGH POTENTIAL  --

7234
05:53:50,560 --> 05:53:52,960
HYPOTHESIZE SOME LEVEL EXHIBITS,

7235
05:53:52,960 --> 05:53:55,000
MAYBE BETA GLUCAN CONTRIBUTES TO

7236
05:53:55,000 --> 05:53:55,320
INFLAMMATION.

7237
05:53:55,320 --> 05:53:58,520
THE LEVEL OF BETA GLUCAN IN

7238
05:53:58,520 --> 05:54:04,000
PLASMA IN THE Y-AXIS CORRELATES.

7239
05:54:04,000 --> 05:54:05,840
THIS IS JUST CORRELATION AND WE

7240
05:54:05,840 --> 05:54:09,400
WANT TO EXAMINE IF THE LEVEL OF

7241
05:54:09,400 --> 05:54:11,480
BETA GLUCAN IN PLASMA OF

7242
05:54:11,480 --> 05:54:14,040
INDIVIDUALS CAN INDEED LEAD TO

7243
05:54:14,040 --> 05:54:14,800
NF-kappaB MEDIATED

7244
05:54:14,800 --> 05:54:15,280
INFLAMMATION.

7245
05:54:15,280 --> 05:54:21,000
IN ORDER TO EXAMINE THAT WE USED

7246
05:54:21,000 --> 05:54:32,000
THIS MODEL, A CELL LINE EXPRESS,

7247
05:54:32,000 --> 05:54:34,920
RECOGNIZED BY BETA GLUCAN,

7248
05:54:34,920 --> 05:54:37,640
LEADING TO SYK SIGNALING AND

7249
05:54:37,640 --> 05:54:38,960
NF-kappaB ACTIVATION WHICH YOU

7250
05:54:38,960 --> 05:54:41,520
CAN MEASURE IN THE CULTURE AND

7251
05:54:41,520 --> 05:55:03,520
USE THIS INHIBITOR FOR SYK

7252
05:55:03,520 --> 05:55:03,800
SIGNALING.

7253
05:55:03,800 --> 05:55:04,840
I WANT TO POINT YOUR ATTENTION

7254
05:55:04,840 --> 05:55:07,800
TO THIS SIDE OF THE GRAPH, CAN

7255
05:55:07,800 --> 05:55:11,400
YOU SEE CLEARLY THE PLASMA FROM

7256
05:55:11,400 --> 05:55:14,440
INDIVIDUALS CAN LEAD TO HIGHER

7257
05:55:14,440 --> 05:55:15,680
NF-kappaB SIGNALING COMPARED

7258
05:55:15,680 --> 05:55:22,440
TO THE PLASMA FROM SARS-COV-2

7259
05:55:22,440 --> 05:55:25,040
NEGATIVE INDIVIDUALS USING THIS

7260
05:55:25,040 --> 05:55:27,880
INHIBITOR TO MITIGATE

7261
05:55:27,880 --> 05:55:28,640
ACTIVATION.

7262
05:55:28,640 --> 05:55:29,480
WE ALSO FOUND POSITIVE

7263
05:55:29,480 --> 05:55:31,840
CORRELATION BETWEEN LEVEL OF

7264
05:55:31,840 --> 05:55:34,240
BETA GLUCAN WE CAN EXAMINE IN

7265
05:55:34,240 --> 05:55:37,760
PLASMA AND DEGREE OF NF-kappaB

7266
05:55:37,760 --> 05:55:42,320
SIGNALING CAN ELICIT IN THIS

7267
05:55:42,320 --> 05:55:44,360
CELL MODEL.

7268
05:55:44,360 --> 05:55:48,600
THE LEVEL IN POST ACUTE SEQUELAE

7269
05:55:48,600 --> 05:55:53,920
ARE CAPABLE OF INDUCING SOME 

7270
05:55:53,920 --> 05:55:56,960
MANNER LINKED TO ACTIVATION

7271
05:55:56,960 --> 05:55:58,920
OF-AND-A-HALF SIGNALING PATHWAY.

7272
05:55:58,920 --> 05:56:01,840
WE THINK IT'S PARTIALLY WHAT

7273
05:56:01,840 --> 05:56:06,560
HAPPENED, MIGHT BE DISRUPTION IN

7274
05:56:06,560 --> 05:56:07,440
TIGHT JUNCTION, THIS

7275
05:56:07,440 --> 05:56:11,640
POLYSACCHARIDE CAN BIND TO ITS 

7276
05:56:11,640 --> 05:56:18,040
SUGAR BINDING PROTEIN DECTIN 1

7277
05:56:18,040 --> 05:56:19,280
LEADING TO ACTIVATION INHIBITED

7278
05:56:19,280 --> 05:56:34,960
USING THIS SMALL MOLECULE 

7279
05:56:34,960 --> 05:56:39,920
INHIBITOR FOR SYK. 

7280
05:56:39,920 --> 05:56:42,640
THE THIRD BAR, THIS COULD BE A

7281
05:56:42,640 --> 05:56:43,800
TOPIC OF SEPARATE PRESENTATION

7282
05:56:43,800 --> 05:57:01,440
AND WOULD LIKE TO GO TO MY

7283
05:57:01,440 --> 05:57:02,840
ACKNOWLEDGMENT SLIDE.

7284
05:57:02,840 --> 05:57:04,480
I WOULD LIKE TO THANK MY

7285
05:57:04,480 --> 05:57:06,840
COLLABORATORS.

7286
05:57:06,840 --> 05:57:14,360
 

7287
05:57:14,360 --> 05:57:16,480
I WILL TAKE QUESTIONS OR FEEL

7288
05:57:16,480 --> 05:57:17,440
FREE TO E-MAIL ME.

7289
05:57:17,440 --> 05:57:20,640
THANK YOU.

7290
05:57:20,640 --> 05:57:26,600
>> FANTASTIC.

7291
05:57:26,600 --> 05:57:28,720
 

7292
05:57:28,720 --> 05:57:29,920
DO WE HAVE QUESTIONS FROM PEOPLE

7293
05:57:29,920 --> 05:57:37,680
IN THE ROOM OR PEOPLE ONLINE?

7294
05:57:37,680 --> 05:57:38,520
WHAT ABOUT USING NF-kappaB

7295
05:57:38,520 --> 05:57:41,520
INHIBITORS RIGHT NOW, COULD YOU

7296
05:57:41,520 --> 05:57:41,920
MULTIPURPOSE THEM?

7297
05:57:41,920 --> 05:57:44,680
>> I'M NOT SURE HOW TOLERABLE

7298
05:57:44,680 --> 05:57:48,440
THAT WILL BE,-AND-A-HALF IS

7299
05:57:48,440 --> 05:57:50,560
OBVIOUSLY IMPORTANT PATHWAY FOR

7300
05:57:50,560 --> 05:57:51,040
IMMUNITY.

7301
05:57:51,040 --> 05:57:54,560
I WILL BE AFRAID IT WILL CAUSE

7302
05:57:54,560 --> 05:57:55,880
SYSTEMIC IMMUNE SEPARATION ALSO

7303
05:57:55,880 --> 05:58:02,560
NOT VERY ATTRACT  ATTRACTIVE,

7304
05:58:02,560 --> 05:58:07,080
IT'S STILL SYK  SIGNALING IS

7305
05:58:07,080 --> 05:58:08,200
IMPORTANT, MAYBE LESS BROAD,

7306
05:58:08,200 --> 05:58:10,040
SOMETHING SPECIFIC FOR BETA

7307
05:58:10,040 --> 05:58:14,560
GLUCAN WILL BE EVEN MUCH BETTER

7308
05:58:14,560 --> 05:58:17,720
OR SOMETHING LIKE TO INCREASE

7309
05:58:17,720 --> 05:58:19,240
THE TIGHTNESS OF THE TIGHT

7310
05:58:19,240 --> 05:58:19,680
JUNCTION.

7311
05:58:19,680 --> 05:58:22,320
FOR EXAMPLE, ACTUAL LIP THERE

7312
05:58:22,320 --> 05:58:26,760
ARE SMALL MOLECULE INHIBITORS

7313
05:58:26,760 --> 05:58:28,400
THAT CAN PREVENT, MAYBE EVEN

7314
05:58:28,400 --> 05:58:31,640
GOING TO THE SOURCE OF THE

7315
05:58:31,640 --> 05:58:36,600
PROBLEM, MAYBE MORE SPECIFIC AND

7316
05:58:36,600 --> 05:58:37,120
SAFER.

7317
05:58:37,120 --> 05:58:37,640
>> TIMELY.

7318
05:58:37,640 --> 05:58:38,320
PEOPLE ARE SUFFERING.

7319
05:58:38,320 --> 05:58:41,240
THANK YOU FOR A FANTASTIC TALK.

7320
05:58:41,240 --> 05:58:41,520
THANK YOU.

7321
05:58:41,520 --> 05:58:44,440
I WILL KEEP YOU POSTED.

7322
05:58:44,440 --> 05:58:45,360
IF PEOPLE POSE QUESTIONS I'LL

7323
05:58:45,360 --> 05:58:49,840
MAKE SURE I GET THOSE E-MAILED

7324
05:58:49,840 --> 05:58:50,000
OUT.

7325
05:58:50,000 --> 05:58:51,600
KEEP QUESTIONS COMING ONLINE.

7326
05:58:51,600 --> 05:58:52,680
SEAN WILL INTRODUCE THE NEXT

7327
05:58:52,680 --> 05:58:53,240
SPEAKER.

7328
05:58:53,240 --> 05:58:54,720
WE'LL TAKE A SWITCHING BREAK.

7329
05:58:54,720 --> 05:59:00,200
>> WE'LL NEXT HAVE THE 

7330
05:59:00,200 --> 05:59:11,000
OPPORTUNITY TO HEAR FROM SETH

7331
05:59:11,000 --> 05:59:13,120
RAKOFF-NAHOUM, GLYCAN-METABOLITE

7332
05:59:13,120 --> 05:59:16,840
EMERGENT PROPERTIES IN THE GUT

7333
05:59:16,840 --> 05:59:18,000
MICROBIOME.

7334
05:59:18,000 --> 05:59:19,120
>> THANK YOU FOR THE INVITATION

7335
05:59:19,120 --> 05:59:21,360
TO SPEAK TODAY.

7336
05:59:21,360 --> 05:59:25,520
I'M GOING TO SET MY TIMER.

7337
05:59:25,520 --> 05:59:28,800
AND TALK TO YOU ABOUT A STORY

7338
05:59:28,800 --> 05:59:30,600
THAT WAS RECENTLY PUBLISHED IN

7339
05:59:30,600 --> 05:59:32,080
THE LAB.

7340
05:59:32,080 --> 05:59:36,760
BUT I WANT TO START WITH

7341
05:59:36,760 --> 05:59:38,640
REALLY -- I'LL PUT MY POINTER

7342
05:59:38,640 --> 05:59:42,640
UP.

7343
05:59:42,640 --> 05:59:48,480
 

7344
05:59:48,480 --> 05:59:50,560
HOW IMPORTANT WE THINK THIS IS,

7345
05:59:50,560 --> 05:59:55,040
ACROSS ORGAN AND TISSUE AND

7346
05:59:55,040 --> 05:59:55,920
PHYSIOLOGICAL SYSTEMS AND

7347
05:59:55,920 --> 05:59:57,360
PATHOPHYSIOLOGICAL SYSTEMS.

7348
05:59:57,360 --> 06:00:00,000
WE CAN ALL AGREE CHALLENGES THAT

7349
06:00:00,000 --> 06:00:02,000
HAVE EMERGED FROM OUR

7350
06:00:02,000 --> 06:00:03,440
ASSOCIATIONS BETWEEN DIFFERENT

7351
06:00:03,440 --> 06:00:05,440
MICRO BIOMES AND THESE HEALTH

7352
06:00:05,440 --> 06:00:08,280
AND DISEASE SPACE ARE TRYING TO

7353
06:00:08,280 --> 06:00:10,560
UNDERSTAND MORE ABOUT THE

7354
06:00:10,560 --> 06:00:12,280
MICROBIOME ITSELF, WHAT ARE THE

7355
06:00:12,280 --> 06:00:14,480
MICROBES DOING, HOW DO THEY

7356
06:00:14,480 --> 06:00:17,840
COLONIZE AND SURVIVE? 

7357
06:00:17,840 --> 06:00:21,240
AND REALLY FROM THIS, ACT ON THE

7358
06:00:21,240 --> 06:00:25,640
MICROBIOME FOR HEALTH, AND TO

7359
06:00:25,640 --> 06:00:28,520
REALLY REALIZE THE

7360
06:00:28,520 --> 06:00:29,800
THERE ARE, OF COURSE, A NUMBER

7361
06:00:29,800 --> 06:00:31,320
OF NEEDS THAT ARE REQUIRED TO

7362
06:00:31,320 --> 06:00:34,400
MEET THESE GOALS, AND I WOULD

7363
06:00:34,400 --> 06:00:37,120
SAY THAT THEY FALL INTO FOUR

7364
06:00:37,120 --> 06:00:38,000
NON-MUTUALLY EXCLUSIVE

7365
06:00:38,000 --> 06:00:41,120
CATEGORIES, WHICH IS WE NEED TO

7366
06:00:41,120 --> 06:00:41,720
BECOME ENVIRONMENTAL MICRO

7367
06:00:41,720 --> 06:00:42,920
BIOLOGISTS FOR EACH OF THESE

7368
06:00:42,920 --> 06:00:45,680
MICROBES THAT WE'VE NEVER HEARD

7369
06:00:45,680 --> 06:00:46,560
OF.

7370
06:00:46,560 --> 06:00:48,920
MOLECULAR BIOLOGISTS FOR THESE

7371
06:00:48,920 --> 06:00:51,840
MICROBES, FOR REDUCTION OF

7372
06:00:51,840 --> 06:00:53,040
STUDIES, USING CLASSIC BACTERIAL

7373
06:00:53,040 --> 06:00:55,720
GENETIC APPROACHES, AND THEN

7374
06:00:55,720 --> 06:00:57,040
ECOLOGISTS AND EVOLUTIONARY

7375
06:00:57,040 --> 06:01:00,000
BIOLOGISTS TO UNDERSTAND HOW

7376
06:01:00,000 --> 06:01:02,440
THESE MICROBES ARE LIVING THERE

7377
06:01:02,440 --> 06:01:03,640
AND WHAT TYPES OF RELATIONSHIPS

7378
06:01:03,640 --> 06:01:04,680
THEY HAVE WITH EACH OTHER AND

7379
06:01:04,680 --> 06:01:08,000
WITH THE HOST.

7380
06:01:08,000 --> 06:01:10,200
AND SO FROM AN ECOLOGICAL

7381
06:01:10,200 --> 06:01:10,840
PERSPECTIVE, WE CAN ASK THE

7382
06:01:10,840 --> 06:01:13,520
QUESTION OF WHAT CONTROLS THE

7383
06:01:13,520 --> 06:01:14,240
MICROBIOME'S FORM AND ITS

7384
06:01:14,240 --> 06:01:15,400
FUNCTION AND REALLY BREAK THIS

7385
06:01:15,400 --> 06:01:17,760
UP INTO THREE NON-MUTUALLY

7386
06:01:17,760 --> 06:01:19,200
EXCLUSIVE CONCEPTUAL CATEGORIES.

7387
06:01:19,200 --> 06:01:25,120
SO THESE CAN BE ABIOTIC, DIET,

7388
06:01:25,120 --> 06:01:27,040
WHICH PROVIDES NUTRIENTS AS

7389
06:01:27,040 --> 06:01:28,800
DEPICTED IN A GREEN POSITIVE

7390
06:01:28,800 --> 06:01:33,520
ARROW, OR A NEGATIVE FACTOR SUCH

7391
06:01:33,520 --> 06:01:36,440
AS ANTIBIOTICS, WHICH KILLS

7392
06:01:36,440 --> 06:01:37,600
MICROBES IN THE GUT.

7393
06:01:37,600 --> 06:01:42,040
THERE'S, OF COURSE, A PLETHORA

7394
06:01:42,040 --> 06:01:43,920
OF ECOLOGICAL -- THOSE SPAN

7395
06:01:43,920 --> 06:01:46,160
COMPETITION TO EXPLOITATION AND

7396
06:01:46,160 --> 06:01:47,440
POSITIVE AND NEGATIVE

7397
06:01:47,440 --> 06:01:51,880
DIRECTIONAL INTERACTIONS BETWEEN

7398
06:01:51,880 --> 06:01:52,920
IN PAIR WISE INTERACTIONS

7399
06:01:52,920 --> 06:01:54,400
BETWEEN MICROBES.

7400
06:01:54,400 --> 06:01:55,200
AND THEN OF COURSE THERE'S THE

7401
06:01:55,200 --> 06:01:56,520
ROLE OF THE HOST WHICH HAS BEEN

7402
06:01:56,520 --> 06:01:57,480
TALKED ABOUT IN A NUMBER OF

7403
06:01:57,480 --> 06:01:59,040
DIFFERENT WAYS TODAY, BOTH AT

7404
06:01:59,040 --> 06:02:01,240
THE ANTIBODY LEVEL AND HOST

7405
06:02:01,240 --> 06:02:03,720
SECRETED LECTINS THAT PLAY ROLES

7406
06:02:03,720 --> 06:02:06,520
IN EITHER NEGATIVELY REGULATING

7407
06:02:06,520 --> 06:02:10,040
WHICH IS THE -- WHEN WE THINK

7408
06:02:10,040 --> 06:02:12,920
ABOUT ANTIMICROBIAL PEPTIDES BUT

7409
06:02:12,920 --> 06:02:14,520
ALSO POTENTIALLY FEEDING OR

7410
06:02:14,520 --> 06:02:16,080
KEEPING CERTAIN MEMBERS OF THE

7411
06:02:16,080 --> 06:02:17,280
MICROBIOME, SUCH AS IN POSITIVE

7412
06:02:17,280 --> 06:02:17,880
SELECTION.

7413
06:02:17,880 --> 06:02:21,520
HOWEVER, IF WE THINK ABOUT THE

7414
06:02:21,520 --> 06:02:22,040
MICROBIOME AND TRYING TO

7415
06:02:22,040 --> 06:02:25,640
UNDERSTAND WHAT ARE THE FACTORS

7416
06:02:25,640 --> 06:02:26,840
ALONG THESE THREE CATEGORIES

7417
06:02:26,840 --> 06:02:29,640
THAT WOULD IMPACT ANY INDIVIDUAL

7418
06:02:29,640 --> 06:02:30,560
MEMBER OF THE MICROBIOME,

7419
06:02:30,560 --> 06:02:32,240
WHETHER IT'S A BUG YOU WANT TO

7420
06:02:32,240 --> 06:02:33,240
COLONIZE THE GUT OR YOU DON'T

7421
06:02:33,240 --> 06:02:36,520
WANT TO COLONIZE THE GUT, WE CAN

7422
06:02:36,520 --> 06:02:40,840
THINK ABOUT HOW DIET IMPACTS THE

7423
06:02:40,840 --> 06:02:42,000
FITNESS OF AND FOR FUNCTION OF

7424
06:02:42,000 --> 06:02:43,960
EACH INDIVIDUAL MEMBER, BUT OF

7425
06:02:43,960 --> 06:02:47,160
COURSE DIET IS MADE OUT OF

7426
06:02:47,160 --> 06:02:50,040
THOUSANDS OF MACRO AND MICRO

7427
06:02:50,040 --> 06:02:51,200
MOLECULES.

7428
06:02:51,200 --> 06:02:54,560
SIMILARLY, MY KROAPS  MICROBES
THEMSELVES

7429
06:02:54,560 --> 06:02:58,520
MAKE A PLETHORA OF METABOLITES,

7430
06:02:58,520 --> 06:03:01,320
PROTEINS, SMALL MOLECULES, AND

7431
06:03:01,320 --> 06:03:02,240
THEN, OF COURSE, THERE'S THE

7432
06:03:02,240 --> 06:03:06,760
HOST WHICH HAS 19,000 GENES IN

7433
06:03:06,760 --> 06:03:08,080
THE IMMUNE SYSTEM AND A NUMBER

7434
06:03:08,080 --> 06:03:10,240
OF GLYCANS AND LECTINS THAT ARE

7435
06:03:10,240 --> 06:03:14,520
LIKE THE IMPACTING MEMBERS OF

7436
06:03:14,520 --> 06:03:15,240
THE MICROBIOME.

7437
06:03:15,240 --> 06:03:16,880
SO WHEN WE THINK ABOUT THIS

7438
06:03:16,880 --> 06:03:21,000
FUNDAMENTAL NICHE OF ALL THE

7439
06:03:21,000 --> 06:03:22,520
POTENTIAL FACTORS THAT CAN BE

7440
06:03:22,520 --> 06:03:24,320
ACTING ON ANY GIVEN MICROBE, IT

7441
06:03:24,320 --> 06:03:26,040
CAN HURT YOUR HEAD.

7442
06:03:26,040 --> 06:03:29,240
AND OF COURSE EACH OF THESE

7443
06:03:29,240 --> 06:03:30,840
FACTORS COULD IMPACT THE

7444
06:03:30,840 --> 06:03:32,000
ECOLOGICAL INTERACTIONS BETWEEN

7445
06:03:32,000 --> 06:03:33,320
WHICH MEMBERS AND WE DON'T KNOW

7446
06:03:33,320 --> 06:03:35,720
WHICH MEMBERS HAVE THOSE PAIR

7447
06:03:35,720 --> 06:03:38,240
WISE INTERACTIONS, WE DON'T KNOW

7448
06:03:38,240 --> 06:03:39,560
WHETHER THEY'RE PASSTIVE AND

7449
06:03:39,560 --> 06:03:43,680
NEGATIVE, AND OF  POSITIVE AND

7450
06:03:43,680 --> 06:03:45,960
NEGATIVE AND WE DON'T UNDERSTAND

7451
06:03:45,960 --> 06:03:47,520
THE MECHANISTIC RELATIONSHIP AT

7452
06:03:47,520 --> 06:03:49,040
THE GENETIC OR MOLECULAR LEVELS.

7453
06:03:49,040 --> 06:03:50,280
SO THAT'S THE GOAL OF MY LAB,

7454
06:03:50,280 --> 06:03:51,360
AND OF COURSE MANY OF YOU THAT

7455
06:03:51,360 --> 06:03:54,080
ARE OUT THERE.

7456
06:03:54,080 --> 06:03:56,160
AND I'LL JUST USE 30 SECONDS TO

7457
06:03:56,160 --> 06:03:59,680
KIND OF TALK ABOUT REALLY -- OUR

7458
06:03:59,680 --> 06:04:01,720
LAB REALLY IS AT THE CROSSROADS

7459
06:04:01,720 --> 06:04:04,040
OF THE MICROBIOME AND

7460
06:04:04,040 --> 06:04:05,440
GLYCOSCIENCE, AND THAT ACTUALLY

7461
06:04:05,440 --> 06:04:07,840
IS SOME PROJECTS IN THE LAB

7462
06:04:07,840 --> 06:04:09,760
WHICH ARE JUST LEARNING OF HOW

7463
06:04:09,760 --> 06:04:10,560
BIZARRE INDIVIDUAL MICROBES IN

7464
06:04:10,560 --> 06:04:16,960
OUR GUT CAN USE GLUCOSE.

7465
06:04:16,960 --> 06:04:20,880
AND HOW CERTAIN BISACCHARIDES

7466
06:04:20,880 --> 06:04:22,640
CAN ACT ASKEWS FOR THE

7467
06:04:22,640 --> 06:04:24,080
MICROBIOME AND HOW THEY HAVE

7468
06:04:24,080 --> 06:04:25,840
COMPLETELY DIFFERENT SENSING

7469
06:04:25,840 --> 06:04:29,440
SYSTEMS FOR SIMPLE SUGARS SUCH

7470
06:04:29,440 --> 06:04:29,760
AS MALTOSE.

7471
06:04:29,760 --> 06:04:30,960
WE HAVE PROJECTS IN THE LAB

7472
06:04:30,960 --> 06:04:32,960
LOOKING AT THE DARK MATTER OF

7473
06:04:32,960 --> 06:04:35,680
DIET SUCH AS THE PLANT

7474
06:04:35,680 --> 06:04:37,720
PHYTOCHEMICALS AND HOW THOSE ARE

7475
06:04:37,720 --> 06:04:38,760
METABOLIZED AND IMPACT THE HOST.

7476
06:04:38,760 --> 06:04:40,040
WE, OF COURSE, ARE DEEP WITHIN

7477
06:04:40,040 --> 06:04:42,120
THE FEMALE GENITAL TRACT

7478
06:04:42,120 --> 06:04:44,720
MICROBIOME, IN PARTICULAR, HOW

7479
06:04:44,720 --> 06:04:47,080
HOST AND ENVIRONMENTAL GLYCANS

7480
06:04:47,080 --> 06:04:49,120
IMPACT FTT MICROBIOME

7481
06:04:49,120 --> 06:04:52,520
COMPOSITION AND FUNCTION.

7482
06:04:52,520 --> 06:04:54,160
AND WORK THAT RICK ALLUDED TO

7483
06:04:54,160 --> 06:04:55,800
EARLIER AS WE'RE TRYING TO

7484
06:04:55,800 --> 06:04:57,360
DEFINE A GLYCAN ATLAS IN THE

7485
06:04:57,360 --> 06:04:59,920
MOUSE AND HUMAN INTESTINE ACROSS

7486
06:04:59,920 --> 06:05:04,120
HEALTH AND DISEASE.

7487
06:05:04,120 --> 06:05:05,240
TODAY I'M GOING TO TELL YOU A

7488
06:05:05,240 --> 06:05:06,520
STORY WE'VE BEEN, WOULDING ON

7489
06:05:06,520 --> 06:05:16,040
PRETTY MUCH  WORKING ON,

7490
06:05:16,040 --> 06:05:18,240
THE SHORT CHAIN FATTY ACIDS THAT

7491
06:05:18,240 --> 06:05:20,640
WERE INTRODUCED EARLIER, AND

7492
06:05:20,640 --> 06:05:23,240
THERE ARE ACTUALLY UNEXPECTED

7493
06:05:23,240 --> 06:05:24,200
RELATIONSHIPS BETWEEN GLYCANS.

7494
06:05:24,200 --> 06:05:26,280
AND SO BEFORE I INTRODUCE OUR

7495
06:05:26,280 --> 06:05:28,160
WORK, I'M GOING TO TELL YOU A

7496
06:05:28,160 --> 06:05:31,520
LITTLE BIT -- MARIO INTRODUCED

7497
06:05:31,520 --> 06:05:32,520
IT AND OTHER PEOPLE HAVE A

7498
06:05:32,520 --> 06:05:33,400
LITTLE BIT.

7499
06:05:33,400 --> 06:05:35,440
SO ABOUT HALF OUR MICROBIOME

7500
06:05:35,440 --> 06:05:38,560
NUMERICALLY ACTUALLY FALL INTO

7501
06:05:38,560 --> 06:05:41,240
THIS ONE ORDER OF BACTERIA

7502
06:05:41,240 --> 06:05:49,040
CALLED THE BACTEROIDALES, ABOUT

7503
06:05:49,040 --> 06:05:51,560
UP TO 15 DIFFERENT SPECIES

7504
06:05:51,560 --> 06:05:52,600
WITHIN THIS GENUS.

7505
06:05:52,600 --> 06:05:53,520
OF COURSE THAT DIFFERS FROM

7506
06:05:53,520 --> 06:05:55,720
WHERE YOU ARE IN THE WORLD, AND

7507
06:05:55,720 --> 06:05:56,960
WHAT'S REALLY EMERGED IS THAT

7508
06:05:56,960 --> 06:06:00,520
DIFFERENT SPECIES AND STRAINS

7509
06:06:00,520 --> 06:06:01,240
HAVE VERY IMPORTANT PROPERTIES

7510
06:06:01,240 --> 06:06:04,040
IN HUMAN HEALTH AND DISEASE

7511
06:06:04,040 --> 06:06:05,400
RANGING FROM WHETHER CERTAIN

7512
06:06:05,400 --> 06:06:09,000
STRAINS HAVE CERTAIN TOX I INS 
TOXINS THA
T

7513
06:06:09,000 --> 06:06:10,040
MIGHT BE INVOLVED IN THE

7514
06:06:10,040 --> 06:06:11,480
DEVELOPMENT OF COLON CANCER OR

7515
06:06:11,480 --> 06:06:13,440
CERTAIN SPECIES AND STRAINS THAT

7516
06:06:13,440 --> 06:06:14,520
HAVE CERTAIN ANTIGENS THAT MIGHT

7517
06:06:14,520 --> 06:06:18,600
BE INVOLVED IN AUTOIMMUNITY AND

7518
06:06:18,600 --> 06:06:21,880
ANTITUMOR RESPONSES OR PRO TUMOR

7519
06:06:21,880 --> 06:06:22,160
RESPONSES.

7520
06:06:22,160 --> 06:06:27,360
AND SO THERE'S A GREAT

7521
06:06:27,360 --> 06:06:28,520
IMPORTANCE AND UNDERSTANDING THE

7522
06:06:28,520 --> 06:06:30,720
ECOLOGY OF -- AT THE STRAIN

7523
06:06:30,720 --> 06:06:34,640
LEVEL AND SPECIES LEVEL OF THE

7524
06:06:34,640 --> 06:06:38,880
HUMAN GUT BACTEROIDETES.

7525
06:06:38,880 --> 06:06:40,320
MARIO ALSO INTRODUCED HOW THEY

7526
06:06:40,320 --> 06:06:45,640
COMPETE IN THE GUT, THROUGH AN

7527
06:06:45,640 --> 06:06:47,400
EVOLUTIONARY ARMS RACE, THEY

7528
06:06:47,400 --> 06:06:50,560
KEEP ADDING AND ADDING MORE

7529
06:06:50,560 --> 06:06:51,560
POLYSACCHARIDE UTILIZATION TO

7530
06:06:51,560 --> 06:06:53,760
USE DIETARY AND HOST GLYCANS AS

7531
06:06:53,760 --> 06:06:57,560
THEIR ENERGY SOURCES.

7532
06:06:57,560 --> 06:06:59,640
MARIO TALKED A LITTLE ABOUT

7533
06:06:59,640 --> 06:07:01,000
THESE LOCI WHICH ALLOWS A GIVEN

7534
06:07:01,000 --> 06:07:08,440
STRAIN OR SPECIES OF THE 
SPECIES TO CHOP 
THEM

7535
06:07:08,440 --> 06:07:14,640
UP AND USE THEM AS ENERGY.

7536
06:07:14,640 --> 06:07:17,160
PREVIOUS WORK IN MY LAB OR MY

7537
06:07:17,160 --> 06:07:18,440
POSTDOCTORAL FELLOWSHIP WAS

7538
06:07:18,440 --> 06:07:21,200
LOOKING OW THEY USE DIFFERENT

7539
06:07:21,200 --> 06:07:23,160
SUGARS AND THEY'RE INVOLVED AS

7540
06:07:23,160 --> 06:07:26,640
PUBLIC GOODS TO FEED OTHER

7541
06:07:26,640 --> 06:07:28,000
BACTERIA, AND THERE'S THIS

7542
06:07:28,000 --> 06:07:29,880
LINEARITY ACTUALLY IN DIET AND

7543
06:07:29,880 --> 06:07:31,240
DIETARY SUGARS, HOW THOSE CHANGE

7544
06:07:31,240 --> 06:07:32,760
THE COMPOSITION OF THE

7545
06:07:32,760 --> 06:07:33,720
MICROBIOME, OF COURSE

7546
06:07:33,720 --> 06:07:34,720
COMPOSITION OF THE MICROBIOME

7547
06:07:34,720 --> 06:07:36,720
IMPACTS THE HOST, BUT A REALLY

7548
06:07:36,720 --> 06:07:40,240
IMPORTANT ASPECT OF THIS DIETARY

7549
06:07:40,240 --> 06:07:43,200
GUT MICROBIOME HOST ACCESS IS

7550
06:07:43,200 --> 06:07:44,760
THE FERMENTATION PRODUCTS OF

7551
06:07:44,760 --> 06:07:46,600
POLYSACCHARIDE AND SUGAR

7552
06:07:46,600 --> 06:07:47,680
UTILIZATION BY MEMBERS OF THE

7553
06:07:47,680 --> 06:07:50,480
GUT MICROBIOME, IN PARTICULAR,

7554
06:07:50,480 --> 06:07:51,200
THE FERMENTATION PRODUCTS KNOWN

7555
06:07:51,200 --> 06:07:52,840
AS THE SHORT CHAIN FATTY ACIDS.

7556
06:07:52,840 --> 06:07:55,120
THESE ARE IN MILIMOLAR

7557
06:07:55,120 --> 06:08:01,040
CONCENTRATIONS WITHIN THE GUT.

7558
06:08:01,040 --> 06:08:02,240
AND THESE PLAY A NUMBER OF

7559
06:08:02,240 --> 06:08:05,080
IMPORTANT ROLES THROUGH MULTIPLE

7560
06:08:05,080 --> 06:08:09,360
MECHANISMS IN HOST HEALTH.

7561
06:08:09,360 --> 06:08:10,520
BUT WHAT'S REALLY NOT WELL

7562
06:08:10,520 --> 06:08:12,000
APPRECIATED IS FOR THESE

7563
06:08:12,000 --> 06:08:13,640
MOLECULES THAT ARE MILIMOLAR

7564
06:08:13,640 --> 06:08:14,720
CONCENTRATIONS WITHIN THE GUT

7565
06:08:14,720 --> 06:08:16,840
IS, ARE THEY PLAYING ANY ROLES

7566
06:08:16,840 --> 06:08:18,120
ON THE MICROBES THEMSELVES.

7567
06:08:18,120 --> 06:08:20,280
AND SO THERE ARE -- THEY ARE

7568
06:08:20,280 --> 06:08:23,600
USED IN ASSIMILATION AS ELECTRON

7569
06:08:23,600 --> 06:08:26,200
DONORS FOR ENERGY AND THAT'S

7570
06:08:26,200 --> 06:08:27,920
BEEN WELL APPRECIATED SINCE THE

7571
06:08:27,920 --> 06:08:28,840
1960s, BUT WE KIND OF TOOK A

7572
06:08:28,840 --> 06:08:30,880
LITTLE BIT OF A DIFFERENT

7573
06:08:30,880 --> 06:08:32,000
APPROACH AND REALLY ASK THE

7574
06:08:32,000 --> 06:08:33,440
QUESTION, DO THESE IMPACT THE

7575
06:08:33,440 --> 06:08:36,440
FITNESS OF MICROBES THAT REALLY

7576
06:08:36,440 --> 06:08:37,880
AREN'T KNOWN TO DO -- TO

7577
06:08:37,880 --> 06:08:39,440
ASSIMILATE SHORT CHAIN FATTY

7578
06:08:39,440 --> 06:08:42,880
ACIDS AS ENERGY SOURCES.

7579
06:08:42,880 --> 06:08:51,240
AND SO WE TOOK A PANEL OF BACT

7580
06:08:51,240 --> 06:08:57,240
EROIDES AND WITH MINIMAL MEDIA,

7581
06:08:57,240 --> 06:08:59,040
WE HAPPEN TO GROW OUR BUGS ON

7582
06:08:59,040 --> 06:09:00,000
GLUCOSE, AND WHAT I'M ABOUT TO

7583
06:09:00,000 --> 06:09:03,280
SHOW YOU IS WE THREW DIFFERENT

7584
06:09:03,280 --> 06:09:05,760
SHORT CHAIN FATTY ACIDS ON THESE

7585
06:09:05,760 --> 06:09:06,000
MEMBERS.

7586
06:09:06,000 --> 06:09:08,040
ACROSS ONE TO THREE CARBON

7587
06:09:08,040 --> 06:09:11,000
INCLUDING A FOUR-CARBON SHORT

7588
06:09:11,000 --> 06:09:16,400
CHAIN FATTY ACID ORGANIC ACID

7589
06:09:16,400 --> 06:09:17,440
SUCCINATE, IF YOU LOOK DOWN EACH

7590
06:09:17,440 --> 06:09:19,120
STRAIN, YOU DON'T SEE MAJOR

7591
06:09:19,120 --> 06:09:21,440
DIFFERENCES IN THE GROWTH OF THE

7592
06:09:21,440 --> 06:09:23,960
BACTE ROIDES SO THEY DON'T SEEM

7593
06:09:23,960 --> 06:09:26,720
TO MIND THESE SHORT CHAIN FATTY

7594
06:09:26,720 --> 06:09:28,040
ACIDS TOO MUCH.

7595
06:09:28,040 --> 06:09:31,920
BUT FOR ONE, BUTERATE, WE

7596
06:09:31,920 --> 06:09:35,640
OBSERVED SOME BACTEROIDES

7597
06:09:35,640 --> 06:09:44,760
MEMBERS DON'T SEEM TO CARE BUT

7598
06:09:44,760 --> 06:09:47,240
OTHERS, DIDN'T GROW AT ALL AND

7599
06:09:47,240 --> 06:09:50,440
THIS WAS REALLY THE START OF THE

7600
06:09:50,440 --> 06:09:54,520
PROJECT.

7601
06:09:54,520 --> 06:09:57,600
WE REALLY EXPANDED THE BASKET

7602
06:09:57,600 --> 06:09:58,960
BACTEROIDES THAT WE LOOKED AT,

7603
06:09:58,960 --> 06:10:01,840
AND WHAT WE FOUND IS THIS

7604
06:10:01,840 --> 06:10:02,640
ANTIMICROBIAL EFFECT WAS

7605
06:10:02,640 --> 06:10:03,800
ACTUALLY STRAIN-DEPENDENT.

7606
06:10:03,800 --> 06:10:05,240
I'LL GIVE YOU AN EXAMPLE HERE,

7607
06:10:05,240 --> 06:10:06,440
YOU'LL BE SEEING THESE, BUT THIS

7608
06:10:06,440 --> 06:10:10,560
IS BASE  BASICALLY A TIME SERIES
AT

7609
06:10:10,560 --> 06:10:13,520
DAY ONE, DAY TWO, DAY THREE, DAY

7610
06:10:13,520 --> 06:10:16,840
FOUR, AND ON THE TOP ROW IS

7611
06:10:16,840 --> 06:10:21,840
WITHOUT BUTYRATE.

7612
06:10:21,840 --> 06:10:26,200
THIS OTHER STRAIN IS HIGHLY

7613
06:10:26,200 --> 06:10:26,560
RESISTANT.

7614
06:10:26,560 --> 06:10:29,000
YOU CAN SEE THE TWO STRAINS OF

7615
06:10:29,000 --> 06:10:30,680
THE SPAIN SPECIES, A RESISTANT

7616
06:10:30,680 --> 06:10:32,840
STRAIN ON THE RIGHT AND A HIGHLY

7617
06:10:32,840 --> 06:10:39,880
SENSITIVE STRAIN ON THE LEFT.

7618
06:10:39,880 --> 06:10:42,280
WE MOSTLY STUDIED SUGAR

7619
06:10:42,280 --> 06:10:43,200
UTILIZATION.

7620
06:10:43,200 --> 06:10:44,360
WE KNOW THEY'RE SEEING ALL THESE

7621
06:10:44,360 --> 06:10:45,800
DIFFERENT SUGARS IN THE GUT, AND

7622
06:10:45,800 --> 06:10:47,120
THAT'S HOW THEY COMPETE TO

7623
06:10:47,120 --> 06:10:47,640
COLONIZE THE GUT.

7624
06:10:47,640 --> 06:10:50,440
SO WE WANTED TO KNOW WHETHER

7625
06:10:50,440 --> 06:10:53,480
THIS BUTYRATE INHIBITION ON THE

7626
06:10:53,480 --> 06:10:54,640
BACTEROIDES WAS ROBUST ACROSS

7627
06:10:54,640 --> 06:10:55,320
DIFFERENT SUGARS.

7628
06:10:55,320 --> 06:10:56,760
SO WE WENT TO THE CANDY STORE IN

7629
06:10:56,760 --> 06:10:59,040
THE LAB AND THREW A NUMBER OF

7630
06:10:59,040 --> 06:10:59,680
DIFFERENT SUGARS.

7631
06:10:59,680 --> 06:11:01,520
WHAT I'VE JUST SHOWN YOU WAS IN

7632
06:11:01,520 --> 06:11:04,840
GLUCOSE, THEN WE START TO SHOW

7633
06:11:04,840 --> 06:11:06,600
OTHER MONOSACCHARIDES SUCH AS

7634
06:11:06,600 --> 06:11:06,840
FRUCTOSE.

7635
06:11:06,840 --> 06:11:08,680
WHAT YOU SEE IS THIS KEY MATCH,

7636
06:11:08,680 --> 06:11:12,640
IF YOU SEE 

7637
06:11:12,640 --> 06:11:13,600
MAP, IF YOU SEE A RED BOX,

7638
06:11:13,600 --> 06:11:14,360
THEY'RE HIGHLY SENSITIVE.

7639
06:11:14,360 --> 06:11:17,440
IF YOU LOOK ACROSS FOR THE GIVEN

7640
06:11:17,440 --> 06:11:19,440
DIFFERENT ISOLATES OF THE HUMAN

7641
06:11:19,440 --> 06:11:21,800
GUT BACTEROIDES, YOU DON'T SEE

7642
06:11:21,800 --> 06:11:24,760
THAT MANY DIFFERENCES, IF

7643
06:11:24,760 --> 06:11:27,200
THEY'RE SENSITIVE IN GLUCOSE,

7644
06:11:27,200 --> 06:11:29,280
THEY'RE SENSITIVE IN MANOSE.

7645
06:11:29,280 --> 06:11:30,760
WE KEPT ON ADDING MORE SUGARS

7646
06:11:30,760 --> 06:11:32,600
AND WHAT WE STARTED TO SEE IS

7647
06:11:32,600 --> 06:11:35,080
DEPENDING ON WHAT SUGAR A GIVEN

7648
06:11:35,080 --> 06:11:37,640
STRAIN OF THE BACTEROIDES WAS

7649
06:11:37,640 --> 06:11:41,040
USING AS CARBON SOURCE, IT WAS

7650
06:11:41,040 --> 06:11:44,040
EITHER RESISTANT OR SENSITIVE TO

7651
06:11:44,040 --> 06:11:44,320
BUTYRATE.

7652
06:11:44,320 --> 06:11:45,480
AND SO WHAT YOU CAN SEE HERE IS

7653
06:11:45,480 --> 06:11:48,120
THESE COLORS ARE CHANGING AS YOU

7654
06:11:48,120 --> 06:11:50,760
ADD -- IF YOU GO -- THIS IS ONE

7655
06:11:50,760 --> 06:11:52,680
OF THE FEW TIMES WHERE I GET TO

7656
06:11:52,680 --> 06:11:53,800
TALK ABOUT THESE SUGAR, THE

7657
06:11:53,800 --> 06:11:56,640
PEOPLE THAT CARE ABOUT THESE

7658
06:11:56,640 --> 06:11:58,480
SUGARS, AND WHAT YOU CAN SEE

7659
06:11:58,480 --> 06:12:01,280
HERE IN CERTAIN SUGARS, AND I'LL

7660
06:12:01,280 --> 06:12:02,800
JUST JUMP TO THE EXAMPLES HERE

7661
06:12:02,800 --> 06:12:07,600
IS, IF YOU GROW THIS BACTEROIDES

7662
06:12:07,600 --> 06:12:09,640
STRAIN IN GLUCOSE, IT'S HIGHLY

7663
06:12:09,640 --> 06:12:11,320
RESISTANT TO BUTYRATE.

7664
06:12:11,320 --> 06:12:17,320
BUT IF YOU GROW IT IN GLICNAC OR

7665
06:12:17,320 --> 06:12:18,080
GALNAC, IT'S DEAD.

7666
06:12:18,080 --> 06:12:19,480
AND THIS WAS REALLY BIZARRE TO

7667
06:12:19,480 --> 06:12:19,920
US.

7668
06:12:19,920 --> 06:12:25,280
WE THEN MOVED ON TO ASK, WELL,

7669
06:12:25,280 --> 06:12:26,800
IN THE GUT, IN THE DISTAL COLON

7670
06:12:26,800 --> 06:12:29,120
OR THE COLON, I SHOULD SAY, IS

7671
06:12:29,120 --> 06:12:31,360
THE BACTEROIDES, THEY COMPETE TO

7672
06:12:31,360 --> 06:12:32,600
USE DIVERSE DIETARY AND HOST

7673
06:12:32,600 --> 06:12:32,920
GLYCANS.

7674
06:12:32,920 --> 06:12:34,440
THAT'S HOW THEY REALLY COMPETE

7675
06:12:34,440 --> 06:12:35,560
AND SURVIVE IN THERE.

7676
06:12:35,560 --> 06:12:37,080
SO HERE WE TOOK A PANEL, AND A

7677
06:12:37,080 --> 06:12:41,840
LOT OF THESE DIETARY GLYCANS

7678
06:12:41,840 --> 06:12:44,200
YOU'LL SEE HERE, THESE ARE

7679
06:12:44,200 --> 06:12:46,840
PRESENT IN PLANTS BUT THEY'RE

7680
06:12:46,840 --> 06:12:57,640
ALSO CANDIDATES AS PREBITE IK OH
PREBIOTIC
S.

7681
06:12:57,640 --> 06:12:59,240
SO HERE'S A PANEL AND YOU CAN

7682
06:12:59,240 --> 06:13:02,640
SEE HERE, THESE ARE ALL BACTERIA

7683
06:13:02,640 --> 06:13:06,240
THAT USE THESE SHOE IMARS 
SUGARS THAT WE

7684
06:13:06,240 --> 06:13:08,000
PROVIDE TO THEM.

7685
06:13:08,000 --> 06:13:12,280
BUT IF YOU PUT IN BUTYRATE, YOU

7686
06:13:12,280 --> 06:13:14,360
CAN'T PREDICT WHICH STRAINS IN

7687
06:13:14,360 --> 06:13:17,440
WHICH GLYCANS WILL BECOME

7688
06:13:17,440 --> 06:13:18,800
SENSITIVE, ARE BASICALLY

7689
06:13:18,800 --> 06:13:24,400
INHIBITED BY BUTYRATE.

7690
06:13:24,400 --> 06:13:25,840
SO THIS IS A REALLY CLEAN

7691
06:13:25,840 --> 06:13:26,600
EXAMPLE OF THAT.

7692
06:13:26,600 --> 06:13:28,160
SO HERE'S ONE PARTICULAR GENERAL

7693
06:13:28,160 --> 06:13:29,480
LIST.

7694
06:13:29,480 --> 06:13:33,080
THIS IS BO CLO3.

7695
06:13:33,080 --> 06:13:35,960
THIS IS LOTS OF DIETARY GLYCANS.

7696
06:13:35,960 --> 06:13:42,840
IT USES PECK TIN, GLUCOMANNAN.

7697
06:13:42,840 --> 06:13:44,680
DEPENDING ON WHAT TIE TRI FIBER

7698
06:13:44,680 --> 06:13:47,240
IT'S USING, IT'S EITHER HIGHLY

7699
06:13:47,240 --> 06:13:48,840
RESISTANT TO BUTYRATE OR HIGHLY

7700
06:13:48,840 --> 06:13:52,160
SENSITIVE TO BUTYRATE.

7701
06:13:52,160 --> 06:13:54,360
AND I DON'T NORMALLY SHOW THIS

7702
06:13:54,360 --> 06:13:56,520
DATA BUT SINCE THIS IS A

7703
06:13:56,520 --> 06:13:57,320
GLYCOSCIENCE AUDIENCE, IF YOU

7704
06:13:57,320 --> 06:14:00,920
LOOK AT LEVAN, IT'S A POLYMER OF

7705
06:14:00,920 --> 06:14:05,280
FRUCTOSE, IF YOU GROW IT IN

7706
06:14:05,280 --> 06:14:06,520
FRUCTOSE.

7707
06:14:06,520 --> 06:14:13,400
IF YOU GO TO -- YOU GROW IT IN

7708
06:14:13,400 --> 06:14:25,720
PULLULAN -- IF YOU GROW IT IN

7709
06:14:25,720 --> 06:14:26,480
CHONDRIOTIN SULFATE -- IT'S

7710
06:14:26,480 --> 06:14:29,840
SENSITIVE IN.

7711
06:14:29,840 --> 06:14:32,360
SIMILARLY, GLUCOMANNAN IS HIGHLY

7712
06:14:32,360 --> 06:14:36,240
RESISTANT TO GLUCOSE OR MANNOSE

7713
06:14:36,240 --> 06:14:38,600
OR GLUCOSE AND MANNOSE.

7714
06:14:38,600 --> 06:14:42,960
THIS ACTUALLY -- AT THE BOND OF

7715
06:14:42,960 --> 06:14:49,360
A DIE SACCHARIDE, IN SUCROSE,

7716
06:14:49,360 --> 06:14:50,960
ALPHA-1 BETA TWO LINKAGE, IT'S

7717
06:14:50,960 --> 06:14:54,600
RESISTANT ALSO, BUT -- IT'S

7718
06:14:54,600 --> 06:14:56,560
SENSITIVE TO BUTYRATE AND THAT'S

7719
06:14:56,560 --> 06:14:58,640
TRUE ALSO FOR HOMO DIMERS OF

7720
06:14:58,640 --> 06:15:02,360
GLUCOSE, WHERE IT'S RESISTANT IN

7721
06:15:02,360 --> 06:15:06,640
GLUCOSE AND MALTOSE.

7722
06:15:06,640 --> 06:15:08,080
SO SUGARS ACT GREATER THAN THE

7723
06:15:08,080 --> 06:15:12,040
SUM OF THE PARTS IN CONTROLLING

7724
06:15:12,040 --> 06:15:12,800
ANTIMICROBIAL -- AT STRAIN

7725
06:15:12,800 --> 06:15:13,240
LEVEL.

7726
06:15:13,240 --> 06:15:15,920
SO WE'VE IDENTIFIED SPECIFIC

7727
06:15:15,920 --> 06:15:18,120
MICROBIAL METABOLITES, THAT THE

7728
06:15:18,120 --> 06:15:20,480
SPECIFIC MICROBIAL METABOLITE

7729
06:15:20,480 --> 06:15:30,600
BUTYRATE IS ANTIMICROBIAL TO THE

7730
06:15:30,600 --> 06:15:32,240
BACTEROIDALES, THAT BUTYRATE

7731
06:15:32,240 --> 06:15:33,560
ANTIMICROBIAL ACTIVITY IS

7732
06:15:33,560 --> 06:15:35,440
STRAIN-SPECIFIC AMONG THE

7733
06:15:35,440 --> 06:15:35,720
BACTEROIDES.

7734
06:15:35,720 --> 06:15:37,720
AND SUGARS ACT AS FITNESS

7735
06:15:37,720 --> 06:15:40,040
SWITCHES BUTYRATE, MORE AS A

7736
06:15:40,040 --> 06:15:41,680
DIMMER WITH EXTREMES ON AND OFF

7737
06:15:41,680 --> 06:15:43,840
AND IN BETWEENS, WITH INDIVIDUAL

7738
06:15:43,840 --> 06:15:45,400
SUGARS RENDERING BUTYRATE

7739
06:15:45,400 --> 06:15:47,240
VULNERABILITY.

7740
06:15:47,240 --> 06:15:49,040
AND THAT'S WHERE WE SEE THAT

7741
06:15:49,040 --> 06:15:51,760
STRAIN LEVEL FITNESS OF THE

7742
06:15:51,760 --> 06:15:53,720
BACTEROIDES SEEMS TO BE

7743
06:15:53,720 --> 06:15:54,680
UNPREDICTABLE IN THE

7744
06:15:54,680 --> 06:15:56,240
INTERACTIONS OF BUTYRATE WITH

7745
06:15:56,240 --> 06:15:59,400
INDIVIDUAL SUGARS.

7746
06:15:59,400 --> 06:16:01,120
AND SO I KNOW THERE'S A TIME

7747
06:16:01,120 --> 06:16:02,880
DELAY IN THIS PRESENTATION, I

7748
06:16:02,880 --> 06:16:05,080
THINK, AND THIS IS WHERE WE

7749
06:16:05,080 --> 06:16:11,440
START TO ASK WHAT THE FUKE IS

7750
06:16:11,440 --> 06:16:12,200
GOING ON HERE.

7751
06:16:12,200 --> 06:16:15,840
WE THEN, THROUGH OUR GENETIC

7752
06:16:15,840 --> 06:16:22,360
TOOLKIT ON THE BACTEROIDALES

7753
06:16:22,360 --> 06:16:23,440
ASKED THIS QUESTION.

7754
06:16:23,440 --> 06:16:32,240
WE STARTED WITH A STRAIN WHICH

7755
06:16:32,240 --> 06:16:36,040
IS HIGHLY RYE SES TANT TO

7756
06:16:36,040 --> 06:16:36,280
BUTYRATE.

7757
06:16:36,280 --> 06:16:38,600
WE BASICALLY BLASTED THE GENOME

7758
06:16:38,600 --> 06:16:40,720
WITH TN INSERTION TO LOOK FOR

7759
06:16:40,720 --> 06:16:41,840
SENSITIVE MUTANTS.

7760
06:16:41,840 --> 06:16:51,040
WE HIT THIS GENE WITH BT 3942.

7761
06:16:51,040 --> 06:16:52,400
WHAT WE FOUND WHEN WE PURIFIED

7762
06:16:52,400 --> 06:16:56,720
IT IS IT CLEAVES BUTYRAL COA AND

7763
06:16:56,720 --> 06:16:59,560
EVEN SOME MEDIUM CHAIN LINK

7764
06:16:59,560 --> 06:17:00,760
FATTY ACIDS, AND SO THIS

7765
06:17:00,760 --> 06:17:08,360
DEMONSTRATED TO US THAT AN

7766
06:17:08,360 --> 06:17:13,760
ACYL-COA THIOESTER HYDROLASE --

7767
06:17:13,760 --> 06:17:16,440
WHEN WE DID TNC CURE, WE HIT

7768
06:17:16,440 --> 06:17:20,480
THIS GEEP CALLED BU -- BVU1163.

7769
06:17:20,480 --> 06:17:26,360
THAT ACTUALLY IS AN ACYL COATE

7770
06:17:26,360 --> 06:17:26,640
TRANSFERASE.

7771
06:17:26,640 --> 06:17:29,320
IT SEEMS TO BE SPECIFIC FOR

7772
06:17:29,320 --> 06:17:32,640
TRANSFERRING BUTYRAL COA WITH

7773
06:17:32,640 --> 06:17:35,440
ACETYL COA, SO WE FOUND THAT A

7774
06:17:35,440 --> 06:17:41,840
SHORT ACYL-COA NEED YAIDZ

7775
06:17:41,840 --> 06:17:46,800
SENSITIVITY TO BUTYRATE IN

7776
06:17:46,800 --> 06:17:49,520
BACTEROIDES VULGATIS.

7777
06:17:49,520 --> 06:17:52,040
SO WHAT'S THE MECHANISM FOR THIS

7778
06:17:52,040 --> 06:17:54,360
SPECIES LEVEL PHENOTYPIC

7779
06:17:54,360 --> 06:17:54,640
VARIATION.

7780
06:17:54,640 --> 06:17:56,040
WHAT WE TOTALLY DIFFERENT

7781
06:17:56,040 --> 06:17:58,520
EXPECT, THESE ARE GENES IN THE

7782
06:17:58,520 --> 06:18:02,240
CORE GENOME, IS THAT THE

7783
06:18:02,240 --> 06:18:06,560
RESISTANT STRAIN AND -- IN THE

7784
06:18:06,560 --> 06:18:10,240
SENSITIVE STRAIN ARE ONLY 51%

7785
06:18:10,240 --> 06:18:11,920
CONSERVED AT THE AMINO ACID

7786
06:18:11,920 --> 06:18:13,600
LEVEL, AND WHEN WE CLONE THEM,

7787
06:18:13,600 --> 06:18:15,280
THEY HAVE TOTALLY DIFFERENT

7788
06:18:15,280 --> 06:18:18,040
FUNCTIONS, SO BASICALLY IN THE

7789
06:18:18,040 --> 06:18:19,240
RESISTANT STRAIN AS IT CONFERS

7790
06:18:19,240 --> 06:18:21,440
RESISTANCE TO BUTYRATE, BUT IT'S

7791
06:18:21,440 --> 06:18:22,840
HOMOLOGUE IN THE SENSITIVE

7792
06:18:22,840 --> 06:18:23,840
STRAIN DOES NOT.

7793
06:18:23,840 --> 06:18:25,840
AND WHEN WE DID SOME ENZYME

7794
06:18:25,840 --> 06:18:27,640
ASSAYS, WE FOUND THAT THEY HAD

7795
06:18:27,640 --> 06:18:29,760
VERY DIFFERENT KINETICS IN THESE

7796
06:18:29,760 --> 06:18:32,600
TWO DIFFERENT SPECIES OF THIS

7797
06:18:32,600 --> 06:18:41,840
FOR BUTTE ROLL SEEN IN BLACK.
BUTYRAL SEEN
 IN BLACK.

7798
06:18:41,840 --> 06:18:46,680
WHAT ABOUT THIS ACYLCOATE

7799
06:18:46,680 --> 06:18:48,080
TRANSFERASE.

7800
06:18:48,080 --> 06:18:49,880
IT WAS 80% CONSERVED AT THE

7801
06:18:49,880 --> 06:18:51,400
AMINO ACID LEVEL, AND IT HAS THE

7802
06:18:51,400 --> 06:18:52,440
SAME FUNCTION, WHICH IS YOU CAN

7803
06:18:52,440 --> 06:18:55,440
CLONE BOTH OF THEM FROM THE

7804
06:18:55,440 --> 06:18:56,240
RESISTANT STRAIN OR THE

7805
06:18:56,240 --> 06:18:58,440
SENSITIVE STRAIN IN CONVERSE

7806
06:18:58,440 --> 06:19:01,800
SENSITIVITY, BUT WHAT WE FOUND

7807
06:19:01,800 --> 06:19:04,040
WAS THAT THIS CONSERVED CORE

7808
06:19:04,040 --> 06:19:06,080
GENOME GENE WAS DIFFERENTIALLY

7809
06:19:06,080 --> 06:19:06,840
EXPRESSED IN THE GROWTH PHASE,

7810
06:19:06,840 --> 06:19:09,120
SO THE RESISTANT STRAIN DOWN

7811
06:19:09,120 --> 06:19:10,560
REGULATES THIS GENE, AND THE

7812
06:19:10,560 --> 06:19:11,880
SENSITIVE STRAIN UPREGULATES THE

7813
06:19:11,880 --> 06:19:15,480
STRAIN JUST WHEN IT'S GROWN.

7814
06:19:15,480 --> 06:19:16,600
AND PROTEIN LEVELS ARE

7815
06:19:16,600 --> 06:19:18,760
COMMENSURATE.

7816
06:19:18,760 --> 06:19:20,520
SO OKAY, THESE TWO DIFFERENT

7817
06:19:20,520 --> 06:19:22,400
SPECIES ARE REGULATING THESE

7818
06:19:22,400 --> 06:19:24,160
CORE GENOME GENES AND THAT'S

7819
06:19:24,160 --> 06:19:26,480
MEDIATING THIS METABOLIC DEFENSE

7820
06:19:26,480 --> 06:19:31,520
TO BUTYRATE SO WE CLONED OUT THE

7821
06:19:31,520 --> 06:19:32,640
PROMOTERS AND MADE THESE

7822
06:19:32,640 --> 06:19:34,160
CONSTRUCTS WITH SWAPPING OUT THE

7823
06:19:34,160 --> 06:19:35,600
PROMOTERS FOR THE DIFFERENT

7824
06:19:35,600 --> 06:19:36,120
CONSERVED GENES.

7825
06:19:36,120 --> 06:19:39,520
AND WHAT WE FOUND WAS THAT THE

7826
06:19:39,520 --> 06:19:40,880
PROMOTERS ARE RESPONSIBLE FOR

7827
06:19:40,880 --> 06:19:42,240
THIS HIGH LEVEL EXPRESSION OR

7828
06:19:42,240 --> 06:19:44,320
THIS LOW LEVEL EXPRESSION, AND

7829
06:19:44,320 --> 06:19:47,520
THEN WHEN WE SWAP -- SO THIS IS

7830
06:19:47,520 --> 06:19:49,600
THE SENSITIVE STRAIN VERSUS THE

7831
06:19:49,600 --> 06:19:50,440
RESISTANT STRAIN HAS HIGH

7832
06:19:50,440 --> 06:19:53,600
EXPRESSION OR LOW EXPRESSION,

7833
06:19:53,600 --> 06:19:55,760
WHICH IS MINUS 200 NUCLEOTIDES

7834
06:19:55,760 --> 06:19:56,920
UPSTREAM AND THAT ACTUALLY

7835
06:19:56,920 --> 06:20:00,440
CONFERS SENSITIVITY OF

7836
06:20:00,440 --> 06:20:01,080
RESISTANCE.

7837
06:20:01,080 --> 06:20:03,040
WE THEN ASKED WHAT'S IN THAT

7838
06:20:03,040 --> 06:20:06,880
MINUS 200, SO THAT'S -- THERE'S

7839
06:20:06,880 --> 06:20:10,560
CANONICAL MINUS 7 AND MINUS

7840
06:20:10,560 --> 06:20:14,080
33 BINDING SITES, AND THERE WAS

7841
06:20:14,080 --> 06:20:16,440
BASICALLY THESE TWO TYPES OF

7842
06:20:16,440 --> 06:20:18,280
POLYMORPHISMS TO THE TWO SPECIES

7843
06:20:18,280 --> 06:20:18,920
OF THE BACTEROIDES.

7844
06:20:18,920 --> 06:20:21,080
SO WE MADE A NUMBER OF

7845
06:20:21,080 --> 06:20:24,400
CONSTRUCTS WHICH WE MU  MUTATED

7846
06:20:24,400 --> 06:20:26,840
THESE DOUBLE TYPE POLYMORPHISMS

7847
06:20:26,840 --> 06:20:30,000
AND WE CAN CON VIRMT THE LOW

7848
06:20:30,000 --> 06:20:31,800
EXPRESSION FROM THESE SNPS INTO

7849
06:20:31,800 --> 06:20:32,960
HIGH EXPRESSION, AND WE CAN TAKE

7850
06:20:32,960 --> 06:20:34,920
THE OTHER BACKBONE, MAKE THOSE

7851
06:20:34,920 --> 06:20:37,880
SAME SNPs, CHANGE THE SNPs,

7852
06:20:37,880 --> 06:20:39,760
CONVERT HIGH EXPRESSION TO A LOW

7853
06:20:39,760 --> 06:20:41,400
EXPRESSION, CONVERT A SENSITIVE

7854
06:20:41,400 --> 06:20:43,080
ORGANISM TO A RESISTANT ORGANISM

7855
06:20:43,080 --> 06:20:46,240
JUST BY THESE SINGLE NUCLEOTIDE

7856
06:20:46,240 --> 06:20:47,640
POLYMORPHISMS IN THE BINDING

7857
06:20:47,640 --> 06:20:49,960
SITES OF THIS CORE GENOME GENE.

7858
06:20:49,960 --> 06:20:51,600
SO THIS PREDICTED TO US, AND

7859
06:20:51,600 --> 06:20:54,520
HERE'S OUR MODEL BASICALLY, IF

7860
06:20:54,520 --> 06:20:55,640
YOU'RE EXPRESSING HIGH AMOUNTS

7861
06:20:55,640 --> 06:21:01,760
OF THIS GENE IN PRESENCE OF HIGH

7862
06:21:01,760 --> 06:21:02,360
BUTYRATE, YOU'RE DEAD.

7863
06:21:02,360 --> 06:21:03,920
AND WE WANTED TO UNDERSTAND WHAT

7864
06:21:03,920 --> 06:21:05,040
THE HUMAN SIGNIFICANCE WAS, AND

7865
06:21:05,040 --> 06:21:08,560
WHAT WE NEEDED FOR THAT WAS A

7866
06:21:08,560 --> 06:21:10,960
MULTI-OMICS COHORT WHERE WE HAVE

7867
06:21:10,960 --> 06:21:12,240
METAGENOMES LOOK AT GENE

7868
06:21:12,240 --> 06:21:13,480
ABUNDANCE, SUCH AS THIS GENE AS

7869
06:21:13,480 --> 06:21:17,440
A PROXY FOR BACTEROIDES

7870
06:21:17,440 --> 06:21:19,480
ABUNDANCE IN THE ECOSYSTEM, META

7871
06:21:19,480 --> 06:21:21,240
TRANSCRIPT SO WE CAN LOOK AT THE

7872
06:21:21,240 --> 06:21:22,240
TRANSCRIPT LEVELS AS PART OF OUR

7873
06:21:22,240 --> 06:21:23,520
MODEL, AND THEN OF COURSE

7874
06:21:23,520 --> 06:21:24,640
MEASURE THE METABOLITES AND THE

7875
06:21:24,640 --> 06:21:26,240
AMOUNT OF METABOLITES, IN

7876
06:21:26,240 --> 06:21:27,000
PARTICULAR, BUTYRATE.

7877
06:21:27,000 --> 06:21:28,840
AND WHEN WE CORRELATED ALL THESE

7878
06:21:28,840 --> 06:21:31,360
THINGS TOGETHER IN HUMAN FECES,

7879
06:21:31,360 --> 06:21:33,520
WE FOUND -- WE ACTUALLY PROVED

7880
06:21:33,520 --> 06:21:35,720
OUR PREDICTION, WHICH IS THAT IF

7881
06:21:35,720 --> 06:21:39,360
YOU EXPRESS HIGH AMOUNTS OF THIS

7882
06:21:39,360 --> 06:21:42,520
ACYL COA TRANSFERASE, ONLY IN

7883
06:21:42,520 --> 06:21:46,120
HIGH BUTYRATE ECOSYSTEMS, YOUR

7884
06:21:46,120 --> 06:21:48,760
FITNESS IS DECREASED FOR THE

7885
06:21:48,760 --> 06:21:49,040
BACTEROIDS.

7886
06:21:49,040 --> 06:21:51,440
SO WHAT WE FOUND USING BOTTOM-UP

7887
06:21:51,440 --> 06:21:53,320
HYPOTHESIS AND MECHANISM IN A

7888
06:21:53,320 --> 06:21:55,160
HUMAN COMPLEX OMICS DATASET WAS

7889
06:21:55,160 --> 06:21:58,840
TO ASSIGN UNKNOWN FUNCTION TO

7890
06:21:58,840 --> 06:22:02,440
THESE NOVEL GENOME GENES TO THIS

7891
06:22:02,440 --> 06:22:03,360
NOVEL INTERACTION AND FOR

7892
06:22:03,360 --> 06:22:05,040
FITNESS AND CONTEXT DEPENDENT

7893
06:22:05,040 --> 06:22:06,440
MANNER THAT'S DEPENDENT ON

7894
06:22:06,440 --> 06:22:07,240
TRANSCRIPT LEVELS.

7895
06:22:07,240 --> 06:22:09,840
AND SO BASICALLY GOING IN VITRO,

7896
06:22:09,840 --> 06:22:11,160
FINDING EMERGENT PROPERTY FOR

7897
06:22:11,160 --> 06:22:14,520
COMBINATION OF METABOLITES AND

7898
06:22:14,520 --> 06:22:17,160
GLYCANS, ASSIGNING CORE GENOME

7899
06:22:17,160 --> 06:22:18,280
REGULATION GOING TO BIG HUMAN

7900
06:22:18,280 --> 06:22:18,640
DATA.

7901
06:22:18,640 --> 06:22:19,920
I'M GOING TO SKIP OUR SUMMARY

7902
06:22:19,920 --> 06:22:22,360
SLIDES, WHICH IS BASICALLY THAT

7903
06:22:22,360 --> 06:22:24,000
EVERY DIFFERENT STRAIN OF THE

7904
06:22:24,000 --> 06:22:25,080
BACTEROIDES DEPENDING ON WHAT

7905
06:22:25,080 --> 06:22:27,200
SUGAR IT USES AND IT COULD USE

7906
06:22:27,200 --> 06:22:29,520
LOTS OF DIFFERENT SUGARS, THAT

7907
06:22:29,520 --> 06:22:30,280
ONE MICROBIAL METABOLITE

7908
06:22:30,280 --> 06:22:32,040
BASICALLY TURNS IT HAPPY OR

7909
06:22:32,040 --> 06:22:32,440
SAID.

7910
06:22:32,440 --> 06:22:34,000
LIVE OR DEAD.

7911
06:22:34,000 --> 06:22:36,720
AND WE'VE DEFINED THE MECHANISMS

7912
06:22:36,720 --> 06:22:38,560
HERE, WHAT OUR WORKING IN MODEL

7913
06:22:38,560 --> 06:22:40,360
IS THAT BUTTE RIGHT IS

7914
06:22:40,360 --> 06:22:41,600
DIFFERENTIALLY METABOLIZED AND

7915
06:22:41,600 --> 06:22:43,640
EACH STRAIN OR SPECIES HAVE

7916
06:22:43,640 --> 06:22:44,760
THESE IDIOSYNCRATIC METABOLIC

7917
06:22:44,760 --> 06:22:46,560
STATE THAT LEAD TO THE BUTYRATE

7918
06:22:46,560 --> 06:22:47,440
VULNERABILITY.

7919
06:22:47,440 --> 06:22:48,760
SO WE'D LIKE TO FICK OUT WHAT

7920
06:22:48,760 --> 06:22:52,160
THE  FIGURE OUT WHAT

7921
06:22:52,160 --> 06:22:55,640
THE LEVELS ARE AT THE GENETIC

7922
06:22:55,640 --> 06:22:56,400
REGULATORY METABOLIC LEVELS AND

7923
06:22:56,400 --> 06:22:57,840
THAT'S WORK WE WOULD LIKE TO

7924
06:22:57,840 --> 06:22:58,600
PURSUE IN OUR LAB.

7925
06:22:58,600 --> 06:23:01,560
AND REALLY TO UNDERSTAND THE

7926
06:23:01,560 --> 06:23:03,760
ECOLOGICAL IMPACT IN USING

7927
06:23:03,760 --> 06:23:04,400
BUTYRATE.

7928
06:23:04,400 --> 06:23:09,200
SO BUTYRATE COMES FROM --

7929
06:23:09,200 --> 06:23:17,040
MICHAEL FISH BACK  BOX FISHBACH,
WITH HIS

7930
06:23:17,040 --> 06:23:18,440
KINDNESS, WE'D LIKE TO -- NOW

7931
06:23:18,440 --> 06:23:22,560
THAT WE CAN DEFINE BY ITS GENES,

7932
06:23:22,560 --> 06:23:24,960
ITS PARTS AND TRANSCRIPT, WE'D

7933
06:23:24,960 --> 06:23:28,920
LIKE TO RE-CREATE IT IN MICE,

7934
06:23:28,920 --> 06:23:32,160
AND TRY TO TOGGLE GENETICALLY

7935
06:23:32,160 --> 06:23:37,640
AND BY GLYCANS STRAIN LEVEL

7936
06:23:37,640 --> 06:23:39,040
COMPOSITION POTENTIALLY IN

7937
06:23:39,040 --> 06:23:40,560
COMPETITION WITH KLOSS TRID YA

7938
06:23:40,560 --> 06:23:42,640
IN  ENCLOSE STRID

7939
06:23:42,640 --> 06:23:44,760
YA IN THE HUMAN GUT.

7940
06:23:44,760 --> 06:23:46,520
WE'D LIKE TO TURN BACK TO

7941
06:23:46,520 --> 06:23:47,640
MULTI-YOE MIBG DATASETS WHERE

7942
06:23:47,640 --> 06:23:49,200
WE'VE BEEN ABLE TO LOOK AT

7943
06:23:49,200 --> 06:23:51,800
COMPOSITIONS OF MICROBIOME, TAKE

7944
06:23:51,800 --> 06:23:53,120
THESE EMERGENT PROPERTIES AT THE

7945
06:23:53,120 --> 06:23:54,560
LEVEL OF GENE ASSIGNING

7946
06:23:54,560 --> 06:23:55,640
FUNCTION, TRANSCRIPTS ASSIGNING

7947
06:23:55,640 --> 06:23:59,240
FUNCTION AND THEN METABOLITES AS

7948
06:23:59,240 --> 06:24:00,440
TUTORS AND REALLY OPENING THIS

7949
06:24:00,440 --> 06:24:02,760
UP TO GLYCOMICS IN COLLABORATION

7950
06:24:02,760 --> 06:24:04,120
WITH THE WORK THAT WE'RE DOING

7951
06:24:04,120 --> 06:24:06,040
WITH RICK, WHICH IS TO SEE HOW

7952
06:24:06,040 --> 06:24:07,640
FINE-TUNED WE CAN LEARN ABOUT

7953
06:24:07,640 --> 06:24:13,240
STRAIN LEVEL COMPOSITION IN

7954
06:24:13,240 --> 06:24:14,600
THESE EMERGING PROPERTIES FOR

7955
06:24:14,600 --> 06:24:15,880
DIETARY GLYCANS AND HEALTH

7956
06:24:15,880 --> 06:24:16,240
GLYCANS.

7957
06:24:16,240 --> 06:24:17,520
SO WITH THAT, YOU REALLY THANK

7958
06:24:17,520 --> 06:24:18,520
EVERYONE FOR THEIR TIME.

7959
06:24:18,520 --> 06:24:20,680
I REALIZE I SPOKE VERY QUICKLY.

7960
06:24:20,680 --> 06:24:22,800
HOPEFULLY THAT WAS FOLLOWABLE.

7961
06:24:22,800 --> 06:24:25,720
AND I'D LIKE TO THANK THE NIH IN

7962
06:24:25,720 --> 06:24:28,920
PARTICULAR FOR THEIR SUPPORT, MY

7963
06:24:28,920 --> 06:24:31,280
KO8 JUST ENDED FROM NIAID, AND

7964
06:24:31,280 --> 06:24:32,760
THANKING FOR OTHER SUPPORT FROM

7965
06:24:32,760 --> 06:24:35,240
THE NIH AND OF COURSE PRIVATE

7966
06:24:35,240 --> 06:24:37,200
FUNDERS IN THE LAB, OF OUR

7967
06:24:37,200 --> 06:24:37,480
LABORATORY.

7968
06:24:37,480 --> 06:24:42,040
THANKS.

7969
06:24:42,040 --> 06:24:43,040
>> AWESOME.

7970
06:24:43,040 --> 06:24:43,840
SUPER.

7971
06:24:43,840 --> 06:24:45,240
YOU HAVE TO BRING YOUR LOVE OF

7972
06:24:45,240 --> 06:24:46,560
SUGARS AND CARBOHYDRATES OUT OF

7973
06:24:46,560 --> 06:24:47,600
THIS COMMUNITY AND EVERYWHERE

7974
06:24:47,600 --> 06:24:50,040
YOU SPEAK AND DO NOT HIDE THOSE.

7975
06:24:50,040 --> 06:24:51,120
I THINK IT WOULD BE REALLY

7976
06:24:51,120 --> 06:24:52,640
IMPORTANT FOR YOU TO DO THAT.

7977
06:24:52,640 --> 06:24:56,120
BUT IT WAS AMAZING, AMAZING,

7978
06:24:56,120 --> 06:24:56,640
AMAZING.

7979
06:24:56,640 --> 06:24:59,640
NEVER HIDE THAT.

7980
06:24:59,640 --> 06:25:00,720
IF YOU HAVE QUESTION, YOU'RE

7981
06:25:00,720 --> 06:25:01,480
LEADING THIS, SEAN.

7982
06:25:01,480 --> 06:25:02,560
GO AHEAD.

7983
06:25:02,560 --> 06:25:03,800
>> DOES ANYONE HAVE ANY

7984
06:25:03,800 --> 06:25:08,680
QUESTIONS?

7985
06:25:08,680 --> 06:25:10,640
>> EVERYBODY UNDERSTOOD

7986
06:25:10,640 --> 06:25:12,280
EVERYTHING I WAS SAYING.

7987
06:25:12,280 --> 06:25:13,080
>> THERE IS A QUESTION IN THE

7988
06:25:13,080 --> 06:25:13,960
CHAT FROM MARK.

7989
06:25:13,960 --> 06:25:17,640
HE SAYS IF BUTYRATE, A KETONE IS

7990
06:25:17,640 --> 06:25:20,680
RESISTANT TO HEALTH, IS THAT --

7991
06:25:20,680 --> 06:25:25,120
TO DIETARY KETOSIS?

7992
06:25:25,120 --> 06:25:30,440
>> YEAH, SO, YOU KNOW, THIS IS

7993
06:25:30,440 --> 06:25:31,720
INTERESTING.

7994
06:25:31,720 --> 06:25:35,640
SO HYDROXYBUTYRATE AS A KETONE

7995
06:25:35,640 --> 06:25:39,040
IN KETOSIS, DEFINITELY, AS FAR

7996
06:25:39,040 --> 06:25:47,880
AS BUTYRATE PER SE,  -- I'M
GOING

7997
06:25:47,880 --> 06:25:49,480
TO GO OFFLINE ON THAT ONE

7998
06:25:49,480 --> 06:25:50,200
BECAUSE THAT'S A FREE

7999
06:25:50,200 --> 06:25:52,240
ASSOCIATION WITH A COUPLE OF

8000
06:25:52,240 --> 06:25:53,640
THEM THAT I'M NOT EXACTLY SURE,

8001
06:25:53,640 --> 06:25:54,560
IF I CAN FIND THAT CHAT.

8002
06:25:54,560 --> 06:25:57,960
>> WE WILL EMAIL TO YOU.

8003
06:25:57,960 --> 06:25:59,160
>> THAT'S A GREAT QUESTION BUT

8004
06:25:59,160 --> 06:26:00,480
IT'S GOT LIKE FOUR DIMENSIONS

8005
06:26:00,480 --> 06:26:02,440
THAT I'M GOING TO SPARE THE TIME

8006
06:26:02,440 --> 06:26:02,600
ON.

8007
06:26:02,600 --> 06:26:03,320
>> THAT'S OKAY.

8008
06:26:03,320 --> 06:26:06,920
THAT'S GREAT.

8009
06:26:06,920 --> 06:26:10,560
EVAN, I SEE YOUR HAND IS UP IN

8010
06:26:10,560 --> 06:26:11,200
THE ZOOM ROOM.

8011
06:26:11,200 --> 06:26:12,720
MAYBE WE CAN DO THAT VIA CHAT

8012
06:26:12,720 --> 06:26:13,920
WITH SETH BECAUSE WE'RE REALLY

8013
06:26:13,920 --> 06:26:15,680
PRESSED FOR TIME AND SEAN AND I

8014
06:26:15,680 --> 06:26:16,760
ARE ALREADY -- WE'VE BEEN

8015
06:26:16,760 --> 06:26:18,520
SCHEMING HOW WE'RE GOING TO MAKE

8016
06:26:18,520 --> 06:26:22,840
OUR TALKS 3 MINUTES.

8017
06:26:22,840 --> 06:26:24,720
SO GREAT JOB.

8018
06:26:24,720 --> 06:26:25,000
THANK YOU.

8019
06:26:25,000 --> 06:26:25,840
>> ALL RIGHT.

8020
06:26:25,840 --> 06:26:34,600
WE'RE GOING TO SHIFT GEARS TO

8021
06:26:34,600 --> 06:26:36,000
DR. KATHARINA RIBBECK, PARTNERS

8022
06:26:36,000 --> 06:26:38,800
IN SLIME, HOW MUCOUS REGULATES

8023
06:26:38,800 --> 06:26:41,720
MICROBIAL VIEWER EU  VIRULENCE.

8024
06:26:41,720 --> 06:26:43,600
>> THANK YOU SO MUCH, CATHERINE

8025
06:26:43,600 --> 06:26:44,800
AND SEAN FOR INCLUDING ME IN

8026
06:26:44,800 --> 06:26:47,520
THIS REALLY OUTSTANDING

8027
06:26:47,520 --> 06:26:47,960
CONFERENCE.

8028
06:26:47,960 --> 06:26:48,960
I'VE HAD A VERY GOOD TIME, I'VE

8029
06:26:48,960 --> 06:26:49,640
LEARNED SO MUCH.

8030
06:26:49,640 --> 06:26:51,360
WE'VE TALKED A LOT ABOUT THE

8031
06:26:51,360 --> 06:26:52,440
MICROBIOME, AND I WANT TO SHIFT

8032
06:26:52,440 --> 06:26:55,520
BACK TO THE HOME OF THE

8033
06:26:55,520 --> 06:26:57,080
MICROBIOME FOR A MOMENT TO THE

8034
06:26:57,080 --> 06:26:57,520
MUCOUS BARRIER.

8035
06:26:57,520 --> 06:26:58,880
THE GOAL OF MY LAB IS TO

8036
06:26:58,880 --> 06:27:00,000
UNDERSTAND HOW IT INTERACTS WITH

8037
06:27:00,000 --> 06:27:03,360
MICROBES AND THEN LEVERAGE THESE

8038
06:27:03,360 --> 06:27:05,360
CONCEPTS AND MOTIF FS WE CAN TO

8039
06:27:05,360 --> 06:27:09,840
MANAGE PROBLEMATIC PATHOGENS.

8040
06:27:09,840 --> 06:27:11,720
SO LET'S GO BACK A FEW STEPS.

8041
06:27:11,720 --> 06:27:15,840
MUCOUS, YOU MAY RECALL, IS A

8042
06:27:15,840 --> 06:27:18,200
HYDROGEL THAT IS BUILT FROM

8043
06:27:18,200 --> 06:27:20,680
POLYMERS THAT ENTANGLE, THEY'RE

8044
06:27:20,680 --> 06:27:23,720
HIGHLY HYDRATED, AT MUCUS COATS

8045
06:27:23,720 --> 06:27:26,280
ENORMOUS SURFACE AREA IN THE

8046
06:27:26,280 --> 06:27:28,840
BODY, 2,000 SQUARE FEET IN THE

8047
06:27:28,840 --> 06:27:30,120
INTESTINE ALONE, BEST KNOWN FOR

8048
06:27:30,120 --> 06:27:32,760
ITS ABILITY TO PRESERVE MOISTURE

8049
06:27:32,760 --> 06:27:35,200
IN UNDERLYING EPITHELIA, IT ALSO

8050
06:27:35,200 --> 06:27:36,080
PRESERVES YOUR STOMACH FROM

8051
06:27:36,080 --> 06:27:36,640
DIGESTING ITSELF.

8052
06:27:36,640 --> 06:27:38,040
BUT WHAT I WANT TO FOCUS ON

8053
06:27:38,040 --> 06:27:45,360
TODAY IS THE ROLE OF MUCUS AS AN

8054
06:27:45,360 --> 06:27:46,680
ECOLOGICAL NICHE THAT

8055
06:27:46,680 --> 06:27:47,880
ACCOMMODATES MICROBES, TRILLIONS

8056
06:27:47,880 --> 06:27:50,160
OF MICROBES THAT LIVE INSIDE THE

8057
06:27:50,160 --> 06:27:56,720
MUCUS IN YOUR GAS TOE 
GASTROINTESTINAL

8058
06:27:56,720 --> 06:27:57,040
TRACT.

8059
06:27:57,040 --> 06:27:58,680
MANY ARE BENIGN BUT THERE ARE

8060
06:27:58,680 --> 06:28:01,240
ALSO A NUMBER OF PATHOGENS THAT

8061
06:28:01,240 --> 06:28:05,920
CAN CAUSE SERIOUS INFECTION.

8062
06:28:05,920 --> 06:28:10,640
MUCUS IS REALLY UNSUNG HEROS FOR

8063
06:28:10,640 --> 06:28:11,400
MAINTAINING PROBLEMATIC

8064
06:28:11,400 --> 06:28:14,240
PATHOGENS AND IT DOES SO WITH

8065
06:28:14,240 --> 06:28:16,640
THE HELP OF POLYMERS, THEY LOOK

8066
06:28:16,640 --> 06:28:19,240
LIKE TINY BOTTLE BRUSHES, AND

8067
06:28:19,240 --> 06:28:22,440
THEY ARE -- THIS IS WHY I'M

8068
06:28:22,440 --> 06:28:24,440
SPEAKING HERE TODAY, THEY

8069
06:28:24,440 --> 06:28:28,080
PROTRUDE DENSE AREAS OF GLYCANS

8070
06:28:28,080 --> 06:28:33,320
INTO THE LUMEN OF MUCUS, AND

8071
06:28:33,320 --> 06:28:36,040
THEY INTERACT WITH MICROBES

8072
06:28:36,040 --> 06:28:36,720
THEMSELVES BUT ALSO WITH

8073
06:28:36,720 --> 06:28:37,720
COMPONENTS FROM THE IMMUNE

8074
06:28:37,720 --> 06:28:38,800
SYSTEM.

8075
06:28:38,800 --> 06:28:40,640
WHEN MUCINS AREN'T PRODUCED

8076
06:28:40,640 --> 06:28:45,160
CORRECTLY OR NOT IN HIGH ENOUGH

8077
06:28:45,160 --> 06:28:49,040
AMOUNTS, THEN THE HOST CAN

8078
06:28:49,040 --> 06:28:52,160
BECOME INFLAMED, COMPROMISED,

8079
06:28:52,160 --> 06:28:54,320
AND MORE SERIOUS DISEASES CAN

8080
06:28:54,320 --> 06:28:55,800
EMERGE, CYSTIC FIBROSIS, WE'VE

8081
06:28:55,800 --> 06:28:57,160
HEARD A NUMBER OF CASES ALREADY.

8082
06:28:57,160 --> 06:29:01,960
SO I'M REALLY EXCITED ABOUT

8083
06:29:01,960 --> 06:29:04,680
MUCUS BECAUSE I'M CONVINCED THAT

8084
06:29:04,680 --> 06:29:05,800
UNDERSTANDING HOW IT MANAGES

8085
06:29:05,800 --> 06:29:08,000
PATHOGENS CAN HELP US FIND NEW

8086
06:29:08,000 --> 06:29:09,320
STRATEGIES TO CONTROL PATHOGENS

8087
06:29:09,320 --> 06:29:10,560
OURSELVES.

8088
06:29:10,560 --> 06:29:13,320
SO THIS IS REALLY THE GOAL OF

8089
06:29:13,320 --> 06:29:14,120
THE LAB.

8090
06:29:14,120 --> 06:29:16,960
IF YOU LOOK THROUGH TEXTBOOK

8091
06:29:16,960 --> 06:29:20,120
MODELS, HOW MUCUS EXACTLY

8092
06:29:20,120 --> 06:29:22,560
MEDIATE BARRIER FUNCTION, YOU'LL

8093
06:29:22,560 --> 06:29:23,320
FIND TWO PREVAILING MODELS.

8094
06:29:23,320 --> 06:29:25,200
ONE IS MUCOUS AS A PHYSICAL

8095
06:29:25,200 --> 06:29:26,880
BARRIER THAT KEEPS MICROBES AT A

8096
06:29:26,880 --> 06:29:28,840
DISTANCE FROM UNDERLYING

8097
06:29:28,840 --> 06:29:29,720
EPITHELIUM, YOU'LL FIND THAT IN

8098
06:29:29,720 --> 06:29:30,840
CERTAIN PARTS OF THE GUT, FOR

8099
06:29:30,840 --> 06:29:32,560
EXAMPLE.

8100
06:29:32,560 --> 06:29:34,520
THE OTHER MECHANISM THAT YOU'LL

8101
06:29:34,520 --> 06:29:36,960
FIND IN TEXTBOOKS IS ONE WHERE

8102
06:29:36,960 --> 06:29:41,080
MU 

8103
06:29:41,080 --> 06:29:45,120
MUCIN ES DIRECTLY BIND AND

8104
06:29:45,120 --> 06:29:46,440
THEREFORE -- WHEN MUCOUS GETS

8105
06:29:46,440 --> 06:29:47,440
REMOVED FROM THE SURFACE OF THE

8106
06:29:47,440 --> 06:29:48,640
BODY.

8107
06:29:48,640 --> 06:29:50,760
THESE MODELS HAVE THEIR PLACE.

8108
06:29:50,760 --> 06:29:52,240
THEY ARE CRITICAL TO MUCUS

8109
06:29:52,240 --> 06:29:52,840
FUNCTION.

8110
06:29:52,840 --> 06:29:55,760
HOWEVER, THEY DO NOT CAPTURE HOW

8111
06:29:55,760 --> 06:29:57,400
MUCUS CAN ACCOMMODATE POTENTIAL

8112
06:29:57,400 --> 06:29:57,640
PATHOGENS.

8113
06:29:57,640 --> 06:30:00,840
AND THIS IS WHAT I WANT TO ZOOM

8114
06:30:00,840 --> 06:30:05,120
IN ON NOW AND TAKE APART WITH

8115
06:30:05,120 --> 06:30:05,280
YOU.

8116
06:30:05,280 --> 06:30:10,120
I WILL TELL BUT THREE  ABOUT
THREE

8117
06:30:10,120 --> 06:30:10,800
HIGHLIGHTS WE'VE DISCOVERED OVER

8118
06:30:10,800 --> 06:30:12,000
THE PAST COUPLE OF YEARS.

8119
06:30:12,000 --> 06:30:14,240
THE FIRST IS WHAT WE'VE LEARNED

8120
06:30:14,240 --> 06:30:17,440
IS THAT MUCIN POLYMERS, THE POLT

8121
06:30:17,440 --> 06:30:20,680
MERES THEMSELVES ARE REALLY GOOD

8122
06:30:20,680 --> 06:30:23,640
AT ATTENUATING THE VIRULENCE OF

8123
06:30:23,640 --> 06:30:24,400
OPPORTUNISTIC PATHOGENS.

8124
06:30:24,400 --> 06:30:25,640
SO WHEN WE FIRST STARTED

8125
06:30:25,640 --> 06:30:28,040
THINKING ABOUT HOW TO UNDERSTAND

8126
06:30:28,040 --> 06:30:29,600
HOW MUCOUS REGULATES IN

8127
06:30:29,600 --> 06:30:30,760
PARTICULAR PATHOGENS, WE WERE

8128
06:30:30,760 --> 06:30:35,520
LOOKING FOR A PATHOGEN THAT CAN

8129
06:30:35,520 --> 06:30:37,040
RESIDE IN HEALTHY MUCOSAL

8130
06:30:37,040 --> 06:30:38,480
BARRIERS WITHOUT CAUSING

8131
06:30:38,480 --> 06:30:42,560
PROBLEMS BUT THEN ALSO HAS THE

8132
06:30:42,560 --> 06:30:44,880
ABILITY TO CAUSE INFECTIONS,

8133
06:30:44,880 --> 06:30:46,600
PSEUDOMONAS IS ONE OF THEM

8134
06:30:46,600 --> 06:30:50,000
PROBABLY BEST UNDERSTOOD FOR ITS

8135
06:30:50,000 --> 06:30:51,520
BIOFILMS OR DENSE AGGREGATES

8136
06:30:51,520 --> 06:30:55,360
INSIDE CYSTIC FIBROSIS MUCUS.

8137
06:30:55,360 --> 06:30:56,800
NOW OTHER GOAL WAS TO

8138
06:30:56,800 --> 06:30:58,440
INTERROGATE TO MUCUS OUR

8139
06:30:58,440 --> 06:31:00,040
INTERACTION WITH THE MICROBES

8140
06:31:00,040 --> 06:31:03,040
STARTING WITH THE MU CIN

8141
06:31:03,040 --> 06:31:07,640
POLYMERS AND BUILD UP

8142
06:31:07,640 --> 06:31:09,520
SUCCESSIVELY AT OTHER FACTORS,

8143
06:31:09,520 --> 06:31:12,280
BUT FIRST BUILDING A THREE

8144
06:31:12,280 --> 06:31:13,040
DIMENSIONAL NETWORK THAT REALLY

8145
06:31:13,040 --> 06:31:16,320
WAS MEANT TO BE COMPLEMENTARY TO

8146
06:31:16,320 --> 06:31:16,960
ALREADY ONGOING IMPORTANT

8147
06:31:16,960 --> 06:31:18,440
RESEARCH THAT USES TWO

8148
06:31:18,440 --> 06:31:21,120
DIMENSIONAL COATINGS OF MUCIN

8149
06:31:21,120 --> 06:31:21,400
POLYMERS.

8150
06:31:21,400 --> 06:31:24,160
SO THIS IS WHAT WE'LL DO, AND

8151
06:31:24,160 --> 06:31:25,440
OUR DAILY BREAD IS NOT GLAMOROUS

8152
06:31:25,440 --> 06:31:32,440
BUT IT'S NEEDED, WE PURIFY

8153
06:31:32,440 --> 06:31:33,960
MUCINS AND RECONFIGURE THEM INTO

8154
06:31:33,960 --> 06:31:37,080
3D NETWORKS AND EMBED MICROBES

8155
06:31:37,080 --> 06:31:40,080
INTO THESE NETWORKS, THE

8156
06:31:40,080 --> 06:31:40,600
INDUSTRIAL/COMMERCIALLY

8157
06:31:40,600 --> 06:31:42,920
AVAILABLE MUCINS DO NOT HAVE

8158
06:31:42,920 --> 06:31:43,880
MANY OF THE PROPERTIES,

8159
06:31:43,880 --> 06:31:45,040
MECHANICAL AND ALSO BIOCHEMICAL,

8160
06:31:45,040 --> 06:31:48,080
THAT YOU'LL NEED FOR THIS TYPE

8161
06:31:48,080 --> 06:31:53,640
OF STUDY.

8162
06:31:53,640 --> 06:31:56,080
SO FIRST EXPERIMENT TO LOOK

8163
06:31:56,080 --> 06:32:03,120
AT -- WHEN YOU JUST LOOK AT --

8164
06:32:03,120 --> 06:32:05,400
THAT IS UNCOATED BY MUCIN

8165
06:32:05,400 --> 06:32:06,600
THEY'LL BIND READILY TO THE

8166
06:32:06,600 --> 06:32:07,240
SURFACE.

8167
06:32:07,240 --> 06:32:08,560
IF THE SURFACE IS, HOWEVER,

8168
06:32:08,560 --> 06:32:12,880
LINED WITH MUCIN, YOU CAN DO THE

8169
06:32:12,880 --> 06:32:14,080
SAME EXPERIMENT WITH MUCUS,

8170
06:32:14,080 --> 06:32:15,880
YOU'LL SEE THAT THEY HAVE A MUCH

8171
06:32:15,880 --> 06:32:17,640
HARDER TIME ASSOCIATING TO THE

8172
06:32:17,640 --> 06:32:19,200
UNDERLYING SURFACE.

8173
06:32:19,200 --> 06:32:22,680
MU CINS ARE ACTUALLY REALLY GOOD

8174
06:32:22,680 --> 06:32:25,600
AT BINDING TO THE SURFACE, BUT

8175
06:32:25,600 --> 06:32:28,440
ALSO EPITHELIAL CELLS, LIVING

8176
06:32:28,440 --> 06:32:28,840
EPITHELIAL CELLS.

8177
06:32:28,840 --> 06:32:30,560
SO THIS IS EXCITING BECAUSE THAT

8178
06:32:30,560 --> 06:32:32,680
MEANS THERE IS THIS

8179
06:32:32,680 --> 06:32:34,280
PROTECTIVE -- THAT'S NOT SO

8180
06:32:34,280 --> 06:32:36,760
SURPRISING AFTER ALL MUCUS IS

8181
06:32:36,760 --> 06:32:38,560
THIS THREE DIMENSIONAL NETWORK,

8182
06:32:38,560 --> 06:32:40,040
IT MIGHT GET STUCK IN THE VOLUME

8183
06:32:40,040 --> 06:32:41,880
AND NEVER PENETRATE THROUGH.

8184
06:32:41,880 --> 06:32:43,280
IF THAT IS THE CASE, ONE SHOULD

8185
06:32:43,280 --> 06:32:44,640
BE ABLE TO SEE THAT IF ONE

8186
06:32:44,640 --> 06:32:45,920
SWITCHES TO THE VOLUME OF THE

8187
06:32:45,920 --> 06:32:46,560
CENTER OF THE GEL.

8188
06:32:46,560 --> 06:32:48,480
IF YOU LOOK AT WHAT MICROBES DO

8189
06:32:48,480 --> 06:32:49,880
WHILE THEY'RE IN MUCUS, YOU'LL

8190
06:32:49,880 --> 06:32:51,400
FIND THAT THEY SWIM.

8191
06:32:51,400 --> 06:32:52,840
THIS IS JUST IN BUFFER FOR NOW.

8192
06:32:52,840 --> 06:32:54,520
YOU'LL FIND THAT THEY SWIM

8193
06:32:54,520 --> 06:32:58,360
OUTSIDE OF MUCUS PRETTY RAPIDLY

8194
06:32:58,360 --> 06:32:59,440
IN A PARTICULAR SWIMMING

8195
06:32:59,440 --> 06:32:59,880
PATTERN.

8196
06:32:59,880 --> 06:33:02,120
IF YOU NOW SURROUND THEM WITH

8197
06:33:02,120 --> 06:33:03,880
MUCINS, NORMALLY WHEN I'M IN A

8198
06:33:03,880 --> 06:33:05,320
LIVE AUDIENCE, I LIKE TO ASK

8199
06:33:05,320 --> 06:33:06,480
STUDENTS WHAT THEY EXPECT WILL

8200
06:33:06,480 --> 06:33:06,720
HAPPEN.

8201
06:33:06,720 --> 06:33:10,800
MOST OF THE TIME, THAT WAS MY

8202
06:33:10,800 --> 06:33:12,320
PREDICTION AS WELL, YOU'LL HEAR

8203
06:33:12,320 --> 06:33:13,440
MICROBES WILL PROBABLY GET TRAP

8204
06:33:13,440 --> 06:33:14,960
AND ARRESTED BY THE MUCOUS

8205
06:33:14,960 --> 06:33:15,680
BARRIER.

8206
06:33:15,680 --> 06:33:17,240
AFTER ALL, WE THINK OF IT AS

8207
06:33:17,240 --> 06:33:20,240
SOME SORT OF STICK ALL, TRAP ALL

8208
06:33:20,240 --> 06:33:20,480
FILTER.

8209
06:33:20,480 --> 06:33:23,640
BUT THAT IS NOT THE CASE, MUCINS

8210
06:33:23,640 --> 06:33:24,600
DO NOT TRAP MICROBES.

8211
06:33:24,600 --> 06:33:25,240
THIS IS ONLY ONE.

8212
06:33:25,240 --> 06:33:26,640
A SERIES OF MICROBES WE LOOKED

8213
06:33:26,640 --> 06:33:28,120
AT FOR THIS PURPOSE, IN FACT,

8214
06:33:28,120 --> 06:33:29,920
THE MICROBES SWIM JUST FINE IN

8215
06:33:29,920 --> 06:33:31,920
CERTAIN CASES THE TOP SPEED IS

8216
06:33:31,920 --> 06:33:32,840
HIGHER EVEN.

8217
06:33:32,840 --> 06:33:36,040
AND IF YOU LOOK AT OUTSIDE OF MU

8218
06:33:36,040 --> 06:33:38,080
KU AND IF YOU LOOK AT LONGER

8219
06:33:38,080 --> 06:33:39,000
TIME POINTS, YOU'LL FIND REALLY

8220
06:33:39,000 --> 06:33:40,840
IN THE ABSENCE OF MUCUS, THEY

8221
06:33:40,840 --> 06:33:44,720
STACK UP MORE AND MORE CELLS,

8222
06:33:44,720 --> 06:33:45,880
BUILD THICK BIOFILMS, THEY DON'T

8223
06:33:45,880 --> 06:33:55,840
DO THAT IN THE PRESENCE OF

8224
06:33:55,840 --> 06:33:56,840
MUCINS, THAT OF COURSE HAS ALL

8225
06:33:56,840 --> 06:33:58,560
SORTS OF CONSEQUENCES FOR THEIR

8226
06:33:58,560 --> 06:34:00,240
ABILITY TO INTERACT WITH EACH

8227
06:34:00,240 --> 06:34:02,240
OTHER TO RESPOND TO AND SIGNAL

8228
06:34:02,240 --> 06:34:05,920
WITH THE ENVIRONMENT, AND WE

8229
06:34:05,920 --> 06:34:09,640
THINK, BY THE WAY, ADHESI IN.

8230
06:34:09,640 --> 06:34:10,960
S WILL BE ESSENTIAL FOR THE

8231
06:34:10,960 --> 06:34:12,000
ABILITY TO DISPERSE THEM.

8232
06:34:12,000 --> 06:34:12,920
AND WE CAN TALK ABOUT THAT

8233
06:34:12,920 --> 06:34:13,240
LATER.

8234
06:34:13,240 --> 06:34:14,520
SO THIS IS INTERESTING, THIS IS

8235
06:34:14,520 --> 06:34:17,280
MATERIAL THAT HAS THE ABILITY TO

8236
06:34:17,280 --> 06:34:20,880
PREVENT MICROBES ALONE BY

8237
06:34:20,880 --> 06:34:21,320
SEPARATING THEM.

8238
06:34:21,320 --> 06:34:25,040
THE QUESTION WAS, IS THIS

8239
06:34:25,040 --> 06:34:28,600
SOMETHING THAT -- FOR

8240
06:34:28,600 --> 06:34:29,840
PSEUDOMONAS OR IS THIS A GENERAL

8241
06:34:29,840 --> 06:34:34,400
FEATURE OF MU  MUCINS THAT --
FOR

8242
06:34:34,400 --> 06:34:37,240
THAT WE TURN TO CANDIDA ALBICANS

8243
06:34:37,240 --> 06:34:40,760
FOR A MOMENT WHICH CONVENIENTLY

8244
06:34:40,760 --> 06:34:42,280
HAS TWO MORPHOLOGICALLY DISTINCT

8245
06:34:42,280 --> 06:34:42,840
FORMS.

8246
06:34:42,840 --> 06:34:45,040
ONE, THE YEAST FORM IS DEBIEN

8247
06:34:45,040 --> 06:34:52,600
SUPPOSEDLY  BENIGN,

8248
06:34:52,600 --> 06:34:54,560
WHEN YOU LOOK AT YEASTS THAT YOU

8249
06:34:54,560 --> 06:34:55,960
GROW INSIDE MEDIUM, IN THE

8250
06:34:55,960 --> 06:35:00,480
ABSENCE OF HOST FACTORS, THEY'LL

8251
06:35:00,480 --> 06:35:09,320
SWITCH THE HYPHAE FORM, IF YOU

8252
06:35:09,320 --> 06:35:12,040
SURROUND YEAST CELLS WITH MUCIN

8253
06:35:12,040 --> 06:35:15,240
POLYMERS, WHAT THEY'LL DO IS

8254
06:35:15,240 --> 06:35:16,760
PROLIFERATE, BUT WHAT THEY WON'T

8255
06:35:16,760 --> 06:35:18,400
DO IS SWITCH INTO THE

8256
06:35:18,400 --> 06:35:19,200
FILAMENTOUS FORM, WHAT THAT

8257
06:35:19,200 --> 06:35:20,280
MEANS IS THEY'RE LOCKED IN A

8258
06:35:20,280 --> 06:35:21,680
STATE THAT IS HOST COMPATIBLE,

8259
06:35:21,680 --> 06:35:23,000
AND THE ABILITY OF MUCINS TO

8260
06:35:23,000 --> 06:35:24,720
PREVENT THE TRANSITION TO THE

8261
06:35:24,720 --> 06:35:26,440
HYPHAE FORM IS SO ACUTE AND

8262
06:35:26,440 --> 06:35:28,280
STRONG THAT YOU CAN TAKE ALREADY

8263
06:35:28,280 --> 06:35:29,560
EXISTING FILAMENTS, IF YOU JUST

8264
06:35:29,560 --> 06:35:31,840
LET THEM DO THEIR THING, THEY'LL

8265
06:35:31,840 --> 06:35:34,240
CONTINUE TO PRODUCE FILAMENTS.

8266
06:35:34,240 --> 06:35:36,080
BUT IF YOU EXPOSE THESE ALREADY,

8267
06:35:36,080 --> 06:35:38,600
THESE FILAMENTS TO MUCINS,

8268
06:35:38,600 --> 06:35:40,360
YOU'LL SEE THAT THE NEXT

8269
06:35:40,360 --> 06:35:42,480
GENERATION HAS REVERSED BACK TO

8270
06:35:42,480 --> 06:35:43,120
YEAST CELLS.

8271
06:35:43,120 --> 06:35:44,760
AND WE ARE OFTEN ASKED, IS THIS

8272
06:35:44,760 --> 06:35:46,160
SOMETHING THAT POLYMERS

8273
06:35:46,160 --> 06:35:47,600
GENERALLY DO OR IS THIS SPECIFIC

8274
06:35:47,600 --> 06:35:49,320
TO THE MUCIN BIOCHEMISTRY?

8275
06:35:49,320 --> 06:35:52,040
AND IT IS SPECIFIC TO THE MUCIN

8276
06:35:52,040 --> 06:35:53,240
BIOCHEMISTRY BECAUSE ANY POLYMER

8277
06:35:53,240 --> 06:35:56,760
THAT WE'VE TESTED SO FAR THAT

8278
06:35:56,760 --> 06:35:59,040
CAN REMOTELY CONSTITUTE MUCIN

8279
06:35:59,040 --> 06:35:59,840
PROPERTIES DOES NOT HAVE THIS

8280
06:35:59,840 --> 06:36:00,280
EFFECT.

8281
06:36:00,280 --> 06:36:02,520
SO THIS REALLY MEANS THAT MUCINS

8282
06:36:02,520 --> 06:36:04,080
PRESENT SOMETHING THAT CAN

8283
06:36:04,080 --> 06:36:06,000
REGULATE TAP INTO THE PHYSIOLOGY

8284
06:36:06,000 --> 06:36:07,840
OF THE MICROBE THAT PREVENTS IT

8285
06:36:07,840 --> 06:36:10,360
FROM TRANSITIONING INTO THAT

8286
06:36:10,360 --> 06:36:12,840
FILAMENTOUS STATE.

8287
06:36:12,840 --> 06:36:15,880
AND SO HOW DOES THAT WORK?

8288
06:36:15,880 --> 06:36:18,640
AND THIS IS THE SECOND

8289
06:36:18,640 --> 06:36:21,920
OBSERVATION WE'VE MADE.

8290
06:36:21,920 --> 06:36:24,080
MUCINS MANAGE PATHOGENS NOT BY

8291
06:36:24,080 --> 06:36:25,560
KILLING THEM, BUT BY DISARMING

8292
06:36:25,560 --> 06:36:25,840
THEM.

8293
06:36:25,840 --> 06:36:28,120
AND I'LL TELL YOU WHAT THIS

8294
06:36:28,120 --> 06:36:29,760
MEANS EXACTLY.

8295
06:36:29,760 --> 06:36:38,000
WHEN YOU NOW EXPOS THE SUED 
EXPOSE TO DIF
FERENT

8296
06:36:38,000 --> 06:36:38,960
SURFACES IN THE BODY, WHAT

8297
06:36:38,960 --> 06:36:40,240
YOU'LL SEE IS THAT MANY GENES

8298
06:36:40,240 --> 06:36:44,840
ARE DOWN DIAGNOSE  DOWNREGULATED
AND

8299
06:36:44,840 --> 06:36:47,600
UPREGULATED, BUT IF YOU

8300
06:36:47,600 --> 06:36:49,320
EXPECT -- YOU'LL FIND MANY OF

8301
06:36:49,320 --> 06:36:51,720
THOSE ARE ASSOCIATED WITH

8302
06:36:51,720 --> 06:36:53,680
VIRULENCE BEHAVIOR, INCLUDING

8303
06:36:53,680 --> 06:36:55,560
BIOINFORMATION, QUORUM SENSING

8304
06:36:55,560 --> 06:36:56,760
TOXINS, CERTAIN TYPES OF

8305
06:36:56,760 --> 06:36:58,280
SECRETION SYSTEMS ARE ALL

8306
06:36:58,280 --> 06:37:02,600
DOWNREGULATED IN THE PRESENCE OF

8307
06:37:02,600 --> 06:37:03,720
MUCINS.

8308
06:37:03,720 --> 06:37:05,840
AND WE HAVE VALIDATED THAT IT

8309
06:37:05,840 --> 06:37:08,680
PUBLISHED WORK THAT INDEED THE

8310
06:37:08,680 --> 06:37:11,440
MICROBES ARE PASSIVATED IN THE

8311
06:37:11,440 --> 06:37:13,400
PRESENCE OF MUCINS FROM

8312
06:37:13,400 --> 06:37:15,800
PHENOTYPIC ACIDS ALL THE  THE
WAY

8313
06:37:15,800 --> 06:37:17,320
FROM CELL CULTURE TO ANIMAL

8314
06:37:17,320 --> 06:37:17,560
MODELS.

8315
06:37:17,560 --> 06:37:19,280
NOW THIS IS EXCITING BECAUSE

8316
06:37:19,280 --> 06:37:20,400
MUCINS, THOSE COMPLEX POLYMERS

8317
06:37:20,400 --> 06:37:22,040
SEEM TO BE VERY POTENT IN

8318
06:37:22,040 --> 06:37:25,800
MANAGING MICROBES IN THAT THEY

8319
06:37:25,800 --> 06:37:26,480
PASSIVATE THEM.

8320
06:37:26,480 --> 06:37:27,920
THEY DON'T SEEM TO KILL THEM.

8321
06:37:27,920 --> 06:37:29,240
BUT WHAT EXACTLY CAN WE DO WITH

8322
06:37:29,240 --> 06:37:29,880
THEM?

8323
06:37:29,880 --> 06:37:30,880
THEY'RE TOO COMPLEX AS IS, SO

8324
06:37:30,880 --> 06:37:33,000
WHAT WE DECIDED TO DO A COUPLE

8325
06:37:33,000 --> 06:37:34,480
YEARS AGO WAS TAKE THEM APART,

8326
06:37:34,480 --> 06:37:37,680
TAKE THEM APART, TAKE THEIR DAWN

8327
06:37:37,680 --> 06:37:39,600
TINGLY COMPLEX BIOCHEMISTRY AS

8328
06:37:39,600 --> 06:37:42,320
FAR AS WE CAN, REMOVE THE

8329
06:37:42,320 --> 06:37:43,440
GLYCANS FROM THE BACKBONE OF THE

8330
06:37:43,440 --> 06:37:47,040
MUCIN POLYMERS, AND THEN

8331
06:37:47,040 --> 06:37:48,400
INTERROGATE IN GLYCAN POOLS FOR

8332
06:37:48,400 --> 06:37:49,520
THEIR FUNCTIONALITIES.

8333
06:37:49,520 --> 06:37:52,960
THE BIG QUESTION, OF COURSE,

8334
06:37:52,960 --> 06:37:55,240
WAS, DO THESE GLYCANS BY

8335
06:37:55,240 --> 06:37:58,320
THEMSELVES HAVE THE ABILITY TO

8336
06:37:58,320 --> 06:37:59,280
REGULATE, DOWNREGULATE,

8337
06:37:59,280 --> 06:38:02,240
SUPPRESS, DISARM THE MICROBES IN

8338
06:38:02,240 --> 06:38:07,840
THE SAME WAY AS MUCINS DO.

8339
06:38:07,840 --> 06:38:10,560
I SHOW YOU THE EXPERIMENT TO

8340
06:38:10,560 --> 06:38:12,320
HIGHLIGHT THE COMPLEXITY OF

8341
06:38:12,320 --> 06:38:14,480
GLYCANS THAT MUCINS DISPLAY,

8342
06:38:14,480 --> 06:38:16,680
YOU'LL HAVE HUNDREDS OF

8343
06:38:16,680 --> 06:38:18,240
STRUCTURES, DIFFERENT DISTINCT

8344
06:38:18,240 --> 06:38:22,480
STRUCTURES THAT ARE EXPOSED,

8345
06:38:22,480 --> 06:38:24,480
DISPLAYED BY MUCIN, SO THEY'RE

8346
06:38:24,480 --> 06:38:27,920
REALLY PLATFORMS OF SMALL

8347
06:38:27,920 --> 06:38:29,240
MOLECULES THAT INTERACT WITH THE

8348
06:38:29,240 --> 06:38:30,000
ENVIRONMENT.

8349
06:38:30,000 --> 06:38:32,320
SO IF YOU TAKE THIS POOL HERE OF

8350
06:38:32,320 --> 06:38:34,040
SOLUBLE GLYCANS IN THE ABSENCE

8351
06:38:34,040 --> 06:38:36,040
OF THE BACKBONE, MUCIN BACKBONE,

8352
06:38:36,040 --> 06:38:37,560
YOU'LL FIND THAT THEY'RE REALLY

8353
06:38:37,560 --> 06:38:40,240
POTENT IN SUPPRESSING VIRULENCE

8354
06:38:40,240 --> 06:38:40,480
TRAIT.

8355
06:38:40,480 --> 06:38:42,520
THE SAME GENE EXPRESSION

8356
06:38:42,520 --> 06:38:44,600
CASCADES THAT ARE RELATED TO

8357
06:38:44,600 --> 06:38:47,840
VIRULENCE AND ENABLE THE MICROBE

8358
06:38:47,840 --> 06:38:50,040
TO INFECT, AND THAT, AGAIN, YOU

8359
06:38:50,040 --> 06:38:52,440
CAN SEE AT BOTH THE GENE

8360
06:38:52,440 --> 06:38:54,080
EXPRESSION LEVEL BUT THEN

8361
06:38:54,080 --> 06:38:55,520
VALIDATE PHENOTYPICALLY BINDING

8362
06:38:55,520 --> 06:38:57,240
ASSAYS TO SURFACES, FOR EXAMPLE,

8363
06:38:57,240 --> 06:39:01,560
WHERE MUCIN GLYCANS, IN THE

8364
06:39:01,560 --> 06:39:03,160
ABSENCE EVEN OF THE GEL

8365
06:39:03,160 --> 06:39:04,320
STRUCTURE ARE REALLY EFFECTIVE

8366
06:39:04,320 --> 06:39:07,800
AT PRESENTING SURFACE

8367
06:39:07,800 --> 06:39:09,440
ASSOCIATION, AND ONE IMPORTANT

8368
06:39:09,440 --> 06:39:12,160
CONTROL IF YOU SEPARATE THE

8369
06:39:12,160 --> 06:39:13,560
MUCIN GLYCAN STRUCTURES INTO

8370
06:39:13,560 --> 06:39:16,200
THEIR COMPOSITES, MONO

8371
06:39:16,200 --> 06:39:19,560
SACCHARIDES, YOU LOSE THAT

8372
06:39:19,560 --> 06:39:20,720
EFFECT.

8373
06:39:20,720 --> 06:39:21,640
THEY DO NOT ACHIEVE THE SAME

8374
06:39:21,640 --> 06:39:23,960
KIND OF ASSAY, JUST A DIFFERENT

8375
06:39:23,960 --> 06:39:25,240
QUANTIFICATION, MUCIN GLYCANS

8376
06:39:25,240 --> 06:39:28,160
REALLY ARE EFFECTIVE AT

8377
06:39:28,160 --> 06:39:30,040
PREVENTING GROUP FORMATION

8378
06:39:30,040 --> 06:39:32,080
MONOSACCHARIDES DO NOT DO THIS,

8379
06:39:32,080 --> 06:39:35,920
AND NUMEROUS GENES RELATED TO

8380
06:39:35,920 --> 06:39:38,880
VIEWER EU LENS 

8381
06:39:38,880 --> 06:39:40,640
VIRULENCE ARE DOWNREGULATED.

8382
06:39:40,640 --> 06:39:44,640
THE QUESTION HERE AGAIN BACK TO

8383
06:39:44,640 --> 06:39:46,600
CANDIDA BRIEFLY IS, HOW SPECIFIC

8384
06:39:46,600 --> 06:39:48,480
IS THIS VIEWER EU LENS

8385
06:39:48,480 --> 06:39:50,600
ATTENUATION EFFECT OF THESE

8386
06:39:50,600 --> 06:39:52,320
GLYCAN POOLS?

8387
06:39:52,320 --> 06:39:53,960
CANDIDA, I REMEMBER THAT MUCIN

8388
06:39:53,960 --> 06:39:56,280
POLYMERS ARE REALLY EFFECTIVE AT

8389
06:39:56,280 --> 06:39:58,440
PREVENTING THAT TRANSITION TO

8390
06:39:58,440 --> 06:40:00,080
FILAMENTS, AND SO ARE THE

8391
06:40:00,080 --> 06:40:01,040
GLYCANS.

8392
06:40:01,040 --> 06:40:03,280
THE GLYCANS, NO MATTER FROM

8393
06:40:03,280 --> 06:40:05,800
WHICH SURFACE HUMAN OR PIG IN

8394
06:40:05,800 --> 06:40:08,040
THIS CASE, SALIVA,

8395
06:40:08,040 --> 06:40:10,040
GASTROINTESTINAL AND INTESTINE

8396
06:40:10,040 --> 06:40:12,440
STOMACH AND INTESTINE, WE

8397
06:40:12,440 --> 06:40:14,080
CHOSE -- THEY WERE ALL REALLY

8398
06:40:14,080 --> 06:40:15,720
POTENT AT SUPPRESSING THAT

8399
06:40:15,720 --> 06:40:19,240
TRANSITION TO THE FILAMENTOUS

8400
06:40:19,240 --> 06:40:20,760
FORM WITHOUT KILLING THE

8401
06:40:20,760 --> 06:40:21,040
MICROBES.

8402
06:40:21,040 --> 06:40:23,960
AND THAT IS REALLY AN IMPORTANT

8403
06:40:23,960 --> 06:40:25,800
POINT OF THEIR FUNCTION.

8404
06:40:25,800 --> 06:40:28,760
AND THE PICTURE THAT IS EE
EMERGING

8405
06:40:28,760 --> 06:40:29,640
NOW, I CAN ONLY TELL YOU THESE

8406
06:40:29,640 --> 06:40:32,720
TWO STORIES, I DON'T HAVE MORE

8407
06:40:32,720 --> 06:40:35,560
TIME BUT I'M HAPPY TO CONNECT

8408
06:40:35,560 --> 06:40:36,640
LATER, THE PICTURE IS EMERGING

8409
06:40:36,640 --> 06:40:42,400
THAT WE'VE SEEN GLYCANS HAVE THE

8410
06:40:42,400 --> 06:40:44,200
REGULATORY POTENTIAL TO SUPPRESS

8411
06:40:44,200 --> 06:40:48,040
ALL SORTS OF MICROBES, PASSIVATE

8412
06:40:48,040 --> 06:40:49,440
ALL SORTS OF PROBLEMATIC

8413
06:40:49,440 --> 06:40:50,200
PATHOGENS.

8414
06:40:50,200 --> 06:40:51,200
YOU'LL SEE A COUPLE OF STORIES

8415
06:40:51,200 --> 06:40:54,160
COMING OUT IN THE NEXT COUPLE OF

8416
06:40:54,160 --> 06:40:56,360
WEEKS AND MONTHS, BUT THE LIST

8417
06:40:56,360 --> 06:40:58,440
IS GROWING, AND IN FACT WE

8418
06:40:58,440 --> 06:41:01,400
HAVEN'T SEEN A PATHOGEN,

8419
06:41:01,400 --> 06:41:02,240
OPPORTUNISTIC PATHOGEN SO FAR

8420
06:41:02,240 --> 06:41:06,480
THAT HAS NOT RESPONDED TO MU
MUCIN

8421
06:41:06,480 --> 06:41:10,480
GLYCANS IN THE WAY CERTAIN GENES

8422
06:41:10,480 --> 06:41:11,240
ARE DOWNREGULATED.

8423
06:41:11,240 --> 06:41:12,320
NOW THIS IS EXCITING BECAUSE

8424
06:41:12,320 --> 06:41:13,640
THIS MEANS THAT WE MIGHT HAVE

8425
06:41:13,640 --> 06:41:17,480
ACTUALLY TOOLS TO APPLY FOR

8426
06:41:17,480 --> 06:41:18,120
THERAPEUTIC PURPOSES.

8427
06:41:18,120 --> 06:41:19,760
THE PROBLEM IS, WE'RE STILL

8428
06:41:19,760 --> 06:41:21,600
WORKING WITH VERY COMPLEX GLYCAN

8429
06:41:21,600 --> 06:41:23,280
POOLS, SO THE QUESTION NOW

8430
06:41:23,280 --> 06:41:27,280
BECAME, HOW CAN WE REDUCE THIS

8431
06:41:27,280 --> 06:41:29,040
COMPLEXITY TO SINGLE STRUCTURES,

8432
06:41:29,040 --> 06:41:31,000
AND IF YOU LOOK ACROSS THE

8433
06:41:31,000 --> 06:41:32,440
BOARD, YOU SEE THAT DIFFERENT

8434
06:41:32,440 --> 06:41:35,240
MUCIN POOLS ARE AT PLAY, AND

8435
06:41:35,240 --> 06:41:37,760
EXPOSED, BUT YOU ALSO HAVE

8436
06:41:37,760 --> 06:41:39,640
CERTAIN GLYCANS THAT OVERLAP

8437
06:41:39,640 --> 06:41:40,640
THAT ARE CONSISTENT BETWEEN THE

8438
06:41:40,640 --> 06:41:44,240
DIFFERENT SUSH  SURFACES, AND
THOSE

8439
06:41:44,240 --> 06:41:46,640
BECAME OUR FOCUS BECAUSE WE SAW

8440
06:41:46,640 --> 06:41:51,240
THESE VIRULENCE ATTENUATION

8441
06:41:51,240 --> 06:41:53,720
EFFECTS TOWARDS CANDIDA

8442
06:41:53,720 --> 06:41:54,840
SPECIFICALLY, SO WE SAID WHY

8443
06:41:54,840 --> 06:41:56,640
DON'T WE LOOK AT THE SIX MOST

8444
06:41:56,640 --> 06:41:57,640
COMMON STRUCTURES IN THIS

8445
06:41:57,640 --> 06:41:59,040
OVERLAPPING POOL THAT ARE

8446
06:41:59,040 --> 06:42:00,640
EXPOSED AND PRESENT ON ALL

8447
06:42:00,640 --> 06:42:02,160
SURFACES AND SYNTHESIZE THEM SO

8448
06:42:02,160 --> 06:42:03,440
WE HAVE REALLY SINGLE

8449
06:42:03,440 --> 06:42:04,560
STRUCTURES.

8450
06:42:04,560 --> 06:42:06,480
LONG STORY SHORT, THESE ARE THE

8451
06:42:06,480 --> 06:42:07,640
MOST COMMON SIX STRUCTURES

8452
06:42:07,640 --> 06:42:09,680
YOU'LL FIND ON SURFACES AND ONE

8453
06:42:09,680 --> 06:42:10,680
OF THEM, THE CORE STRUCTURE, IS

8454
06:42:10,680 --> 06:42:11,240
REALLY EFFECTIVE.

8455
06:42:11,240 --> 06:42:13,440
SO YOU CAN TAKE THE SINGLE

8456
06:42:13,440 --> 06:42:14,960
GLYCAN, PRESENT THE TRANSITION

8457
06:42:14,960 --> 06:42:17,360
TO FILL MEN TAKES TO THE HYPHAE

8458
06:42:17,360 --> 06:42:18,800
FORM BY SINGLE STRUCTURE AND

8459
06:42:18,800 --> 06:42:21,840
SOME MODIFICATIONS ARE

8460
06:42:21,840 --> 06:42:24,240
TOLERATED, OTHERS LIKE -- ACID

8461
06:42:24,240 --> 06:42:34,800
ARE  SIALIC

8462
06:42:34,800 --> 06:42:38,040
ACID, A NOT.

8463
06:42:38,040 --> 06:42:39,200
 ARE NOT.

8464
06:42:39,200 --> 06:42:41,360
THAT NOW BECOMES LEVERAGABLE,

8465
06:42:41,360 --> 06:42:43,040
YOU SHOULD SEE THE STORY VERY

8466
06:42:43,040 --> 06:42:44,440
SHORTLY, IN THE NEXT TWO OR SO

8467
06:42:44,440 --> 06:42:45,840
WEEKS, IF YOU'RE INTERESTED.

8468
06:42:45,840 --> 06:42:47,480
SO TO SUMMARIZE, MUCINS ARE

8469
06:42:47,480 --> 06:42:48,240
THERAPEUTIC GOLD MINES.

8470
06:42:48,240 --> 06:42:54,000
THEY ARE REALLY RESERVOIRS OF

8471
06:42:54,000 --> 06:42:55,520
SMALL MOLECULES THAT ARE

8472
06:42:55,520 --> 06:42:58,520
BIOACTIVE, HAVE A BROAD RANGE OF

8473
06:42:58,520 --> 06:42:59,880
VIRULENCE ATTENUATING BEHAVIOR,

8474
06:42:59,880 --> 06:43:02,400
AND WE HAVEN'T EVEN STARTED TO

8475
06:43:02,400 --> 06:43:09,240
LOOK AT COMEN  -- THE NEXT TIME
YOU

8476
06:43:09,240 --> 06:43:10,720
BLOW YOUR NOSE, I WANT YOU TO

8477
06:43:10,720 --> 06:43:14,320
REMEMBER MUCINS ARE VERY GOOD AT

8478
06:43:14,320 --> 06:43:15,840
MANAGING PATHOGENS, I DID NOT

8479
06:43:15,840 --> 06:43:16,960
HAVE TIME TO TALK ABOUT THIS,

8480
06:43:16,960 --> 06:43:19,840
BUT AS YOU CAN GUESS ALSO FROM

8481
06:43:19,840 --> 06:43:24,400
SETH'S WORK, THIS NOT ONLY

8482
06:43:24,400 --> 06:43:25,480
PREVENTS INFECTION OUTGROWTH OF

8483
06:43:25,480 --> 06:43:26,800
CERTAIN MICROBES SPECIFICALLY,

8484
06:43:26,800 --> 06:43:29,920
BUT GENERALLY DRIVES DIVERSITY

8485
06:43:29,920 --> 06:43:32,600
BECAUSE WE HAVE DECREASED

8486
06:43:32,600 --> 06:43:33,240
INTERSPECIES COMPOSITION.

8487
06:43:33,240 --> 06:43:34,560
I WANT TO THANK A BIG TEAM OVER

8488
06:43:34,560 --> 06:43:38,040
THE YEARS, STUDENTS WHO HAVE

8489
06:43:38,040 --> 06:43:40,680
REALLY CHARTED NEW TERRITORY AND

8490
06:43:40,680 --> 06:43:42,120
REALLY WERE CREATIVE IN THE

8491
06:43:42,120 --> 06:43:43,400
TECHNIQUES THEY DEVELOPED AND

8492
06:43:43,400 --> 06:43:46,160
THE CONCEPTS THEY HAVE TESTED

8493
06:43:46,160 --> 06:43:48,240
AND PROVED AND DISPROVED OVER

8494
06:43:48,240 --> 06:43:52,920
AND OVER AGAIN UNTIL THE DATA

8495
06:43:52,920 --> 06:43:53,680
REALLY HELD.

8496
06:43:53,680 --> 06:43:56,120
AND OUR COLLABORATORS, OUR

8497
06:43:56,120 --> 06:44:01,440
EXPERTS IN GLYCAN SCIENCES AND

8498
06:44:01,440 --> 06:44:02,560
MICROBIOLOGY, A NUMBER OF THEM

8499
06:44:02,560 --> 06:44:04,040
ARE HERE, AND OF COURSE WITHOUT

8500
06:44:04,040 --> 06:44:06,360
FUNDING, WE WOULD NOT HAVE DONE

8501
06:44:06,360 --> 06:44:08,040
MUCH OF THIS WORK AT ALL.

8502
06:44:08,040 --> 06:44:08,800
AND I THANK YOU FOR YOUR

8503
06:44:08,800 --> 06:44:11,440
ATTENTION.

8504
06:44:11,440 --> 06:44:12,800
>> THANK YOU SO MUCH, THAT WAS A

8505
06:44:12,800 --> 06:44:14,360
BEAUTIFUL TALK.

8506
06:44:14,360 --> 06:44:16,240
ONCE AGAIN, I ENCOURAGE EVERYONE

8507
06:44:16,240 --> 06:44:17,640
TO SUBMIT THEIR QUESTIONS INTO

8508
06:44:17,640 --> 06:44:18,640
THE CHAT.

8509
06:44:18,640 --> 06:44:20,120
I'M NOT SURE IF YOU HAVE

8510
06:44:20,120 --> 06:44:21,040
QUESTIONS IN GENERAL BUT JUST

8511
06:44:21,040 --> 06:44:23,800
RIGHT OFF THE BAT JUST KIND OF A

8512
06:44:23,800 --> 06:44:25,520
VERY GENERAL QUESTION REGARDING

8513
06:44:25,520 --> 06:44:27,520
MECHANISM, I KNOW THIS IS NOT

8514
06:44:27,520 --> 06:44:28,720
SIMPLE STUFF THAT YOU'RE

8515
06:44:28,720 --> 06:44:31,200
STUDYING BUT EVEN WITH THE LAST

8516
06:44:31,200 --> 06:44:32,840
PART OF THE STUDY, JUST SOME OF

8517
06:44:32,840 --> 06:44:34,600
THE IDEAS YOU HAVE REGARDING HOW

8518
06:44:34,600 --> 06:44:37,640
THAT VERY SIMPLE DIE SACCHARIDE

8519
06:44:37,640 --> 06:44:40,280
IS ACTUALLY REGULATING SOME OF

8520
06:44:40,280 --> 06:44:40,640
THESE MICROBES.

8521
06:44:40,640 --> 06:44:42,320
>> SO WE HAVE DIFFERENT MICROBES

8522
06:44:42,320 --> 06:44:44,600
HAVE DIFFERENT MECHANISMS FOR

8523
06:44:44,600 --> 06:44:47,000
PSEUDOMONAS, WE WERE ABLE TO

8524
06:44:47,000 --> 06:44:48,320
IDENTIFY TWO COMPONENT SYSTEMS

8525
06:44:48,320 --> 06:44:51,480
THAT DIRECTLY BINDS TO GLYCANS.

8526
06:44:51,480 --> 06:44:52,880
FOR CANDIDA, THAT ES A LITTLE

8527
06:44:52,880 --> 06:44:53,240
MORE DIFFICULT.

8528
06:44:53,240 --> 06:44:54,840
WE HAVE THE PATHWAYS THAT LEAD

8529
06:44:54,840 --> 06:44:56,320
TO THE REPRESSION, WE DO NOT

8530
06:44:56,320 --> 06:44:57,720
HAVE THE RECEPTOR YET.

8531
06:44:57,720 --> 06:44:59,120
BUT THOSE WILL BE THE KINDS OF

8532
06:44:59,120 --> 06:45:01,760
STUDIES THAT NEED TO COME OUT,

8533
06:45:01,760 --> 06:45:05,880
AND I'M ANTICIPATING THAT

8534
06:45:05,880 --> 06:45:09,200
NUMEROUS -- WILL PLAY NUMEROUS

8535
06:45:09,200 --> 06:45:13,680
ROLES AND.

8536
06:45:13,680 --> 06:45:17,400
>> GREAT TALK.

8537
06:45:17,400 --> 06:45:18,000
BEAUTIFUL.

8538
06:45:18,000 --> 06:45:23,400
SO I'M WONDERING, IN CYSTIC

8539
06:45:23,400 --> 06:45:24,040
FIBROSIS PATIENTS, WHAT HAPPENS

8540
06:45:24,040 --> 06:45:25,680
TO THE MUCINS OR MAYBE IT'S NOT

8541
06:45:25,680 --> 06:45:29,240
TO THE MUCINS BUT THAT ALLOWS

8542
06:45:29,240 --> 06:45:32,000
THE PSEUDOMONAS TO BEGIN TO

8543
06:45:32,000 --> 06:45:34,040
PRODUCE BIOFILM AND BECOME

8544
06:45:34,040 --> 06:45:35,160
PROBLEMATIC OR INFECTIVE, WHAT

8545
06:45:35,160 --> 06:45:37,880
CAUSES THE IMBALANCE?

8546
06:45:37,880 --> 06:45:38,880
>> CYSTIC FIBROCIRCLES JUST LIKE

8547
06:45:38,880 --> 06:45:41,040
ON OTHER SURFACES AS WELL, WE

8548
06:45:41,040 --> 06:45:43,800
KNOW ONE FACTOR THAT CHANGES IS

8549
06:45:43,800 --> 06:45:45,120
GLYCANS INDEED CHANGE, AND THERE

8550
06:45:45,120 --> 06:45:47,720
HAS JUST A STUDY BEEN PUBLISHED,

8551
06:45:47,720 --> 06:45:49,080
I THINK IT'S PUBLISHED ALREADY,

8552
06:45:49,080 --> 06:45:54,280
NOT FROM US, UNC CHAPEL HILL ON

8553
06:45:54,280 --> 06:45:55,520
GLYCAN -- HOW THEY CHANGE,

8554
06:45:55,520 --> 06:45:56,600
CONSEQUENCE IS NOT CLEAR.

8555
06:45:56,600 --> 06:45:58,560
FOR US, THE MOST SIGNIFICANT

8556
06:45:58,560 --> 06:46:00,840
FACTOR THAT TRIGGERS THAT CAN

8557
06:46:00,840 --> 06:46:04,360
OVERRIDE MUCIN FUNCTION IS

8558
06:46:04,360 --> 06:46:05,240
ACTUALLY DNA.

8559
06:46:05,240 --> 06:46:07,440
SO EXTRACELLULAR DNA AS IT'S

8560
06:46:07,440 --> 06:46:09,080
EXPELLED BY MICROBES, AFTER A

8561
06:46:09,080 --> 06:46:11,240
CERTAIN CONCENTRATION, IT

8562
06:46:11,240 --> 06:46:12,240
COMPLETELY OVERRIDES MUCIN

8563
06:46:12,240 --> 06:46:12,880
EFFECTS.

8564
06:46:12,880 --> 06:46:21,440
MU SIGN IT'S REALLY OTHER

8565
06:46:21,440 --> 06:46:22,840
POLYSACCHARIDES OR DEGRADATION,

8566
06:46:22,840 --> 06:46:25,480
LOSS OF MUCINS THAT ARE

8567
06:46:25,480 --> 06:46:26,640
PRESUMABLY MOST PROMINENT.

8568
06:46:26,640 --> 06:46:28,600
>> THANK YOU.

8569
06:46:28,600 --> 06:46:30,200
>> SO WE'RE GOING TO SHIFT GEARS

8570
06:46:30,200 --> 06:46:32,840
A LITTLE BIT.

8571
06:46:32,840 --> 06:46:34,640
STEVE TOWNSEND ASKED TO GO EARLY

8572
06:46:34,640 --> 06:46:37,520
AND ACTUALLY WAS SCHEDULED TO GO

8573
06:46:37,520 --> 06:46:38,960
AT 3:40 SO TO HELP HIM ACTUALLY

8574
06:46:38,960 --> 06:46:40,240
BE ABLE TO GIVE HIS TALK AT THE

8575
06:46:40,240 --> 06:46:41,520
TIME HE WAS SLOTTED FOR

8576
06:46:41,520 --> 06:46:42,400
ORIGINALLY, WE'RE GOING TO HAVE

8577
06:46:42,400 --> 06:46:43,240
HIM GO NEXT.

8578
06:46:43,240 --> 06:46:45,120
STEVE IS FROM VANDERBILT, AND

8579
06:46:45,120 --> 06:46:47,880
HE'S GOING TO TALK ABOUT HUMAN

8580
06:46:47,880 --> 06:46:51,840
MILK OLIGOSACCHARIDES AS

8581
06:46:51,840 --> 06:46:52,600
MICROBIOME MODULATORS.

8582
06:46:52,600 --> 06:46:56,400
>> I APPRECIATE THAT, SEAN, AND

8583
06:46:56,400 --> 06:46:57,600
ALL OF THE ORGANIZERS AND

8584
06:46:57,600 --> 06:46:59,240
EVERYONE FOR PUTTING ON A GREAT

8585
06:46:59,240 --> 06:47:00,440
SYMPOSIUM AND ACCOMMODATING ME

8586
06:47:00,440 --> 06:47:02,240
SO I COULD MAKE TO PICK UP MY

8587
06:47:02,240 --> 06:47:03,680
ANGRY TODDLER ON TIME.

8588
06:47:03,680 --> 06:47:04,720
ALTHOUGH IF SHE SPENT THE

8589
06:47:04,720 --> 06:47:06,040
WEEKEND THERE, I PROBABLY

8590
06:47:06,040 --> 06:47:07,360
WOULDN'T BE DEVASTATED.

8591
06:47:07,360 --> 06:47:12,440
BUT WE'RE HERE TO TALK ABOUT

8592
06:47:12,440 --> 06:47:14,640
HUMAN MILK OLIGOSACCHARIDES IN

8593
06:47:14,640 --> 06:47:15,640
MODULATING THE MICROBIOME.

8594
06:47:15,640 --> 06:47:16,640
IN ADDITION TO THAT, WE'RE GOING

8595
06:47:16,640 --> 06:47:18,240
TO TALK ABOUT SOME OF OUR MORE

8596
06:47:18,240 --> 06:47:19,680
RECENT STUDIES AND TARGET

8597
06:47:19,680 --> 06:47:20,200
IDENTIFICATION.

8598
06:47:20,200 --> 06:47:22,000
THESE ARE IN COLLABORATION WITH

8599
06:47:22,000 --> 06:47:26,440
MIGRATE FRIEND AND COLLEAGUE AND

8600
06:47:26,440 --> 06:47:31,840
COLLABORATOR, DR. FANG YAN FROM

8601
06:47:31,840 --> 06:47:32,440
VANDERBILT UNIVERSITY MEDICAL

8602
06:47:32,440 --> 06:47:32,640
CENTER.

8603
06:47:32,640 --> 06:47:35,200
THE WAY WE CAN START TO TALK IS

8604
06:47:35,200 --> 06:47:36,640
GIVE A QUICK INTRODUCTION TO OUR

8605
06:47:36,640 --> 06:47:37,040
GROUP.

8606
06:47:37,040 --> 06:47:39,640
SO FOR THE PAST EIGHT YEARS AT

8607
06:47:39,640 --> 06:47:44,840
VEAN DER 

8608
06:47:44,840 --> 06:47:47,080
VANDERBILT, WE'RE INTERESTED IN

8609
06:47:47,080 --> 06:47:47,560
GLYCOSCIENCE.

8610
06:47:47,560 --> 06:47:48,760
THE BIGGEST PROGRAM THAT WE'VE

8611
06:47:48,760 --> 06:47:52,600
WORKED ON SO FAR IS OUR HUMAN

8612
06:47:52,600 --> 06:47:53,240
MILK OLIGOSACCHARIDE PROGRAM.

8613
06:47:53,240 --> 06:47:55,280
AND YOU CAN SEE FROM THE

8614
06:47:55,280 --> 06:47:56,840
DISPLAY, WE BECAME INTERESTED IN

8615
06:47:56,840 --> 06:47:59,240
THESE COMPOUNDS KNOWN AS HMOs

8616
06:47:59,240 --> 06:48:01,440
BECAUSE THEY'RE NOT PRESENT IN

8617
06:48:01,440 --> 06:48:04,640
COW'S MILK IN LARGE QUANTITY.

8618
06:48:04,640 --> 06:48:06,360
WE THUS WANTED TO FIGURE OUT WHY

8619
06:48:06,360 --> 06:48:07,400
THESE COMPOUNDS ARE SPECIAL,

8620
06:48:07,400 --> 06:48:08,760
WHAT TYPES OF HEALTH BENEFITS

8621
06:48:08,760 --> 06:48:14,160
MIGHT THEY CONFIRM TO FORMULA

8622
06:48:14,160 --> 06:48:15,040
THAT FORMULA-FED BABIES WOULDN'T

8623
06:48:15,040 --> 06:48:16,120
HAVE ACCESS TO.

8624
06:48:16,120 --> 06:48:17,160
OFTENTIMES WE GET THE QUESTION

8625
06:48:17,160 --> 06:48:18,600
IS HUMAN MILK REALLY THAT

8626
06:48:18,600 --> 06:48:21,320
SPECIAL IN ITS MACROMOLECULAR

8627
06:48:21,320 --> 06:48:21,920
CONTENT, SPECIFICALLY

8628
06:48:21,920 --> 06:48:22,880
CARBOHYDRATES, AND THE ANSWER IS

8629
06:48:22,880 --> 06:48:23,800
CERTAINLY YES.

8630
06:48:23,800 --> 06:48:26,680
HUMANS PRODUCE ABOUT 200 UNIQUE

8631
06:48:26,680 --> 06:48:28,200
OLIGOSACCHARIDES TO THE TUNE OF

8632
06:48:28,200 --> 06:48:30,320
ABOUT 8 TO 20 GRAMS PER LITER.

8633
06:48:30,320 --> 06:48:32,280
SO THIS IS A SIGNIFICANT AMOUNT

8634
06:48:32,280 --> 06:48:33,680
OF -- MOLECULES AND WE DON'T

8635
06:48:33,680 --> 06:48:36,960
REALLY SEE THIS CYBER PATTERN IN

8636
06:48:36,960 --> 06:48:38,200
ANY OTHER ANIMAL, SPECIFICALLY

8637
06:48:38,200 --> 06:48:39,600
LOOKING AT BOVINE.

8638
06:48:39,600 --> 06:48:41,360
NOW, IF WE WERE TO ASK ANYONE IN

8639
06:48:41,360 --> 06:48:42,640
THE AUDIENCE TODAY WHAT ARE THE

8640
06:48:42,640 --> 06:48:44,520
PURPOSE OF CARBOHYDRATES, MOST

8641
06:48:44,520 --> 06:48:46,720
WOULD GIVE A METABOLIC ANSWER OR

8642
06:48:46,720 --> 06:48:48,880
SAY THAT THESE ARE THE SOURCES

8643
06:48:48,880 --> 06:48:49,600
OF TARGETS.

8644
06:48:49,600 --> 06:48:51,720
WELL, IT TURNS OUT IN ONE OF THE

8645
06:48:51,720 --> 06:48:53,400
WONDERS OF HUMAN EVOLUTION, A

8646
06:48:53,400 --> 06:48:55,400
WOMAN WILL SPEND ABOUT TREE 50

8647
06:48:55,400 --> 06:48:57,640
TO 500-CALORIES PER DAY

8648
06:48:57,640 --> 06:48:59,840
SYNTHESIZING MULTIPLE GRAMS OF

8649
06:48:59,840 --> 06:49:00,520
OLIGOSACCHARIDES, YET THE CHILD

8650
06:49:00,520 --> 06:49:02,280
WON'T GET ANY TYPE OF NUTRITION

8651
06:49:02,280 --> 06:49:03,400
FROM THEM.

8652
06:49:03,400 --> 06:49:06,040
ONLY ABOUT 5% ACTUALLY REESM THE

8653
06:49:06,040 --> 06:49:08,360
CIRCULATION AND THE REST GO OUT

8654
06:49:08,360 --> 06:49:09,040
THE OTHER DIRECTION.

8655
06:49:09,040 --> 06:49:10,360
SO WITH THAT BEING SAID, WHAT

8656
06:49:10,360 --> 06:49:12,240
ARE THEY GENERALLY FOR?

8657
06:49:12,240 --> 06:49:14,960
WELL, WE KNOW THAT THEY ACT ON

8658
06:49:14,960 --> 06:49:16,400
MICROORGANISMS IN THE 80s AND

8659
06:49:16,400 --> 06:49:18,080
90s, IT WAS TEASED APART THAT

8660
06:49:18,080 --> 06:49:23,600
THESE COMPOUNDS ARE PREBITE
BIOTICS,

8661
06:49:23,600 --> 06:49:26,240
WE KNOW THEY'RE ANTIADHESIVE

8662
06:49:26,240 --> 06:49:27,160
ANTIMICROBIALS, SO IN THIS

8663
06:49:27,160 --> 06:49:28,120
MECHANISM, YOU COULD THINK ABOUT

8664
06:49:28,120 --> 06:49:30,640
THEM SERVING AS RECEPTOR DECOYS

8665
06:49:30,640 --> 06:49:33,840
SO THEY BIND PATHOGENS TO

8666
06:49:33,840 --> 06:49:35,440
PREVENT THEM FROM BINDING FROM

8667
06:49:35,440 --> 06:49:36,080
YOU.

8668
06:49:36,080 --> 06:49:37,680
OUR GROUP AND OTHERS HAVE DONE A

8669
06:49:37,680 --> 06:49:41,680
GOOD DEAL OF WORK BOTH FROM A

8670
06:49:41,680 --> 06:49:43,320
PHENOTYPIC AND MECHANISTIC

8671
06:49:43,320 --> 06:49:46,400
STANDPOINT, OF CHARACTERIZING

8672
06:49:46,400 --> 06:49:49,120
THEIR BEHAVIOR, AND -- AND

8673
06:49:49,120 --> 06:49:50,200
EVERYTHING WE DESCRIBED OF

8674
06:49:50,200 --> 06:49:52,000
COURSE IS ACTING ON

8675
06:49:52,000 --> 06:49:56,120
MICROORGANISMS, BUT WHAT ABOUT

8676
06:49:56,120 --> 06:49:58,840
THAT 5% THAT REACH SYSTEMIC

8677
06:49:58,840 --> 06:49:59,200
CIRCULATION?

8678
06:49:59,200 --> 06:50:01,040
WE KNOW THAT THESE COMPOUNDS ARE

8679
06:50:01,040 --> 06:50:02,840
ABLE TO MODULATE THE IMMUNE

8680
06:50:02,840 --> 06:50:03,040
SYSTEM.

8681
06:50:03,040 --> 06:50:04,880
THEY ACT ON THE BRAIN SO THEY'RE

8682
06:50:04,880 --> 06:50:07,480
RESPONSIBLE IN PART FOR SYSTEM

8683
06:50:07,480 --> 06:50:08,480
AND BRAIN DEVELOPMENT.

8684
06:50:08,480 --> 06:50:10,520
WE ALSO KNOW THESE COMPOUNDS

8685
06:50:10,520 --> 06:50:12,000
MODULATE THE GROWTH AND

8686
06:50:12,000 --> 06:50:17,080
DEVELOPMENT OF THE EPITHELIUM

8687
06:50:17,080 --> 06:50:18,760
AND HAVE -- MUCOSAL LAYER EARLY

8688
06:50:18,760 --> 06:50:19,440
ON IN LIFE.

8689
06:50:19,440 --> 06:50:21,640
SO IT WAS WITH THAT PRINCIPAL IN

8690
06:50:21,640 --> 06:50:25,240
MIND THAT WE REALLY TOOK AN

8691
06:50:25,240 --> 06:50:28,560
INTEREST TO FIGURE OUT HOW CAN

8692
06:50:28,560 --> 06:50:30,400
WE REALLY THINK ABOUT APPLYING

8693
06:50:30,400 --> 06:50:31,400
THESE COMPOUNDS AS THERAPEUTICS.

8694
06:50:31,400 --> 06:50:32,760
I WANT TO BRING YOUR ATTENTION

8695
06:50:32,760 --> 06:50:34,640
TO THE EPIDERMAL GROWTH FACTOR

8696
06:50:34,640 --> 06:50:37,920
RECEPTOR AND ALSO THE CONCEPT OF

8697
06:50:37,920 --> 06:50:38,480
MUCOSITIS.

8698
06:50:38,480 --> 06:50:40,440
THIS REALLY REFERS TO MUCOSAL

8699
06:50:40,440 --> 06:50:42,200
DAMAGE THAT REALLY IS A COMMON

8700
06:50:42,200 --> 06:50:43,400
SYMPTOM OF A LOT OF ILLNESSES,

8701
06:50:43,400 --> 06:50:44,920
SUCH AS IRRITABLE BOWEL

8702
06:50:44,920 --> 06:50:45,360
DISEASES.

8703
06:50:45,360 --> 06:50:47,080
IN THIS CASE, WE'RE TALKING

8704
06:50:47,080 --> 06:50:48,720
ABOUT CROEN DISEASE, ULCERATIVE

8705
06:50:48,720 --> 06:50:50,240
COLITIS.

8706
06:50:50,240 --> 06:50:51,240
ONE CAN ALSO THINK ABOUT THIS

8707
06:50:51,240 --> 06:50:55,960
BEING A SIDE EFFECT OF CELIAC

8708
06:50:55,960 --> 06:50:56,440
DISEASE -- CHEMOTHERAPY

8709
06:50:56,440 --> 06:50:56,720
RADIATION.

8710
06:50:56,720 --> 06:50:58,920
SO IN TOTALITY, ABOUT 10% OF ALL

8711
06:50:58,920 --> 06:50:59,920
AMERICANS ARE GOING TO DEAL WITH

8712
06:50:59,920 --> 06:51:02,000
SOME TYPE OF MUCOSAL TRAUMA OVER

8713
06:51:02,000 --> 06:51:05,480
THE COURSE OF THEIR LIFE, IT'S

8714
06:51:05,480 --> 06:51:06,480
TYPICALLY QIENT PAINFUL,

8715
06:51:06,480 --> 06:51:07,840
REQUIRES PAIN RELIEF.

8716
06:51:07,840 --> 06:51:10,000
MY MOM IS A 10 YEAR BREAST

8717
06:51:10,000 --> 06:51:11,240
CANCER SURVIVOR, SHE TALKED

8718
06:51:11,240 --> 06:51:12,120
ABOUT HER MUCOSITIS AND HOW IT

8719
06:51:12,120 --> 06:51:13,120
WAS SO DAMAGING BUT THEY

8720
06:51:13,120 --> 06:51:14,160
ACTUALLY HAD TO GIVE HER A

8721
06:51:14,160 --> 06:51:16,880
DIFFERENT CHEMOTHERAPY.

8722
06:51:16,880 --> 06:51:17,960
SO WHEN WE THINK ABOUT

8723
06:51:17,960 --> 06:51:18,840
PREVENTING THIS TYPE OF ILLNESS,

8724
06:51:18,840 --> 06:51:20,400
WHETHER IT'S FOR CROHN'S OR

8725
06:51:20,400 --> 06:51:24,880
CANCER TREATMENT, ONE OF THE

8726
06:51:24,880 --> 06:51:26,080
FRONTIER TREATMENTS FOR HEALING

8727
06:51:26,080 --> 06:51:28,560
MUCOSITIS IS THE IDEA OF

8728
06:51:28,560 --> 06:51:30,640
TARGETING THE EPIDERMAL --

8729
06:51:30,640 --> 06:51:31,280
RECEPTORS BECAUSE IF YOU DO

8730
06:51:31,280 --> 06:51:32,800
THAT, YOU CAN THINK ABOUT

8731
06:51:32,800 --> 06:51:34,560
INDUCING DISEASE REMISSION JUST

8732
06:51:34,560 --> 06:51:37,640
BY DIRECTLY TARGETING MUCOSAL

8733
06:51:37,640 --> 06:51:37,960
HEALING.

8734
06:51:37,960 --> 06:51:40,320
SO AT THIS POINT IN TIME --

8735
06:51:40,320 --> 06:51:43,000
PUTTING TOGETHER THIS PROGRAM

8736
06:51:43,000 --> 06:51:44,400
THAT WE DEVELOPING THE

8737
06:51:44,400 --> 06:51:48,240
HYPOTHESIS THAT HUMAN MILK

8738
06:51:48,240 --> 06:51:50,560
OLIGOSACCHARIDES MIGHT ACT ON

8739
06:51:50,560 --> 06:51:53,160
THE HUMAN GROWTH FACTOR

8740
06:51:53,160 --> 06:51:56,760
RECEPTOR -- HELP THAT MUCOSAL

8741
06:51:56,760 --> 06:51:58,720
LAYER, IN A REALLY ROBUST

8742
06:51:58,720 --> 06:51:59,040
MANNER.

8743
06:51:59,040 --> 06:52:01,920
IF WE CAN ACTIVATE THIS WITH

8744
06:52:01,920 --> 06:52:03,880
HMOs, WE CAN THINK ABOUT

8745
06:52:03,880 --> 06:52:04,360
PREVENTING MUCOSITIS.

8746
06:52:04,360 --> 06:52:05,520
SO THE QUESTION BECOMES WHAT

8747
06:52:05,520 --> 06:52:07,840
COMPOUNDS DO WE WANT TO USE.

8748
06:52:07,840 --> 06:52:09,400
BECAUSE WE HAVE A LOT OF

8749
06:52:09,400 --> 06:52:09,640
CHOICES.

8750
06:52:09,640 --> 06:52:11,120
THERE ARE 200 COMPOUNDS IN HUMAN

8751
06:52:11,120 --> 06:52:11,440
MILK.

8752
06:52:11,440 --> 06:52:13,080
FROM A MECHANISTIC STANDPOINT,

8753
06:52:13,080 --> 06:52:16,400
WE DIDN'T WANT TO -- ISOLATED

8754
06:52:16,400 --> 06:52:19,440
DIRECTLY FROM MILK BECAUSE THEN

8755
06:52:19,440 --> 06:52:20,520
WE CAN'T -- SO JUST TO GET TO

8756
06:52:20,520 --> 06:52:32,960
THE POINT, WE DECIDED TO USE --

8757
06:52:32,960 --> 06:52:34,280
FUCOSYLATED -- MOST COMMON IN

8758
06:52:34,280 --> 06:52:35,920
MILK FOR ALL PEOPLE BUT IT'S NOT

8759
06:52:35,920 --> 06:52:37,040
UBIQUITOUS.

8760
06:52:37,040 --> 06:52:39,520
80% OF THE POPULATION WILL BE

8761
06:52:39,520 --> 06:52:43,440
DEFINED AS SECRETERS, THUS CAN

8762
06:52:43,440 --> 06:52:45,840
GENERATE SUGARS THAT HAVE THAT

8763
06:52:45,840 --> 06:52:47,840
GEICO SYTIC BOND AND FOR THOSE

8764
06:52:47,840 --> 06:52:50,280
PEOPLE, THE MAJORITY OF SUGAR IN

8765
06:52:50,280 --> 06:52:52,840
MILK WILL BE 2 PRIME FL.

8766
06:52:52,840 --> 06:52:55,400
INTERESTINGLY FOR THOSE WHO ARE

8767
06:52:55,400 --> 06:52:56,800
NON-SECRETER, THEY DON'T HAVE

8768
06:52:56,800 --> 06:53:04,040
THIS -- MACHINERY, WILL BE 3FL

8769
06:53:04,040 --> 06:53:10,240
OR L NFP2, THE MOST COMMON SUGAR

8770
06:53:10,240 --> 06:53:12,440
IN MILK FOR NON-SECRETERS ARE

8771
06:53:12,440 --> 06:53:12,600
LNT.

8772
06:53:12,600 --> 06:53:13,840
I LIKE TO SAY FOR ALL THE

8773
06:53:13,840 --> 06:53:14,920
TRAINEES IN THE AUDIENCE, IF I

8774
06:53:14,920 --> 06:53:16,280
CAN GIVE YOU A SALES PITCH OR

8775
06:53:16,280 --> 06:53:17,360
TRY TO INSPIRE YOU, I WOULD SAY

8776
06:53:17,360 --> 06:53:18,840
GO OFF INTO THE WORLD OF

8777
06:53:18,840 --> 06:53:21,560
SYNTHETIC BIOLOGY AND

8778
06:53:21,560 --> 06:53:22,520
CHEMOENZYMATIC SYNTHESIS TO TRY

8779
06:53:22,520 --> 06:53:23,640
TO MAKE THESE SUGARS.

8780
06:53:23,640 --> 06:53:24,720
OVER THE PAST COUPLE OF YEARS,

8781
06:53:24,720 --> 06:53:26,360
WE HAD SOME VERY GENEROUS

8782
06:53:26,360 --> 06:53:28,280
FRIENDS IN THE FIELD, BOTH

8783
06:53:28,280 --> 06:53:29,680
ACADEMIA AND INDUSTRY, WHO HAVE

8784
06:53:29,680 --> 06:53:31,440
HELPED GET US -- BUT ULTIMATELY

8785
06:53:31,440 --> 06:53:32,840
THESE ARE ALWAYS SMALL

8786
06:53:32,840 --> 06:53:34,680
QUANTITIES.

8787
06:53:34,680 --> 06:53:36,480
SO IF I WANT TO DO SOME ANIMAL

8788
06:53:36,480 --> 06:53:37,640
STUDIES LIKE I'M GOING TO SHOW

8789
06:53:37,640 --> 06:53:40,040
YOU TODAY, WE NEED 100 GRAMS OF

8790
06:53:40,040 --> 06:53:40,280
COMPOUND.

8791
06:53:40,280 --> 06:53:42,640
SO THE SECOND I SAY WE NEED

8792
06:53:42,640 --> 06:53:44,240
100 GRAMS OR 10 GRAMS, PEOPLE NO

8793
06:53:44,240 --> 06:53:47,720
LONGER ARE SMILING AND THE SMILE

8794
06:53:47,720 --> 06:53:48,200
TURNS UPSIDE-DOWN.

8795
06:53:48,200 --> 06:53:51,240
SO JUST TO GET TO THE POINT,

8796
06:53:51,240 --> 06:53:53,000
WE'RE USING SYNTHETIC MATERIAL

8797
06:53:53,000 --> 06:53:55,640
FOR ALL OF OUR MOUSE STUDIES.

8798
06:53:55,640 --> 06:53:56,840
USING CHEMICAL SYNTHESIS, YOU

8799
06:53:56,840 --> 06:53:59,840
CAN STILL GET 2 PRIME FL AT 50

8800
06:53:59,840 --> 06:54:04,240
CENTS A GRAM.

8801
06:54:04,240 --> 06:54:11,560
FOR NLT,  LNT, I CAN HAVE AN
UNDERGRAD

8802
06:54:11,560 --> 06:54:14,280
WAIT MAKE A KILO -- REALLY STILL

8803
06:54:14,280 --> 06:54:15,840
NOT COST-EFFECTIVE USING MOST

8804
06:54:15,840 --> 06:54:19,680
MODERN STRATEGIES.

8805
06:54:19,680 --> 06:54:20,760
SO GOING FORWARD RIGHT AGAIN,

8806
06:54:20,760 --> 06:54:21,960
WE'RE THINKING ABOUT THIS

8807
06:54:21,960 --> 06:54:24,360
ADDITIONAL HYPOTHESIS THAT HUMAN

8808
06:54:24,360 --> 06:54:25,240
MILK OLIGOSACCHARIDES, IN THIS

8809
06:54:25,240 --> 06:54:28,560
CASE WE'RE GOING TO BE WORKING

8810
06:54:28,560 --> 06:54:30,640
WITH 2 PRIME FL AND ACTIVATE

8811
06:54:30,640 --> 06:54:32,480
GROWTH FACTOR RECEPTOR, HERE'S A

8812
06:54:32,480 --> 06:54:36,520
WESTERN BLOT THAT SHOWS YOU AT

8813
06:54:36,520 --> 06:54:38,600
LEAST PRELIMINARILY THAT THIS IS

8814
06:54:38,600 --> 06:54:42,560
THE CASE, MANY DOWNSTREAM

8815
06:54:42,560 --> 06:54:47,360
TARGETS LIKE ERK1 AND ERK2 IN

8816
06:54:47,360 --> 06:54:48,440
MOUSE EPITHELIAL CELLS.

8817
06:54:48,440 --> 06:54:50,120
AT THIS POINT IN THE GAME, WHICH

8818
06:54:50,120 --> 06:54:53,440
HAVE A LOT OF OPERATION,

8819
06:54:53,440 --> 06:54:54,120
MECHANISTIC DRIVEN THEIR PEW

8820
06:54:54,120 --> 06:54:55,560
TICK, AND WE WANT TO SEE WHAT WE

8821
06:54:55,560 --> 06:54:56,760
CAN ACTUALLY DO WITH IT.

8822
06:54:56,760 --> 06:54:59,840
AT THIS POINT, I'M GOING TO

8823
06:54:59,840 --> 06:55:01,760
INTRODUCE YOU SO THE MODEL OF

8824
06:55:01,760 --> 06:55:02,240
COLITIS.

8825
06:55:02,240 --> 06:55:04,280
THIS IS AN ANIMAL MODEL THAT'S

8826
06:55:04,280 --> 06:55:05,560
USED OFTEN BECAUSE IT SHARES A

8827
06:55:05,560 --> 06:55:08,480
LOT OF HOMOLOGIES WITH HUMAN

8828
06:55:08,480 --> 06:55:08,840
CROHN'S DISEASE.

8829
06:55:08,840 --> 06:55:10,600
SO THE WAY THIS EXPERIMENT WORKS

8830
06:55:10,600 --> 06:55:14,520
IS WE'RE GOING TO GIVE IT FOR

8831
06:55:14,520 --> 06:55:16,200
ABOUT FOUR WEEKS, INDUCED

8832
06:55:16,200 --> 06:55:20,440
INFLAMMATION USING TNBS.

8833
06:55:20,440 --> 06:55:22,560
FOUR DAYS, THEN DO AN AUTOPSY IN

8834
06:55:22,560 --> 06:55:23,760
ORDER TO FIGURE OUT WHAT THE

8835
06:55:23,760 --> 06:55:24,680
OUTCOME OF THE EXPERIMENT WAS.

8836
06:55:24,680 --> 06:55:25,680
SO IN THIS CASE IT'S PRETTY

8837
06:55:25,680 --> 06:55:27,600
COOL, WE ARE ABLE TO SEE THAT IF

8838
06:55:27,600 --> 06:55:37,320
WE DOSE THE TOXIN ALONGSIDE

8839
06:55:37,320 --> 06:55:38,320
FUCOSYLLACTOSE -- IF WE GO AHEAD

8840
06:55:38,320 --> 06:55:39,520
AND LOOK AT A COUPLE OF PICTURES

8841
06:55:39,520 --> 06:55:41,240
IT TURNS OUT THE EPITHELIAL

8842
06:55:41,240 --> 06:55:41,800
LAYER, SPECIFICALLY THE

8843
06:55:41,800 --> 06:55:44,240
JUNCTIONS AND THE VILLI, THEY

8844
06:55:44,240 --> 06:55:46,840
ALL REALLY MIRROR THAT OF A

8845
06:55:46,840 --> 06:55:48,600
CONTROL, SHOWING WE CAN MITIGATE

8846
06:55:48,600 --> 06:55:50,400
DAMAGE BY THIS REALLY NICE MODEL

8847
06:55:50,400 --> 06:55:53,840
OF COLITIS.

8848
06:55:53,840 --> 06:55:55,440
NOW TO HIT THE POINT HOME A

8849
06:55:55,440 --> 06:55:58,040
LITTLE BIT FURTHER, AT THIS

8850
06:55:58,040 --> 06:55:58,760
POINT IN THE GAME WE'RE GOING

8851
06:55:58,760 --> 06:55:59,640
BACK INTO THE EXPERIMENT AND

8852
06:55:59,640 --> 06:56:03,240
WE'RE COMPARING A STANDARDS WILD

8853
06:56:03,240 --> 06:56:04,480
TYPE MOUSE TO THAT OF ONE THAT

8854
06:56:04,480 --> 06:56:07,280
HAS THE KNOCKOUT FOR EGFR, THIS

8855
06:56:07,280 --> 06:56:09,240
AGAIN IS IN THEIR EPITHELIAL

8856
06:56:09,240 --> 06:56:09,920
CELLS.

8857
06:56:09,920 --> 06:56:11,960
WHAT'S PRETTY COOL IS WE CAN

8858
06:56:11,960 --> 06:56:12,960
SHOW THE 2 PRIME FL STIMULATION

8859
06:56:12,960 --> 06:56:14,640
OF THIS RECEPTOR IS RESPONSIBLE

8860
06:56:14,640 --> 06:56:16,240
FOR PREVENTING COLITIS IN THIS

8861
06:56:16,240 --> 06:56:18,760
MODEL, AND SORT OF REALLY LIKE A

8862
06:56:18,760 --> 06:56:21,880
NICE COOL PRELIMINARY FINDING AS

8863
06:56:21,880 --> 06:56:25,640
WE GO FORWARD.

8864
06:56:25,640 --> 06:56:28,760
OKAY.

8865
06:56:28,760 --> 06:56:31,400
SO WE KNOW WE HAVE ACTIVATION OF

8866
06:56:31,400 --> 06:56:33,120
EGFR IS AT PLAY FOR THE HEALING

8867
06:56:33,120 --> 06:56:34,120
THAT WE ARE EXPERIENCING.

8868
06:56:34,120 --> 06:56:35,440
WE ALSO WANTED TO TURN OUR

8869
06:56:35,440 --> 06:56:37,840
ATTENTION TO THE MICROBIOME, AND

8870
06:56:37,840 --> 06:56:39,480
WHAT EFFECTS THAT MIGHT HAVE ON

8871
06:56:39,480 --> 06:56:40,400
PREVENTING MUCOSITIS.

8872
06:56:40,400 --> 06:56:44,640
SO WE WENT IN TO ANALYZE THE

8873
06:56:44,640 --> 06:56:45,920
FLORA OF THE MOUSE IN THE

8874
06:56:45,920 --> 06:56:50,440
CONTEXT OF THE WILD TYPE VERSES

8875
06:56:50,440 --> 06:56:51,680
ONE -- AND THE DRINKING WATER OF

8876
06:56:51,680 --> 06:56:52,040
THE MICE.

8877
06:56:52,040 --> 06:56:53,680
THIS GOES ON FOR ABOUT FOUR

8878
06:56:53,680 --> 06:56:55,120
WEEKS, AND THEN WE ARE DOING

8879
06:56:55,120 --> 06:56:58,280
SEQUENCING OF THEIR FECAL

8880
06:56:58,280 --> 06:56:58,600
MICROBIOME.

8881
06:56:58,600 --> 06:57:00,360
SO OF NOTE WE FOUND THAT 2 PRIME

8882
06:57:00,360 --> 06:57:04,280
FL JEPLY HAS  GENERALLY HAS THE
ABILITY TO

8883
06:57:04,280 --> 06:57:06,240
INCREASE THE COUNTS OF

8884
06:57:06,240 --> 06:57:08,680
MICROORGANISMS ASSOCIATED WITH

8885
06:57:08,680 --> 06:57:10,600
ANTIINFLAMMATION BUT ALSO BY

8886
06:57:10,600 --> 06:57:13,600
DECREASING THE SPECIES THAT ARE

8887
06:57:13,600 --> 06:57:14,600
PRO INFLAMMATORY, SO A PRETTY

8888
06:57:14,600 --> 06:57:17,920
COOL FINDING ONCE AGAIN.

8889
06:57:17,920 --> 06:57:18,840
NOW AT THIS STAGE OF THE GAME,

8890
06:57:18,840 --> 06:57:20,680
KEEP IN MIND WE KNOW FROM

8891
06:57:20,680 --> 06:57:23,920
PRECEDENT IN BOTH OUR MOST

8892
06:57:23,920 --> 06:57:26,640
RECENT DATA THAT HUMAN MILK

8893
06:57:26,640 --> 06:57:27,920
OLIGOSACCHARIDES ACT ON SPECIFIC

8894
06:57:27,920 --> 06:57:29,280
PROTEIN TARGETS, WE KNOW THEY

8895
06:57:29,280 --> 06:57:35,080
HAVE A PROTEIN IN THE -- THIS

8896
06:57:35,080 --> 06:57:36,920
TIME FROM THE STANDPOINT OF

8897
06:57:36,920 --> 06:57:37,240
CHEMOTHERAPY.

8898
06:57:37,240 --> 06:57:38,240
SO WHAT I'M SHOWING YOU HERE AND

8899
06:57:38,240 --> 06:57:39,800
WHAT WILL BE REALLY ANALYZED FOR

8900
06:57:39,800 --> 06:57:42,080
THE REMAINING 8 MINUTES OR SO IS

8901
06:57:42,080 --> 06:57:45,560
OUR DATA THAT COMES OUT OF THIS

8902
06:57:45,560 --> 06:57:48,800
MODEL OF CHEMOTHERAPY AND

8903
06:57:48,800 --> 06:57:49,040
RADIATION.

8904
06:57:49,040 --> 06:57:51,040
SO 5FU IS A REALLY PHENOMENAL

8905
06:57:51,040 --> 06:57:52,240
MODEL BECAUSE IT REALLY MIMICS

8906
06:57:52,240 --> 06:57:53,840
AND SHOWS A LOT OF HOMOLOGY WITH

8907
06:57:53,840 --> 06:57:54,960
PATIENTS THAT ARE RECEIVING HIGH

8908
06:57:54,960 --> 06:57:56,840
DOSE CHEMOTHERAPY OR RADIATION.

8909
06:57:56,840 --> 06:57:59,960
IT CAUSES SIGNIFICANT DAMAGE,

8910
06:57:59,960 --> 06:58:01,240
AND WE FELT IF WE COULD REALLY

8911
06:58:01,240 --> 06:58:02,640
MAKE A DIFFERENCE HERE IN

8912
06:58:02,640 --> 06:58:03,480
PREVENTING DAMAGE FROM

8913
06:58:03,480 --> 06:58:05,120
CHEMOTHERAPY OR FROM HEALING

8914
06:58:05,120 --> 06:58:06,000
CHEMOTHERAPY, THIS WOULD BE

8915
06:58:06,000 --> 06:58:07,120
REALLY COOL FOR PATIENTS AS WE

8916
06:58:07,120 --> 06:58:10,400
TRY TO TRANSLATE MAYBE INTO THE

8917
06:58:10,400 --> 06:58:13,240
CLINIC.

8918
06:58:13,240 --> 06:58:14,520
SO IN THIS CASE RIGHT OFF THE

8919
06:58:14,520 --> 06:58:21,000
BAT, WE WENT IN TO EXAMINE

8920
06:58:21,000 --> 06:58:25,040
WHETHER 2 PRIME FL COULD INDUCE

8921
06:58:25,040 --> 06:58:26,640
APOPTOSIS, THIS IS A MECHANISM

8922
06:58:26,640 --> 06:58:29,600
HOWL MANY CHEMOTHERAPIES KILL

8923
06:58:29,600 --> 06:58:30,240
TRANSFORM CELLS.

8924
06:58:30,240 --> 06:58:31,720
INTERESTINGLY IT DOES PREVENT

8925
06:58:31,720 --> 06:58:32,400
CHEMOTHERAPY FROM PREVENTING THE

8926
06:58:32,400 --> 06:58:34,320
GROWTH OF HEALTHY MOUTH EP THREE

8927
06:58:34,320 --> 06:58:36,040
YELL CELLS, BUT INTERESTINGLY,

8928
06:58:36,040 --> 06:58:37,520
IT DOES NOT PROVIDE ANY

8929
06:58:37,520 --> 06:58:38,720
PROTECTION FOR TRANSFORMED

8930
06:58:38,720 --> 06:58:42,640
CANCER CELLS SUCH AS AGS OR

8931
06:58:42,640 --> 06:58:43,000
AT29.

8932
06:58:43,000 --> 06:58:44,440
SO THAT WAS ANOTHER COOL

8933
06:58:44,440 --> 06:58:48,080
FINDING, WE COULD USE 2 PRIME FL

8934
06:58:48,080 --> 06:58:49,840
TO PROTECT NON-HEALTHY TRANSPORT

8935
06:58:49,840 --> 06:58:51,520
CELLS BUT IT DOESN'T PROVIDE THE

8936
06:58:51,520 --> 06:58:55,840
SAME BENEFIT TO THOSE THAT ARE

8937
06:58:55,840 --> 06:58:56,800
ALREADY CANCERS.

8938
06:58:56,800 --> 06:58:58,440
MOVING FORWARD WE INITIATED A

8939
06:58:58,440 --> 06:59:00,400
STUDY WHERE WE WANTED TO

8940
06:59:00,400 --> 06:59:01,400
EVALUATE INFLAMMATION IN THE

8941
06:59:01,400 --> 06:59:06,600
SMALL INTESTINE OF A MOUSE

8942
06:59:06,600 --> 06:59:09,200
COHORT WITH VARYING LENGTH OF

8943
06:59:09,200 --> 06:59:11,800
EXPOSURE AND VARYING LENGTH OF

8944
06:59:11,800 --> 06:59:12,440
TREATMENT.

8945
06:59:12,440 --> 06:59:16,280
WHAT WE HEARD, REGARDLESS OF HOW

8946
06:59:16,280 --> 06:59:18,600
LONG THE MICE ARE ON

8947
06:59:18,600 --> 06:59:19,560
CHEMOTHERAPY, TYPICALLY

8948
06:59:19,560 --> 06:59:20,760
DECREASES INFLAMMATION

8949
06:59:20,760 --> 06:59:21,720
SIGNIFICANTLY BUT THAT

8950
06:59:21,720 --> 06:59:22,640
COTREATMENT DOESN'T WORK IF THE

8951
06:59:22,640 --> 06:59:26,040
HOUSE HAS ALREADY BEEN GIVEN

8952
06:59:26,040 --> 06:59:28,440
CHEMO BEFORE IT WAS GIVEN

8953
06:59:28,440 --> 06:59:33,480
2 PRIME FL.

8954
06:59:33,480 --> 06:59:35,160
NOW COMPARED WITH 5 URACIL

8955
06:59:35,160 --> 06:59:38,840
TREATMENT ALONE, IT TURNS OUT

8956
06:59:38,840 --> 06:59:47,600
THE 2 PRIME FL PRE-TREATMENT --

8957
06:59:47,600 --> 06:59:48,960
DECREASE BODY WEIGHT AND

8958
06:59:48,960 --> 06:59:49,840
IMPROVE -- SCORES.

8959
06:59:49,840 --> 06:59:51,040
SO IF YOU THINK ABOUT

8960
06:59:51,040 --> 06:59:52,440
CHEMOTHERAPY, IT'S GOING TO

8961
06:59:52,440 --> 06:59:53,560
CAUSE SIGNIFICANT ULCERATION AND

8962
06:59:53,560 --> 06:59:55,400
INFLAMMATION IN ANY SUBJECT, BUT

8963
06:59:55,400 --> 06:59:56,920
THESE ABNORMALITIES ARE ALWAYS

8964
06:59:56,920 --> 07:00:00,040
DECREASED WHEN WE PRE-TREAT WITH

8965
07:00:00,040 --> 07:00:03,560
2 PRIME FL.

8966
07:00:03,560 --> 07:00:06,120
NOW, LASTLY BEFORE RETURNING

8967
07:00:06,120 --> 07:00:07,560
BACK TO THE MICROBIOTA, IT'S

8968
07:00:07,560 --> 07:00:08,520
REALLY IMPORTANT TO NOTE, I

8969
07:00:08,520 --> 07:00:09,800
GUESS, FOR MANY OF THE TRAINEES

8970
07:00:09,800 --> 07:00:11,960
IN THE AUDIENCE, YOU'VE HEARD A

8971
07:00:11,960 --> 07:00:13,800
LOT OF THE MUCUS SURFACES TOED.

8972
07:00:13,800 --> 07:00:16,680
IF YOU THINK ABOUT IT, THE

8973
07:00:16,680 --> 07:00:18,520
MUCOSAL SURFACE IS REALLY

8974
07:00:18,520 --> 07:00:20,760
IMPORTANT IN PROTECTING --

8975
07:00:20,760 --> 07:00:21,640
BACTERIAL INFECTION, VIRAL

8976
07:00:21,640 --> 07:00:22,560
ASSAULT, EERCH MECHANICAL DAMAGE

8977
07:00:22,560 --> 07:00:25,000
FROM JUST A NORMAL FUNCTION OF

8978
07:00:25,000 --> 07:00:28,080
THE DP  G.I. TRACT.

8979
07:00:28,080 --> 07:00:31,160
SO CENTRAL TO THIS WHOLE ARE

8980
07:00:31,160 --> 07:00:33,040
GOBLIN CELLS, THESE ARE MUCIN

8981
07:00:33,040 --> 07:00:33,680
PRODUCING.

8982
07:00:33,680 --> 07:00:35,760
THEY GO PEL THE CELL, KOWNDZ ARE

8983
07:00:35,760 --> 07:00:37,280
DECREASED AND THESE CELLS ARE

8984
07:00:37,280 --> 07:00:39,640
REALLY JUST ATTACKED AND

8985
07:00:39,640 --> 07:00:39,960
ERADICATED.

8986
07:00:39,960 --> 07:00:40,760
SO WHAT WAS COOL ABOUT THIS

8987
07:00:40,760 --> 07:00:41,760
PORTION OF THE EXPERIMENT THAT

8988
07:00:41,760 --> 07:00:43,200
I'M SHOWING YOU IS WOULD HE

8989
07:00:43,200 --> 07:00:47,480
FOUND OUT THE 2 PRIME FL -- WE

8990
07:00:47,480 --> 07:00:48,720
CAN KEEP A NICE MAINTENANCE OF

8991
07:00:48,720 --> 07:00:49,960
THIS POPULATION THROUGHOUT THE

8992
07:00:49,960 --> 07:00:51,200
DURATION OF TREATMENT WITH THE

8993
07:00:51,200 --> 07:00:54,720
CHEMOTHERAPY.

8994
07:00:54,720 --> 07:00:55,120
ALL RIGHT.

8995
07:00:55,120 --> 07:00:57,320
SO AS WE RETURN BACK TO THE

8996
07:00:57,320 --> 07:00:58,440
MICROBIOME WHEN WE CLOSE THIS

8997
07:00:58,440 --> 07:00:59,720
OUT, THIS WAS A PRETTY COOL

8998
07:00:59,720 --> 07:01:01,920
FINDING AND I REALLY LIKE THE

8999
07:01:01,920 --> 07:01:03,560
IDEA OF USING THESE COMPOUNDS TO

9000
07:01:03,560 --> 07:01:05,600
HIT SPECIFIC PROTEIN TARGETS,

9001
07:01:05,600 --> 07:01:07,840
BUT ALSO MODULATING THE PLY CROW

9002
07:01:07,840 --> 07:01:08,840
BIOME TO GET ADDED BENEFIT.

9003
07:01:08,840 --> 07:01:11,760
IN THIS CASE WHAT WE OBSERVED IS

9004
07:01:11,760 --> 07:01:15,280
THAT 2 PRIME FL DECREASES

9005
07:01:15,280 --> 07:01:17,440
5 FLUOROURACIL AND INDUCES

9006
07:01:17,440 --> 07:01:19,640
ULCERATION OF THE MICROBIOTA IN

9007
07:01:19,640 --> 07:01:20,040
OUR MOUSE MODEL.

9008
07:01:20,040 --> 07:01:21,280
SO THIS CAN BE CONSIDERED

9009
07:01:21,280 --> 07:01:22,480
IMPORTANT BECAUSE IT'S BEEN

9010
07:01:22,480 --> 07:01:25,120
REPORTED THAT CHEMOTHERAPY IS

9011
07:01:25,120 --> 07:01:26,560
OFTEN ASSOCIATED WITH DYSBIOSIS

9012
07:01:26,560 --> 07:01:29,440
OF PATIENTS, SO WE WANTED TO

9013
07:01:29,440 --> 07:01:30,640
EVALUATE WHAT HAPPENS TO THE

9014
07:01:30,640 --> 07:01:32,200
OVERALL FECAL BACTERIAL

9015
07:01:32,200 --> 07:01:33,640
COMPOSITION, SUCH AS BETA

9016
07:01:33,640 --> 07:01:35,240
DIVERSITY SHOWN IN THE MIDDLE OR

9017
07:01:35,240 --> 07:01:37,320
OUR SHANNON AND SIMPSON INDICES

9018
07:01:37,320 --> 07:01:38,560
WHICH IS A REPRESENTATION OF

9019
07:01:38,560 --> 07:01:40,600
ALPHA DIVERSITY WHEN WE TREAT

9020
07:01:40,600 --> 07:01:42,240
THESE ANIMALS WITH 2 PRIME FL

9021
07:01:42,240 --> 07:01:44,640
VERSUS JUST CHEMOTHERAPEUTIC.

9022
07:01:44,640 --> 07:01:47,440
SO WE GENERALLY OBSERVE, AGAIN,

9023
07:01:47,440 --> 07:01:49,880
THAT 2 PRIME FL PRE-TREATMENT

9024
07:01:49,880 --> 07:01:50,880
AND ACTUALLY CONCURRENT

9025
07:01:50,880 --> 07:01:52,840
TREATMENT BOTH ELICIT A PARTIAL

9026
07:01:52,840 --> 07:01:55,240
SHIFT OF THE COMPOSITION OF THE

9027
07:01:55,240 --> 07:01:56,680
GUT MICROBIOTA AND ANIMALS THAT

9028
07:01:56,680 --> 07:01:58,000
WERE EXPOSED TO CHEMOTHERAPY

9029
07:01:58,000 --> 07:01:59,640
BACK TO NORMAL, BACK TO THE WILD

9030
07:01:59,640 --> 07:01:59,960
TYPE.

9031
07:01:59,960 --> 07:02:02,760
AND AS YOU MIGHT EXPECT,

9032
07:02:02,760 --> 07:02:04,000
DIFFERENT SPECIES OF BACTERIA

9033
07:02:04,000 --> 07:02:05,440
THAT ARE KNOWN TO BE

9034
07:02:05,440 --> 07:02:07,480
ANTI-INFLAMMATORY OR SLIGHTLY

9035
07:02:07,480 --> 07:02:09,440
UPREGULATED AND THOSE THAT ARE

9036
07:02:09,440 --> 07:02:14,200
PRO INFLAMMATORY ARE GENERALLY

9037
07:02:14,200 --> 07:02:14,520
DOWNREGULATED.

9038
07:02:14,520 --> 07:02:16,280
SO WITH THAT, WE'VE HIT THE

9039
07:02:16,280 --> 07:02:17,160
16-MINUTE MARK.

9040
07:02:17,160 --> 07:02:18,880
THE ONLY THING LEFT TO DO IS

9041
07:02:18,880 --> 07:02:21,200
THANK ALL OF THE FANTASTIC

9042
07:02:21,200 --> 07:02:22,440
TRAINEES WHO WORKED ON THIS

9043
07:02:22,440 --> 07:02:23,280
SPECIFIC PROJECT.

9044
07:02:23,280 --> 07:02:25,080
IN THIS CASE THERE ARE THREE

9045
07:02:25,080 --> 07:02:30,640
FROM THE YAN LAB AND FROM MY

9046
07:02:30,640 --> 07:02:32,520
GROUP -- THEY'VE DONE PHENOMENAL

9047
07:02:32,520 --> 07:02:34,040
WORK IN THESE STUDIES THAT ARE

9048
07:02:34,040 --> 07:02:35,240
REALLY TRANSLATIONAL, POWERFUL.

9049
07:02:35,240 --> 07:02:36,600
COULDN'T HAVE DONE IT WITHOUT

9050
07:02:36,600 --> 07:02:36,880
THEM.

9051
07:02:36,880 --> 07:02:39,080
ALSO WANT TO THANK NIH AUTHOR

9052
07:02:39,080 --> 07:02:40,920
FAIR SUPPORT, AND TAKE ANY

9053
07:02:40,920 --> 07:02:41,920
QUESTIONS THAT YOU MIGHT HAVE.

9054
07:02:41,920 --> 07:02:45,160
>> THANK YOU.

9055
07:02:45,160 --> 07:02:46,400
AND I LIKE YOUR STATEMENT,

9056
07:02:46,400 --> 07:02:53,160
SUPPORT THE NIH, THAT'S GOOD.

9057
07:02:53,160 --> 07:02:55,440
YOU HAD YOUR HAND UP.

9058
07:02:55,440 --> 07:02:56,160
>> WHAT'S UP, STEVE.

9059
07:02:56,160 --> 07:02:57,320
I ALWAYS WANTED TO MEET YOU SO

9060
07:02:57,320 --> 07:02:59,520
IT'S NICE TO MEET YOU IN PERSON.

9061
07:02:59,520 --> 07:03:01,480
>> SAME HERE, AND I LIKE YOUR

9062
07:03:01,480 --> 07:03:01,640
HAT.

9063
07:03:01,640 --> 07:03:03,240
>> IT'S A GOLDEN STATE WARRIORS

9064
07:03:03,240 --> 07:03:04,080
HAT.

9065
07:03:04,080 --> 07:03:06,280
IT WAS JUST FROM TRAVELING.

9066
07:03:06,280 --> 07:03:07,920
ANYWAY, SORRY.

9067
07:03:07,920 --> 07:03:09,800
SO OKAY.

9068
07:03:09,800 --> 07:03:12,200
SO I RECALL A PAPER A WHILE AGO

9069
07:03:12,200 --> 07:03:17,120
WHICH WAS ABOUT MAYBE LIKE 3SL

9070
07:03:17,120 --> 07:03:20,080
IN COLITIS.

9071
07:03:20,080 --> 07:03:21,040
AND REALLY -- I THINK THEY

9072
07:03:21,040 --> 07:03:24,440
PROPOSED THAT IT ACTUALLY WAS

9073
07:03:24,440 --> 07:03:25,320
ACTIVATING TOLL-LIKE RECEPTORS

9074
07:03:25,320 --> 07:03:30,520
DIRECTLY IN A PRO-ACTIVATION

9075
07:03:30,520 --> 07:03:32,040
MODE AND WORSE, COLITIS.

9076
07:03:32,040 --> 07:03:33,480
WHICH LEADS TO KIND OF LIKE THIS

9077
07:03:33,480 --> 07:03:36,920
QUESTION I HAVE WHICH IS, OF THE

9078
07:03:36,920 --> 07:03:41,600
DIFFERENT SYLATED OR FEW COST

9079
07:03:41,600 --> 07:03:43,520
LATED HUMAN MILK

9080
07:03:43,520 --> 07:03:44,240
OLIGOSACCHARIDES, DO YOU THINK

9081
07:03:44,240 --> 07:03:46,600
THERE ARE FUNCTIONAL

9082
07:03:46,600 --> 07:03:48,840
DIFFERENCES, EVEN EVOLUTIONARY,

9083
07:03:48,840 --> 07:03:50,160
BETWEEN THESE TWO BECAUSE IT

9084
07:03:50,160 --> 07:03:51,960
SEEMS LIKE YOU HAVE A FEW COST

9085
07:03:51,960 --> 07:03:53,840
LATED ONE THAT'S PROTECTIVE AND

9086
07:03:53,840 --> 07:03:55,160
YOU HAVE ONES THAT ARE

9087
07:03:55,160 --> 07:04:05,800
PATHOGENIC IN SOME WAY.

9088
07:04:05,800 --> 07:04:07,440
KIND FTD RHYME OR REASON OF

9089
07:04:07,440 --> 07:04:08,640
DIFFERENT HUMAN MILK

9090
07:04:08,640 --> 07:04:09,040
OLIGOSACCHARIDES.

9091
07:04:09,040 --> 07:04:11,920
MAYBE NOT SO MUCH AT THE

9092
07:04:11,920 --> 07:04:15,360
SUGARRIZATION LEVEL OF THE

9093
07:04:15,360 --> 07:04:17,640
MICROBIOME OR -- IT'S

9094
07:04:17,640 --> 07:04:17,920
OPEN-ENDED.

9095
07:04:17,920 --> 07:04:22,680
WHY WOULD ONE OF THEM BE PRO

9096
07:04:22,680 --> 07:04:27,680
COLITIC AND ONE ANTI-COLITED?

9097
07:04:27,680 --> 07:04:30,440
>> THAT'S A REASONABLE QUESTION.

9098
07:04:30,440 --> 07:04:32,120
SOL THE WHY, I DON'T KNOW

9099
07:04:32,120 --> 07:04:33,680
BECAUSE I HAVEN'T DOVE INTO THE

9100
07:04:33,680 --> 07:04:34,480
EVOLUTIONARY THOUGHT ABOUT IT.

9101
07:04:34,480 --> 07:04:37,640
SAME THING ABOUT WHY DOES DNA

9102
07:04:37,640 --> 07:04:40,240
HAVE FEWER KNOW CYST INSTEAD OF

9103
07:04:40,240 --> 07:04:41,880
PYRO KNOW CYST WHEN PYRO KNOW

9104
07:04:41,880 --> 07:04:43,360
CYST ARE THERMALLY MORE STABLE.

9105
07:04:43,360 --> 07:04:45,280
WHEN IT COMES TO FEW COST LATED

9106
07:04:45,280 --> 07:04:49,640
SUGARS, IF WE EXAMINE MILK,

9107
07:04:49,640 --> 07:04:50,720
SOMEHOW GARS DOMINATE OVER

9108
07:04:50,720 --> 07:04:51,840
SIALYLATED SUGARS.

9109
07:04:51,840 --> 07:04:56,800
IT ABOUT 85 TO 15, WHEREAS IN

9110
07:04:56,800 --> 07:04:59,720
COW'S MILK, THEY'RE MY SYLATED.

9111
07:04:59,720 --> 07:05:03,080
IF WE BOUNCE THIS BACK TO

9112
07:05:03,080 --> 07:05:04,280
COLITIS, EVEN THOUGH THERE'S NOT

9113
07:05:04,280 --> 07:05:07,680
A TON OF SUGARS IN THERE FROM

9114
07:05:07,680 --> 07:05:10,520
THOSE THAT ARE FORMULA-FED FROM

9115
07:05:10,520 --> 07:05:12,640
A MECHANISTIC PERSPECTIVE, I

9116
07:05:12,640 --> 07:05:14,760
THINK THAT'S TBD, BUT THERE'S

9117
07:05:14,760 --> 07:05:18,280
REASONS WHY HUMANS HAVE -- --

9118
07:05:18,280 --> 07:05:19,240
[INAUDIBLE] GLYCOSYLATED WHERE A

9119
07:05:19,240 --> 07:05:21,240
LOT OF FOUR CHAMBERED STOMACH

9120
07:05:21,240 --> 07:05:24,280
ANIMALS HAVE SYLATED COMPOUNDS

9121
07:05:24,280 --> 07:05:27,240
AND VERY LITTLE FUCOS.

9122
07:05:27,240 --> 07:05:28,080
I JUST KNOW THE WHY.

9123
07:05:28,080 --> 07:05:30,040
>> DO YOU THINK THERE MIGHT BE

9124
07:05:30,040 --> 07:05:33,880
SOME HOST RECOGNITION SUCH AS

9125
07:05:33,880 --> 07:05:37,560
PERHAPS SIGNALING -- FOR SOME

9126
07:05:37,560 --> 07:05:39,440
MODIFICATION OF FUCOSE?

9127
07:05:39,440 --> 07:05:44,800
I DON'T KNOW OF TOO MANY, BUT

9128
07:05:44,800 --> 07:05:47,160
NOT SO MUCH FUCOSES, ALTHOUGH

9129
07:05:47,160 --> 07:05:49,960
MAYBE THIS IS WHERE THEY SAY NO,

9130
07:05:49,960 --> 07:05:53,440
THERE'S A LOT OF FUCOSYLATION

9131
07:05:53,440 --> 07:05:56,600
THAT LEAD TO SOME SINGLING

9132
07:05:56,600 --> 07:05:56,840
LECTINS.

9133
07:05:56,840 --> 07:05:58,600
>> SO I DON'T KNOW THAT, AND I

9134
07:05:58,600 --> 07:05:59,800
HAVEN'T READ A TON OF LITERATURE

9135
07:05:59,800 --> 07:06:01,240
OR CAN RECALL A TON OF

9136
07:06:01,240 --> 07:06:02,000
LITERATURE THAT'S TEASING ANY OF

9137
07:06:02,000 --> 07:06:03,480
THIS APART, WHICH I THINK FOR

9138
07:06:03,480 --> 07:06:05,080
OUR TRAINEES WHO ARE WATCHING,

9139
07:06:05,080 --> 07:06:06,760
GO AHEAD AND GET YOURSELF TENURE

9140
07:06:06,760 --> 07:06:10,240
WITH ONE OF THESE TOPICS.

9141
07:06:10,240 --> 07:06:11,800
YOU

9142
07:06:11,800 --> 07:06:13,240
>> MAYBE TBR THE MICROBICIDE,

9143
07:06:13,240 --> 07:06:14,520
BUT I DON'T KNOW MANY FROM OUR

9144
07:06:14,520 --> 07:06:18,520
SIDE.

9145
07:06:18,520 --> 07:06:20,960
>>  -- THE MODIFICATION OF

9146
07:06:20,960 --> 07:06:21,960
LACTOSE BUT I DON'T THINK IT

9147
07:06:21,960 --> 07:06:23,040
BEEN LOOKED AT.

9148
07:06:23,040 --> 07:06:26,760
RICK DID SOME BEAUTIFUL STUDY,

9149
07:06:26,760 --> 07:06:32,520
BUT I THINK THERE'S A LOT BE

9150
07:06:32,520 --> 07:06:33,720
DONE BEYOND THE SPECIFICITY,

9151
07:06:33,720 --> 07:06:34,960
WHICH IS AN IMPORTANT ONE TO ASK

9152
07:06:34,960 --> 07:06:36,360
AND NOT AN EASY ONE TO ANSWER,

9153
07:06:36,360 --> 07:06:38,080
WHAT DOES THAT MEAN WITH RESPECT

9154
07:06:38,080 --> 07:06:39,520
TO WHAT THEY'RE DOING HALF THE

9155
07:06:39,520 --> 07:06:41,480
TIME ANYWAY FRANKLY.

9156
07:06:41,480 --> 07:06:42,480
BECAUSE THEY'RE EVERYWHERE AND

9157
07:06:42,480 --> 07:06:43,240
THEY BIND EVERYTHING.

9158
07:06:43,240 --> 07:06:44,440
AS MUCH AS I LOVE THEM.

9159
07:06:44,440 --> 07:06:46,520
BUT YEAH, THREE QUESTIONS.

9160
07:06:46,520 --> 07:06:47,320
GREAT QUESTIONS.

9161
07:06:47,320 --> 07:06:48,960
I DON'T WANT TO SHIFT GEARS, I

9162
07:06:48,960 --> 07:06:50,560
WISH WE COULD HANG OUT ALL NIGHT

9163
07:06:50,560 --> 07:06:52,240
ON ZOOM, BUT I DO WANT TO TRY TO

9164
07:06:52,240 --> 07:06:54,280
END BY 5:00 BECAUSE A FEW PEOPLE

9165
07:06:54,280 --> 07:06:56,160
NEED TO GO.

9166
07:06:56,160 --> 07:06:58,160
ONE OF THE PEOPLE THAT NEED TO

9167
07:06:58,160 --> 07:06:59,800
CATCH -- WE HAVE A FEW DAYCARE

9168
07:06:59,800 --> 07:07:00,440
APPOINTMENTS.

9169
07:07:00,440 --> 07:07:02,320
I WISH MY KIDS WERE IN DAYCARE

9170
07:07:02,320 --> 07:07:02,520
STILL.

9171
07:07:02,520 --> 07:07:07,640
BUT THEY'RE NOT.

9172
07:07:07,640 --> 07:07:08,840
SO -- WAIT UNTIL YOU HAVE

9173
07:07:08,840 --> 07:07:09,840
TEENAGERS AND YOU'LL UNDERSTAND

9174
07:07:09,840 --> 07:07:11,280
WHAT I'M TALKING ABOUT.

9175
07:07:11,280 --> 07:07:18,840
SO NADINE SAMARA IS GOING TO

9176
07:07:18,840 --> 07:07:25,440
TALK NEXT FROM NIDCR, "DI
DIVERSE

9177
07:07:25,440 --> 07:07:27,560
SUBSTRATE SPECIFICITIES OF

9178
07:07:27,560 --> 07:07:34,760
MUCIN-TYPE

9179
07:07:34,760 --> 07:07:36,600
O-GLYCOSYLTRANSFERASES.

9180
07:07:36,600 --> 07:07:38,400
>> SO LET ME MOVE THIS ZOOM

9181
07:07:38,400 --> 07:07:40,720
CAMERA SO IT NOT BLOCKING MY

9182
07:07:40,720 --> 07:07:40,960
SLIDES.

9183
07:07:40,960 --> 07:07:41,840
SO FIRST OF ALL, THANK YOU SO

9184
07:07:41,840 --> 07:07:44,600
MUCH FOR THIS IP I  INVITATION.

9185
07:07:44,600 --> 07:07:47,320
THIS HAS BEEN A GREAT SYMPOSIUM.

9186
07:07:47,320 --> 07:07:49,960
AND I WILL TRY TO BE QUICK AND

9187
07:07:49,960 --> 07:07:51,600
GET EVERYBODY HOME FOR THE

9188
07:07:51,600 --> 07:07:54,760
WEEKEND, SO MY NAME IS NADINE

9189
07:07:54,760 --> 07:07:55,240
SAMARA.

9190
07:07:55,240 --> 07:07:56,800
I'M AT THE NATIONAL INSTITUTE OF

9191
07:07:56,800 --> 07:07:58,240
DENTAL AND CRANIOFACIAL RESEARCH

9192
07:07:58,240 --> 07:08:00,720
AT THE NIH.

9193
07:08:00,720 --> 07:08:01,960
TODAY I'LL BE TELLING YOU ABOUT

9194
07:08:01,960 --> 07:08:04,320
THE DIVERSE SUBSTRATE

9195
07:08:04,320 --> 07:08:07,960
SPECIFICITIES OF MUCIN-TYPE O

9196
07:08:07,960 --> 07:08:08,440
GLYCOSYL TRANSFERASES.

9197
07:08:08,440 --> 07:08:10,040
MY TALK IS GOING TO BE A LITTLE

9198
07:08:10,040 --> 07:08:11,720
MORE ME CAN  MECHANISTIC, JUST A
WARNING

9199
07:08:11,720 --> 07:08:12,800
TO EVERYBODY WHO'S STILL

9200
07:08:12,800 --> 07:08:13,440
WATCHING.

9201
07:08:13,440 --> 07:08:14,520
BUT JUST BEFORE I GET INTO THE

9202
07:08:14,520 --> 07:08:16,160
RESEARCH, I JUST WANT TO

9203
07:08:16,160 --> 07:08:20,120
INTRODUCE MYSELF AND MY GROUP.

9204
07:08:20,120 --> 07:08:23,480
SO I ESTABLISHED THE STRUCTURAL

9205
07:08:23,480 --> 07:08:24,680
BIOCHEMISTRY UNIT AT THE DENTAL

9206
07:08:24,680 --> 07:08:28,320
INSTITUTE IN AUGUST 2019.

9207
07:08:28,320 --> 07:08:29,360
WHICH IS GREAT TIMING.

9208
07:08:29,360 --> 07:08:36,440
BUT ANYWAY, SO OUR STUDIES OF

9209
07:08:36,440 --> 07:08:37,120
GLYCOSYL TRANSFERASES AND WE

9210
07:08:37,120 --> 07:08:38,760
WERE ALSO INTERESTED IN THE O

9211
07:08:38,760 --> 07:08:41,680
GLYCANS AND THEIR ROLES AT THE

9212
07:08:41,680 --> 07:08:46,840
HOST MICROBE INTERFACE, SO WE

9213
07:08:46,840 --> 07:08:48,040
SPROJS ON BOTH SIDES, ON THE

9214
07:08:48,040 --> 07:08:49,680
HOST SIDE, AND THOSE ARE -- YOU

9215
07:08:49,680 --> 07:08:54,720
KNOW, I THINK YOU'VE ALREADY

9216
07:08:54,720 --> 07:08:56,840
HEARD ABOUT THE MUCIN

9217
07:08:56,840 --> 07:08:58,040
GLYCOSYLATION SO I'LL BE TALKING

9218
07:08:58,040 --> 07:08:58,720
ABOUT THAT TODAY.

9219
07:08:58,720 --> 07:09:00,400
MY LAB IS SHOWILY SHIFTING

9220
07:09:00,400 --> 07:09:02,640
TOWARDS THE MICROBICIDE, AND WE

9221
07:09:02,640 --> 07:09:03,560
HAVE SOME PRELIMINARY PROJECTS

9222
07:09:03,560 --> 07:09:12,200
TO TRY AND UNDERSTAND

9223
07:09:12,200 --> 07:09:13,440
EXOPOLYSACCHARIDE BIOSYNTHESIS

9224
07:09:13,440 --> 07:09:14,800
AND THE ROLE NOT JUST IN THE

9225
07:09:14,800 --> 07:09:17,440
MATRIX BUT ALSO IN

9226
07:09:17,440 --> 07:09:19,920
PERIODONTITIS, SO WE'RE USING A

9227
07:09:19,920 --> 07:09:22,560
VARIETY OF DIFFERENT METHODS,

9228
07:09:22,560 --> 07:09:24,080
INCLUDING MICROBIOLOGY,

9229
07:09:24,080 --> 07:09:24,840
COMPARATIVE GENOMICS AND

9230
07:09:24,840 --> 07:09:27,640
HOPEFULLY STARTING TO USE SOME

9231
07:09:27,640 --> 07:09:28,760
IMEU LOGICAL METHODS AS WELL TO

9232
07:09:28,760 --> 07:09:31,040
TRY TO UNDERSTAND THE ROLE OF

9233
07:09:31,040 --> 07:09:32,040
THOSE EXOPOLYSACCHARIDES IN

9234
07:09:32,040 --> 07:09:32,800
DISEASE AS WELL.

9235
07:09:32,800 --> 07:09:34,520
SO FOR TODAY, I'M GOING TO BE

9236
07:09:34,520 --> 07:09:35,640
TALKING ABOUT MUCIN TYPE OF

9237
07:09:35,640 --> 07:09:36,720
GLYCOSYLATION, AND I THINK

9238
07:09:36,720 --> 07:09:38,240
KATRINA DID A GREAT JOB

9239
07:09:38,240 --> 07:09:41,560
INTRODUCING MUCINS, BUT JUST AN

9240
07:09:41,560 --> 07:09:45,640
OVERVIEW, SO THIS IS A POST

9241
07:09:45,640 --> 07:09:46,560
TRANSLATIONAL MODIFICATION.

9242
07:09:46,560 --> 07:09:48,440
IT OCCURS ON MANY SUBSTRATES,

9243
07:09:48,440 --> 07:09:52,040
ALMOST 80% OF PROTEINS THAT GO

9244
07:09:52,040 --> 07:09:54,160
THROUGH THE SECRETORY PATHWAY

9245
07:09:54,160 --> 07:10:06,080
ARE MUSE  MUCYLATED.

9246
07:10:06,080 --> 07:10:08,360
SOME OF THEM ARE LOCATED ON THE

9247
07:10:08,360 --> 07:10:10,120
CELL SURFACE, OTHERS ARE

9248
07:10:10,120 --> 07:10:13,400
SECRETED INTO THE MUCOUS LAYER.

9249
07:10:13,400 --> 07:10:17,200
AND SO BOTH MEMBRANE TETHERED --

9250
07:10:17,200 --> 07:10:19,040
PROTECT AGAINST PATHOGENS,

9251
07:10:19,040 --> 07:10:21,200
PROTECT THE UNDERLYING LAYERS

9252
07:10:21,200 --> 07:10:23,280
FROM PATHOGEN AND VISION, AND

9253
07:10:23,280 --> 07:10:25,400
SECRETED MUCINS HAVE SIMILAR

9254
07:10:25,400 --> 07:10:27,480
RULES AND PROTECTION AGAINST

9255
07:10:27,480 --> 07:10:29,840
INFECTION, AS WELL AS MODULATING

9256
07:10:29,840 --> 07:10:30,440
ATTRACTIONS OF THE MICROBIOME

9257
07:10:30,440 --> 07:10:34,320
AND PLOA  PROTECTING OTHER
LAYERS FROM

9258
07:10:34,320 --> 07:10:34,920
PHYSICAL AND CHEMICAL DAMAGE.

9259
07:10:34,920 --> 07:10:36,760
SO THESE ROLES ARE REALLY

9260
07:10:36,760 --> 07:10:37,640
IMPORTANT AS WE'VE HEARD TODAY

9261
07:10:37,640 --> 07:10:42,320
FROM OTHER TALKS, AND IN

9262
07:10:42,320 --> 07:10:43,560
MAINTAINING HOMEOSTATIC STATE

9263
07:10:43,560 --> 07:10:44,840
AND IMMUNE RESPONSE.

9264
07:10:44,840 --> 07:10:54,160
SO THE  THE ENZYMES THAT WE
STUDY ARE

9265
07:10:54,160 --> 07:10:54,840
THE -- BASICALLY I'D LIKE TO

9266
07:10:54,840 --> 07:10:56,640
THINK THAT THER RESPONSIBLE FOR

9267
07:10:56,640 --> 07:10:58,200
ESTABLISHING THE FOUNDATION FOR

9268
07:10:58,200 --> 07:10:59,600
THIS VERY IMPORTANT

9269
07:10:59,600 --> 07:10:59,920
MODIFICATION.

9270
07:10:59,920 --> 07:11:01,800
IF YOU DON'T HAVE THIS INITIAL

9271
07:11:01,800 --> 07:11:06,520
FOUNDATION, YOU CAN'T LET THE

9272
07:11:06,520 --> 07:11:08,440
PROPER GLYCAN, I GUESS -- I

9273
07:11:08,440 --> 07:11:10,320
DON'T KNOW, CAN'T FIND THE RIGHT

9274
07:11:10,320 --> 07:11:11,080
WORD, FRIDAY AFTERNOON.

9275
07:11:11,080 --> 07:11:17,240
BUT SO THESE ARE GOLJI TYPE

9276
07:11:17,240 --> 07:11:19,480
PROTEINS AND CONTAIN TWO DOMAINS

9277
07:11:19,480 --> 07:11:20,680
VERY IMPORTANT FOR THE FUNCTION.

9278
07:11:20,680 --> 07:11:22,560
FIRST YOU HAVE THE CATALYTIC

9279
07:11:22,560 --> 07:11:23,880
DOMAIN SHOWN IN GREEN, THIS IS

9280
07:11:23,880 --> 07:11:25,440
TETHERED TO THE LECTIN DOMAIN.

9281
07:11:25,440 --> 07:11:30,560
SO WE HEARD EARLIER ABOUT LECTIN

9282
07:11:30,560 --> 07:11:33,560
FROM LAURA, SO THESE FAMILY OF

9283
07:11:33,560 --> 07:11:35,720
ENZYMES ARE RARE AGAINST THE

9284
07:11:35,720 --> 07:11:36,720
GLYCOSYL TRANS PHRASE FAMILIES

9285
07:11:36,720 --> 07:11:41,960
IN THAT THEY CONTINUE TO -- THIS

9286
07:11:41,960 --> 07:11:45,040
LECTIN DOMAIN, AROUND 10 AMINO

9287
07:11:45,040 --> 07:11:45,880
ACID -- I'LL TELL YOU MORE ABOUT

9288
07:11:45,880 --> 07:11:47,880
IT LATER BUT IT'S IMPORTANT FOR

9289
07:11:47,880 --> 07:11:49,920
SUBSTRATE BINDING AND

9290
07:11:49,920 --> 07:11:50,240
RECOGNITION.

9291
07:11:50,240 --> 07:11:52,360
SO THE ACTIVITY, THE CHEMISTRY

9292
07:11:52,360 --> 07:11:53,800
HAPPENS IN THE CATALYTIC DOMAIN,

9293
07:11:53,800 --> 07:11:55,680
SO WHAT YOU HAVE ARE TWO

9294
07:11:55,680 --> 07:11:56,760
SUBSTRATES, YOU HAVE THE DONOR

9295
07:11:56,760 --> 07:11:58,920
SUBSTRATE WHICH IS A U VP -- YOU

9296
07:11:58,920 --> 07:12:08,200
CAN HAVE THE -- AND A MANGANESE

9297
07:12:08,200 --> 07:12:11,000
DEPENDENT MANNER, THE TRANSFER

9298
07:12:11,000 --> 07:12:17,320
OF GALNAC.

9299
07:12:17,320 --> 07:12:20,760
THEY EXTEND THESE CHAINS TO FORM

9300
07:12:20,760 --> 07:12:21,480
THESE DENSE, DENSE -- MOST OF

9301
07:12:21,480 --> 07:12:23,200
THE TIME, THERE'S A CAVEAT HERE

9302
07:12:23,200 --> 07:12:24,520
AND I'LL MENTION IT IN A SECOND,

9303
07:12:24,520 --> 07:12:26,600
MOST OF THE TIME YOU HAVE DENSE

9304
07:12:26,600 --> 07:12:30,560
OLD GLYCANS ON THESE --

9305
07:12:30,560 --> 07:12:34,600
ESPECIALLY THESE MUCIN

9306
07:12:34,600 --> 07:12:36,400
SUBSTRATE.

9307
07:12:36,400 --> 07:12:37,680
SO HERE'S THE BIG QUESTION, YOU

9308
07:12:37,680 --> 07:12:39,440
HAVE NUMEROUS DIVERSE

9309
07:12:39,440 --> 07:12:40,160
SUBSTRATES, SO MANY DIFFERENT

9310
07:12:40,160 --> 07:12:41,520
TYPES OF SUBSTRATES, THEY DON'T

9311
07:12:41,520 --> 07:12:43,240
SHARE CONSENSUS SEQUENCE.

9312
07:12:43,240 --> 07:12:45,800
MANY OF THESE SUBSTRATES LIKE

9313
07:12:45,800 --> 07:12:48,440
MUCINS ARE DENSELY GLYCOSYLATED

9314
07:12:48,440 --> 07:12:52,560
BUT THERE ARE -- A LOT OF TIMES

9315
07:12:52,560 --> 07:12:54,280
IT DISREGULATES THE PROTEOLYTIC

9316
07:12:54,280 --> 07:12:55,080
CLEAVAGE OF A SUBSTRATE.

9317
07:12:55,080 --> 07:12:58,440
SO IN A SITUATION LIKE THIS, HOW

9318
07:12:58,440 --> 07:13:00,360
DOES NATURE ACCOMPLISH THIS TASK

9319
07:13:00,360 --> 07:13:04,200
OF CORRECT  CORRECTLY OR
EFFICIENTLY

9320
07:13:04,200 --> 07:13:05,320
GLYCOSYLATING THESE SUBSTRATES

9321
07:13:05,320 --> 07:13:07,400
SO THEY'RE FUNCTIONAL OR THAT WE

9322
07:13:07,400 --> 07:13:13,680
CAN UNDERGO FURTHER GLIE 

9323
07:13:13,680 --> 07:13:15,360
GLYCOSYLATION -- SO WHAT NATURE

9324
07:13:15,360 --> 07:13:17,680
HAS DONE IS MADE 20 DIFFERENT

9325
07:13:17,680 --> 07:13:20,880
VERSIONS OF THIS ENZYME AND AT

9326
07:13:20,880 --> 07:13:25,440
LEAST IN HUMANS, THERE ARE 20,

9327
07:13:25,440 --> 07:13:31,000
AND THESE ENZYMES SHARE A LOT OF

9328
07:13:31,000 --> 07:13:33,080
SIMILAR FUNCTIONS AND WE KNOW

9329
07:13:33,080 --> 07:13:35,480
THIS BECAUSE YOU HAVE A MOUSE

9330
07:13:35,480 --> 07:13:37,360
KNOCKOUT, IT'S NOT NECESSARILY

9331
07:13:37,360 --> 07:13:40,840
LETHAL, SO THERE'S SOME OVERLAP.

9332
07:13:40,840 --> 07:13:42,680
AS A SIDE NOTE, WE'VE BEEN

9333
07:13:42,680 --> 07:13:47,040
THINKING ABOUT SUBSTRATE

9334
07:13:47,040 --> 07:13:49,240
SPECIFICITY, I RECENTLY HAD A

9335
07:13:49,240 --> 07:13:50,120
CONVERSATION WITH JESSICA KRAMER

9336
07:13:50,120 --> 07:13:56,800
WHO STUDIES MEU SINS AS  MUCINS
AS WELL.

9337
07:13:56,800 --> 07:13:59,080
IT MADE ME THINK ABOUT

9338
07:13:59,080 --> 07:14:00,480
CONFIRMATION, AND SO YOU HAVE A

9339
07:14:00,480 --> 07:14:03,760
LOT OF PROLINES AND I WAS JUST

9340
07:14:03,760 --> 07:14:05,240
THINKING ABOUT IT.

9341
07:14:05,240 --> 07:14:07,640
ON THE OVERALL CONFIRMATION OF

9342
07:14:07,640 --> 07:14:08,040
THESE MUCINS.

9343
07:14:08,040 --> 07:14:10,360
AS YOU ADD MORE SUGARS, THAT'S

9344
07:14:10,360 --> 07:14:12,400
ALSO GOING TO INFLUENCE THE

9345
07:14:12,400 --> 07:14:13,720
OVERALL CONFIRMATION.

9346
07:14:13,720 --> 07:14:14,800
AND ONE THING I WAS THINKING

9347
07:14:14,800 --> 07:14:17,280
ABOUT TODAY IS THAT IF YOU THINK

9348
07:14:17,280 --> 07:14:19,680
ABOUT SOME OF THESE TRANSFERASE,

9349
07:14:19,680 --> 07:14:20,720
THEY'RE ACTUALLY PRETTY

9350
07:14:20,720 --> 07:14:23,800
CONSERVED AMONGST LIKE, LET'S

9351
07:14:23,800 --> 07:14:27,240
SAY, T1 IS SIMILAR IN HUMANS AND

9352
07:14:27,240 --> 07:14:32,400
MICE BUT A LOT ARE NOT -- MAYBE

9353
07:14:32,400 --> 07:14:34,560
WHAT'S NOT IMPORTANT SL THE --

9354
07:14:34,560 --> 07:14:38,560
BUT THE CONFIRMATION AND HOW

9355
07:14:38,560 --> 07:14:40,080
THAT CONFIRMATION FITS INTO THE

9356
07:14:40,080 --> 07:14:41,000
AK SIEVE SITE OR THE REGION OF

9357
07:14:41,000 --> 07:14:44,040
THE ENZYME THAT'S POSH FOR
IMPORTANT FOR

9358
07:14:44,040 --> 07:14:44,480
ACTIVITY.

9359
07:14:44,480 --> 07:14:45,840
BUT THAT'S A SIDE NOTE JU TO GET

9360
07:14:45,840 --> 07:14:47,560
BACK TO THE POINT OF THIS TALK.

9361
07:14:47,560 --> 07:14:50,000
A LOT OF THESE ENZYMES ALSO HAVE

9362
07:14:50,000 --> 07:14:51,880
SPECIFIC FUNCTIONS AND

9363
07:14:51,880 --> 07:14:54,040
SUBSTRATES, FOR EXAMPLE, T1 IS

9364
07:14:54,040 --> 07:14:56,600
INVOLVED IN HEART DEVELOPMENT,

9365
07:14:56,600 --> 07:14:59,920
ALTHOUGH WE DON'T KNOW WHAT

9366
07:14:59,920 --> 07:15:04,080
SUBSTRATE IT IS.

9367
07:15:04,080 --> 07:15:07,320
 -- WHICH REGULATES THE --

9368
07:15:07,320 --> 07:15:10,440
CLEANAGE OF THAT PROTEIN.

9369
07:15:10,440 --> 07:15:11,960
TIER 3 IS SPECIFICALLY

9370
07:15:11,960 --> 07:15:14,680
ASSOCIATED WITH THE PATIENT

9371
07:15:14,680 --> 07:15:16,040
MUTATIONS IN THIS ENZYME AS WELL

9372
07:15:16,040 --> 07:15:18,520
AS IN THE SUBSTRATE -- ONE OF

9373
07:15:18,520 --> 07:15:20,720
ITS SUBSTRATES, FGF23.

9374
07:15:20,720 --> 07:15:22,040
T12 WHICH IS ONE OF THE ENZYMES

9375
07:15:22,040 --> 07:15:23,160
WE'RE INTERESTED IN IS

9376
07:15:23,160 --> 07:15:24,440
ASSOCIATED WITH COLON CANCER,

9377
07:15:24,440 --> 07:15:27,320
AND THAT'S BEEN SHOWN IN SEVERAL

9378
07:15:27,320 --> 07:15:28,640
DIFFERENT PATIENT COHORTS.

9379
07:15:28,640 --> 07:15:31,120
AGAIN IN THIS CASE WITH SORT OF

9380
07:15:31,120 --> 07:15:33,120
THE MISSING FACTOR HERE IS THAT

9381
07:15:33,120 --> 07:15:35,840
WE DON'T KNOW WHAT THE SUBSTRATE

9382
07:15:35,840 --> 07:15:40,440
OR SUBSTRATES ARE, SO WE THINK

9383
07:15:40,440 --> 07:15:42,600
PERHAPS MAYBE THIS IS TOTAL HAND

9384
07:15:42,600 --> 07:15:43,960
WAVING, INFLUENCING THE MY

9385
07:15:43,960 --> 07:15:45,920
COBIOTA OR SOMETHING IN THE

9386
07:15:45,920 --> 07:15:47,440
IMMUNE SYSTEM BUT WE DON'T

9387
07:15:47,440 --> 07:15:48,440
REALLY KNOW, SO THAT'S STILL

9388
07:15:48,440 --> 07:15:52,040
KIND OF A BIG QUESTION.

9389
07:15:52,040 --> 07:15:53,600
BUT THOSE MUTATIONS ACTUALLY

9390
07:15:53,600 --> 07:15:54,840
DECREASE THE ACTIVITY OF T12 AS

9391
07:15:54,840 --> 07:15:56,280
I'LL SHOW LATER.

9392
07:15:56,280 --> 07:15:58,680
DOWN AT T11 IS INVOLVED IN

9393
07:15:58,680 --> 07:16:00,440
REGULATING KIDNEY FUNCTION

9394
07:16:00,440 --> 07:16:06,560
THROUGH THE GLYCOSYLATION OF THE

9395
07:16:06,560 --> 07:16:10,520
KIDNEY PROTEIN.

9396
07:16:10,520 --> 07:16:17,480
THEY SHOW GAL KNACK

9397
07:16:17,480 --> 07:16:18,040
D2 ACTIVATES -- THROUGH GLIE

9398
07:16:18,040 --> 07:16:19,760
COST LIN OF THE RECEPTOR.

9399
07:16:19,760 --> 07:16:21,080
SO THERE'S SO MUCH GOING ON

9400
07:16:21,080 --> 07:16:24,720
HERE, SO MUCH DIVERSITY, BURR

9401
07:16:24,720 --> 07:16:29,600
THERE'S ALSO MANY LAYERS OF --

9402
07:16:29,600 --> 07:16:34,160
YOU HAVE LAYER AT EXPRESSION

9403
07:16:34,160 --> 07:16:35,160
LEVEL ACROSS DIFFERENT CELLS

9404
07:16:35,160 --> 07:16:37,440
TYPES SO THEY'RE NOT EQUALLY

9405
07:16:37,440 --> 07:16:38,440
EXPRESSED THROUGH CELLS.

9406
07:16:38,440 --> 07:16:40,440
AND YOU ALSO HAVE DIFFERENTIAL

9407
07:16:40,440 --> 07:16:41,480
EXPRESSION THROUGH DEVELOPMENT.

9408
07:16:41,480 --> 07:16:44,520
AND WHAT WE'RE INTERESTED IN AS

9409
07:16:44,520 --> 07:16:46,480
STRUCTURAL BIOLOGISTS AND ENS

9410
07:16:46,480 --> 07:16:48,720
I'MOLOGISTS IS THE RULES, THE

9411
07:16:48,720 --> 07:16:51,040
DIVERSE RULES FOR HOW THEY

9412
07:16:51,040 --> 07:16:53,320
RECOGNIZE SUBSTRATES AND HOW

9413
07:16:53,320 --> 07:16:56,720
THEY CATALYZED THE REACTION.

9414
07:16:56,720 --> 07:16:58,240
SO SOME OF THESE DIVERSE RULES

9415
07:16:58,240 --> 07:16:59,640
CAN BE SORT OF PUT INTO BOXES

9416
07:16:59,640 --> 07:17:02,160
BUT THEY'RE VERY GENERAL BOXES,

9417
07:17:02,160 --> 07:17:03,920
SO A LOT OF THE ENZYMES CAN

9418
07:17:03,920 --> 07:17:06,080
RECOGNIZE SOME OF THE

9419
07:17:06,080 --> 07:17:08,200
UNGLYCOSYLATED PROTEIN OR TEP

9420
07:17:08,200 --> 07:17:09,480
TIED AND MODIFY THAT.

9421
07:17:09,480 --> 07:17:12,080
AND SO AGAIN, I SAID THERE'S NO

9422
07:17:12,080 --> 07:17:13,240
CONSENSUS SEQUENCE BUT I'LL COME

9423
07:17:13,240 --> 07:17:14,440
BACK TO SOME CERTAIN

9424
07:17:14,440 --> 07:17:15,480
CHARACTERISTICS THAT CAN BE

9425
07:17:15,480 --> 07:17:16,400
RECOGNIZED BY THESE ENZYMES.

9426
07:17:16,400 --> 07:17:22,760
A LOT OF THE ENZYMES CAN

9427
07:17:22,760 --> 07:17:25,160
RECOGNIZE PRIOR GALNACs EITHER

9428
07:17:25,160 --> 07:17:28,280
VIA THE LECTIN DOMAIN, WHICH IS

9429
07:17:28,280 --> 07:17:33,080
NOT SURPRISING, THESE CONTAIN

9430
07:17:33,080 --> 07:17:38,480
HASH KIED RATES, AND OFTEN TOIMS

9431
07:17:38,480 --> 07:17:40,440
THEY GO QUITE UNIQUE TO THE

9432
07:17:40,440 --> 07:17:41,840
ENZYMES THAT HAPPEN.

9433
07:17:41,840 --> 07:17:44,000
AND IN MOST CASES, THE ENZYMES

9434
07:17:44,000 --> 07:17:46,320
IS A COMBINATION OF DIFFERENT

9435
07:17:46,320 --> 07:17:47,760
BINDING MODES, IT'S NOT JUST ONE

9436
07:17:47,760 --> 07:17:48,200
OR THE OTHER.

9437
07:17:48,200 --> 07:17:49,480
A LOT IS USUALLY GOING ON IN

9438
07:17:49,480 --> 07:17:51,600
TERMS OF HOW THESE ENZYMES

9439
07:17:51,600 --> 07:17:54,080
FUNCTION.

9440
07:17:54,080 --> 07:17:55,400
SO BASED ON ALL WE KNOW AND ALL

9441
07:17:55,400 --> 07:17:57,880
THE LAYERS OF REGULATION WE JUST

9442
07:17:57,880 --> 07:18:03,680
MENTIONED, THE CURRENT MODEL --

9443
07:18:03,680 --> 07:18:05,880
FIRST YOU HAVE THIS

9444
07:18:05,880 --> 07:18:06,960
UNGLYCOSYLATED SUBSTRATE GOING

9445
07:18:06,960 --> 07:18:09,400
THROUGH THE GOLGI AND THE SUBSET

9446
07:18:09,400 --> 07:18:14,360
OF THESE ENZYMES ARE CALLED THE

9447
07:18:14,360 --> 07:18:16,120
EARLY GALNAC TEASE.

9448
07:18:16,120 --> 07:18:18,920
ANOTHER SUBSET MIGHT ABLE TO

9449
07:18:18,920 --> 07:18:20,640
RM -- ON THE SUBSTRATE AND ADD

9450
07:18:20,640 --> 07:18:24,400
MORE, AND THEN YOU HAVE -- AT

9451
07:18:24,400 --> 07:18:26,040
FURTHER MODIFY THE SUBSTRATE TO

9452
07:18:26,040 --> 07:18:32,320
OBTAIN THIS DENSELY GLYCOSYLATED

9453
07:18:32,320 --> 07:18:33,280
PROTEIN.

9454
07:18:33,280 --> 07:18:34,640
SO WHAT WE'RE TRYING TO

9455
07:18:34,640 --> 07:18:36,880
UNDERSTAND OR THE QUESTIONS WE

9456
07:18:36,880 --> 07:18:38,560
ASK IF OUR LAB FOR THIS SET OF

9457
07:18:38,560 --> 07:18:40,600
PROJECTS IS WHAT ARE THE PLEAK

9458
07:18:40,600 --> 07:18:44,880
ALREADY BASIS OF  WHAT ARE

9459
07:18:44,880 --> 07:18:46,600
THE MOLECULAR BASIS OF THE

9460
07:18:46,600 --> 07:18:47,280
RULES.

9461
07:18:47,280 --> 07:18:48,400
WE'RE MOSTLY INTERESTED IN

9462
07:18:48,400 --> 07:18:50,080
REALLY LIKE LOOKING AT THE

9463
07:18:50,080 --> 07:18:51,520
CRYSTAL STRUCTURES AND DOING

9464
07:18:51,520 --> 07:18:52,640
KINETICS TO UNDERSTAND WHAT

9465
07:18:52,640 --> 07:18:55,120
THOSE RULES MEAN.

9466
07:18:55,120 --> 07:18:57,440
AND SO I DID MENTION THAT THERE

9467
07:18:57,440 --> 07:18:58,480
IS NO CONSENSUS SEQUENCE BUT

9468
07:18:58,480 --> 07:19:00,640
WHAT I WANT TO SAY IN TERMS OF

9469
07:19:00,640 --> 07:19:03,240
JUST THIS POLYPEPTIDE BINDING IS

9470
07:19:03,240 --> 07:19:09,600
AS I MENTIONED, MUCIN REPETS,

9471
07:19:09,600 --> 07:19:11,480
MOST OF THESE ENZYMES, 17 OUT OF

9472
07:19:11,480 --> 07:19:13,960
20 OF THEM, WE THINK -- SO THE

9473
07:19:13,960 --> 07:19:16,400
ONLY ONES THAT DON'T FROM WHAT I

9474
07:19:16,400 --> 07:19:23,120
KNOW ARE T10, T7 ABANDONS 7 AND
T17.

9475
07:19:23,120 --> 07:19:25,280
RECOGNIZE A PROLINE, C TERMINAL

9476
07:19:25,280 --> 07:19:27,880
TO THE ACCEPTOR SITE.

9477
07:19:27,880 --> 07:19:29,320
AND THIS PAROLING POCKET, HERE

9478
07:19:29,320 --> 07:19:32,800
I'M SHOWING THIS PAROLING POCKET

9479
07:19:32,800 --> 07:19:38,200
FROM T12, HYDROPHOBIC RESIDUES,

9480
07:19:38,200 --> 07:19:40,040
SO MOST ENZYMES HAVE THIS

9481
07:19:40,040 --> 07:19:43,560
POCKET, SO IF YOU SEE A PROLINE,

9482
07:19:43,560 --> 07:19:46,080
FOR EXAMPLE, YOU CAN PREDICT

9483
07:19:46,080 --> 07:19:49,160
THAT IS LIKELY TO GET GLIE 

9484
07:19:49,160 --> 07:19:50,640
GLYCOSYLATE BID MOST ENZYMES

9485
07:19:50,640 --> 07:19:53,480
OTHER THAN T10, T17.

9486
07:19:53,480 --> 07:20:00,200
I MENTIONED -- HAS BEEN QOIT --
I MENTIONE
D COLON

9487
07:20:00,200 --> 07:20:01,440
CAB SE SO WHAT I'M SHOWING HERE

9488
07:20:01,440 --> 07:20:04,000
IS FROM A PAPER FROM 2009 WHERE

9489
07:20:04,000 --> 07:20:05,640
THEY SHOW THAT IF YOU HAVE THESE

9490
07:20:05,640 --> 07:20:08,840
DEACTIVATING MUTATIONS, THAT

9491
07:20:08,840 --> 07:20:11,080
PEOPLE WITH COLON CANCER, THESE

9492
07:20:11,080 --> 07:20:12,760
ARE DIFFERENT CASES, I THINK

9493
07:20:12,760 --> 07:20:13,840
EACH ONE IS A SINGLE PATIENT.

9494
07:20:13,840 --> 07:20:16,560
THEY HAVE MUTATIONS IN T12 THAT

9495
07:20:16,560 --> 07:20:20,680
ARE DIE ACTIVATING. 
DEACTIVATING.

9496
07:20:20,680 --> 07:20:23,000
THE OTHER THING THAT'S REALLY

9497
07:20:23,000 --> 07:20:30,320
INTERESTING ABOUT D12, SHOWING 
SHOWING

9498
07:20:30,320 --> 07:20:33,280
PRIOR GALNAC BINDING

9499
07:20:33,280 --> 07:20:34,480
PREFERENCES.

9500
07:20:34,480 --> 07:20:36,360
I MENTIONED EARLIER MOST OF THE

9501
07:20:36,360 --> 07:20:39,640
ENZYMES REALLY PREFER PROLINE AT

9502
07:20:39,640 --> 07:20:42,840
THE T12 POSITION, BUT -- LIKES

9503
07:20:42,840 --> 07:20:44,760
GALNAC AT THE T12 POSITION.

9504
07:20:44,760 --> 07:20:50,000
SO T12 DOES HAVE A -- US A

9505
07:20:50,000 --> 07:20:51,440
ALTERNATIVELY CAN -- LET'S SAY

9506
07:20:51,440 --> 07:20:54,840
THEIR STUDY SHOWED THAT GALNAC

9507
07:20:54,840 --> 07:20:56,800
AT THAT POSITION ENHANCES THE

9508
07:20:56,800 --> 07:20:58,440
ACTIVITY OF T12.

9509
07:20:58,440 --> 07:21:02,680
AT THE SAME TIME, T12 HAS A

9510
07:21:02,680 --> 07:21:05,280
GALN AC BINDING POCKET IN ITS

9511
07:21:05,280 --> 07:21:06,840
LECTIN DOMAIN SO IT SEEMS TO

9512
07:21:06,840 --> 07:21:10,320
HAVE THESE 2GALN AC BINDING

9513
07:21:10,320 --> 07:21:12,840
POCKETS WORKING IN CONCERT,

9514
07:21:12,840 --> 07:21:15,360
SUGGESTING IT WORKS LATER IN THE

9515
07:21:15,360 --> 07:21:15,960
PROCESS OF GLYCOSYLATION.

9516
07:21:15,960 --> 07:21:19,240
SO TO UNDERSTAND THE BASIS OF

9517
07:21:19,240 --> 07:21:21,480
THIS ENHANCEMENT, WE SOLVED THE

9518
07:21:21,480 --> 07:21:24,880
CRYSTAL STRUCTURE OF GAL KNACK

9519
07:21:24,880 --> 07:21:36,640
T12 WITH THIS PEPTIDE.

9520
07:21:36,640 --> 07:21:39,040
THE GALNACs ARE SHOAB  SHOWN IN

9521
07:21:39,040 --> 07:21:40,440
YELLOW, THE PEPTIDES ARE SHOWN

9522
07:21:40,440 --> 07:21:41,600
IN MAGENTA.

9523
07:21:41,600 --> 07:21:45,760
HERE'S THE 3D -- AND TO SORT OF

9524
07:21:45,760 --> 07:21:47,920
UNDERSTAND THE BASIS OF THIS

9525
07:21:47,920 --> 07:21:50,120
UNIQUE PLUS-THREE PREFERENCE I'M

9526
07:21:50,120 --> 07:21:52,000
GOING TO ZOOM INTO THIS GALNAC

9527
07:21:52,000 --> 07:21:53,000
BINDING SITE REAL QUICK SO WHAT

9528
07:21:53,000 --> 07:21:54,840
YOU SEE IS MAINLY BACKBONE

9529
07:21:54,840 --> 07:21:56,880
INTERACTIONS BETWEEN THE ENZYME

9530
07:21:56,880 --> 07:22:03,800
SIDE CHAINS WITH THE EXCEPTION

9531
07:22:03,800 --> 07:22:06,040
OF N270.

9532
07:22:06,040 --> 07:22:06,720
SO BASICALLY THIS BIND BEING

9533
07:22:06,720 --> 07:22:11,840
POCKET IS UNIQUE, BUT ON TOP OF

9534
07:22:11,840 --> 07:22:13,760
THAT, THIS N270 OVER HERE IS NOT

9535
07:22:13,760 --> 07:22:15,240
CONSERVED IN ANY OF THE

9536
07:22:15,240 --> 07:22:16,680
ISOENZYMES IN THE HUMAN FAMILY.

9537
07:22:16,680 --> 07:22:18,080
SO IT'S ACTUALLY JUST THIS ONE

9538
07:22:18,080 --> 07:22:22,800
RES DUAL THAT BASICALLY DICTATES

9539
07:22:22,800 --> 07:22:23,840
THIS PREFERENCE FOR GALNAC AT

9540
07:22:23,840 --> 07:22:24,880
THE PLUS 3 POSITION.

9541
07:22:24,880 --> 07:22:29,240
ON THE OTHER HAND, THIS GALNAC

9542
07:22:29,240 --> 07:22:30,200
BINDING SITE IN THE LECTIN

9543
07:22:30,200 --> 07:22:32,840
DOMAIN IS HIGHLY CONSERVED, AND

9544
07:22:32,840 --> 07:22:34,120
I'LL TALK ABOUT THAT IN THE NEXT

9545
07:22:34,120 --> 07:22:35,560
SLOID BUT I WANTED TO FIRST

9546
07:22:35,560 --> 07:22:39,480
INTRODUCE THE LECTIN DOMAIN MORE

9547
07:22:39,480 --> 07:22:40,680
SPECIFICALLY, SO THIS LECTIN

9548
07:22:40,680 --> 07:22:42,360
DOMAIN CONTAINS THREE REPEATS

9549
07:22:42,360 --> 07:22:43,440
WITH SUGAR BINDING POTENTIAL,

9550
07:22:43,440 --> 07:22:45,080
AND WHAT WE MEAN BY POTENTIAL IS

9551
07:22:45,080 --> 07:22:46,640
THAT YOU HAVE TO HAVE THE RIGHT

9552
07:22:46,640 --> 07:22:49,440
RESIDUES TO ACTUALLY INTERACT

9553
07:22:49,440 --> 07:22:50,880
WITH THE SUGAR AND THOSE

9554
07:22:50,880 --> 07:22:55,600
RESIDUES ARE SHOWN HERE UNDER

9555
07:22:55,600 --> 07:22:57,400
STAR -- THAT ALL INTERACT WITH

9556
07:22:57,400 --> 07:22:58,480
GALNAC.

9557
07:22:58,480 --> 07:22:59,640
SO THIS REPEAT POCKET OR THIS

9558
07:22:59,640 --> 07:23:04,960
BINDING POCKET IS CONSERVED, IF

9559
07:23:04,960 --> 07:23:06,960
YOU LOOK AT MOST OF THE

9560
07:23:06,960 --> 07:23:10,480
STRUCTURES, AT LEAST THE -- CAN

9561
07:23:10,480 --> 07:23:12,440
YOU BASICALLY SUPER IMPOSE THOSE

9562
07:23:12,440 --> 07:23:13,640
BINDING POCKETS.

9563
07:23:13,640 --> 07:23:16,120
AND SO THE POTENTIAL, THE WORD

9564
07:23:16,120 --> 07:23:16,840
POTENTIAL COMES FROM THE FACT

9565
07:23:16,840 --> 07:23:18,000
THAT IF YOU LOOK AT THE THREE

9566
07:23:18,000 --> 07:23:19,640
LECTIN DOMAINS AND YOU LOOK AT

9567
07:23:19,640 --> 07:23:20,800
THEM IN ALIGNMENT, YOU CAN SEE,

9568
07:23:20,800 --> 07:23:23,120
IN FACT, NOT -- IT'S NOT ALWAYS

9569
07:23:23,120 --> 07:23:25,440
THE CASE THAT THESE THREE

9570
07:23:25,440 --> 07:23:26,680
RESIDUES OR ONE OF THEM IS

9571
07:23:26,680 --> 07:23:27,880
ALWAYS MISSING SOMETHING, MAKES

9572
07:23:27,880 --> 07:23:30,440
IT SEEM AS IF THAT BINDING

9573
07:23:30,440 --> 07:23:34,520
POTENTIAL FOR TBAL  GALNAC IS
NOT

9574
07:23:34,520 --> 07:23:34,960
NECESSARILY BRENT.

9575
07:23:34,960 --> 07:23:43,000
A LOT OF  PRESENT.

9576
07:23:43,000 --> 07:23:44,160
THAT'S NOT ALWAYS THE CASE, I'LL

9577
07:23:44,160 --> 07:23:45,680
SHOW YOU ONE IN A FEW MINUTES

9578
07:23:45,680 --> 07:23:48,840
THAT HAS TWO ACTIVE REPEATS.

9579
07:23:48,840 --> 07:23:50,160
AND SO WHAT IS INTERESTING ABOUT

9580
07:23:50,160 --> 07:23:52,440
THE LECTIN DOMAIN, YES, THE BIND

9581
07:23:52,440 --> 07:23:53,640
BEING POCKET IS CONSERVED BUT

9582
07:23:53,640 --> 07:23:55,080
THE ORIENTATION OF THE LECTIN

9583
07:23:55,080 --> 07:23:57,400
DOMAIN SEEMS TO REALLY INFLUENCE

9584
07:23:57,400 --> 07:23:58,560
HOW THESE ENZYMES FUNCTION.

9585
07:23:58,560 --> 07:24:02,040
SO HERE WHAT I'M SHOWING ARE TWO

9586
07:24:02,040 --> 07:24:03,880
CRYSTAL STRUCTURE, ONE OF GALNAC

9587
07:24:03,880 --> 07:24:07,880
T12 AND ONE OF T2.

9588
07:24:07,880 --> 07:24:11,040
SO IF YOU SUPER IMPOSE THE

9589
07:24:11,040 --> 07:24:14,560
CATALYTIC DOMAIN OF T2 AND T12,

9590
07:24:14,560 --> 07:24:15,840
MAYBE BY LOOKING AT THIS ALPHA

9591
07:24:15,840 --> 07:24:18,240
HERE AND ALPHA HERE, IT'S NOT

9592
07:24:18,240 --> 07:24:19,120
VERY OBVIOUS, I'M JUST LOOKING

9593
07:24:19,120 --> 07:24:21,480
AT THE SUPER POSITION, BUT THE

9594
07:24:21,480 --> 07:24:22,960
ALPHA REPEATS AND ARE ON

9595
07:24:22,960 --> 07:24:24,200
OPPOSITE SIDES COMPARED TO THE

9596
07:24:24,200 --> 07:24:26,320
CATALYTIC DOMAIN.

9597
07:24:26,320 --> 07:24:27,720
AND SO I JUST WANT TO SAY THAT

9598
07:24:27,720 --> 07:24:29,760
THE STRUCTURE OF T4 WAS ALSO

9599
07:24:29,760 --> 07:24:31,040
SOLVED PRIOR TO THE STRUCTURE OF

9600
07:24:31,040 --> 07:24:33,040
T12 AND IT'S THE CLOSEST

9601
07:24:33,040 --> 07:24:35,720
HOMOLOGUE TO T12.

9602
07:24:35,720 --> 07:24:41,080
SO T4 AND T12 ARE DOING

9603
07:24:41,080 --> 07:24:43,480
BASICALLY THE SAME THING SO

9604
07:24:43,480 --> 07:24:45,560
WHAT'S REALLY INTERESTING HERE

9605
07:24:45,560 --> 07:24:47,280
IS THAT THE PEPTIDE BINDS FROM

9606
07:24:47,280 --> 07:24:49,240
THE END DIRECTION OF THE LECTIN

9607
07:24:49,240 --> 07:24:51,720
DOMAIN AND THEN THIS C TERMINAL

9608
07:24:51,720 --> 07:24:53,640
OF THIS PEPTIDE IS IN THE

9609
07:24:53,640 --> 07:24:57,040
CATALYTIC DOMAIN, WHEREAS IN T

9610
07:24:57,040 --> 07:24:58,840
IT, IT STARTS IN THE C-TERMINUS

9611
07:24:58,840 --> 07:25:01,440
AND ENDS AT THE END TERMINUS IN

9612
07:25:01,440 --> 07:25:02,280
THE CATALYTIC DOMAIN.

9613
07:25:02,280 --> 07:25:03,640
AND WHAT DOES THIS MEAN?

9614
07:25:03,640 --> 07:25:05,800
SO THIS BASICALLY PROVIDES

9615
07:25:05,800 --> 07:25:07,360
EVIDENCE FOR WHAT WAS OBSERVED

9616
07:25:07,360 --> 07:25:09,760
FROM BIOCHEMICAL STUDIES OF

9617
07:25:09,760 --> 07:25:12,600
DIRECTIONALITY, SO SUBSET OF THE

9618
07:25:12,600 --> 07:25:14,240
ENZYMES COMBINE PEPTIDE OR

9619
07:25:14,240 --> 07:25:15,320
PROTEIN -- WELL IN THIS CASE

9620
07:25:15,320 --> 07:25:18,280
JUST PEPTIDES, AT THE C-TERMINUS

9621
07:25:18,280 --> 07:25:22,560
IN THE END TERMINAL DIRECTION,

9622
07:25:22,560 --> 07:25:23,680
GLYCOSYLATE IN THE C TERMINAL

9623
07:25:23,680 --> 07:25:24,200
DIRECTION.

9624
07:25:24,200 --> 07:25:27,960
SO I MENTIONED EARLIER -- WAS

9625
07:25:27,960 --> 07:25:28,720
ALSO SOLVED AND THE PEOPLE WHO

9626
07:25:28,720 --> 07:25:34,240
DID THIS WORK IN SPAIN -- SHOWED

9627
07:25:34,240 --> 07:25:36,120
THAT IF YOU TAKE THE LINGER FROM

9628
07:25:36,120 --> 07:25:39,320
T2 AND THEN YOU PUT IT INTO T4,

9629
07:25:39,320 --> 07:25:40,600
YOU CAN ACTUALLY SWITCH THE

9630
07:25:40,600 --> 07:25:41,720
DIRECTIONALITY OF T4.

9631
07:25:41,720 --> 07:25:44,000
SO WHAT THEY PROPOSE WAS THE

9632
07:25:44,000 --> 07:25:48,800
LINGER WHICH DICTATES THE LECTIN

9633
07:25:48,800 --> 07:25:50,440
DOMAIN POSITION WHICH INFLUENCES

9634
07:25:50,440 --> 07:25:51,200
DIRECTIONALITY OF THE ENZYME.

9635
07:25:51,200 --> 07:25:52,480
SO THIS IS INTERESTING AND I

9636
07:25:52,480 --> 07:25:53,840
THINK IT REALLY DOES APPLY TO

9637
07:25:53,840 --> 07:25:55,840
THAT CASE, BUT ONE THING THAT I

9638
07:25:55,840 --> 07:25:56,800
WAS THINKING ABOUT FOR A WHILE

9639
07:25:56,800 --> 07:25:58,320
IS I DID THE SAME SORT OF

9640
07:25:58,320 --> 07:26:00,520
THOUGHT EXPERIMENT WITH GALNAC

9641
07:26:00,520 --> 07:26:01,560
T1 AND T2 AND THESE ARE SORT OF

9642
07:26:01,560 --> 07:26:03,360
THE HOUSEKEEPING ENZYMES THAT

9643
07:26:03,360 --> 07:26:05,320
CAN GLYCOSYLATE ANYTHING.

9644
07:26:05,320 --> 07:26:08,880
THEY'RE THE MOST ROBUST AND SO

9645
07:26:08,880 --> 07:26:10,800
FARWELL STUDIED OF ALL THE

9646
07:26:10,800 --> 07:26:12,800
ISOENZYMES IN THIS FAMILY, AND

9647
07:26:12,800 --> 07:26:15,400
IF YOU DO SORT OF THE SAME

9648
07:26:15,400 --> 07:26:16,880
EXPERIMENT HERE, YOU COULD SEE

9649
07:26:16,880 --> 07:26:19,320
THAT T1s ALPHA AND -- ARE ALSO

9650
07:26:19,320 --> 07:26:20,960
NOT ON THE SAME SIDE OF THE

9651
07:26:20,960 --> 07:26:22,040
CATALYTIC DOMAIN.

9652
07:26:22,040 --> 07:26:23,600
BUT THEY SEEM TO HAVE THE SAME

9653
07:26:23,600 --> 07:26:29,680
DIRECTIONALITY BASED ON STUDY

9654
07:26:29,680 --> 07:26:31,560
FROM TOM'S GROUP AT CASE

9655
07:26:31,560 --> 07:26:31,800
WESTERN.

9656
07:26:31,800 --> 07:26:34,480
SO WHY IS THAT?

9657
07:26:34,480 --> 07:26:36,120
SO I WAS THINKING ABOUT THIS

9658
07:26:36,120 --> 07:26:38,320
RIGHT BEFORE THE PANDEMIC HIT

9659
07:26:38,320 --> 07:26:40,080
AND THE POSTBAC IN THE LAB IS

9660
07:26:40,080 --> 07:26:41,720
LOOKING FOR A PROJECT AND SO WE

9661
07:26:41,720 --> 07:26:44,800
WERE JUST KIND OF STARING AT

9662
07:26:44,800 --> 07:26:49,880
THIS CRYSTAL STRUCTURE, THAT

9663
07:26:49,880 --> 07:26:50,880
CONTAINS GALNAC AT THE

9664
07:26:50,880 --> 07:26:54,600
C-TERMINUS SO THIS IS BOUND IN

9665
07:26:54,600 --> 07:26:56,560
THE ALPHA SUBUNIT STARTING FROM

9666
07:26:56,560 --> 07:26:57,880
THE C TERMINAL END, AND THEN I

9667
07:26:57,880 --> 07:26:59,640
WAS ALSO STARING AT THIS CRYSTAL

9668
07:26:59,640 --> 07:27:01,680
STRUCTURE OF T1 THAT WAS SOLVED

9669
07:27:01,680 --> 07:27:03,920
MANY YEARS AGO IN LARRY TABAK'S

9670
07:27:03,920 --> 07:27:06,560
LAB SO THIS IS LIKE THE FIRST

9671
07:27:06,560 --> 07:27:10,160
CRYSTAL STRUCTURE THAT DOESN'T

9672
07:27:10,160 --> 07:27:11,240
CONTAIN ANY SUBSTRATES BUT JUST

9673
07:27:11,240 --> 07:27:13,640
BY STARING AT THESE TWO PROTEIN,

9674
07:27:13,640 --> 07:27:15,240
I NOTICED THE ALPHA AND BETA

9675
07:27:15,240 --> 07:27:18,040
REPEAT WERE BASICALLY IN THE

9676
07:27:18,040 --> 07:27:19,440
SAME POSITION IN SPACE COMPARED

9677
07:27:19,440 --> 07:27:21,400
TO THE CATALYTIC DOMAIN, AND SO

9678
07:27:21,400 --> 07:27:25,400
WHAT I PROPOSED WAS THAT IT'S

9679
07:27:25,400 --> 07:27:29,200
POSSIBLE THAT MUC5AC13 WAS BOUND

9680
07:27:29,200 --> 07:27:30,720
TO T1 USING THE BETA AND NOT THE

9681
07:27:30,720 --> 07:27:31,320
ALPHA REPEAT.

9682
07:27:31,320 --> 07:27:32,840
SO YOU'RE GOING TO ASK ME, YOU

9683
07:27:32,840 --> 07:27:34,560
SAID ONLY ONE LECTIN REPEAT IS

9684
07:27:34,560 --> 07:27:37,880
USUALLY ACTIVE BUT IN FACT,

9685
07:27:37,880 --> 07:27:39,560
THERE ARE JUST A FEW ENZYMES

9686
07:27:39,560 --> 07:27:40,960
WHERE TWO LECTIN REPEATS ARE

9687
07:27:40,960 --> 07:27:42,720
ACTIVE AND IN THIS CASE, T1 IS

9688
07:27:42,720 --> 07:27:44,360
ONE OF THOSE ENZYMES WHERE BOTH

9689
07:27:44,360 --> 07:27:46,400
ALPHA AND BETA WERE SHOWN TO

9690
07:27:46,400 --> 07:27:50,720
HAVE ACTIVE LECTIN REPEATS BY A

9691
07:27:50,720 --> 07:27:53,000
GROUP A WHILE BACK AND I'LL CITE

9692
07:27:53,000 --> 07:27:54,080
THEM IN THE NEXT SLIDE.

9693
07:27:54,080 --> 07:27:59,440
BUT IF YOU CRYSTALLIZE T1 WITH

9694
07:27:59,440 --> 07:28:00,440
MUC5 -- THAT KIND OF EXPLAINS

9695
07:28:00,440 --> 07:28:02,400
WHY THE TWO ENZYMES HAVE THE

9696
07:28:02,400 --> 07:28:02,840
SAME DIRECTIONALITY.

9697
07:28:02,840 --> 07:28:11,040
IT'S NOT REALLY BECAUSE OF

9698
07:28:11,040 --> 07:28:12,600
THE -- POSITIONED THE SAME WAY

9699
07:28:12,600 --> 07:28:14,480
IN SPACE.

9700
07:28:14,480 --> 07:28:18,240
AND SO WE JUST -- WE'RE

9701
07:28:18,240 --> 07:28:18,920
CURRENTLY TRYING TO ASSESS WHAT

9702
07:28:18,920 --> 07:28:22,000
THIS MEANS, SO THE GROUP I

9703
07:28:22,000 --> 07:28:23,520
MENTIONED THAT FIRST DISCOVERED

9704
07:28:23,520 --> 07:28:26,760
THIS THAT BOTH REPEATS IN T1 ARE

9705
07:28:26,760 --> 07:28:28,040
ACTIVE, FROM 2002, BUT WE'RE

9706
07:28:28,040 --> 07:28:30,480
SORT OF FOLLOWING UP DOING

9707
07:28:30,480 --> 07:28:36,840
FURTHER STUDIES ON THIS, AND

9708
07:28:36,840 --> 07:28:38,240
HERE'S -- NOW WE'RE REALLY

9709
07:28:38,240 --> 07:28:39,520
TRYING TO UNDERSTAND FIRST OF

9710
07:28:39,520 --> 07:28:42,640
ALL WHY DOES T1 EVEN HAVE TO

9711
07:28:42,640 --> 07:28:44,320
REPEAT, WHY DOES IT NEED TO HAVE

9712
07:28:44,320 --> 07:28:46,560
TWO, WHEN IT'S REALLY ACTIVE

9713
07:28:46,560 --> 07:28:47,760
AGAINST A LOT OF SUBSTRATES THAT

9714
07:28:47,760 --> 07:28:49,640
DON'T EVEN NEED TO BE

9715
07:28:49,640 --> 07:28:50,680
GLYCOSYLATED TO FURTHER -- TO

9716
07:28:50,680 --> 07:28:52,560
ADD AN INITIAL GALNAC?

9717
07:28:52,560 --> 07:28:55,760
SO THAT'S REALLY NOW THE

9718
07:28:55,760 --> 07:28:57,040
QUESTION AND THE BASIS OF THE

9719
07:28:57,040 --> 07:28:58,360
STUDY WE'RE TRYING TO WRAP UP.

9720
07:28:58,360 --> 07:29:01,080
BUT IF YOU LOOK AT THE SECOND --

9721
07:29:01,080 --> 07:29:02,080
AGAINST THESE DIFFERENT

9722
07:29:02,080 --> 07:29:04,160
PEPTIDES, SO THESE PEPTIDES

9723
07:29:04,160 --> 07:29:05,640
EITHER CONTAIN TWO, SO THE BLUE

9724
07:29:05,640 --> 07:29:08,000
ONE CONTAINS TWO ACCEPTOR SITES,

9725
07:29:08,000 --> 07:29:10,600
AND THE RED AND THE GREEN ONES

9726
07:29:10,600 --> 07:29:11,720
CONTAIN EITHER AN ACCEPTOR SITE

9727
07:29:11,720 --> 07:29:13,400
AT THE END TERMINUS OR AN

9728
07:29:13,400 --> 07:29:15,240
ACCEPTOR SITE AT THE C-TERMINUS,

9729
07:29:15,240 --> 07:29:18,160
AND IF YOU LOOK AT JUST THIS

9730
07:29:18,160 --> 07:29:19,400
SPECIFICITY OF THIS ENZYME

9731
07:29:19,400 --> 07:29:22,320
AGAINST ALL THESE DIFFERENT

9732
07:29:22,320 --> 07:29:23,920
LIGHT SUBSTRATES, WHAT WE'LL

9733
07:29:23,920 --> 07:29:25,360
NOTICE IS IN THE WILD TYPE,

9734
07:29:25,360 --> 07:29:26,760
GALNAC IS ACTUALLY ENHANCING THE

9735
07:29:26,760 --> 07:29:28,400
ACTIVITY OF THIS ENZYME, WHETHER

9736
07:29:28,400 --> 07:29:29,920
IT'S THIS SUBSTRATE OR THAT

9737
07:29:29,920 --> 07:29:30,720
SUBSTRATE.

9738
07:29:30,720 --> 07:29:35,400
AND IF YOU MAKE A MUTATION -- TO

9739
07:29:35,400 --> 07:29:36,840
KNOCK OUT THE BINDING YOU CAN

9740
07:29:36,840 --> 07:29:38,440
REALLY REDUCE THE SPECIFICITY

9741
07:29:38,440 --> 07:29:40,640
TOWARDS THIS SUBSTRATE AND WITH

9742
07:29:40,640 --> 07:29:42,520
NO INFLUENCE ON THE SPECIFICITY

9743
07:29:42,520 --> 07:29:45,080
OF THIS SUBSTRATE.

9744
07:29:45,080 --> 07:29:46,240
AND THEN IF YOU MAKE A MUTATION

9745
07:29:46,240 --> 07:29:48,520
IN THE BETA, YOU CAN REDUCE THE

9746
07:29:48,520 --> 07:29:50,400
SPECIFICITY TOWARDS THE BETA

9747
07:29:50,400 --> 07:29:51,840
SUBSTRATE, AND SOMEHOW REDUCE

9748
07:29:51,840 --> 07:29:53,840
THE ALPHA SUBSTRATE BUT THE

9749
07:29:53,840 --> 07:29:55,000
ERROR BAR HERE IS HIGH AND

9750
07:29:55,000 --> 07:29:56,040
THERE'S A TWOFOLD DIFFERENCE SO

9751
07:29:56,040 --> 07:29:57,640
I DON'T WANT TO OVERTHINK THIS.

9752
07:29:57,640 --> 07:30:01,840
AND THEN IF YOU REMOVE BOTH BETA

9753
07:30:01,840 --> 07:30:03,240
AND ALPHA REPEAT BINDING YOU

9754
07:30:03,240 --> 07:30:05,360
REDUCE THE SPECIFICITY TOWARDS

9755
07:30:05,360 --> 07:30:06,360
BOTH GLYCOSUBSTRATES AND IT'S

9756
07:30:06,360 --> 07:30:07,640
ESSENTIALLY AS IF THERE'S NO

9757
07:30:07,640 --> 07:30:08,640
LECTIN DOMAIN OVER THERE.

9758
07:30:08,640 --> 07:30:11,280
SO THESE LECTIN REPEATS ARE

9759
07:30:11,280 --> 07:30:12,440
CERTAINLY ENHANCING THE ACTIVITY

9760
07:30:12,440 --> 07:30:15,400
OR SPECIFICITY OF GALNAC

9761
07:30:15,400 --> 07:30:16,520
T1 TOWARDS GLYCOSYLATED

9762
07:30:16,520 --> 07:30:17,200
SUBSTRATES.

9763
07:30:17,200 --> 07:30:18,400
SO I JUST WANT TO BRING YOU THE

9764
07:30:18,400 --> 07:30:20,040
LAST SLIDE, I HOPE I DIDN'T GO

9765
07:30:20,040 --> 07:30:21,880
TOO LONG AND I APOLOGIZE IF I

9766
07:30:21,880 --> 07:30:25,600
DID AND I HOPE CATH LIN 
CATHERINE STOP ME

9767
07:30:25,600 --> 07:30:26,160
IF I AM.

9768
07:30:26,160 --> 07:30:27,800
I SAID EARLIER I KIND OF PUT

9769
07:30:27,800 --> 07:30:29,840
THESE ENZYMES IN DIFFERENT

9770
07:30:29,840 --> 07:30:31,280
BOXES, EARLY, INTERMEDIATE AND

9771
07:30:31,280 --> 07:30:32,600
LATE, BUT IT'S WAY MORE

9772
07:30:32,600 --> 07:30:33,440
COMPLICATED THAN THAT, RIGHT,

9773
07:30:33,440 --> 07:30:36,520
BECAUSE I SAID THAT GALNAC

9774
07:30:36,520 --> 07:30:37,840
T1 CAN DO -- GLYCOSYLATE

9775
07:30:37,840 --> 07:30:38,880
SOMETHING THAT'S NEVER BEEN

9776
07:30:38,880 --> 07:30:41,240
TOUCHED AND IT SEEMS TO BE

9777
07:30:41,240 --> 07:30:47,360
ENHANCED BY EITHER ONE OR TWO OR

9778
07:30:47,360 --> 07:30:48,840
SO WE'VE BEEN USING THESE SHORT

9779
07:30:48,840 --> 07:30:50,200
PEPTIDES BUT IF YOU ENVISION A

9780
07:30:50,200 --> 07:30:51,720
LONGER PEPTIDE WITH TWO GALNACS

9781
07:30:51,720 --> 07:30:53,680
ON IT, YOU CAN ENVISION THAT

9782
07:30:53,680 --> 07:30:55,560
GALNAC T1 MIGHT BE JUST

9783
07:30:55,560 --> 07:30:57,600
GLYCOSYLATING BETWEEN TWO

9784
07:30:57,600 --> 07:30:58,760
GALNACs THAT HAVE BEEN ADDED

9785
07:30:58,760 --> 07:31:02,280
BY SOMETHING ELSE, MAYBE -- BUT

9786
07:31:02,280 --> 07:31:04,840
THE POINT IS LIKE -- CONTEXT

9787
07:31:04,840 --> 07:31:06,400
MATTERS AND IT'S REALLY

9788
07:31:06,400 --> 07:31:07,400
IMPORTANT LIKE WHAT THE

9789
07:31:07,400 --> 07:31:09,000
SUBSTRATE IS, WHAT THE CELL IS,

9790
07:31:09,000 --> 07:31:10,520
WHAT HAPPENED BEFORE OR AFTER.

9791
07:31:10,520 --> 07:31:12,640
SO IT'S NOT AS SIMPLE AS THESE

9792
07:31:12,640 --> 07:31:13,720
ENZYMES JUST FITTING INTO

9793
07:31:13,720 --> 07:31:14,240
CERTAIN CATEGORIES.

9794
07:31:14,240 --> 07:31:16,120
IT REALLY -- YOU KNOW, IT'S

9795
07:31:16,120 --> 07:31:17,320
REALLY MUCH MORE COMPLICATED

9796
07:31:17,320 --> 07:31:18,520
THAN THAT AS WE'RE SEEING WITH

9797
07:31:18,520 --> 07:31:22,600
THE T1 EXAMPLE.

9798
07:31:22,600 --> 07:31:24,440
SO THESE ARE THE CONCLUSIONS.

9799
07:31:24,440 --> 07:31:25,840
I HOPE TODAY THAT I SHOWED YOU

9800
07:31:25,840 --> 07:31:30,080
THAT SELECTIVITY IS REALLY

9801
07:31:30,080 --> 07:31:34,880
COATED WITHIN VERY SPECIFIC

9802
07:31:34,880 --> 07:31:36,640
RESIDUES OR REGIONS, AND EACH

9803
07:31:36,640 --> 07:31:37,480
FAMILY MEMBER SEEMS TO FOLLOW

9804
07:31:37,480 --> 07:31:39,640
ITS OWN RULES, AND OF COURSE

9805
07:31:39,640 --> 07:31:41,360
FROM MORE BIOMEDICAL

9806
07:31:41,360 --> 07:31:42,440
PERSPECTIVE, KNOWING THAT EACH

9807
07:31:42,440 --> 07:31:44,320
ONE IS SPECIFIC IN TERMS OF ITS

9808
07:31:44,320 --> 07:31:46,080
FUNCTION, CAN WE DESIGN SPECIFIC

9809
07:31:46,080 --> 07:31:49,000
INHIBITORS OR ATTENUATORS, AND

9810
07:31:49,000 --> 07:31:50,120
USE THIS INFORMATION TO

9811
07:31:50,120 --> 07:31:51,760
CORRECTLY PREDICT BUY LOGICAL

9812
07:31:51,760 --> 07:31:54,280
SUBSTRATES BECAUSE AS I

9813
07:31:54,280 --> 07:31:55,160
MENTIONED A LOT OF TIMES WE

9814
07:31:55,160 --> 07:31:58,240
DON'T REALLY KNOW WHAT THE

9815
07:31:58,240 --> 07:31:59,480
SUBSTRATES OR SITES ARE OF

9816
07:31:59,480 --> 07:31:59,960
GLYCOSYLATION.

9817
07:31:59,960 --> 07:32:01,680
I WANT TO FINISH MY TALK BY

9818
07:32:01,680 --> 07:32:04,840
SAYING OUR LAB IS GROWING, IT'S

9819
07:32:04,840 --> 07:32:06,000
PRETTY AWESOME, I LOVE HOW MUCH

9820
07:32:06,000 --> 07:32:07,600
IS BEING DONE AND HOW EXCITED

9821
07:32:07,600 --> 07:32:08,800
EVERYBODY IS.

9822
07:32:08,800 --> 07:32:12,840
WE COLLABORATE A LOT WITH KELLY

9823
07:32:12,840 --> 07:32:15,880
10 HAGEN AND LARRY TABAK,

9824
07:32:15,880 --> 07:32:17,440
THEY'RE BOTH AMAZING MENTORS.

9825
07:32:17,440 --> 07:32:19,080
A LOT OF THE PEOPLE THAT DID THE

9826
07:32:19,080 --> 07:32:20,840
WORK I SHOWED TODAY ARE IN GREEN

9827
07:32:20,840 --> 07:32:23,920
AND THOSE CONTINUING TO DO WORK

9828
07:32:23,920 --> 07:32:25,120
HIGHLIGHTED IN GREEN AS WELL.

9829
07:32:25,120 --> 07:32:31,520
WE COLLABORATED WITH TOM GERKEN.

9830
07:32:31,520 --> 07:32:33,600
WE'RE CONTINUING TO COLLABORATE

9831
07:32:33,600 --> 07:32:35,800
WITH BEN SCHUMANN AT THE CRICK

9832
07:32:35,800 --> 07:32:37,840
ON T12 TRYING TO FIGURE OUT WHAT

9833
07:32:37,840 --> 07:32:38,640
THESE SUBSTRATES MIGHT BE.

9834
07:32:38,640 --> 07:32:40,120
WITH THAT I WANT TO SAY THANK

9835
07:32:40,120 --> 07:32:41,240
YOU FOR YOUR ATTENTION, I KNOW

9836
07:32:41,240 --> 07:32:44,960
IT'S THE END OF THE DAY.

9837
07:32:44,960 --> 07:32:45,840
HOPEFULLY EVERYONE HAS TIME TO

9838
07:32:45,840 --> 07:32:46,640
TELL THEIR STORIES.

9839
07:32:46,640 --> 07:32:49,080
THANK YOU VERY MUCH.

9840
07:32:49,080 --> 07:32:50,640
>> REALLY GREAT, NADINE.

9841
07:32:50,640 --> 07:32:51,080
THANK YOU.

9842
07:32:51,080 --> 07:32:54,800
THANK YOU.

9843
07:32:54,800 --> 07:32:56,800
WE HAVE TIME FOR ONE QUICK

9844
07:32:56,800 --> 07:32:57,560
QUESTION, JOHN?

9845
07:32:57,560 --> 07:32:58,320
WHAT DO YOU THINK?

9846
07:32:58,320 --> 07:32:59,640
>> SURE.

9847
07:32:59,640 --> 07:33:00,920
SOMEONE HAS A QUESTION, DO THESE

9848
07:33:00,920 --> 07:33:04,440
LECTIN DOMAINS ALSO BIND GEL OR

9849
07:33:04,440 --> 07:33:08,040
ARE  GAL OR

9850
07:33:08,040 --> 07:33:10,640
ARE THEY VERY GALNAC --

9851
07:33:10,640 --> 07:33:12,080
>> THAT'S A GREAT QUESTION.

9852
07:33:12,080 --> 07:33:16,680
SO I CAN SAY THAT LIKE FOR THE

9853
07:33:16,680 --> 07:33:18,120
T1 STORY, WE'RE DOING A LOT OF

9854
07:33:18,120 --> 07:33:21,600
COMPETITION ASSAYS.

9855
07:33:21,600 --> 07:33:26,200
JUST TO MAKE SURE -- WE'RE

9856
07:33:26,200 --> 07:33:28,920
DOING -- MY POSTBAC WAS DOING

9857
07:33:28,920 --> 07:33:30,080
COMPETITION ASSAYS WITH GALNAC

9858
07:33:30,080 --> 07:33:32,280
TO MAKE SURE THAT WE'RE ACTUALLY

9859
07:33:32,280 --> 07:33:33,640
REMOVING GALNAC BINDING, AND SHE

9860
07:33:33,640 --> 07:33:36,840
DID TRY DIFFERENT SUGARS, AND I

9861
07:33:36,840 --> 07:33:37,800
DON'T REMEMBER THE DATA, BUT

9862
07:33:37,800 --> 07:33:38,800
THERE WERE SOME OTHER SUGARS

9863
07:33:38,800 --> 07:33:41,200
THAT SEEMED TO BE COMPETING WITH

9864
07:33:41,200 --> 07:33:41,640
THE PEPTIDES.

9865
07:33:41,640 --> 07:33:44,040
SO I CAN GET BACK TO YOU LATER,

9866
07:33:44,040 --> 07:33:44,280
LAURA.

9867
07:33:44,280 --> 07:33:45,680
I JUST HAVE TO KIND OF GO BACK

9868
07:33:45,680 --> 07:33:47,640
AND LOOK AT THAT TO SEE.

9869
07:33:47,640 --> 07:33:50,400
I THINK MANNOSE WAS ONE THAT WAS

9870
07:33:50,400 --> 07:33:51,920
COMPETEING WITH THE GLYCOSYLATED

9871
07:33:51,920 --> 07:33:54,560
PEPTIDE BUT I'M NOT 100% SURE.

9872
07:33:54,560 --> 07:33:56,280
SORRY.

9873
07:33:56,280 --> 07:33:58,600
>> I JUST THOUGHT MAYBE THAT N

9874
07:33:58,600 --> 07:34:00,840
GLYCANS MIGHT HELP RECRUIT THE

9875
07:34:00,840 --> 07:34:03,720
ENZYME, AND THAT MIGHT BE AN

9876
07:34:03,720 --> 07:34:04,840
INTERESTING ROLE.

9877
07:34:04,840 --> 07:34:05,800
>> YEAH.

9878
07:34:05,800 --> 07:34:07,440
YEAH, THAT'S A REALLY GOOD

9879
07:34:07,440 --> 07:34:07,640
POINT.

9880
07:34:07,640 --> 07:34:08,960
SO ACTUALLY IF YOU LOOK AT THE

9881
07:34:08,960 --> 07:34:11,920
CRYSTAL STRUCTURE OF T1, IT ALSO

9882
07:34:11,920 --> 07:34:13,640
HAS N GLYCANS ON IT SELF, AND

9883
07:34:13,640 --> 07:34:14,640
SOMETIMES I THINK ABOUT THE WAY

9884
07:34:14,640 --> 07:34:16,000
THEY'RE PACKING IN THE CRYSTAL

9885
07:34:16,000 --> 07:34:17,080
STRUCTURE AND I'M WONDERING IF

9886
07:34:17,080 --> 07:34:19,360
THAT CAN GIVE YOU ANY INSIGHT

9887
07:34:19,360 --> 07:34:22,240
INTO NOT JUST, YOU KNOW, N

9888
07:34:22,240 --> 07:34:23,480
GLYCANS ON THE SUBSTRATE BUT

9889
07:34:23,480 --> 07:34:24,800
ALSO N GLYCANS ON THE PROTEINS

9890
07:34:24,800 --> 07:34:27,000
THEMSELVES AND HOW THEY COULD BE

9891
07:34:27,000 --> 07:34:28,160
MODULATING THE ENZYME FUNCTION.

9892
07:34:28,160 --> 07:34:30,560
BECAUSE IN SOME CASE, I CAN

9893
07:34:30,560 --> 07:34:31,880
REMOVE THE N GLYCANS OF THE

9894
07:34:31,880 --> 07:34:33,200
PROTEINS FINE AND THE ACTIVITY

9895
07:34:33,200 --> 07:34:34,200
IS NOT TOTALLY GONE, BUT IN

9896
07:34:34,200 --> 07:34:36,040
OTHER CASES IF I REMOVE THE

9897
07:34:36,040 --> 07:34:37,240
N-GLYCAN, IT KILLS THE ENZYME.

9898
07:34:37,240 --> 07:34:39,080
I DON'T KNOW IF IT'S BECAUSE

9899
07:34:39,080 --> 07:34:44,120
IT'S JUST DESTABILIZINGITY

9900
07:34:44,120 --> 07:34:45,000
OVERALL STABILITY BUT IT'S

9901
07:34:45,000 --> 07:34:46,520
SOMETHING I THINK ABOUT TOO, SO

9902
07:34:46,520 --> 07:34:53,960
THAT'S A REALLY GREAT POINT.

9903
07:34:53,960 --> 07:34:55,040
>> THANK YOU.

9904
07:34:55,040 --> 07:34:58,240
>> THANKS, NADINE, FOR A GREAT

9905
07:34:58,240 --> 07:34:58,760
TALK.

9906
07:34:58,760 --> 07:35:04,440
OUR NEXT SPEAKER IS SEAN

9907
07:35:04,440 --> 07:35:05,720
STOWELL, AND HE'S GOING TO TALK

9908
07:35:05,720 --> 07:35:07,400
TO US ABOUT DISCOVERING

9909
07:35:07,400 --> 07:35:08,880
DETERMINANTS OF NATURALLY

9910
07:35:08,880 --> 07:35:10,120
OCCURRING ANTIBODY FORMATION.

9911
07:35:10,120 --> 07:35:12,080
SO THANKS, SEAN.

9912
07:35:12,080 --> 07:35:13,280
>> ALL RIGHT.

9913
07:35:13,280 --> 07:35:14,160
SO I REALLY APPRECIATE THE

9914
07:35:14,160 --> 07:35:15,360
OPPORTUNITY TO WORK WITH

9915
07:35:15,360 --> 07:35:19,080
CATHERINE ON THE SYMPOSIUM.

9916
07:35:19,080 --> 07:35:20,480
I REALLY WANT TO GIVE HER TIME,

9917
07:35:20,480 --> 07:35:22,360
IT'S BEEN WONDERFUL TO LISTEN TO

9918
07:35:22,360 --> 07:35:24,640
EVERYONE'S SCIENCE AND I'M JUST

9919
07:35:24,640 --> 07:35:25,600
GOING TO -- A OPPORTUNITY TO

9920
07:35:25,600 --> 07:35:27,120
TAKE A BREAK FROM EVERYTHING

9921
07:35:27,120 --> 07:35:29,960
ELSE AND LISTEN TO A LOT OF

9922
07:35:29,960 --> 07:35:32,040
GREAT TALKS ON AREAS RELATED TO

9923
07:35:32,040 --> 07:35:33,800
THE MICROBIOME AND GLYCOBIOLOGY

9924
07:35:33,800 --> 07:35:36,680
IN GENERAL.

9925
07:35:36,680 --> 07:35:37,760
SO ONE OF THE THINGS THAT OUR

9926
07:35:37,760 --> 07:35:39,840
LAB IS INTERESTED IN IS ANTIBODY

9927
07:35:39,840 --> 07:35:41,240
REPERTOIRES AND HOW THEY

9928
07:35:41,240 --> 07:35:41,480
DEVELOP.

9929
07:35:41,480 --> 07:35:42,400
MOST OF US ARE VERY FAMILIAR

9930
07:35:42,400 --> 07:35:44,440
WITH OBVIOUSLY ACQUIRED

9931
07:35:44,440 --> 07:35:46,600
DEVELOPMENT OR CHANGES IN

9932
07:35:46,600 --> 07:35:47,640
ANTIBODY REPERTOIRE AS A RESULT

9933
07:35:47,640 --> 07:35:49,960
OF INFECTION OR VACCINATION, OF

9934
07:35:49,960 --> 07:35:51,720
COURSE WITH COVID IT'S BEEN A

9935
07:35:51,720 --> 07:35:54,640
TOM IK 

9936
07:35:54,640 --> 07:35:57,240
TOPIC DU OP JOUR.

9937
07:35:57,240 --> 07:35:59,440
SOMETHING THAT RECEIVES A LITTLE

9938
07:35:59,440 --> 07:36:00,680
LESS ATTENTION IS ANTIBODIES.

9939
07:36:00,680 --> 07:36:08,320
THESE ARE M SO OF  SOME OF OF
THE FIRST

9940
07:36:08,320 --> 07:36:09,120
ANTIBODIES DISCOVERED, THEY ARE

9941
07:36:09,120 --> 07:36:10,880
REALLY IMPORTANT IN TRANSPLANT,

9942
07:36:10,880 --> 07:36:12,480
TRANSFUSION TOLERANCE, AND ALSO

9943
07:36:12,480 --> 07:36:15,480
HAVE BEEN SHOWN TO REGULATE

9944
07:36:15,480 --> 07:36:16,160
AUTOIMMUNITY.

9945
07:36:16,160 --> 07:36:17,040
THE FUNDAMENTAL QUESTIONS ABOUT

9946
07:36:17,040 --> 07:36:18,880
HOW THESE ANTIBODIES FORM AND

9947
07:36:18,880 --> 07:36:20,840
HOW THEY SHAPE THE REPERTOIRE

9948
07:36:20,840 --> 07:36:28,120
EACH OF US HAVE INDIVIDUALLY,

9949
07:36:28,120 --> 07:36:29,720
EXTREMELY DISTINCT AND HAVE VERY

9950
07:36:29,720 --> 07:36:30,720
LITTLE OVERLAP AS YOU CAN SEE

9951
07:36:30,720 --> 07:36:33,040
HERE IN THE CENTER OF THIS

9952
07:36:33,040 --> 07:36:34,040
SCHEMATIC.

9953
07:36:34,040 --> 07:36:36,320
THE FIRST NATURALLY OCCURRING

9954
07:36:36,320 --> 07:36:37,600
ANTIBODIES THAT WERE DESCRIBED

9955
07:36:37,600 --> 07:36:38,840
IN MANY WAYS TO BE THE MOST

9956
07:36:38,840 --> 07:36:40,480
COMMONLY KNOWN, THOSE ARE

9957
07:36:40,480 --> 07:36:43,440
ANTIBODIES AGAINST A AND B BLOOD

9958
07:36:43,440 --> 07:36:47,640
GROUP ANTIGENS.

9959
07:36:47,640 --> 07:36:48,680
 -- THOSE ARE IMPORTANT

9960
07:36:48,680 --> 07:36:51,840
ANTIBODIES IN TERMS OF IMMUNE

9961
07:36:51,840 --> 07:36:53,960
DIFFICULTIES WITH RESPECT TO

9962
07:36:53,960 --> 07:36:54,920
TRANSPLANTATION AND TRANSFUSION

9963
07:36:54,920 --> 07:36:57,440
THAT CAN CAUSE IMMUNE REJECTION

9964
07:36:57,440 --> 07:36:59,840
AND COMPLICATIONS, THEY'RE VERY

9965
07:36:59,840 --> 07:37:02,600
SEVERE, AND WERE ACTUALLY THE

9966
07:37:02,600 --> 07:37:06,840
ANTIGENS TARGETED BY THESE

9967
07:37:06,840 --> 07:37:08,240
ANTIBODIES -- LIKE CARL

9968
07:37:08,240 --> 07:37:09,880
LANSTEINER IN 1900, OVER 20

9969
07:37:09,880 --> 07:37:11,440
YEARS AGO, WHEN SHE GOT THE

9970
07:37:11,440 --> 07:37:13,400
NOBEL PRIZE IN 1930, SO THERE

9971
07:37:13,400 --> 07:37:16,640
HAVE BEEN A LOT OF DIFFERENT

9972
07:37:16,640 --> 07:37:18,760
IDEAS ABOUT HOW NATURALLY

9973
07:37:18,760 --> 07:37:24,200
OCCURRING ANTIBODIES DEVELOP.

9974
07:37:24,200 --> 07:37:25,760
THE EARLIEST STUDIES ACTUALLY

9975
07:37:25,760 --> 07:37:27,880
BEFORE ANTIBODIES WERE REALLY

9976
07:37:27,880 --> 07:37:29,520
EVEN DEFINED SUGGESTED MAYBE

9977
07:37:29,520 --> 07:37:32,360
THERE WAS A HAPLOTYPE, OBVIOUSLY

9978
07:37:32,360 --> 07:37:34,640
BEFORE SCIENTIFIC DISCOVERIES AS

9979
07:37:34,640 --> 07:37:38,920
A RESULT IN THE UNDERSTANDING

9980
07:37:38,920 --> 07:37:41,360
OF -- GERM-FREE MICE SUGGESTED

9981
07:37:41,360 --> 07:37:42,520
THAT MICROBIAL EXPOSURE HAD NO

9982
07:37:42,520 --> 07:37:45,920
INFLUENCE REALLY ON IGM LEVELS

9983
07:37:45,920 --> 07:37:46,680
OR REPERTOIRE AND THESE STUDIES

9984
07:37:46,680 --> 07:37:49,000
WERE REALLY IMPORTANT IN SHAPING

9985
07:37:49,000 --> 07:37:50,200
CURRENT UNDERSTANDING REQUIRING

9986
07:37:50,200 --> 07:37:52,200
POTENTIAL INFLUENCE OR LACK

9987
07:37:52,200 --> 07:37:53,360
THEREOF THE MICROBIOTA ON THE

9988
07:37:53,360 --> 07:37:56,760
DEVELOPMENT OF ANTIBODIES.

9989
07:37:56,760 --> 07:37:57,720
THESE STUDIES ARE CORROBORATED

9990
07:37:57,720 --> 07:37:59,240
BY A STUDY BEAUTIFULLY DONE A

9991
07:37:59,240 --> 07:38:01,320
FEW YEARS BACK LOOKING AT BOTH

9992
07:38:01,320 --> 07:38:04,880
IGM AND MOSTLY IGA IN TERMS OF

9993
07:38:04,880 --> 07:38:10,080
THE ACTUAL REPERTOIRE OF B CELL

9994
07:38:10,080 --> 07:38:13,200
RECEPTORS PRESENT IN MICE.

9995
07:38:13,200 --> 07:38:15,160
THEY FOUND THAT THE ANTIBODIES

9996
07:38:15,160 --> 07:38:18,720
PRESENT EITHER IN GERM-FREE OR

9997
07:38:18,720 --> 07:38:20,280
CONVENTIONALLY HOUSED MICE WERE

9998
07:38:20,280 --> 07:38:22,160
REALLY NOT TOO DIFFERENT, THEY

9999
07:38:22,160 --> 07:38:23,920
WERE QUITE POLYREACTIVE IN

10000
07:38:23,920 --> 07:38:25,040
NATURE, SUGGESTING THAT ONCE

10001
07:38:25,040 --> 07:38:26,840
AGAIN THEET ANTIBODIES NOT ONLY

10002
07:38:26,840 --> 07:38:29,520
FORMED BUT THEY -- THESE RESULTS

10003
07:38:29,520 --> 07:38:35,640
SUGGESTED ONCE AGAIN THAT THE

10004
07:38:35,640 --> 07:38:36,800
MICROBIOTA ARE YOU THINK 
UNLIKELY INVOLVE
D

10005
07:38:36,800 --> 07:38:41,800
IN SHAPING -- ONE OF THE

10006
07:38:41,800 --> 07:38:43,000
CHALLENGES IN STUDYING

10007
07:38:43,000 --> 07:38:45,520
CLINICALLY RELEVANT NATURALLY

10008
07:38:45,520 --> 07:38:48,800
OCCURRING ANTIBODIES THE

10009
07:38:48,800 --> 07:38:50,440
ANTIGENS ARE NOT POLYMORPHIC IN

10010
07:38:50,440 --> 07:38:51,840
MOST OF THE MODELS WE STUDIED IN

10011
07:38:51,840 --> 07:38:58,280
PARTICULAR MICE.

10012
07:38:58,280 --> 07:38:59,920
THEY DO NOT MAKE ANTIBODIES

10013
07:38:59,920 --> 07:39:02,040
UNTIL LATE IN LIFE, SO FOUR OR

10014
07:39:02,040 --> 07:39:03,440
FIVE MONTHS, PEOPLE REPORT THESE

10015
07:39:03,440 --> 07:39:04,160
ANTIBODIES, THEY DON'T DEVELOP

10016
07:39:04,160 --> 07:39:06,520
ON A TIME SCALE THAT DEVELOPS

10017
07:39:06,520 --> 07:39:06,920
NORMALLY.

10018
07:39:06,920 --> 07:39:09,000
AS ALL OF YOU KNOW, A AND B

10019
07:39:09,000 --> 07:39:10,840
ANTIGENS ARE GLYCANS AND THEY'RE

10020
07:39:10,840 --> 07:39:18,520
SYNTHESIZED DUE TO THE --

10021
07:39:18,520 --> 07:39:23,760
SYNTHESIS.

10022
07:39:23,760 --> 07:39:28,080
DUE TO THE -- WE WANTED TO KNOW

10023
07:39:28,080 --> 07:39:29,840
IF WE TOOK MICE AND KNOCKED OUT

10024
07:39:29,840 --> 07:39:32,240
THIS ENZYME WHEN WE CAN MAKE AN

10025
07:39:32,240 --> 07:39:33,880
O AND B PAIR TO STUDY THE

10026
07:39:33,880 --> 07:39:35,440
FORMATION OF SPONTANEOUS

10027
07:39:35,440 --> 07:39:37,160
FORMATION IN NATURALLY OCCURRING

10028
07:39:37,160 --> 07:39:37,840
ANTIBODIES AGAINST THE B

10029
07:39:37,840 --> 07:39:38,280
ANTIGEN.

10030
07:39:38,280 --> 07:39:39,720
THIS IS IN PART IMPORTANT ONCE

10031
07:39:39,720 --> 07:39:43,440
AGAIN BECAUSE OF THE BARRIERS OF

10032
07:39:43,440 --> 07:39:46,040
NATURALLY OCCURRING -- CAUSE IN

10033
07:39:46,040 --> 07:39:48,840
TRANSFUSION AND TRANSPLANTATION

10034
07:39:48,840 --> 07:39:49,640
CLINICALLY INVOLVED IN

10035
07:39:49,640 --> 07:39:50,560
TRANSFUSION MEDICINE, SO THIS IS

10036
07:39:50,560 --> 07:39:52,080
SOMETHING WE TEST EVERY DAY AND

10037
07:39:52,080 --> 07:39:54,160
PROBABLY THE MOST COMMON

10038
07:39:54,160 --> 07:39:55,040
IMMUNOLOGICAL TEST DONE IN THE

10039
07:39:55,040 --> 07:39:56,480
WORLD BECAUSE ANYONE WHO GETS

10040
07:39:56,480 --> 07:39:59,520
ANY TYPE OF BLOOD TRANSFUSION

10041
07:39:59,520 --> 07:40:01,200
GETS AN ABO TYPING WHICH

10042
07:40:01,200 --> 07:40:02,840
INCLUDES BOTH THE ANTIGEN AND

10043
07:40:02,840 --> 07:40:04,040
THE ANTIBODY.

10044
07:40:04,040 --> 07:40:05,240
SO THE FIRST THING YOU WANT TO

10045
07:40:05,240 --> 07:40:08,400
DO IS MAKE SURE THESE O MICE OR

10046
07:40:08,400 --> 07:40:10,040
DETERMINE WHETHER THESE O MICE

10047
07:40:10,040 --> 07:40:11,800
MAKE NATURALLY OCCURRING

10048
07:40:11,800 --> 07:40:15,960
ANTIBODIES.

10049
07:40:15,960 --> 07:40:21,040
O MICE FORM ANTI-B ANTIBODIES.

10050
07:40:21,040 --> 07:40:23,120
NOT ONLY IGM BUT ALSO IGG.

10051
07:40:23,120 --> 07:40:25,040
SO THESE ARE ANTIBODIES THAT

10052
07:40:25,040 --> 07:40:26,960
FORMED AS THE MICE WERE HANGING

10053
07:40:26,960 --> 07:40:29,800
OUT DOWNSTAIRS WITHOUT ANY KNOWN

10054
07:40:29,800 --> 07:40:30,200
STIMULUS.

10055
07:40:30,200 --> 07:40:31,960
THE NEXT THING WE WANT TO DO IS

10056
07:40:31,960 --> 07:40:33,240
DETERMINE WHERE THESE ANTIBODIES

10057
07:40:33,240 --> 07:40:35,400
ARE CAPABLE OF CAUSING A

10058
07:40:35,400 --> 07:40:35,720
REACTION.

10059
07:40:35,720 --> 07:40:37,800
WE ACTUALLY PERFORM ANTIBODIES

10060
07:40:37,800 --> 07:40:40,440
AGAINST A VARIETY OF -- THAT ARE

10061
07:40:40,440 --> 07:40:45,040
POLYMORPHIC THAT ACTUALLY ARE

10062
07:40:45,040 --> 07:40:46,840
NOT CLINICALLY RELEVANT TO

10063
07:40:46,840 --> 07:40:47,680
INDUCE -- IF WE'RE GOING TO

10064
07:40:47,680 --> 07:40:49,640
MODEL WHAT WE CARE ABOUT

10065
07:40:49,640 --> 07:40:52,240
CLINICALLY FOR THESE ANTIBODIES

10066
07:40:52,240 --> 07:40:55,360
ARE CAPABLE OF CAUSING -- OF THE

10067
07:40:55,360 --> 07:40:57,280
HEMOLYSIS WE'RE TRYING TO AVOID.

10068
07:40:57,280 --> 07:40:58,680
SO TO DO THAT WE LABELED UP THE

10069
07:40:58,680 --> 07:41:03,440
RED CELLS AND TRANSFUSED FIRST B

10070
07:41:03,440 --> 07:41:05,400
POSITIVE RED BLOOD CELLS, NO

10071
07:41:05,400 --> 07:41:06,400
CLEARANCE OBSERVED WHICH IS WHAT

10072
07:41:06,400 --> 07:41:07,800
YOU'D EXPECT WITH A FULLY

10073
07:41:07,800 --> 07:41:08,600
COMPATIBLE TRANSFUSION.

10074
07:41:08,600 --> 07:41:10,520
WHEN WE TRANSFUSED THAT SAME

10075
07:41:10,520 --> 07:41:11,840
BLOOD INTO OB BLOOD WE SAW

10076
07:41:11,840 --> 07:41:13,880
VARYING LEVELS OF CLEARANCE.

10077
07:41:13,880 --> 07:41:15,520
CLEARED THE BLOOD COMPLETELY AND

10078
07:41:15,520 --> 07:41:17,440
SOME EXPERIENCED LITTLE

10079
07:41:17,440 --> 07:41:18,480
CLEARANCE AT ALL.

10080
07:41:18,480 --> 07:41:19,680
THIS VARIABILITY IS NOT EASY TO

10081
07:41:19,680 --> 07:41:21,120
STUDY WHEN WE'RE LOOKING AT

10082
07:41:21,120 --> 07:41:22,600
REDUCTION OF SYSTEMS BUT IT'S

10083
07:41:22,600 --> 07:41:24,040
ACTUALLY EXACTLY WHAT HAPPENS

10084
07:41:24,040 --> 07:41:24,840
CLINICALLY.

10085
07:41:24,840 --> 07:41:31,560
WHEN PEOPLE GET ABO PANEL BLOOD

10086
07:41:31,560 --> 07:41:34,560
WHICH DOESN'T HAPPY -- SOME

10087
07:41:34,560 --> 07:41:35,840
PEOPLE CAN GET A WHOLE UNIT OF

10088
07:41:35,840 --> 07:41:40,840
BLOOD AND EXPERIENCE NO CLINICAL

10089
07:41:40,840 --> 07:41:44,760
SEQUELAE.

10090
07:41:44,760 --> 07:41:50,480
LEL IT'S NOT A CORRELATION
STRONG

10091
07:41:50,480 --> 07:41:51,680
ENOUGH TO PREDICT AND RESULT IN

10092
07:41:51,680 --> 07:41:53,000
ANY TYPE OF CLINICAL

10093
07:41:53,000 --> 07:41:54,520
DECISION-MAKING BASED ON THIS.

10094
07:41:54,520 --> 07:41:55,720
BUT IT IS SOMETHING THAT WE SEE

10095
07:41:55,720 --> 07:41:57,560
IN SOME WAYS CLINICALLY AS WELL.

10096
07:41:57,560 --> 07:41:58,800
SO THE QUESTION WE HAD WAS,

10097
07:41:58,800 --> 07:42:03,640
WHERE DOES THIS VARIABILITY IN

10098
07:42:03,640 --> 07:42:04,240
ANTIBLOOD -- B ANTIBODY COME

10099
07:42:04,240 --> 07:42:05,840
FROM IN THESE MICE BECAUSE THESE

10100
07:42:05,840 --> 07:42:10,000
MICE ARE A MODEL AND ONCE AGAIN

10101
07:42:10,000 --> 07:42:16,960
A REDUCTION -- ACTUALLY CAN

10102
07:42:16,960 --> 07:42:19,120
CAUSE A HEMOLYTIC TRANSFUSION

10103
07:42:19,120 --> 07:42:19,400
REACTION.

10104
07:42:19,400 --> 07:42:25,920
WE DIDN'T WANT TO USE -- THE

10105
07:42:25,920 --> 07:42:27,560
IMMUNE SYSTEM IS OBVIOUSLY VERY

10106
07:42:27,560 --> 07:42:28,640
DIFFERENT IN THOSE MICE AND

10107
07:42:28,640 --> 07:42:29,920
ALTHOUGH THERE'S A LOT OF

10108
07:42:29,920 --> 07:42:30,680
IMPORTANT STUDIES THAT CAN BE

10109
07:42:30,680 --> 07:42:32,880
DONE THAT WAY, WE REALLY WANTED

10110
07:42:32,880 --> 07:42:33,880
TO UNDERSTAND WHAT THIS

10111
07:42:33,880 --> 07:42:35,080
DIFFERENCE LOOKS LIKE UNDER

10112
07:42:35,080 --> 07:42:38,240
CONVENTIONAL CONDITIONS AT LEAST

10113
07:42:38,240 --> 07:42:39,600
INITIALLY IN MOMS THAT HAD

10114
07:42:39,600 --> 07:42:42,560
DIFFERENT LEVELS OF ANTI -- SO

10115
07:42:42,560 --> 07:42:44,280
WE TOOK MOMS AND DID HAVE SOME

10116
07:42:44,280 --> 07:42:47,240
IN STERILE CONTAINERS AFTER

10117
07:42:47,240 --> 07:42:48,880
THEY'VE BEEN CONVENTIONALLY

10118
07:42:48,880 --> 07:42:56,640
HOUSED AND ONLY DID THAT SIMPLY

10119
07:42:56,640 --> 07:43:01,160
TO REDUCE IN OUR MIND OVER

10120
07:43:01,160 --> 07:43:02,480
MULTIPLE GENERATIONS.

10121
07:43:02,480 --> 07:43:03,960
AND EVALUATE ANTIB ANTIBODIES

10122
07:43:03,960 --> 07:43:04,360
OVER TIME.

10123
07:43:04,360 --> 07:43:05,440
WE DID THE SAME THING WITH MOMS

10124
07:43:05,440 --> 07:43:06,880
HIGHER ANTIBODIES, WE TOOK THEIR

10125
07:43:06,880 --> 07:43:09,160
PUPS AND CROSS FOSTERED WITH

10126
07:43:09,160 --> 07:43:10,440
MOMS THAT HAD THE HIGHEST

10127
07:43:10,440 --> 07:43:12,040
ANTIBODY LEVELS OVER SUBSEQUENT

10128
07:43:12,040 --> 07:43:14,120
GENERAL RAIGS TO SEE IF THIS

10129
07:43:14,120 --> 07:43:15,240
ANTIBODY WAS A TRAIT WE COULD

10130
07:43:15,240 --> 07:43:16,840
FOLLOW OVER TIME AND IN SELECT

10131
07:43:16,840 --> 07:43:17,040
FORM.

10132
07:43:17,040 --> 07:43:20,600
USING THIS APPROACH WHAT WE

10133
07:43:20,600 --> 07:43:23,000
FOUND WAS THAT MOMS THAT HAD LOW

10134
07:43:23,000 --> 07:43:24,520
ANTIBODY LEVELS PRODUCED PUPS

10135
07:43:24,520 --> 07:43:26,480
THAT HAD LOW ANTIBODY LEVELS AND

10136
07:43:26,480 --> 07:43:27,800
OVER SUBSEQUENT GENERATIONS WERE

10137
07:43:27,800 --> 07:43:30,120
ABLE TO SELECT A KOL KNEEL THAT

10138
07:43:30,120 --> 07:43:31,040
VIRTUALLY PRODUCED VERY LITTLE

10139
07:43:31,040 --> 07:43:34,840
IF ANY -- USING TRADITIONAL

10140
07:43:34,840 --> 07:43:36,040
ASSAYS EMPLOYED IN THE BLOOD

10141
07:43:36,040 --> 07:43:38,280
BANK, BUT WHEN WE TOOK MOMS THEY

10142
07:43:38,280 --> 07:43:39,560
HAD AS CONTROL ANTIBODY LEVELS

10143
07:43:39,560 --> 07:43:41,280
THAT WERE HIGHER AND ONCE AGAIN

10144
07:43:41,280 --> 07:43:42,640
EVALUATED THEIR ANTIBODY LEVELS

10145
07:43:42,640 --> 07:43:44,040
OVER TIME OVER SUBSEQUENT

10146
07:43:44,040 --> 07:43:45,760
GENERATIONS FOUND THEY HAD

10147
07:43:45,760 --> 07:43:46,520
SUSTAINED ANTIBODY LEVELS.

10148
07:43:46,520 --> 07:43:47,440
SO THESE RESULTS SUGGEST THAT

10149
07:43:47,440 --> 07:43:49,040
THERE MAY BE AN ENVIRONMENTAL

10150
07:43:49,040 --> 07:43:50,840
FACTOR THAT INFLUENCES

10151
07:43:50,840 --> 07:43:52,560
ANTIBODIES AND SO WE DID WHAT

10152
07:43:52,560 --> 07:43:55,560
EVERYONE DOES, WE DID A SEQUENCE

10153
07:43:55,560 --> 07:43:57,840
ANALYSIS OF THE MYOBIOME AND

10154
07:43:57,840 --> 07:44:00,360
FOUND THERE WAS VARIABILITY, DID

10155
07:44:00,360 --> 07:44:01,840
NOT CORRELATE WITH THESE

10156
07:44:01,840 --> 07:44:02,160
ANTIBODIES.

10157
07:44:02,160 --> 07:44:03,760
SO NEXT WE WANT TO MAKE SURE

10158
07:44:03,760 --> 07:44:05,000
THAT THESE PUPS AND THE MOMS

10159
07:44:05,000 --> 07:44:07,440
THAT WE WERE FOLLOWING COULD

10160
07:44:07,440 --> 07:44:08,920
ACTUALLY MAKE ANTIBODIES OR

10161
07:44:08,920 --> 07:44:11,680
DETERMINE IN CONTRAST WE

10162
07:44:11,680 --> 07:44:14,840
SELECTED FOR -- A STRAIN OF MICE

10163
07:44:14,840 --> 07:44:15,880
THAT FOR WHATEVER REASON

10164
07:44:15,880 --> 07:44:18,240
COULDN'T MAKE ANTIBODIES OVER

10165
07:44:18,240 --> 07:44:20,680
TIME.

10166
07:44:20,680 --> 07:44:22,200
WE TOOK MICE THAT HAD BEEN

10167
07:44:22,200 --> 07:44:23,360
FOSTERED OR ACTUALLY OFFSPRING

10168
07:44:23,360 --> 07:44:27,120
OF A MOM THAT DEPARTMENT HAVE
DIDN'T HAVE

10169
07:44:27,120 --> 07:44:28,280
ANTIBODIES AND CROSS FOSTERED

10170
07:44:28,280 --> 07:44:29,960
INTO A MOM THAT HAD ANTIBODY,

10171
07:44:29,960 --> 07:44:32,160
TOOK LITTER MATES AND CROSS

10172
07:44:32,160 --> 07:44:33,600
FOSTERED A MOM THAT DIDN'T HAVE

10173
07:44:33,600 --> 07:44:34,240
ANTIBODIES.

10174
07:44:34,240 --> 07:44:37,520
WHAT WE FOUND IS WHEN WE DID THE

10175
07:44:37,520 --> 07:44:39,320
LATTER, CROSS FOSTERING PUPS ON

10176
07:44:39,320 --> 07:44:42,720
TO MOMS THAT DIDN'T HAVE --

10177
07:44:42,720 --> 07:44:44,040
RESULTED IN OFFSPRING THAT ALSO

10178
07:44:44,040 --> 07:44:46,520
AFTER FOSTERING WERE UNABLE TO

10179
07:44:46,520 --> 07:44:47,880
PRODUCE ANTIB ANTIBODIES BUT

10180
07:44:47,880 --> 07:44:50,600
WHEN WE TOOK LITTER MATES THAT

10181
07:44:50,600 --> 07:44:51,720
HAD ANTIBODIES, NOW THESE PUPS

10182
07:44:51,720 --> 07:44:55,560
WERE ABLE TO PRODUCE BOTH IG PL.

10183
07:44:55,560 --> 07:45:00,600
ANTI-B ANTIBODIES AND ALSO IGG.

10184
07:45:00,600 --> 07:45:01,680
THAT ANTIBODIES COULD BE INDUCED

10185
07:45:01,680 --> 07:45:02,920
AND THIS WAS LIKELY AN

10186
07:45:02,920 --> 07:45:03,680
ENVIRONMENTAL OUTCOME OF THE

10187
07:45:03,680 --> 07:45:05,520
TYPE OF EXPOSURE EVENTS THAT ARE

10188
07:45:05,520 --> 07:45:06,440
OCCURRING.

10189
07:45:06,440 --> 07:45:07,960
THE FOLLOWING SLIDES GO WITHOUT

10190
07:45:07,960 --> 07:45:09,160
SAYING WITH RESPECT TO THIS

10191
07:45:09,160 --> 07:45:10,600
AUDIENCE, OBVIOUSLY THE TYPICAL

10192
07:45:10,600 --> 07:45:14,600
STRUCTURE WE LOOKED AT IN TERMS

10193
07:45:14,600 --> 07:45:18,080
OF SCHEMATIC MEMORY IS

10194
07:45:18,080 --> 07:45:22,040
RELATIVELY SIMPLE -- YOU CAN'T

10195
07:45:22,040 --> 07:45:24,200
SEE ANYTHING, IT'S VERY SIMILAR,

10196
07:45:24,200 --> 07:45:26,480
IT JUST MAKES SENSE FOR ME IN

10197
07:45:26,480 --> 07:45:28,360
MANY WAYS OF A SMALL TOWN IN THE

10198
07:45:28,360 --> 07:45:31,240
MIDWEST WHERE YOU CAN SEE A LOT

10199
07:45:31,240 --> 07:45:32,520
OF DIFFERENT COMPONENTS OF THIS

10200
07:45:32,520 --> 07:45:34,280
TOWN IN TERMS OF SCHOOLS AND

10201
07:45:34,280 --> 07:45:36,120
CHURCHES AND STREETS, AND A FEW

10202
07:45:36,120 --> 07:45:36,680
TREES HERE.

10203
07:45:36,680 --> 07:45:38,920
BUT THIS IS NOT AT ALL AS WE

10204
07:45:38,920 --> 07:45:41,040
KNOW THE SURFACE OF A CELL LOOKS

10205
07:45:41,040 --> 07:45:44,320
LIKE, THAT'S COVERED IN THE

10206
07:45:44,320 --> 07:45:45,960
GLYCOHELIX MUCH MORE SIMILAR TO

10207
07:45:45,960 --> 07:45:47,280
URBAN ATLANTA, WHICH IS WHERE I

10208
07:45:47,280 --> 07:45:50,640
DID MY TRAINING IN THE CUMMINGS

10209
07:45:50,640 --> 07:45:52,440
LAB, THERE'S A WHOLE CITY HERE

10210
07:45:52,440 --> 07:45:54,720
BETWEEN EMORY WHICH IS WHERE

10211
07:45:54,720 --> 07:45:56,440
THIS PICTURE WAS TAKEN IN

10212
07:45:56,440 --> 07:45:57,160
DOWNTOWN ATLANTA BUT THAT'S

10213
07:45:57,160 --> 07:45:58,640
REALLY DIFFICULT TO PERCEIVE

10214
07:45:58,640 --> 07:46:03,520
BECAUSE OF THIS RILEY  RYE
REALLY URBAN

10215
07:46:03,520 --> 07:46:04,480
FOREST THAT COVERS THE CITY.

10216
07:46:04,480 --> 07:46:07,960
THE QUESTION IS IS THERE A --

10217
07:46:07,960 --> 07:46:09,440
RED CELL THAT MAY BE RESPONSIVE

10218
07:46:09,440 --> 07:46:11,000
FOR STIMULATING THESE

10219
07:46:11,000 --> 07:46:11,280
ANTIBODIES.

10220
07:46:11,280 --> 07:46:14,520
SO THE ANSWER TO THIS QUESTION,

10221
07:46:14,520 --> 07:46:17,640
WE USE A REALLY OLD BLOOD BANK

10222
07:46:17,640 --> 07:46:22,040
TRICK IN THE 30s, WE TOOK

10223
07:46:22,040 --> 07:46:25,000
SERUM THAT HAD ANTI-B ANTIBODIES

10224
07:46:25,000 --> 07:46:27,040
PRESENT, WE SIMPLY WASHED AWAY

10225
07:46:27,040 --> 07:46:29,720
THE ANTIBODIES THAT DID NOT

10226
07:46:29,720 --> 07:46:32,880
BOUND, ASKED FOR THESE

10227
07:46:32,880 --> 07:46:36,240
ANTIBODIES, REACTED WITH -- SO

10228
07:46:36,240 --> 07:46:37,640
USING THIS APPROACH WE WERE ABLE

10229
07:46:37,640 --> 07:46:38,880
TO DETERMINE THERE WAS A SMALL

10230
07:46:38,880 --> 07:46:41,000
POPULATION OF MICROBES THAT WE

10231
07:46:41,000 --> 07:46:42,240
COULD DETECT THAT APPEARED TO

10232
07:46:42,240 --> 07:46:44,240
REACT WITH THE ANTIBODY AND WHEN

10233
07:46:44,240 --> 07:46:47,000
WE SORTED THEM OUT, TO

10234
07:46:47,000 --> 07:46:48,520
INDIVIDUAL POPULATIONS AND THEN

10235
07:46:48,520 --> 07:46:49,760
WE CULTURED THOSE POPULATIONS.

10236
07:46:49,760 --> 07:46:52,000
WE WERE ABLE TO IDENTIFY ONE

10237
07:46:52,000 --> 07:46:53,200
STRAIN IN PARTICULAR THAT WHEN

10238
07:46:53,200 --> 07:46:55,120
WE TOOK THAT SAME ANTIBODY

10239
07:46:55,120 --> 07:46:57,440
PREPARATION, INK  INCUBATED WITH
THIS

10240
07:46:57,440 --> 07:46:58,440
INDIVIDUAL COLONY THAT HAD

10241
07:46:58,440 --> 07:47:00,840
SIGNIFICANT REACTIVITY, THIS WAS

10242
07:47:00,840 --> 07:47:03,680
NOT SOMETHING COMMON AMONG CUBS

10243
07:47:03,680 --> 07:47:05,160
BECAUSE WE LOOKED AT ANOTHER

10244
07:47:05,160 --> 07:47:06,240
STRAIN THAT WAS ISOLATED THAT

10245
07:47:06,240 --> 07:47:08,640
HAD REALLY A VERY LITTLE IF ANY

10246
07:47:08,640 --> 07:47:09,120
REACTIVITY.

10247
07:47:09,120 --> 07:47:10,720
SO THE NEXT QUESTION WE WANT TO

10248
07:47:10,720 --> 07:47:12,760
ASK WAS WHETHER THERE WAS

10249
07:47:12,760 --> 07:47:16,360
SPECIFICITY TO THIS INTERACTION

10250
07:47:16,360 --> 07:47:17,960
BETWEEN THE ANTIBODY AND THE

10251
07:47:17,960 --> 07:47:18,560
ACTUAL ANTIGEN.

10252
07:47:18,560 --> 07:47:22,400
SO TO DO THIS, WE ACTUALLY

10253
07:47:22,400 --> 07:47:24,120
ISOLATED THE POLYSACCHARIDE FROM

10254
07:47:24,120 --> 07:47:25,880
THESE MICROBES WE'VE BEEN DOING

10255
07:47:25,880 --> 07:47:27,440
THIS WITH A LOT OF OTHER

10256
07:47:27,440 --> 07:47:28,560
MICROBES BUT I WANT TO

10257
07:47:28,560 --> 07:47:29,400
SPECIFICALLY FOCUS ON THE

10258
07:47:29,400 --> 07:47:31,040
MICROBES WE ANALYZED WITH THIS

10259
07:47:31,040 --> 07:47:31,720
PARTICULAR -- THIS EXPERIMENT WE

10260
07:47:31,720 --> 07:47:33,840
WERE DOING.

10261
07:47:33,840 --> 07:47:38,240
AS I MENTIONED PREVIOUSLY, MANY

10262
07:47:38,240 --> 07:47:40,880
ANTIBODIES WERE THOUGHT TO BE

10263
07:47:40,880 --> 07:47:43,600
POLYSPECIFIC, INCLUDING A LOT OF

10264
07:47:43,600 --> 07:47:44,640
SO CALLED AUTO ANTIGENS THAT

10265
07:47:44,640 --> 07:47:46,640
WERE USED IN THE PREVIOUS STUDY

10266
07:47:46,640 --> 07:47:49,680
THAT ARE THOUGHT TO BE LIKE

10267
07:47:49,680 --> 07:47:52,800
EVIDENCE OF OR SUGGESTIVE OF

10268
07:47:52,800 --> 07:47:54,000
POLYMER ACTIVITY IN GENERAL.

10269
07:47:54,000 --> 07:47:57,320
HOWEVER WHEN WE TOOK THE

10270
07:47:57,320 --> 07:47:59,400
ANTIBODIES -- THE POSITIVE RED

10271
07:47:59,400 --> 07:48:02,240
CELL WE USED TO BIND THESE

10272
07:48:02,240 --> 07:48:03,280
MICROBES, YOU HAVE THIS B

10273
07:48:03,280 --> 07:48:05,120
ANTIGEN AND THE ONE STRAIN OF

10274
07:48:05,120 --> 07:48:09,440
LPS THAT WE ISOLATE FROM THAT

10275
07:48:09,440 --> 07:48:09,640
MICROBE.

10276
07:48:09,640 --> 07:48:10,720
SO THESE RESULTS SUGGEST AT

10277
07:48:10,720 --> 07:48:14,360
LEAST SOME NATURALLY OCCURRING

10278
07:48:14,360 --> 07:48:15,680
ANTIPO DE -- MAY INDEED BE

10279
07:48:15,680 --> 07:48:17,200
INDUCED BY INDIVIDUAL STRAINS OF

10280
07:48:17,200 --> 07:48:19,920
MICROBES THAT ARE DECORATED WITH

10281
07:48:19,920 --> 07:48:20,640
UNIQUE GLYCAN SIGNATURE.

10282
07:48:20,640 --> 07:48:21,920
AND OF COURSE THERE'S ONCE AGAIN

10283
07:48:21,920 --> 07:48:23,360
NO CROSS REACTIVITY WITH ALL

10284
07:48:23,360 --> 07:48:26,280
THESE OTHER ANTIGENS THAT HAVE

10285
07:48:26,280 --> 07:48:27,920
BEEN DEMONSTRATED FOR OTHER

10286
07:48:27,920 --> 07:48:29,640
ANTIBODIES WHICH CERTAINLY

10287
07:48:29,640 --> 07:48:30,040
OCCURS.

10288
07:48:30,040 --> 07:48:32,440
NEXT WE WANTED TO KNOW WHETHER

10289
07:48:32,440 --> 07:48:35,960
THEY WERE ACTUALLY CAPABLE OF

10290
07:48:35,960 --> 07:48:36,840
INTRODUCING ANTIBODY FORMATION

10291
07:48:36,840 --> 07:48:39,000
SO TO DO THAT WE ACTUALLY

10292
07:48:39,000 --> 07:48:44,600
EXPOSED THE MICE TO MICROBES AND

10293
07:48:44,600 --> 07:48:46,280
WE FOUND ANTIBODIES COULD BE

10294
07:48:46,280 --> 07:48:49,280
DETECTED IF THE O MICE TREATED

10295
07:48:49,280 --> 07:48:51,440
OR EXPOSED TO THE BLOOD GROUP

10296
07:48:51,440 --> 07:48:52,200
POSITIVE MICROBES.

10297
07:48:52,200 --> 07:48:54,040
WE DID NOT SEE MICE FORM IF WE

10298
07:48:54,040 --> 07:48:56,240
GAVE THEM THE NEGATIVE MICROBES.

10299
07:48:56,240 --> 07:48:57,760
THIS IS NOT A RESULT OF

10300
07:48:57,760 --> 07:48:59,160
DIFFERENCES IN COLONIZATION

10301
07:48:59,160 --> 07:49:01,040
BECAUSE THEY'RE VERY SIMILAR

10302
07:49:01,040 --> 07:49:03,440
COLONIZATION RATES BETWEEN THE

10303
07:49:03,440 --> 07:49:03,600
TWO.

10304
07:49:03,600 --> 07:49:04,760
FINALLY WANT TO DETERMINE

10305
07:49:04,760 --> 07:49:05,960
WHETHER THERE WAS AN ABILITY NOT

10306
07:49:05,960 --> 07:49:09,440
ONLY OF THESE MICROBES TO INDUCE

10307
07:49:09,440 --> 07:49:10,880
ANTIBODIES BUT WHETHER THESE

10308
07:49:10,880 --> 07:49:13,120
ANTIBODIES ARE ABLE TO CAUSE --

10309
07:49:13,120 --> 07:49:14,600
WE DID THE EXACT SAME

10310
07:49:14,600 --> 07:49:17,360
EXPERIMENT, WE EXPOSED O MICE TO

10311
07:49:17,360 --> 07:49:18,840
THE POSITIVE OR NEGATIVE MICROBE

10312
07:49:18,840 --> 07:49:21,640
AND TRANSFUSED THESE MICE.

10313
07:49:21,640 --> 07:49:23,120
THE O RECIPIENTS THAT GOT THE

10314
07:49:23,120 --> 07:49:24,960
POSITIVE MICROBES WERE ABLE TO

10315
07:49:24,960 --> 07:49:27,040
INDUCE A HEMOTRANSFUSION

10316
07:49:27,040 --> 07:49:30,080
REACTION BUT IF WE TOOK THEM AND

10317
07:49:30,080 --> 07:49:32,640
GAVE THEM NEGATIVE MICROBES,

10318
07:49:32,640 --> 07:49:35,640
THEY WEREN'T ABLE TO -- SO THESE

10319
07:49:35,640 --> 07:49:37,840
RESULTS SUGGEST MICROBES EXIST,

10320
07:49:37,840 --> 07:49:39,360
THEY'RE ABLE TO DECORATE

10321
07:49:39,360 --> 07:49:40,640
THEMSELVES IN SUGAR STRUCTURES

10322
07:49:40,640 --> 07:49:41,880
THAT LOOK VERY SIMILAR TO RED

10323
07:49:41,880 --> 07:49:43,760
CELLS AND THAT EXPOSURE TO THESE

10324
07:49:43,760 --> 07:49:45,920
MICROBES CAN STIMULATE ANTIBLOOD

10325
07:49:45,920 --> 07:49:46,800
GROUP ANTIBODIES THAT ARE

10326
07:49:46,800 --> 07:49:50,520
CAPABLE OF CAUSING POTENTIAL

10327
07:49:50,520 --> 07:49:52,600
HEMOTRANSFUSION REACTION

10328
07:49:52,600 --> 07:49:53,400
TRANSPLANT REJECTION AND MAYBE

10329
07:49:53,400 --> 07:49:54,880
RELEVANT OR OTHER SETTINGS WRR

10330
07:49:54,880 --> 07:49:57,240
EXPOSURE TO STUFF LIKE ANTIGENS

10331
07:49:57,240 --> 07:50:00,360
COULD IB FLEUNS  INFLUENCE THE
REPERTOIRE

10332
07:50:00,360 --> 07:50:03,480
OF ANTIBODY.

10333
07:50:03,480 --> 07:50:04,760
WITH THAT, I'LL THANK CONNIE

10334
07:50:04,760 --> 07:50:06,040
ARTHUR, SHE HAS HER OWN LAB NOW

10335
07:50:06,040 --> 07:50:07,360
AND SHE'S ACTUALLY DOWN THE HALL

10336
07:50:07,360 --> 07:50:07,960
FROM ME.

10337
07:50:07,960 --> 07:50:09,000
RICK CUMMINGS WHO WE'VE BEEN

10338
07:50:09,000 --> 07:50:10,840
DOING THESE STUDIES WITH AND

10339
07:50:10,840 --> 07:50:12,600
SETH WHO WE'VE BEEN

10340
07:50:12,600 --> 07:50:13,160
COLLABORATING WITH ON THIS

10341
07:50:13,160 --> 07:50:14,600
PROJECT AS WELL, AND WITH THAT,

10342
07:50:14,600 --> 07:50:16,840
I WILL TAKE ANY QUESTIONS THAT

10343
07:50:16,840 --> 07:50:17,440
YOU HAVE.

10344
07:50:17,440 --> 07:50:18,720
SORRY I WENT THROUGH THAT REALLY

10345
07:50:18,720 --> 07:50:20,040
QUICKLY BUT I'M TRYING TO GET US

10346
07:50:20,040 --> 07:50:26,640
BACK ON TIME.

10347
07:50:26,640 --> 07:50:29,440
>> FANTASTIC TALK, JOHN.

10348
07:50:29,440 --> 07:50:32,320
I'M MONITORING THE CHAT NOW.

10349
07:50:32,320 --> 07:50:34,640
I NO YOU'RE ALSO A PRACTICING

10350
07:50:34,640 --> 07:50:35,840
CLINICIAN WHICH I THINK IS

10351
07:50:35,840 --> 07:50:37,320
AMAZING SO IF YOU PUT THAT HAT

10352
07:50:37,320 --> 07:50:38,440
BACK ON IT AND THINK ABOUT HOW

10353
07:50:38,440 --> 07:50:39,440
YOU CAN USE WHAT YOU FOUND NOW

10354
07:50:39,440 --> 07:50:41,040
IN THE CLINIC, WHAT DO YOU THINK

10355
07:50:41,040 --> 07:50:42,240
ABOUT -- HOW WOULD YOU DO THAT?

10356
07:50:42,240 --> 07:50:43,160
WHAT WOULD YOU DO?

10357
07:50:43,160 --> 07:50:44,040
>> APPRECIATE THE QUESTION.

10358
07:50:44,040 --> 07:50:45,240
I THINK THE MOST RELEVANT

10359
07:50:45,240 --> 07:50:49,640
SETTING ACTUALLY IS PROBABLY NOT

10360
07:50:49,640 --> 07:50:55,320
MANIPULATION OF THE

10361
07:50:55,320 --> 07:50:56,200
MICROBIOTA -- PATIENTS WITH

10362
07:50:56,200 --> 07:50:57,720
SICKLE CELL DISEASE OR

10363
07:50:57,720 --> 07:50:59,360
THALASSEMIA OR IN THE SETTING OF

10364
07:50:59,360 --> 07:51:00,440
HEART TRANSPLANT, SO IF YOU HAD

10365
07:51:00,440 --> 07:51:03,920
A LITTLE KIDDO WITH A CONGENITAL

10366
07:51:03,920 --> 07:51:05,240
HEART DISEASE, IT IS THE NUMBER

10367
07:51:05,240 --> 07:51:06,480
ONE BARRIER TO TRANSPLANTATION.

10368
07:51:06,480 --> 07:51:07,680
WE THINK OF HLA BECAUSE THAT'S

10369
07:51:07,680 --> 07:51:08,960
THE THING THAT IT'S REALLY HARD

10370
07:51:08,960 --> 07:51:10,200
TO MATCH FOR BECAUSE THERE'S SO

10371
07:51:10,200 --> 07:51:12,040
MANY DIFFERENT POLYMORPHISMS BUT

10372
07:51:12,040 --> 07:51:15,280
THE FIRST QUESTION IS ALWAYS

10373
07:51:15,280 --> 07:51:19,120
ABOUT ID YOE COMPATIBILITY.

10374
07:51:19,120 --> 07:51:21,640
YOU CAN TRANSPLANT ACROSS

10375
07:51:21,640 --> 07:51:24,320
BARRIER, THERE'S A TOLERANCE

10376
07:51:24,320 --> 07:51:26,680
PROGRAM THAT'S LISTED, SO WE'RE

10377
07:51:26,680 --> 07:51:29,560
HOPEFUL THAT IF WE CAN

10378
07:51:29,560 --> 07:51:30,840
UNDERSTAND MECHANISTICALLY HOW

10379
07:51:30,840 --> 07:51:32,880
THESE ANTIBODIES FORM AND HOW

10380
07:51:32,880 --> 07:51:35,320
THE MICROBIOTA SHAPES THESE

10381
07:51:35,320 --> 07:51:37,960
ANTIBODIES, WE COULD FAVORABLY

10382
07:51:37,960 --> 07:51:39,040
MANIPULATE AND SELECT PATIENTS

10383
07:51:39,040 --> 07:51:40,800
IN NEED OF TRANSPLANTATION OR

10384
07:51:40,800 --> 07:51:42,880
TRANSFUSION THERAPY SO

10385
07:51:42,880 --> 07:51:43,920
IMMUNOLOGICAL BARRIERS ARE NOT

10386
07:51:43,920 --> 07:51:46,800
AS PRESENT, THERE'S MORE

10387
07:51:46,800 --> 07:51:47,800
OPPORTUNITY -- FOR THEM.

10388
07:51:47,800 --> 07:51:48,520
SO WE'LL SEE.

10389
07:51:48,520 --> 07:51:49,840
YOU KNOW HOW SCIENCE GOES.

10390
07:51:49,840 --> 07:51:51,440
>> NO, IT COOL.

10391
07:51:51,440 --> 07:51:53,040
THAT'S REALLY NEAT.

10392
07:51:53,040 --> 07:51:55,560
THANKS.

10393
07:51:55,560 --> 07:51:57,960
LAURA, I SAW YOU TURNING YOUR

10394
07:51:57,960 --> 07:51:59,280
CAMERA ON BUT YOU'RE MUTED.

10395
07:51:59,280 --> 07:52:01,360
>> I DIDN'T KNOW IF WE HAD TIME.

10396
07:52:01,360 --> 07:52:03,280
CAN I JUST ASK REALLY QUICKLY, I

10397
07:52:03,280 --> 07:52:07,760
WONDER IF YOU COULD FLIP THIS

10398
07:52:07,760 --> 07:52:10,640
AROUND BECAUSE CLEB CAN COLONIZE

10399
07:52:10,640 --> 07:52:14,840
MANY PANCREATIC TUMORS, AND I

10400
07:52:14,840 --> 07:52:15,800
WAS WONDERING IF YOU THINK IT

10401
07:52:15,800 --> 07:52:19,040
MIGHT BE POSSIBLE TO FLIP THIS,

10402
07:52:19,040 --> 07:52:21,520
TO USE THIS KIND OF THING TO

10403
07:52:21,520 --> 07:52:21,880
YOUR ADVANTAGE.

10404
07:52:21,880 --> 07:52:22,840
>> I COULDN'T AGREE WITH YOU

10405
07:52:22,840 --> 07:52:23,520
MORE.

10406
07:52:23,520 --> 07:52:24,160
THAT'S ONE OF THE THINGS I'VE

10407
07:52:24,160 --> 07:52:26,960
BEEN INTERESTED IN THE GET-GO

10408
07:52:26,960 --> 07:52:29,280
IS, BEING ABLE TO SHAPE ANTIBODY

10409
07:52:29,280 --> 07:52:32,800
REPERTOIRES, TUMOR ASSOCIATED

10410
07:52:32,800 --> 07:52:33,680
CARBOHYDRATE -- I THINK REALLY

10411
07:52:33,680 --> 07:52:35,440
IF WE COULD NOT ONLY SHAPE IT

10412
07:52:35,440 --> 07:52:37,040
WITHIN THE MICROBIOME OF THE GUT

10413
07:52:37,040 --> 07:52:38,680
BUT ACTUALLY WITHIN THE TUMOR, I

10414
07:52:38,680 --> 07:52:40,120
THINK EVERYONE IS AWARE THESE

10415
07:52:40,120 --> 07:52:41,640
MICROBES ARE PRESENT IN TUMORS

10416
07:52:41,640 --> 07:52:43,600
AT A LEVEL I THINK I DIDN'T

10417
07:52:43,600 --> 07:52:44,440
APPRECIATE 10 YEARS AGO, THERE

10418
07:52:44,440 --> 07:52:46,120
MAY BE A REAL OPPORTUNITY TO

10419
07:52:46,120 --> 07:52:49,520
LEVERAGE THIS IN A POSITIVE WAY

10420
07:52:49,520 --> 07:52:56,040
TO SHAPE ANTIBODY REP 
REPERTOIRES

10421
07:52:56,040 --> 07:52:58,320
FOR THOSE THINGS WE WANT THEM TO

10422
07:52:58,320 --> 07:52:59,320
BE DOING, TYPICAL STRUCTURES

10423
07:52:59,320 --> 07:53:01,960
THAT ARE NOT PRESENT IN NORMAL

10424
07:53:01,960 --> 07:53:03,160
TISSUE, SO ABSOLUTELY, I THINK

10425
07:53:03,160 --> 07:53:04,400
IT'S AN EXCELLENT IDEA.

10426
07:53:04,400 --> 07:53:05,840
I THINK THE CHALLENGE IN TERMS

10427
07:53:05,840 --> 07:53:07,040
OF VACCINATION IN THIS KIND OF

10428
07:53:07,040 --> 07:53:08,440
STUFF IS THAT REALLY FROM THE

10429
07:53:08,440 --> 07:53:09,920
IMMUNE PERSPECTIVE, WE DON'T

10430
07:53:09,920 --> 07:53:12,240
UNDERSTAND THE RULES.

10431
07:53:12,240 --> 07:53:15,200
DOES THIS RESPONSE PRODUCE -- IS

10432
07:53:15,200 --> 07:53:16,480
IT CONTINUAL STIMULATION, ALL

10433
07:53:16,480 --> 07:53:19,240
THESE QUESTIONS ABOUT IMMUNOLOGY

10434
07:53:19,240 --> 07:53:20,760
I THINK ARE PRETTY -- I DON'T

10435
07:53:20,760 --> 07:53:22,960
MEAN TO OFFEND ANYONE, I THINK

10436
07:53:22,960 --> 07:53:25,040
THEY'RE PRETTY OPEN-ENDED AND

10437
07:53:25,040 --> 07:53:25,800
UNKNOWN, SO THIS IS AN

10438
07:53:25,800 --> 07:53:27,040
OPPORTUNITY TO REALLY START TO

10439
07:53:27,040 --> 07:53:29,320
FERRET THIS OUT.

10440
07:53:29,320 --> 07:53:30,200
AT LEAST THAT'S OUR HOPE.

10441
07:53:30,200 --> 07:53:33,440
THANK YOU.

10442
07:53:33,440 --> 07:53:34,240
>> SUPER NICE STUFF, JOHN.

10443
07:53:34,240 --> 07:53:35,040
>> THANK YOU SO MUCH.

10444
07:53:35,040 --> 07:53:37,080
ALL RIGHT.

10445
07:53:37,080 --> 07:53:38,400
SO IT IS MY ABSOLUTE PLEASURE TO

10446
07:53:38,400 --> 07:53:40,600
BE ABLE TO INTRODUCE OUR FINAL

10447
07:53:40,600 --> 07:53:41,040
SPEAKER.

10448
07:53:41,040 --> 07:53:42,560
WE SAVED THE BEST FOR LAST

10449
07:53:42,560 --> 07:53:44,400
OBVIOUSLY.

10450
07:53:44,400 --> 07:53:45,640
AND SO FOR EVERYONE KIND OF

10451
07:53:45,640 --> 07:53:48,880
HANGING ON HERE UNTIL THE VERY

10452
07:53:48,880 --> 07:53:50,040
END, CATHERINE GRIMES IS AT THE

10453
07:53:50,040 --> 07:53:51,000
UNIVERSITY OF DELAWARE, AND

10454
07:53:51,000 --> 07:53:52,320
SHE'S BEEN AN ABSOLUTE PLEASURE

10455
07:53:52,320 --> 07:53:53,400
TO WORK WITH, HAS BEEN THE

10456
07:53:53,400 --> 07:53:55,800
PERSON THAT REALLY HAS HELD THE

10457
07:53:55,800 --> 07:53:58,280
GLYCOMICS -- OR THE GLYCOTOOL

10458
07:53:58,280 --> 07:53:59,920
MEETINGS TOGETHER FOR MANY YEARS

10459
07:53:59,920 --> 07:54:03,360
AND PATIENTLY NUDGES US WHEN WE

10460
07:54:03,360 --> 07:54:05,360
FAIL TO RESPOND TO EMAILS IN A

10461
07:54:05,360 --> 07:54:06,560
VERY KIND AND UNDERSTANDING WAY

10462
07:54:06,560 --> 07:54:08,040
AND IS REALLY THE BIG DRIVER

10463
07:54:08,040 --> 07:54:09,360
BEHIND THIS MEETING THAT WE'VE

10464
07:54:09,360 --> 07:54:10,880
ALL BEEN ABLE TO PARTICIPATE IN

10465
07:54:10,880 --> 07:54:12,240
TODAY, SO JUST A BIG SHOUT OUT

10466
07:54:12,240 --> 07:54:14,240
TO CATHERINE, ALL OF HER WORK

10467
07:54:14,240 --> 07:54:15,360
NOT ONLY FOR THIS MEETING BUT

10468
07:54:15,360 --> 07:54:16,840
JUST FOR THE FILM.

10469
07:54:16,840 --> 07:54:17,720
>> THANKS, SEAN.

10470
07:54:17,720 --> 07:54:19,400
IT'S BEEN REALLY FUN ORGANIZING

10471
07:54:19,400 --> 07:54:20,560
THIS WITH YOU TOO, AND I FEEL

10472
07:54:20,560 --> 07:54:22,240
LIKE THIS WAS AN AMAZING

10473
07:54:22,240 --> 07:54:23,120
SYMPOSIUM AND EVERY TALK, I

10474
07:54:23,120 --> 07:54:25,080
THOUGHT THEY WERE SUPER FUN,

10475
07:54:25,080 --> 07:54:29,040
AMAZING TALKS.

10476
07:54:29,040 --> 07:54:30,800
SO SUPER JOB ORGANIZING IT.

10477
07:54:30,800 --> 07:54:33,080
I ALSO WANT TO THANK PAM FOR

10478
07:54:33,080 --> 07:54:34,400
INVITING WHOEVER WE WANTED, SHE

10479
07:54:34,400 --> 07:54:36,360
WAS LIKE GOOD, GO AHEAD AND TRY

10480
07:54:36,360 --> 07:54:36,800
AND INVITE THEM.

10481
07:54:36,800 --> 07:54:37,880
IT WAS REALLY AMAZING.

10482
07:54:37,880 --> 07:54:39,520
I WILL TRY TO CAP IT OUT IN A

10483
07:54:39,520 --> 07:54:41,440
WAY THAT YOU GUYS CAN APPRECIATE

10484
07:54:41,440 --> 07:54:42,400
AT THIS LATE HOUR.

10485
07:54:42,400 --> 07:54:44,160
I KNOW IT WILL BE HOPEFULLY

10486
07:54:44,160 --> 07:54:47,080
SIMPLE IN THAT SENSE.

10487
07:54:47,080 --> 07:54:48,640
SO IT BEEN REALLY FUN BEING PART

10488
07:54:48,640 --> 07:54:50,840
OF THAT GLYCOSCIENCE -- I'LL

10489
07:54:50,840 --> 07:54:52,240
TALK TO YOU ABOUT THE WORK MY

10490
07:54:52,240 --> 07:54:53,320
GROUP HAS DONE AS PART OF THAT

10491
07:54:53,320 --> 07:54:56,040
AS WELL.

10492
07:54:56,040 --> 07:54:59,200
SO FIRST OFF JUST IN CASE WE DO

10493
07:54:59,200 --> 07:55:00,520
WRUN OUT 

10494
07:55:00,520 --> 07:55:01,640
RUN OUT OF TIME, I WANT TO

10495
07:55:01,640 --> 07:55:03,040
ACKNOWLEDGE MY GROUP, I HAVE A

10496
07:55:03,040 --> 07:55:04,240
FANTASTIC GROUP OF INDIVIDUALS,

10497
07:55:04,240 --> 07:55:05,680
ALL OF YOU HAVE AMAZING TEAMS,

10498
07:55:05,680 --> 07:55:07,520
I'M LUCKY TO HAVE AN AMAZING

10499
07:55:07,520 --> 07:55:10,160
TEAM AS WELL IN FUNDING AND A

10500
07:55:10,160 --> 07:55:12,200
GROUP OF COLLABORATORS SO I'M

10501
07:55:12,200 --> 07:55:13,040
GRATEFUL FOR ALL OF THAT AND

10502
07:55:13,040 --> 07:55:14,160
THEY ARE THE FORCE BEHIND THE

10503
07:55:14,160 --> 07:55:15,080
WORK I'M GOING TO TELL YOU

10504
07:55:15,080 --> 07:55:18,680
ABOUT, WHICH IS ALL IN THESE

10505
07:55:18,680 --> 07:55:19,320
BACTERIAL PEPTIDOGLYCANS WHICH

10506
07:55:19,320 --> 07:55:20,360
SURROUND ALL THE BACTERIA THAT

10507
07:55:20,360 --> 07:55:24,000
WE HEARD ABOUT TODAY, THEY MAKE

10508
07:55:24,000 --> 07:55:27,480
AN AIZ MAZING TARGET FOR

10509
07:55:27,480 --> 07:55:28,040
ANTIBIOTICS, TARGETS THE

10510
07:55:28,040 --> 07:55:28,960
DESTRUCTION OF THESE BUGS BUT

10511
07:55:28,960 --> 07:55:33,080
THEY ALSO MAKE AMAZING IMMUNE

10512
07:55:33,080 --> 07:55:34,080
RECOGNITION CALLING CARDS SO

10513
07:55:34,080 --> 07:55:36,000
YOUR BODY IS NOT UNAWARE OF THE

10514
07:55:36,000 --> 07:55:36,840
FACT THAT INDEPENDENT OF THE

10515
07:55:36,840 --> 07:55:38,680
PRESENCE OF AN ANTIBIOTIC, THEY

10516
07:55:38,680 --> 07:55:40,080
CAN USE THESE FRAGMENTS THEY'RE

10517
07:55:40,080 --> 07:55:42,280
IN TO GENERATE A PROPER IMMUNE

10518
07:55:42,280 --> 07:55:44,160
RESPONSE AND GENERATE AN INNATE

10519
07:55:44,160 --> 07:55:44,640
IMMUNE REACTION.

10520
07:55:44,640 --> 07:55:45,840
SO THAT'S THE TYPE OF THING THAT

10521
07:55:45,840 --> 07:55:47,240
MY GROUP AND I ARE REALLY

10522
07:55:47,240 --> 07:55:49,440
INTERESTED IN LOOKING AT, IS THE

10523
07:55:49,440 --> 07:55:50,640
INNATE IMMUNE RESPONSE, SO WE

10524
07:55:50,640 --> 07:55:54,200
GOT YOUR BODY'S FIRST --

10525
07:55:54,200 --> 07:55:55,520
REPRESENTING THE INNATE IMMUNE

10526
07:55:55,520 --> 07:55:56,680
SYSTEM.

10527
07:55:56,680 --> 07:55:59,640
YOU CAN IMAGINE, THIS MASH PHAGE

10528
07:55:59,640 --> 07:56:00,880
LOOKS FOR THINGS DIFFERENT THAN

10529
07:56:00,880 --> 07:56:07,920
ITSELF, SUCH AS THESE FLA JE 

10530
07:56:07,920 --> 07:56:09,440
FLAGELLIN -- AND NOBEL PRIZE

10531
07:56:09,440 --> 07:56:13,560
WINNING WORK HELPED IDENTIFY A

10532
07:56:13,560 --> 07:56:15,080
SERIES OF INNATE IMMUNE

10533
07:56:15,080 --> 07:56:17,400
RECEPTORS THAT RESIZE ON

10534
07:56:17,400 --> 07:56:19,160
MEMBRANES AND THESE THAT RESIDE

10535
07:56:19,160 --> 07:56:20,640
IN THE CYTOPLASM THAT WORK IN

10536
07:56:20,640 --> 07:56:22,880
CONCERT TO GENERATE AN

10537
07:56:22,880 --> 07:56:23,720
INFLAMMATORY RESPONSE AND THEN

10538
07:56:23,720 --> 07:56:26,240
ALSO GO ON TO ACTIVATE THE

10539
07:56:26,240 --> 07:56:30,720
ADAPTIVE IMMUNE RESPONSE.

10540
07:56:30,720 --> 07:56:32,360
SO THIS ALL LOOKS NEAT AND CLEAN

10541
07:56:32,360 --> 07:56:33,760
BUT AS A CHEMIST AND AS WE SAW

10542
07:56:33,760 --> 07:56:38,440
TODAY IN , BIOLOGY IS NOTHING
THAT'S

10543
07:56:38,440 --> 07:56:38,920
NEAT AND CLEAN.

10544
07:56:38,920 --> 07:56:41,840
SO AS WE CONSIDER THE

10545
07:56:41,840 --> 07:56:43,280
MICROBIOME, THIS GETS MESSY, SO

10546
07:56:43,280 --> 07:56:44,720
WE KNOW WE'RE CARRYING AROUND

10547
07:56:44,720 --> 07:56:46,160
LOADS AND LOADS OF BACTERIA.

10548
07:56:46,160 --> 07:56:50,680
WE TALKED ABOUT THEM ALL DAY.

10549
07:56:50,680 --> 07:56:52,640
SO WE LIKE THIS CARTOON, YOU

10550
07:56:52,640 --> 07:56:54,240
HAVE 2 TO 5 POUNDS OF BACTERIA

10551
07:56:54,240 --> 07:56:57,040
ON YOU, WE LIKE TO THINK OF IT

10552
07:56:57,040 --> 07:56:58,160
MORE COMPLICATED, IF YOU GO BACK

10553
07:56:58,160 --> 07:56:59,440
TO THE ENVELOPE OF CALCULATION,

10554
07:56:59,440 --> 07:57:01,760
YOU MIGHT BE CARRYING ABOUT 1 TO

10555
07:57:01,760 --> 07:57:18,120
3 POUNDS OF THESE THROW IN THE

10556
07:57:18,120 --> 07:57:19,640
3 TO 5 POUNDS, YOUR BODY IS

10557
07:57:19,640 --> 07:57:22,920
CHARGES WITH A TREMENDOUS TASK

10558
07:57:22,920 --> 07:57:24,600
TO RECOGNIZE THE PATHOGEN -- TO

10559
07:57:24,600 --> 07:57:27,200
MAKE SURE THAT IT TURNS ON THE

10560
07:57:27,200 --> 07:57:27,960
INFLAMMATORY RESPONSE CORRECTLY

10561
07:57:27,960 --> 07:57:29,720
AND WE KNOW IF IT DOESN'T, A

10562
07:57:29,720 --> 07:57:33,320
VARIETY OF DISEASES CAN ENSUE.

10563
07:57:33,320 --> 07:57:35,440
AND SO MY GROUP AND I ARE REALLY

10564
07:57:35,440 --> 07:57:37,360
VERY INTERESTED IN THINKING

10565
07:57:37,360 --> 07:57:40,840
ABOUT THE BACTERIAL PEP 

10566
07:57:40,840 --> 07:57:43,160
PEPTIDOGLYCAN AND THEIR

10567
07:57:43,160 --> 07:57:44,360
RECEPTOR, SO MY GROUP AND I HAVE

10568
07:57:44,360 --> 07:57:45,760
DONE A LOT OF BIOCHEMISTRY TO

10569
07:57:45,760 --> 07:57:49,280
KIND OF HELP DELINEATE HOW

10570
07:57:49,280 --> 07:57:54,520
NOD-LIKE RECEPTORS BIND TO, BUT

10571
07:57:54,520 --> 07:57:56,440
HOW DO WE SENSE AND REA SPOND TO

10572
07:57:56,440 --> 07:57:58,680
THESE BACTERIAL WALL FRAGMENTS

10573
07:57:58,680 --> 07:58:00,080
AT THE MOLECULAR LEVEL.

10574
07:58:00,080 --> 07:58:01,120
IF I'M GOING TO TALK TO YOU

10575
07:58:01,120 --> 07:58:02,560
ABOUT MOLECULES, I SHOULD SHOW

10576
07:58:02,560 --> 07:58:03,840
YOU SOME MOLECULES.

10577
07:58:03,840 --> 07:58:06,280
SO IT'S A REPEATING UNIT OF TWO

10578
07:58:06,280 --> 07:58:10,240
SUGARS NOW.

10579
07:58:10,240 --> 07:58:14,960
THIS OTHER SUGAR THAT LINKS

10580
07:58:14,960 --> 07:58:17,480
TOGETHER GIVING THE JACKETTITY

10581
07:58:17,480 --> 07:58:19,120
STRENGTH AND RIGIDITY.

10582
07:58:19,120 --> 07:58:21,480
IT LONG BEEN KNOWN THAT VERY

10583
07:58:21,480 --> 07:58:22,720
SMALL SYNTHETIC FRAGMENT SUCH AS

10584
07:58:22,720 --> 07:58:24,360
THE ONE SHOWN HERE, SO NOW JUST

10585
07:58:24,360 --> 07:58:25,920
ONE SUGAR AND TWO AMINO ACIDS,

10586
07:58:25,920 --> 07:58:27,760
ARE ABLE TO GENERATE AN IMMUNE

10587
07:58:27,760 --> 07:58:28,640
RESPONSE IN HUMANS.

10588
07:58:28,640 --> 07:58:30,440
IT'S USED IN ADJUVANTS, FOR

10589
07:58:30,440 --> 07:58:31,600
EXAMPLE.

10590
07:58:31,600 --> 07:58:36,280
THERE IS SOME SPES  SPECIFICITY

10591
07:58:36,280 --> 07:58:36,880
INVOLVED.

10592
07:58:36,880 --> 07:58:38,200
YOU LOSE THE ABILITY TO HAVE THE

10593
07:58:38,200 --> 07:58:39,120
SIM LA TRI ACTIVITY.

10594
07:58:39,120 --> 07:58:40,320
SO MY GROUP AND I ARE REALLY

10595
07:58:40,320 --> 07:58:41,480
INTERESTED IN THINKING ABOUT HOW

10596
07:58:41,480 --> 07:58:43,320
IS THIS POLYMER PROCESSED TO

10597
07:58:43,320 --> 07:58:46,280
PRODUCE THESE IMMUNOSTIMULATORY

10598
07:58:46,280 --> 07:58:47,880
FRAGMENTS SO THE RED IS

10599
07:58:47,880 --> 07:58:50,000
HIGHLIGHTED IN RED SO WON KER

10600
07:58:50,000 --> 07:58:52,440
WHAT ENZYMES  WONDER

10601
07:58:52,440 --> 07:58:55,080
WHAT ENZYMES ARE RESPONSIBLE --

10602
07:58:55,080 --> 07:58:57,000
UNIQUE SET OF CELL WALL

10603
07:58:57,000 --> 07:58:58,440
BACTERIAL CELL WALL FRAGMENTS

10604
07:58:58,440 --> 07:58:59,520
WHICH WOULD BE YET ANOTHER WAY

10605
07:58:59,520 --> 07:59:01,040
FROM ALL THE DIFFERENT THINGS WE

10606
07:59:01,040 --> 07:59:02,160
HEARD ABOUT TODAY TO KIND OF

10607
07:59:02,160 --> 07:59:03,320
DELINEATE BETWEEN THE DIFFERENT

10608
07:59:03,320 --> 07:59:05,600
TYPES OF MICROBES THAT ARE

10609
07:59:05,600 --> 07:59:07,320
LIVING IN OR ON YOUR BODY.

10610
07:59:07,320 --> 07:59:10,400
SO OUR HYPOTHESIS THAT DIFFERENT

10611
07:59:10,400 --> 07:59:12,520
BACTERIA PRODUCE A VARIETY OF

10612
07:59:12,520 --> 07:59:14,520
FRAGMENTS, THERE'S MORE THAN ONE

10613
07:59:14,520 --> 07:59:16,320
WARRANTED TO STUDY AND THINKING

10614
07:59:16,320 --> 07:59:17,840
ABOUT IMPORTANT BIOLOGICAL

10615
07:59:17,840 --> 07:59:18,600
CONSEQUENCES.

10616
07:59:18,600 --> 07:59:19,720
SO WE THINK THERE'S SOME

10617
07:59:19,720 --> 07:59:20,760
DIVERSITY INVOLVED NOT ONLY IN

10618
07:59:20,760 --> 07:59:23,160
THE WAY THAT THE PEPTIDOGLYCANS

10619
07:59:23,160 --> 07:59:25,640
LINK TO OTHER SHEATHS, SO GRAM

10620
07:59:25,640 --> 07:59:26,640
POSITIVE FOR EXAMPLE WILL TAKE

10621
07:59:26,640 --> 07:59:28,800
ADVANTAGE OF THESE BRIDGE,

10622
07:59:28,800 --> 07:59:29,920
GRAM-NEGATIVES AND SOME GRAM

10623
07:59:29,920 --> 07:59:31,520
POSITIVES TAKE ADVANTAGE OF

10624
07:59:31,520 --> 07:59:35,440
THESE ACIDS WHICH RL THIS

10625
07:59:35,440 --> 07:59:37,640
UNUSUAL DIE CARBOYXLATED AMINO

10626
07:59:37,640 --> 07:59:39,480
ACID, AND THEN IN ADDITION, SOME

10627
07:59:39,480 --> 07:59:43,720
USE ORNATHENE.

10628
07:59:43,720 --> 07:59:46,040
ACETYLATION PATTERNS ARE REALLY

10629
07:59:46,040 --> 07:59:48,760
IMPORTANT, BECOME RESISTANT --

10630
07:59:48,760 --> 07:59:51,240
IMMUNE RECOGNITION.

10631
07:59:51,240 --> 07:59:52,600
AND MYCOBACTERIUM HAVE -- WHICH

10632
07:59:52,600 --> 07:59:55,000
WILL ADD A HYDROXYL GROUP TO

10633
07:59:55,000 --> 07:59:56,640
THAT ACETATE RENDERING IT

10634
07:59:56,640 --> 07:59:58,560
RESISTANCE TO SOME OF THESE

10635
07:59:58,560 --> 08:00:00,640
INNATE IMMUNE MECHANISMS.

10636
08:00:00,640 --> 08:00:02,160
WILL GO TO GREAT LINGT TO

10637
08:00:02,160 --> 08:00:03,640
REMODEL ITS CELL WALL TO BECOME

10638
08:00:03,640 --> 08:00:05,920
RESISTANT TO THE ANTIBIOTIC

10639
08:00:05,920 --> 08:00:06,240
VANCOMYCIN.

10640
08:00:06,240 --> 08:00:08,440
SO WE REALLY WANT TO EXPAND THE

10641
08:00:08,440 --> 08:00:09,320
DIVERSITY THAT'S AVAILABLE.

10642
08:00:09,320 --> 08:00:10,560
WHEN SETH WAS TALKING HE SAID HE

10643
08:00:10,560 --> 08:00:12,800
WANTS TO GO TO THE CANDY SHOP

10644
08:00:12,800 --> 08:00:14,040
AND BUY SOME THINGS, SO IF YOU

10645
08:00:14,040 --> 08:00:16,400
WANT TO BUY SOME STUFF THE ONE

10646
08:00:16,400 --> 08:00:18,280
COMPOUND YOU CAN BUY IS --

10647
08:00:18,280 --> 08:00:20,320
PEPTIDE THAT'S BEEN READILY

10648
08:00:20,320 --> 08:00:23,880
AVAILABLE AND RIGOROUSLY STUDIED

10649
08:00:23,880 --> 08:00:25,160
BY IMMUNOLOGISTS FOR A VERY LONG

10650
08:00:25,160 --> 08:00:25,440
TIME.

10651
08:00:25,440 --> 08:00:27,640
SO WE WONDERED, COULD WE EXPAND

10652
08:00:27,640 --> 08:00:30,440
THE TYPES OF FRAGMENTS THAT ARE

10653
08:00:30,440 --> 08:00:31,320
AVAILABLE, AND THE ONE WE

10654
08:00:31,320 --> 08:00:33,280
THOUGHT ABOUT WAS MAKING THESE

10655
08:00:33,280 --> 08:00:39,560
SORT OF N GLYCOALLELE --

10656
08:00:39,560 --> 08:00:40,760
DEVELOPED THE SYNTHESIS OF THIS

10657
08:00:40,760 --> 08:00:43,680
AND JUST LIKE WHEN STEVE

10658
08:00:43,680 --> 08:00:45,000
TOWNSEND WAS TALKING, WE DO

10659
08:00:45,000 --> 08:00:46,480
SYNTHTHIS IN OUR GROUP AND IT

10660
08:00:46,480 --> 08:00:47,840
REALLY IMPORTANT TO THINK WE CAN

10661
08:00:47,840 --> 08:00:48,800
CHEMICALLY ACCESS THESE

10662
08:00:48,800 --> 08:00:49,040
COMPOUNDS.

10663
08:00:49,040 --> 08:00:50,440
SO I WON'T WALK YOU THROUGH IT

10664
08:00:50,440 --> 08:00:52,000
FOR THE SAKE OF TIME, BUT JIM

10665
08:00:52,000 --> 08:00:55,040
DEVELOPED A REALLY NICE STRATEGY

10666
08:00:55,040 --> 08:00:57,280
THAT MAKES THIS 2 AMINO -- WHICH

10667
08:00:57,280 --> 08:00:59,960
WILL NOW ALLOW US TO ACETYLATE

10668
08:00:59,960 --> 08:01:02,240
OR ALKYLATE A VARIETY OF THINGS

10669
08:01:02,240 --> 08:01:03,880
ON THESE COMPOUNDS TO BEGIN TO

10670
08:01:03,880 --> 08:01:04,240
STUDY THEM.

10671
08:01:04,240 --> 08:01:05,280
IN ADDITION, WE THOUGHT HOW

10672
08:01:05,280 --> 08:01:07,440
ABOUT TAKING AND UNDERSTANDING

10673
08:01:07,440 --> 08:01:08,200
WHAT ARE SOME OF THE ONES THAT

10674
08:01:08,200 --> 08:01:09,640
COULD BE LIVING IN YOUR GUT, SO

10675
08:01:09,640 --> 08:01:11,440
WE SET UP THESE REACTORS IN OUR

10676
08:01:11,440 --> 08:01:15,040
LAB WHERE WE GREW UP

10677
08:01:15,040 --> 08:01:15,960
LACTOBACILLUS -- AND THEN WE

10678
08:01:15,960 --> 08:01:19,040
TREATED IT WITH LISOSIME AND

10679
08:01:19,040 --> 08:01:20,080
USED MASS SPECTROMETRY TO

10680
08:01:20,080 --> 08:01:21,160
UNDERSTAND WHAT ARE THE NAY

10681
08:01:21,160 --> 08:01:22,760
JUROR FRAGMENTS BEING PRODUCED,

10682
08:01:22,760 --> 08:01:24,960
AND WHAT WE SEE ARE THESE SORT

10683
08:01:24,960 --> 08:01:29,160
OF DIE SK RIDE TYPE FRAGMENT,

10684
08:01:29,160 --> 08:01:33,560
TRY PEPTIDE, DID THIS WORK IN MY

10685
08:01:33,560 --> 08:01:34,320
GROUP.

10686
08:01:34,320 --> 08:01:36,520
SO CLAIRE WENT ON -- YOU CAN'T

10687
08:01:36,520 --> 08:01:38,840
BUY THIS GMTT TYPE FRAGMENT SO

10688
08:01:38,840 --> 08:01:40,080
CLAIRE WENT ON TO DEVELOP THE

10689
08:01:40,080 --> 08:01:41,800
SYNTHESIS OF IT, AND I WILL

10690
08:01:41,800 --> 08:01:45,400
BREEZE THROUGH THIS IN RAPID

10691
08:01:45,400 --> 08:01:46,600
FASHION, AND THIS IS PUBLISHED,

10692
08:01:46,600 --> 08:01:52,640
SO SHE CAN MAKE THIS AND SHE CAN

10693
08:01:52,640 --> 08:01:58,520
RAPIDLY ADD ON A VARIETY OF

10694
08:01:58,520 --> 08:02:01,280
PEPTIDES, AND THESE ARE ECK QIS

10695
08:02:01,280 --> 08:04:11,120
EXQUISITELY PURE.

10696
08:04:11,120 --> 08:04:12,480
SO WE THINK ABOUT OTHER

10697
08:04:12,480 --> 08:04:16,760
BACTERIA, WE DID THIS IN E OWE
E. COLI

10698
08:04:16,760 --> 08:04:17,440
MODEL SYSTEM.

10699
08:04:17,440 --> 08:04:19,160
THIS IS WHERE WORKING WITH THE

10700
08:04:19,160 --> 08:04:20,360
COMMON FUND HAS BEEN AN AMAZING

10701
08:04:20,360 --> 08:04:22,240
GIFT TO OUR LAB, SO IN WORKING

10702
08:04:22,240 --> 08:04:23,400
WITH THE COMMON FUND, WE'VE BEEN

10703
08:04:23,400 --> 08:04:26,520
ABLE TO SHARROW PROBE LARGELY

10704
08:04:26,520 --> 08:04:30,320
WITH THE HELP OF MY PARTNERS IN

10705
08:04:30,320 --> 08:04:32,600
CRIME ON THIS U01 AWARD THAT WE

10706
08:04:32,600 --> 08:04:34,800
WERE GIVEN BY THE COMMON FUND TO

10707
08:04:34,800 --> 08:04:36,600
SHARE, PROBE AND VERIFY PROTOCOL

10708
08:04:36,600 --> 08:04:37,720
WITH A VARIETY OF DIFFERENT

10709
08:04:37,720 --> 08:04:38,080
GROUPS.

10710
08:04:38,080 --> 08:04:39,240
SO THIS HAS BEEN REALLY FUN TO

10711
08:04:39,240 --> 08:04:40,720
DO AND IT REALLY NICE WHEN WE

10712
08:04:40,720 --> 08:04:44,400
GET LABELING BACK AND THAT WE'RE

10713
08:04:44,400 --> 08:04:45,800
ACTUALLY ABLE TO SEE LABELING IN

10714
08:04:45,800 --> 08:04:47,240
A VARIETY OF DIFFERENT TYPES OF

10715
08:04:47,240 --> 08:04:47,800
BACTERIA.

10716
08:04:47,800 --> 08:04:50,720
THIS HAS BEEN A LOT OF FUN TO

10717
08:04:50,720 --> 08:04:52,520
SEE THESE LABELS OF THESE

10718
08:04:52,520 --> 08:04:53,360
DIFFERENT ORGANISMS.

10719
08:04:53,360 --> 08:04:54,640
AS WE'RE MAKING AND DISTRIBUTING

10720
08:04:54,640 --> 08:04:56,720
MORE AND MORE -- WE WISH WE HAD

10721
08:04:56,720 --> 08:04:57,720
A VERY EFFICIENT WAY TO MAKE IT,

10722
08:04:57,720 --> 08:05:02,080
SO OUR FIRST GENERATION OF

10723
08:05:02,080 --> 08:05:04,200
SYNTHTHIS UTILIZES -- WE TRY NOT

10724
08:05:04,200 --> 08:05:05,920
TO DO IT ON TOO HIGH OF A SCALE

10725
08:05:05,920 --> 08:05:07,320
BECAUSE WE DON'T WANT OUR LAB

10726
08:05:07,320 --> 08:05:09,000
MEMBERS TO LOSE HANDS, SO ASHLEY

10727
08:05:09,000 --> 08:05:12,760
BROWN HAS STARTED, ONE OF THE

10728
08:05:12,760 --> 08:05:15,440
REGIONS CAN BE A CONTACT -- ASH

10729
08:05:15,440 --> 08:05:16,920
LEA BROWN HAS DEVELOPED A NEW

10730
08:05:16,920 --> 08:05:17,840
SYNTHESIS WHICH IS SCALABLE SO

10731
08:05:17,840 --> 08:05:19,520
NOW WE CAN DO THIS ON 15-GRAM

10732
08:05:19,520 --> 08:05:24,840
SCALE TO PRODUCE THIS DERIVATIVE

10733
08:05:24,840 --> 08:05:25,920
THIS 2 AMINO THAT WE CAN

10734
08:05:25,920 --> 08:05:27,920
DECORATE WITH OUR BIOOR THOG NAT

10735
08:05:27,920 --> 08:05:29,640
PROBE SO IT'S A REALLY NICE WAY.

10736
08:05:29,640 --> 08:05:31,720
ASH LE HOOS LOOKED AT OPTIMIZING

10737
08:05:31,720 --> 08:05:34,400
THIS ALONG WITH STEVEN HIGHLAND

10738
08:05:34,400 --> 08:05:35,240
AND GLYCOBIOLOGY AND MAJOR WAY

10739
08:05:35,240 --> 08:05:37,640
YOU DO THIS IS EITHER -- OR CAP

10740
08:05:37,640 --> 08:05:39,920
WITH THE METHYL ESTER YOUR PROBE

10741
08:05:39,920 --> 08:05:41,600
THEAND YOU CAN GAIN MORE

10742
08:05:41,600 --> 08:05:42,920
EFFICIENT ENTRY INTO THE

10743
08:05:42,920 --> 08:05:44,520
CYTOPLASM, HOWEVER, WE FIND

10744
08:05:44,520 --> 08:05:46,240
BACTERIA DO NOT HAVE THE

10745
08:05:46,240 --> 08:05:49,440
ESTERASES TO REMOVE THESE

10746
08:05:49,440 --> 08:05:50,240
ACETATES FROM THE SUGAR SO IF WE

10747
08:05:50,240 --> 08:05:53,520
TRY TO LABEL IT WITH AN

10748
08:05:53,520 --> 08:05:55,360
ACETYLATED FRAGMENT, WE CAN NO

10749
08:05:55,360 --> 08:05:57,880
LONG 

10750
08:05:57,880 --> 08:06:02,000
LONGER LABEL BUT WE CAN GET AWAY

10751
08:06:02,000 --> 08:06:04,320
WITH THIS METHYL ESTER CAPE.

10752
08:06:04,320 --> 08:06:06,600
WONDERING CAN WE DO THIS IN

10753
08:06:06,600 --> 08:06:11,320
REALTIME USING COPPER FREE CLICK

10754
08:06:11,320 --> 08:06:13,120
CHEMISTRY OR SPEC, WE CAN

10755
08:06:13,120 --> 08:06:15,080
PRELABEL OUR BACTERIA WITH SPEC

10756
08:06:15,080 --> 08:06:16,960
AND INCUBATE THESE BACTERIA WITH

10757
08:06:16,960 --> 08:06:20,000
MIKE PHAGE 

10758
08:06:20,000 --> 08:06:23,000
MICROPHAGE AND LOOK UNDER A MIKE

10759
08:06:23,000 --> 08:06:25,080
SCEEP TO SEE WHAT WE CAN SEE,

10760
08:06:25,080 --> 08:06:26,440
HOW THEY'RE INTERACTING WITH THE

10761
08:06:26,440 --> 08:06:27,800
MACROPHAGE, WE'RE BEGINNING TO

10762
08:06:27,800 --> 08:06:29,880
VISUALIZE THE BREAKDOWN PRODUCTS

10763
08:06:29,880 --> 08:06:32,120
WITHIN THESE CELLS, AND NOW

10764
08:06:32,120 --> 08:06:33,960
WE'RE DOING ENDO SOMOL STAINING

10765
08:06:33,960 --> 08:06:35,600
TO WATCH THE BRAKE BREAK DOWN OF

10766
08:06:35,600 --> 08:06:36,880
THE BACTERIA WITHIN THE MACRO

10767
08:06:36,880 --> 08:06:37,120
PHAGE.

10768
08:06:37,120 --> 08:06:39,120
AS WE THINK ABOUT THIS, WE CAN

10769
08:06:39,120 --> 08:06:43,200
SEE SOME MACROPHAGES LOTS OF

10770
08:06:43,200 --> 08:06:45,320
DIFFERENT TYPES OF BACTERIA, YOU

10771
08:06:45,320 --> 08:06:47,080
CAN SEE THESE LYSING INSIDE, AND

10772
08:06:47,080 --> 08:06:49,400
WE WANT TO START TO SEE THE

10773
08:06:49,400 --> 08:06:51,120
BACTERIA BREAK DOWN WITHIN THE

10774
08:06:51,120 --> 08:06:52,320
MACROPHAGES BUT THEN WE ALSO

10775
08:06:52,320 --> 08:06:55,120
WONDER WHAT IS THE FATE OF THESE

10776
08:06:55,120 --> 08:06:56,600
FRAGMENTS.

10777
08:06:56,600 --> 08:06:58,560
SO IS ONE OF THE I THINK INNER

10778
08:06:58,560 --> 08:07:00,520
INTERESTING WAYS WHERE THESE

10779
08:07:00,520 --> 08:07:02,320
FRAGMENTS COULD BE GOING IS THE

10780
08:07:02,320 --> 08:07:02,680
BRAIN.

10781
08:07:02,680 --> 08:07:07,120
WOULD HE THINK WE THINK A LOT
ABOUT THINGS
 THAT

10782
08:07:07,120 --> 08:07:08,440
CAN PASS INTO THE BRAIN AND WE

10783
08:07:08,440 --> 08:07:11,280
THINK THESE SUGARS MIGHT BE

10784
08:07:11,280 --> 08:07:11,920
IMMUNOPRIVILEGES THAT THEY OUGHT

10785
08:07:11,920 --> 08:07:13,480
TO BE ABLE TO PASS THE BLOOD

10786
08:07:13,480 --> 08:07:14,640
BRAIN BARRIER.

10787
08:07:14,640 --> 08:07:17,080
WE KNOW THE INNATE IMMUNE

10788
08:07:17,080 --> 08:07:18,280
RECEPTORS -- ARE PRESENT IN THE

10789
08:07:18,280 --> 08:07:21,240
BRAIN, SO WE WONDERED, COULD

10790
08:07:21,240 --> 08:07:24,520
BACTERIA COLONIZING IN THE GUT

10791
08:07:24,520 --> 08:07:25,920
CROSS THE BLOOD BRAIN BARRIER

10792
08:07:25,920 --> 08:07:26,920
AND CAUSE A LOCAL EFFECT.

10793
08:07:26,920 --> 08:07:29,560
WE THOUGHT ABOUT DOING THIS IN

10794
08:07:29,560 --> 08:07:31,200
COLLABORATION WITH JACKIE

10795
08:07:31,200 --> 08:07:32,360
SCHWARTZ AT THE UNIVERSITY OF

10796
08:07:32,360 --> 08:07:33,120
DELAWARE, WHO'S A BRAIN

10797
08:07:33,120 --> 08:07:38,400
SCIENTIST AND STUDIES MICRO --

10798
08:07:38,400 --> 08:07:39,360
THE IMMUNE CELLS IN THE BRAIN

10799
08:07:39,360 --> 08:07:44,360
AND THEY EXPRESS NOD2 SO ASHLEY

10800
08:07:44,360 --> 08:07:46,800
HAS MADE THIS THAT CONTAINS A

10801
08:07:46,800 --> 08:07:48,480
BIO ORTHOGONAL ANGLE.

10802
08:07:48,480 --> 08:07:50,120
WE INJECTED IT INTO MICE AND

10803
08:07:50,120 --> 08:07:51,320
THEN DID 10 COURSES WHERE WE

10804
08:07:51,320 --> 08:07:52,800
WERE GOING TO TRACK IN DIFFERENT

10805
08:07:52,800 --> 08:07:58,680
ORGANS TO SEE WHAT KIND OF

10806
08:07:58,680 --> 08:07:59,640
IMMUNE RESPONSES WE'RE ABLE TO

10807
08:07:59,640 --> 08:08:00,520
SEE.

10808
08:08:00,520 --> 08:08:02,520
WE SEE IT CAN INDUCE

10809
08:08:02,520 --> 08:08:04,120
INFLAMMATION IN THE BRAIN, THE

10810
08:08:04,120 --> 08:08:06,200
HYPOTHALAMUS, WE IS SEE BOTH

10811
08:08:06,200 --> 08:08:09,920
IL-1B AND I WILL 16 ROBUST

10812
08:08:09,920 --> 08:08:11,240
EXPRESSION AFTER FOUR HOURS

10813
08:08:11,240 --> 08:08:12,920
IMPLYING THE SYNTHETIC FRAGMENT

10814
08:08:12,920 --> 08:08:14,240
IS INDEED REACHING THE BRAIN.

10815
08:08:14,240 --> 08:08:16,960
WE CAN EVEN VISUALIZE IT INSIDE

10816
08:08:16,960 --> 08:08:19,040
A MICRO GILLIA THAT WE CULTURE

10817
08:08:19,040 --> 08:08:21,000
FROM THOSE TREATED RATS AND WE

10818
08:08:21,000 --> 08:08:23,840
CAN SEE THE WORK FROM NICOLE

10819
08:08:23,840 --> 08:08:29,360
HAAS SHOWING THE MICROGLIA IN IN

10820
08:08:29,360 --> 08:08:31,920
GREEN AND RED, WE CAN SEE THE --

10821
08:08:31,920 --> 08:08:34,120
PEPTIDE INSIDE THE CELL.

10822
08:08:34,120 --> 08:08:35,000
IN ADDITION, ASHLEY HAS WORKED

10823
08:08:35,000 --> 08:08:36,480
OUT A REALLY COOL WORKFLOW IN

10824
08:08:36,480 --> 08:08:38,920
WHICH WE CAN NOW HARVEST THE

10825
08:08:38,920 --> 08:08:43,160
BRAIN, AND WE CAN LOOK INSIDE

10826
08:08:43,160 --> 08:08:44,920
WITH THE MICROSCOPE AFTER SHE

10827
08:08:44,920 --> 08:08:47,320
LYSES AND WE CAN USE SIM AND WE

10828
08:08:47,320 --> 08:08:49,200
CAN START LOOKING AT SPECIFIC

10829
08:08:49,200 --> 08:08:50,080
FRAGMENTS INSIDE THE BRAIN, AND

10830
08:08:50,080 --> 08:08:51,920
WE CAN SEE THESE FRAGMENTS IN

10831
08:08:51,920 --> 08:08:53,000
OUR MASS SPEC.

10832
08:08:53,000 --> 08:08:54,120
AND IN A REALLY NICE

10833
08:08:54,120 --> 08:08:55,120
COMPLEMENTARY APPROACH THAT WAS

10834
08:08:55,120 --> 08:08:57,600
JUST PUBLISHED IN SCIENCE IN

10835
08:08:57,600 --> 08:08:59,640
2015, OR THIS PAST -- ON

10836
08:08:59,640 --> 08:09:02,120
APRIL 15TH, WE CAN SEE ANOTHER

10837
08:09:02,120 --> 08:09:04,440
GROUP USED RADIOACTIVITY IN

10838
08:09:04,440 --> 08:09:06,520
WHICH THEY CAN TRACK NOW THESE

10839
08:09:06,520 --> 08:09:07,560
FRAGMENTS UP IN THE BRAIN AS

10840
08:09:07,560 --> 08:09:09,120
WELL, SO WE THINK THIS IS GOING

10841
08:09:09,120 --> 08:09:11,280
TO BE A COMPLEMENTARY WAY TO

10842
08:09:11,280 --> 08:09:13,120
START THINKING ABOUT KNOWING THE

10843
08:09:13,120 --> 08:09:13,920
MOLECULES MAKING THEIR WAY UP

10844
08:09:13,920 --> 08:09:14,680
INTO THE BRAIN.

10845
08:09:14,680 --> 08:09:15,880
SO WE'VE DONE A LOT OF WORK TO

10846
08:09:15,880 --> 08:09:20,000
BE ABLE TO MAKE SORT OF DESIGNER

10847
08:09:20,000 --> 08:09:21,880
BACTERIA WHERE WE CAN REMODEL

10848
08:09:21,880 --> 08:09:23,840
THEM WITH A VARIETY OF DIFFERENT

10849
08:09:23,840 --> 08:09:25,040
PROBES, WE'RE USING A VARIETY OF

10850
08:09:25,040 --> 08:09:26,240
DIFFERENT APPROACHES AND WE'RE

10851
08:09:26,240 --> 08:09:27,760
REALLY EXCITED ABOUT THINKING OF

10852
08:09:27,760 --> 08:09:29,720
WHERE AND HOW THESE DIFFERENT

10853
08:09:29,720 --> 08:09:31,320
FRAGMENTS CAN TURN ON DIFFERENT

10854
08:09:31,320 --> 08:09:33,040
TRANSCRIPTIONAL PROGRAMS NOT

10855
08:09:33,040 --> 08:09:34,240
ONLY IN THE GUT NOW BUT

10856
08:09:34,240 --> 08:09:34,880
POTENTIALLY IF THE BRAIN.

10857
08:09:34,880 --> 08:09:36,720
SO I'D LIKE TO THANK MY LAB ONE

10858
08:09:36,720 --> 08:09:37,080
MORE TIME.

10859
08:09:37,080 --> 08:09:38,200
YOU FOR YOUR TIME AND ATTENTION

10860
08:09:38,200 --> 08:09:40,320
FOR HANGING ON SO LONG.

10861
08:09:40,320 --> 08:09:41,880
I'M SORRY ABOUT THE INTERRUPTION

10862
08:09:41,880 --> 08:09:43,200
FOR MY DAUGHTER, SHE IS

10863
08:09:43,200 --> 08:09:46,120
OBVIOUSLY HOME FROM SCHOOL.

10864
08:09:46,120 --> 08:09:48,000
AND I WILL -- AGAIN I WANT TO

10865
08:09:48,000 --> 08:09:50,120
THANK SEAN FOR DOING THIS WITH

10866
08:09:50,120 --> 08:09:51,520
ME, FOR ORGANIZING THIS

10867
08:09:51,520 --> 08:09:51,920
SYMPOSIUM.

10868
08:09:51,920 --> 08:09:53,520
IT'S BEEN REALLY FUN, AND PAM

10869
08:09:53,520 --> 08:09:55,200
FOR THE OPPORTUNITY TO DO THAT.

10870
08:09:55,200 --> 08:09:56,840
AND IF YOU FIND YOURSELF THIRSTY

10871
08:09:56,840 --> 08:09:59,480
FOR MORE AND WANTING MORE

10872
08:09:59,480 --> 08:10:00,520
GLYCOSCIENCE, YOU'RE IN LUCK

10873
08:10:00,520 --> 08:10:02,320
BECAUSE YOUR OPPORTUNITY WILL

10874
08:10:02,320 --> 08:10:04,360
PRESENT TO YOURSELF NEXT MONDAY,

10875
08:10:04,360 --> 08:10:04,960
TUESDAY, WEDNESDAY WHERE WE'LL

10876
08:10:04,960 --> 08:10:07,200
HAVE OUR GLYCOSCIENCE COMMON

10877
08:10:07,200 --> 08:10:08,080
FUND MEETING THAT'S OPEN TO THE

10878
08:10:08,080 --> 08:10:09,960
PUBLIC, AND WE VIDEOCAST IS TO

10879
08:10:09,960 --> 08:10:11,480
THE LINK IS THERE, AND WE WOULD

10880
08:10:11,480 --> 08:10:12,680
LOVE TO SEE YOU ON THERE AS

10881
08:10:12,680 --> 08:10:13,040
WELL.

10882
08:10:13,040 --> 08:10:14,920
SO THANK YOU SO MUCH FOR HANGING

10883
08:10:14,920 --> 08:10:17,080
OUT WITH US ALL DAY, AND

10884
08:10:17,080 --> 08:10:18,200
HOPEFULLY THIS WAS A SWEET END

10885
08:10:18,200 --> 08:10:18,520
TO YOUR DAY.

10886
08:10:18,520 --> 08:10:19,840
SO THANK YOU.

10887
08:10:19,840 --> 08:10:21,360
>> THANK YOU SO MUCH, CATHERINE.

10888
08:10:21,360 --> 08:10:23,120
THAT WAS AMAZING.

10889
08:10:23,120 --> 08:10:25,920
I THOUGHT YOUR ABILITY TO HANDLE

10890
08:10:25,920 --> 08:10:28,120
YOUR DAUGHTER IN A SEAMLESS WAY

10891
08:10:28,120 --> 08:10:29,320
WAS QUITE IMPRESSIVE.

10892
08:10:29,320 --> 08:10:30,320
>> THAT'S OKAY.

10893
08:10:30,320 --> 08:10:31,440
THAT WAS LIKE TRAINING OVER THE

10894
08:10:31,440 --> 08:10:31,640
YEARS.

10895
08:10:31,640 --> 08:10:33,680
>> REALLY IMPRESSIVE.

10896
08:10:33,680 --> 08:10:34,400
LAURA HAS A QUESTION.

10897
08:10:34,400 --> 08:10:36,240
>> OH, I THINK I'M GOING TO

10898
08:10:36,240 --> 08:10:38,160
DEFER FIRST TO SETH, BECAUSE HE

10899
08:10:38,160 --> 08:10:40,200
HAD HIS HAND UP BEFORE ME.

10900
08:10:40,200 --> 08:10:42,160
>> I WASN'T PAYING ATTENTION TO

10901
08:10:42,160 --> 08:10:46,920
WHO HAD THEIR HAND UP FIRST.

10902
08:10:46,920 --> 08:10:49,120
I THINK YOU'RE MUTED, BUDDY.

10903
08:10:49,120 --> 08:10:49,960
I LOVE THE QUESTION, I CAN TELL

10904
08:10:49,960 --> 08:10:51,480
IT'S GOING TO BE GREAT.

10905
08:10:51,480 --> 08:10:53,160
>> MY FIRST ONE IS A COMMENT

10906
08:10:53,160 --> 08:10:55,960
WHICH IS, LIKE, OH, MY GOODNESS,

10907
08:10:55,960 --> 08:10:57,720
I WAS GIVING A TALK AND I HAD A

10908
08:10:57,720 --> 08:11:01,520
BLOODY CHILD COME UP TO ME LIKE,

10909
08:11:01,520 --> 08:11:01,720
SO YEAH.

10910
08:11:01,720 --> 08:11:03,280
>> BUT SHE WASN'T BLOODY.

10911
08:11:03,280 --> 08:11:05,280
SHE WAS PROBABLY JUST DIRTY

10912
08:11:05,280 --> 08:11:06,920
BECAUSE SHE PROBABLY ATE A LOT

10913
08:11:06,920 --> 08:11:07,760
OF CHOCOLATE OR SOMETHING.

10914
08:11:07,760 --> 08:11:09,160
I DON'T THINK SHE WAS BLOODY.

10915
08:11:09,160 --> 08:11:09,640
>> THAT WAS GREAT.

10916
08:11:09,640 --> 08:11:11,280
I HAD TO DO LIKE FIRST AID

10917
08:11:11,280 --> 08:11:12,720
DURING A TALK ONCE.

10918
08:11:12,720 --> 08:11:18,720
>> SO YOU HAD TO DO THAT.

10919
08:11:18,720 --> 08:11:31,520
OKAY.

10920
08:11:31,520 --> 08:11:32,960
GLYCOLIPIDS, THERE'S MAYBE

10921
08:11:32,960 --> 08:11:35,320
FUNGAL GLYCANS.

10922
08:11:35,320 --> 08:11:37,760
THEY'RE PRETTY DIVERSE

10923
08:11:37,760 --> 08:11:40,440
CHEMICALLY.

10924
08:11:40,440 --> 08:11:46,320
I DID NOT -- WE'RE TALKING ABOUT

10925
08:11:46,320 --> 08:11:46,960
PEPTIDE -- A -- BACKBONE

10926
08:11:46,960 --> 08:11:48,160
BASICALLY BUT WITH THESE

10927
08:11:48,160 --> 08:11:49,080
MODIFICATIONS THAT YOU'RE

10928
08:11:49,080 --> 08:11:49,520
SHOWING.

10929
08:11:49,520 --> 08:11:49,760
>> RIGHT.

10930
08:11:49,760 --> 08:11:51,600
>> WHICH I THINK IS AWESOME, BUT

10931
08:11:51,600 --> 08:11:55,640
MY QUESTION IS, WE HAVEN'T EVEN

10932
08:11:55,640 --> 08:11:58,720
UNDERSTOOD HOW TLRS BIND TO

10933
08:11:58,720 --> 08:11:59,520
THESE CHEMICALLY DIVERSE -- AND

10934
08:11:59,520 --> 08:12:02,280
SOME PEOPLE HAVE THEORIES ABOUT

10935
08:12:02,280 --> 08:12:04,160
CD14, MD2, CORECEPTORS.

10936
08:12:04,160 --> 08:12:05,680
DO YOU THINK THERE'S ACCESSORY

10937
08:12:05,680 --> 08:12:06,960
MOLECULES THAT ARE LEADING TO

10938
08:12:06,960 --> 08:12:09,920
THE SPECIFICITY OR AT LEAST THE

10939
08:12:09,920 --> 08:12:11,280
SPECIFIC PROGRAMS THAT YOU'RE

10940
08:12:11,280 --> 08:12:11,520
SEEING?

10941
08:12:11,520 --> 08:12:15,200
>> O  OH DEFINITELY.

10942
08:12:15,200 --> 08:12:16,680
THAT'S WHAT WE WANT TO START TO

10943
08:12:16,680 --> 08:12:17,920
TEASE OUT NOW WITH THE DIFFERENT

10944
08:12:17,920 --> 08:12:20,000
FRAGMENTS WE HAVE AT THE PROBES

10945
08:12:20,000 --> 08:12:23,080
WE'RE MAKING AND BRINGING

10946
08:12:23,080 --> 08:12:23,400
ONLINE.

10947
08:12:23,400 --> 08:12:25,320
WEE DONE THE CLEAN SPAIRT BUT I

10948
08:12:25,320 --> 08:12:27,440
THINK LAURA HAS DONE THE COOL

10949
08:12:27,440 --> 08:12:28,520
EXPERIMENT WHEN SHE STARTS

10950
08:12:28,520 --> 08:12:30,560
MIXINGS ALL OF HER BACTERIA

10951
08:12:30,560 --> 08:12:32,120
TOGETHER AND STARTS TO SEE

10952
08:12:32,120 --> 08:12:33,000
SPECIFICITIES FOR THE LECTIN.

10953
08:12:33,000 --> 08:12:35,720
WE CAN BE VERY CONTROLLED NOW

10954
08:12:35,720 --> 08:12:37,040
BECAUSE WE'VE MADE THEM WHAT

10955
08:12:37,040 --> 08:12:38,720
THEY ARE, I DON'T KNOW IF THAT

10956
08:12:38,720 --> 08:12:39,040
MAKES SENSE.

10957
08:12:39,040 --> 08:12:39,560
>> IT DOES.

10958
08:12:39,560 --> 08:12:41,760
CAN I FOLLOW UP WITH THAT WHICH

10959
08:12:41,760 --> 08:12:43,520
IS AN IMMUNOLOGICAL THEORY WHICH

10960
08:12:43,520 --> 08:12:45,760
BASED ON THE THEORY OF INNATE

10961
08:12:45,760 --> 08:12:48,320
CONTROL OF ADAPTIVE IMMUNITY,

10962
08:12:48,320 --> 08:12:50,200
AND BASICALLY HOW DIFFERENT PRR,

10963
08:12:50,200 --> 08:12:51,840
DEPENDING ON WHETHER THEY'RE

10964
08:12:51,840 --> 08:12:53,000
INTRACELLULAR OR EXTRACELLULAR

10965
08:12:53,000 --> 08:12:55,840
OR FUNGAL OR VIRAL OR BACTERIAL

10966
08:12:55,840 --> 08:12:58,560
LEAD TO DIFFERENT IMMUNE

10967
08:12:58,560 --> 08:12:59,000
MODULES.

10968
08:12:59,000 --> 08:13:00,720
DO YOU -- SO THE MODIFICATIONS

10969
08:13:00,720 --> 08:13:05,520
YOU SHOWED WERE IN LACTOBACILLI,

10970
08:13:05,520 --> 08:13:09,280
NOT INTRACELLULAR, WE THINK.

10971
08:13:09,280 --> 08:13:12,760
IN MICOBACTERIA, IN STAPH.

10972
08:13:12,760 --> 08:13:14,320
CAN YOU COME UP WITH A RHYME OR

10973
08:13:14,320 --> 08:13:17,320
REASON AS TO IF THIS IS REALLY A

10974
08:13:17,320 --> 08:13:20,000
HOST ADAPTATION IN ANY WAY FOR

10975
08:13:20,000 --> 08:13:21,280
DIFFERENT IMMUNE MODULES BASED

10976
08:13:21,280 --> 08:13:22,600
ON THE MODIFICATIONS THAT YOU

10977
08:13:22,600 --> 08:13:27,520
MIGHT BE SEEING IN PEP 

10978
08:13:27,520 --> 08:13:28,520
PEPTIDOGLYCAN, AND CAN THE

10979
08:13:28,520 --> 08:13:29,560
HOST -- THE WAY IT WORKS IS THAT

10980
08:13:29,560 --> 08:13:30,720
THE HOST BASICALLY SAYS, OH,

10981
08:13:30,720 --> 08:13:31,920
IT'S THAT TYPE OF INFECTION,

10982
08:13:31,920 --> 08:13:33,680
WE'RE GOING TO DO THAT TYPE OF

10983
08:13:33,680 --> 08:13:34,120
IMMUNE RESPONSE.

10984
08:13:34,120 --> 08:13:35,200
DO YOU THINK THAT SYSTEM WOULD

10985
08:13:35,200 --> 08:13:40,320
BE WORKING FOR NOD2, MAYBE NOD 1
PEPTIDOGL
YCAN MODIFICATIONS IN

10986
08:13:40,320 --> 08:13:42,000
ANY WAY?

10987
08:13:42,000 --> 08:13:44,120
BECAUSE I CAN'T SEE IT, YOU

10988
08:13:44,120 --> 08:13:44,520
KNOW?

10989
08:13:44,520 --> 08:13:48,000
MEANING, LIKE --

10990
08:13:48,000 --> 08:13:49,320
>> I THINK MORE LIKE YOU WERE

10991
08:13:49,320 --> 08:13:50,840
ALLUDING TO BEFORE, THERE'S

10992
08:13:50,840 --> 08:13:52,160
CORECEPTORS AND THERE'S OTHER --

10993
08:13:52,160 --> 08:13:55,160
I DON'T JUST THINK IT'S A NOD2,

10994
08:13:55,160 --> 08:13:55,760
NOD 1 TYPE OF PROBLEM.

10995
08:13:55,760 --> 08:13:56,520
SO I THINK --

10996
08:13:56,520 --> 08:14:00,200
>> CAN IT TELL THE TYPE OF --

10997
08:14:00,200 --> 08:14:00,440
LIKE --

10998
08:14:00,440 --> 08:14:02,400
>> I DON'T THINK IT'S OPERATING

10999
08:14:02,400 --> 08:14:03,240
BY ITSELF.

11000
08:14:03,240 --> 08:14:04,800
AND I FEEL LIKE WE'VE BEEN DOING

11001
08:14:04,800 --> 08:14:06,440
REALLY GOOD DURING THIS

11002
08:14:06,440 --> 08:14:07,960
SYMPOSIUM, RIGHT, LIKE THIS IS A

11003
08:14:07,960 --> 08:14:09,280
SYSTEM THAT I'M INTERESTED IN

11004
08:14:09,280 --> 08:14:11,480
BUT IT'S OBVIOUSLY OPERATING IN

11005
08:14:11,480 --> 08:14:12,720
THIS VERY COMPLEX AREA, BUT WE

11006
08:14:12,720 --> 08:14:14,800
HAVE TO UNDERSTAND, JUST LIKE

11007
08:14:14,800 --> 08:14:16,320
WHEN NADINE WAS TALKING ABOUT

11008
08:14:16,320 --> 08:14:17,640
THE BIOPHYSICAL PROPERTIES, WE

11009
08:14:17,640 --> 08:14:19,720
HAVE TO UNDERSTAND THAT TOO, AND

11010
08:14:19,720 --> 08:14:21,200
THEN THE CONTEXT OF THIS LARGER

11011
08:14:21,200 --> 08:14:22,120
FIELD AND THAT'S WHY I THINK

11012
08:14:22,120 --> 08:14:23,160
THIS FIELD IS AWESOME, BECAUSE

11013
08:14:23,160 --> 08:14:25,040
WE ALL HAVE TO WORK TOGETHER TO

11014
08:14:25,040 --> 08:14:26,720
UNDERSTAND DIFFERENT ASPECTS OF

11015
08:14:26,720 --> 08:14:27,360
THOSE COMPONENTS.

11016
08:14:27,360 --> 08:14:28,800
DOES THAT MAKE SENSE?

11017
08:14:28,800 --> 08:14:32,160
>> OH, TOTALLY MAKES SENSE.

11018
08:14:32,160 --> 08:14:33,400
>> I THINK MY QUESTION IS

11019
08:14:33,400 --> 08:14:35,400
ACTUALLY REALLY RELATED TO WHAT

11020
08:14:35,400 --> 08:14:36,480
SETH WAS ASKING AND I'LL BE

11021
08:14:36,480 --> 08:14:37,520
PRETTY FAST.

11022
08:14:37,520 --> 08:14:39,520
I JUST WAS THINKING YOU HAVE

11023
08:14:39,520 --> 08:14:41,480
SUCH A GREAT TOOL NOW, AND I

11024
08:14:41,480 --> 08:14:42,800
KNOW THIS ISN'T EXACTLY WHAT

11025
08:14:42,800 --> 08:14:44,000
YOU'RE INTERESTED IN, BUT THE

11026
08:14:44,000 --> 08:14:47,720
DIFFERENCE IN UPTAKE BY THE

11027
08:14:47,720 --> 08:14:48,680
MACROPHAGES OF THE DIFFERENT

11028
08:14:48,680 --> 08:14:50,160
BACTERIA IS REALLY COOL, AND I

11029
08:14:50,160 --> 08:14:53,200
THINK YOU COULD GET AT SOME OF

11030
08:14:53,200 --> 08:14:54,760
THE HOST PART AND DOWNSTREAM

11031
08:14:54,760 --> 08:14:57,120
SIGNALING BY DOING LIKE SINGLE

11032
08:14:57,120 --> 08:14:58,360
CELL RNA SEQ ON THESE, BECAUSE

11033
08:14:58,360 --> 08:15:02,520
YOU HAVE A GREAT TOOL TO SORT

11034
08:15:02,520 --> 08:15:04,320
NOW DIFFERENT --

11035
08:15:04,320 --> 08:15:06,360
>> WITH THE BACTERIA INSIDE OF

11036
08:15:06,360 --> 08:15:08,200
IT, WE CAN SORT AND LOOK AND DO

11037
08:15:08,200 --> 08:15:09,440
SINGLE CELL WITH THE LABELING

11038
08:15:09,440 --> 08:15:11,560
TECHNOLOGY PART OF IT, YES.

11039
08:15:11,560 --> 08:15:13,720
>> I THINK THAT COULD BE A

11040
08:15:13,720 --> 08:15:16,000
REALLY GOOD USE OF YOUR COOL

11041
08:15:16,000 --> 08:15:16,200
TOOLS.

11042
08:15:16,200 --> 08:15:17,000
>> THIS IS COOL.

11043
08:15:17,000 --> 08:15:18,400
I'M REALLY GLAD THESE ARE ALL

11044
08:15:18,400 --> 08:15:19,560
RECORDED SO THAT I'LL REMEMBER

11045
08:15:19,560 --> 08:15:20,040
ALL THIS STUFF TOO.

11046
08:15:20,040 --> 08:15:23,920
THIS IS AWESOME.

11047
08:15:23,920 --> 08:15:26,680
THIS IS GOOD.

11048
08:15:26,680 --> 08:15:29,160
>> AND YOU GUYS ARE AMAZING,

11049
08:15:29,160 --> 08:15:30,720
SEAN AND CATHERINE, AND THEN

11050
08:15:30,720 --> 08:15:31,280
I'LL STOP TALKING.

11051
08:15:31,280 --> 08:15:33,480
>> I THINK THIS IS AN AMAZING

11052
08:15:33,480 --> 08:15:33,720
COMMUNITY.

11053
08:15:33,720 --> 08:15:34,720
WE JUST BRING OUT THE BEST IN

11054
08:15:34,720 --> 08:15:36,480
EACH OTHER AND IT'S REALLY BEEN

11055
08:15:36,480 --> 08:15:38,240
AWESOME AND IT'S FUN GOING

11056
08:15:38,240 --> 08:15:39,400
FORWARD.

11057
08:15:39,400 --> 08:15:40,640
MARIO, I SAW YOU TURN YOUR

11058
08:15:40,640 --> 08:15:41,080
CAMERA ON.

11059
08:15:41,080 --> 08:15:42,360
I DON'T KNOW IF THAT MEANS

11060
08:15:42,360 --> 08:15:46,120
YOU'RE HAPPY THIS IS ALL OVER.

11061
08:15:46,120 --> 08:15:47,120
>> SEE YOU FOR A LITTLE BIT AT

11062
08:15:47,120 --> 08:15:50,800
THE END, I THOUGHT IT WAS NICE

11063
08:15:50,800 --> 08:15:52,280
TO -- I JUST WANTED TO BE PART

11064
08:15:52,280 --> 08:15:52,880
OF IT.

11065
08:15:52,880 --> 08:15:53,520
>> GREAT.

11066
08:15:53,520 --> 08:15:55,320
NO, I THINK THIS IS A REALLY

11067
08:15:55,320 --> 08:15:56,200
AMAZING DAY.

11068
08:15:56,200 --> 08:15:57,240
AND I AM GLAD IT IS RECORDED

11069
08:15:57,240 --> 08:15:58,720
BECAUSE I THINK IT WILL BE GOOD

11070
08:15:58,720 --> 08:15:59,920
TO GO BACK AND WATCH SOME OF

11071
08:15:59,920 --> 08:16:01,440
THESE THINGS AGAIN, AND THIS WAS

11072
08:16:01,440 --> 08:16:04,560
REALLY FUN AND I THINK THIS IS A

11073
08:16:04,560 --> 08:16:08,320
REALLY NEAT COMMUNITY AND SO

11074
08:16:08,320 --> 08:16:10,160
HOPEFULLY WE GET TO HANG OUT

11075
08:16:10,160 --> 08:16:12,920
MORE AT NIH TBLIE COSCIENCE DAY

11076
08:16:12,920 --> 08:16:15,120
AT THE TIME THE COMMON FUND

11077
08:16:15,120 --> 08:16:16,520
DOES, ALL OF THOSE THINGS ARE

11078
08:16:16,520 --> 08:16:17,960
HOW WE CAN STAY CLOSE TOGETHER,

11079
08:16:17,960 --> 08:16:19,760
BUT I FEEL LIKE WE'VE IDENTIFIED

11080
08:16:19,760 --> 08:16:21,520
AN AREA WHERE GLYCOBIOLOGY IS

11081
08:16:21,520 --> 08:16:22,400
EXTREMELY IMPORTANT, RIGHT?

11082
08:16:22,400 --> 08:16:24,160
SO LET'S KEEP WORKING ON IT

11083
08:16:24,160 --> 08:16:25,160
TOGETHER.

11084
08:16:25,160 --> 08:16:25,440
>> AGREE.

11085
08:16:25,440 --> 08:16:27,560
THAT WOULD BE WONDERFUL TO GET

11086
08:16:27,560 --> 08:16:28,440
OUT AND GET DINNER TOGETHER.

11087
08:16:28,440 --> 08:16:30,720
BUT HOPEFULLY WE CAN DO THIS IN

11088
08:16:30,720 --> 08:16:32,120
PERSON.

11089
08:16:32,120 --> 08:16:35,440
LOGISTICALLY IT'S DIFFERENT BUT

11090
08:16:35,440 --> 08:16:36,720
THIS IS A GREAT OPPORTUNITY.

11091
08:16:36,720 --> 08:16:39,880
LIKE CATHERINE SAID, I THINK

11092
08:16:39,880 --> 08:16:40,480
IT'S A -- COMMUNITY AND

11093
08:16:40,480 --> 08:16:43,360
OPPORTUNITY TO BRING A LOT OF

11094
08:16:43,360 --> 08:16:44,040
COMMONLY DISPARATE DISCIPLINES

11095
08:16:44,040 --> 08:16:45,120
TOGETHER IN A FUN WAY.

11096
08:16:45,120 --> 08:16:46,640
I LOVE THE CHEMISTRY, THE MICRO

11097
08:16:46,640 --> 08:16:48,520
AND THE BIOCHEMISTRY AND JUST

11098
08:16:48,520 --> 08:16:49,680
IMMUNOLOGY ALL IN ONE PLACE,

11099
08:16:49,680 --> 08:16:50,920
WHICH IS NOT COMMON, AT LEAST IN

11100
08:16:50,920 --> 08:16:51,720
MY EXPERIENCE.

11101
08:16:51,720 --> 08:16:53,800
SO IT'S BEEN A LOT OF FUN.

11102
08:16:53,800 --> 08:16:55,160
IT'S BEEN GREAT.

11103
08:16:55,160 --> 08:16:56,480
SURE APPRECIATE EVERYBODY GIVING

11104
08:16:56,480 --> 08:16:57,240
SUCH WONDERFUL TALKS.

11105
08:16:57,240 --> 08:16:58,720
IT'S REALLY BEEN FUN.

11106
08:16:58,720 --> 08:16:59,680
>> NO, THIS IS GREAT.

11107
08:16:59,680 --> 08:17:01,440
THANK YOU ALL FOR HANGING ON SO

11108
08:17:01,440 --> 08:17:02,480
LONG, TOO.

11109
08:17:02,480 --> 08:17:04,320
AND MANY OF YOU, WE WILL BE

11110
08:17:04,320 --> 08:17:05,520
TOGETHER DOWN IN BETHESDA

11111
08:17:05,520 --> 08:17:07,120
MONDAY, TUESDAY AND WEDNESDAY,

11112
08:17:07,120 --> 08:17:09,040
SO THAT WILL BE NICE TO SEE MANY

11113
08:17:09,040 --> 08:17:11,120
OF YOU IN PERSON TOO.

11114
08:17:11,120 --> 08:17:11,520
SO THANK YOU ALL.

11115
08:17:11,520 --> 08:17:12,000
THANK YOU.

11116
08:17:12,000 --> 08:17:12,680
THANK YOU.

11117
08:17:12,680 --> 08:17:13,760
TAKE CARE.

11118
08:17:13,760 --> 08:17:14,120
BYE.

11119
08:17:14,120 --> 00:00:00,000
>> THANKS, EVERYONE.