Axonal Neuropathy Cure

Gtgt OKAY, GOOD AFTERNOON, I THINK WE’LL GET STARTED. I HAVE A COUPLE OF SORT OF BRIEF ANNOUNCEMENTS TO MAKE. ONE, THE FOR THOSE WHO WISH TO TAKE IT AND THOSE WHO GET ABOVE A CERTAIN GRADE, YOU WILL GET A CERTIFICATE. YOU CAN ACCESS IT THROUGH OUR WEB SITE THROUGH THE LIST SERVE, I SENT IT AROUND AND I THINK YOU HAVE UNTIL THE 15th OF MAY TO TAKE THE EXAM. SOMEONE HAS REGISTERED FOR IT THREE TIMES AND DIDN’T ANSWER ANYTHING AND I DIDN’T KNOW WHETHER THAT MEANT BECAUSE THE.

FIRST PERSON WAS TERRIFIED AT THE TRUE AND FALSE QUESTIONS YOU SHOULDN’T BE. OR MAYBE THEY MADE A MISTAKE AND ACCESSED THE WRONG THING. SO AT ANY RATE, THAT’S THAT. SO NEXT WEEK IS THE LAST SESSION OF THIS 12th YEAR. JOHN HANOVER WILL SHARE A DISCUSSION WITH JOHN GOWAN WHO’S THE CLINICAL DIRECTOR, CLINICAL CENTER, AND JONATHAN LORSCH WHO’S THE DIRECTOR OF THE GENERAL MEDICAL CENTER OF SCIENCE INSTITUTE, IT’S DESIGNED PRIMARILY FOR STUDENTS AND FELLOWS, WELL, ANYONE BUT PARTICULARLY THAT GROUP BECAUSE THE TOPIC IS WHAT DOES YOUR FUTURE LOOK LIKE.

OR WHAT PART OF THE REAL OPPORTUNITIES AND YOU KNOW, HOW GOOD OR HOW BAD IS THE CURRENT SCENE LIKELY TO BE AND SO THERE WILL BE MULTIPLE VIEWS THAT WILL BE PRESENTED BRIEFLY AND IS A FREE FLOWING DISCUSSION FROM YOU FOLKS AND THE THREE SPEAKERS. I REGRET THAT I WILL NOT BE THERE, BUT I WILL BE THINKING OF YOU ALL. OKAY IS THERE ANYTHING ELSE YES. THERE IS A VERY INTERESTING ARTICLE IN THE CURRENT SCIENCE THAT CAME TODAY RELEVANT TO THE DISCUSSION TWO WEEKS AGO ON FERTILITY AND MITOCHONDRIAL.

Demystifying Medicine 2015 Glycoprotein Disease Important, Unrecognized and Challenging

REPLACEMENT THERAPY AND HAPPY FOR MITOCHONDRIAL INHERITABLE DISEASES. IT’S A WONDERFUL DISCUSSION, POINTING OUT THE BRITISH HAVE ACCEPTED THIS PROCEDURE AND ARE FULLY BEHIND IT AND THAT THE MOMENT IT’S UNDER DISCUSSION, INTENSIVE DISCUSSION IN THE UNITED STATES AND THIS IS A VERYI THOUGHT WELL BALANCED AND INTERESTING SHORT ARTICLE. NOW, SPEAKING OF ARTICLES, TODAY’S PROGRAM ACTUALLY CHOSE THE VIRTUE OF READING OUTSIDE OF ONE’S FIELD. SO ONE OF MY HABITS IS WHEN I CAN’T SLEEP AT NIGHT, I PECK UP A COPY OF ONE OF THE MAGAZINES THAT’S BEEN PILING UP BY THE.

SIDE OF MY DESK OR SO AND THIS HAPPENED TO BE THE NEW YORKER OF JULY 21st 2014. REMARKABLE THEONE OF THE PARTICIPANTS IN THIS STORY IS ONE OF OUR SPEAKERS TODAY, SEARUN SANYAL, AND I THOUGHT AHA! THIS A GREAT TOPIC FOR DEMYSTIFYING MEDICINE FOR GLUE MARIOUS COPROTEINS AND THAT’S JOHN HANOVER, SO MAYBE IF WE GET THESE TWO FOLKS TOGETHER, WE CAN ALL LEARN A GREAT DEAL ABOUT THESE RARE, VERY RARE DISEASES AND WHAT THEY IMPLY IN TERMS OF MECHANISMS, IN TERMS OF HOW PATIENTS REACT AND WHAT.

THEMWHERE’S THEOH. SO I JUST POUT DOWN SOME OF THESE ARE MY THOUGHTS AND SUPPOSE SOMEBODY HAS A TRIAL WHO HAS SOME EXTRAORDINARY DISEASE MANIFESTED BY, YOU KNOW STRANGE DEHAIR, ACTIVITIES, ALL SORTS OF DIFFERENT THINGS, AND NOBODY SEEMS TO KNOW WHAT’S GOING ON. LOCAL PHYSICIAN, THE LOCAL CONSULTANT, MAYBE THE LOCAL MEDICAL SCHOOL, EXPERT, THEY ALL DO THEIR BEST. BUT IN THE LAST ANALYSIS, THEY DON’T KNOW WHAT IT IS. AND WHERE DOES SOMEONE LIKE THAT GO TO HAVE A DISEASE LIKE THAT DIAGINOSED AND MAYBE TREATED , MAYBE PREVENTED IF IT’S A.

GENETIC DISEASE AND THE FAMILY WANTS TO HAVE MORE CHILDREN AND WHAT REALLY HAPPENS WHEN PHYSICIANS SAY, YOU KNOW I’VE NEVER SEEN THIS BEFORE AND IF THE PHYSICIAN HAPPENS TO BE SOMEBODY, LET’S SAY AT A BIG GENETICS CENTER OR SOMETHING WHERE PEOPLE COME AND STILL THEY SAY, I DON’T KNOW WHAT THIS IS, I’VE NEVER SEEN IT BEFORE. WHAT DOES THE FAMILY DO AND THAT’S WHAT THE STORY IS IN THE NEW YORKER, IT’S AN AMAZING STORY THAT I WON’T REITERATE BUT I WOULD URGE YOU TO READ IT BECAUSE IT TOUCHES ON VERY.

SENSITIVE ISSUES OF GENETICS, HOW IT’S PRACTICED, HOW INFORMATION IS SHARED OR IS NOT SHARED. HOW PATIENTS TAKE IT IN THEIR OWN HANDS AND FOR EXAMPLE, IN THE CASE OF HERE, OF IT WAS THE FAMILY HA THAT MANAGED TO FIND OTHER FAMILIES OR OTHER PATIENTS AROUND THE WORLD, COLLECTING NINE TOTAL FROM ALL OVER THE WORLD AND THEY THEN BECAME A SUPPORT MECHANISM FOR THEMSELVES AND THEIR DRIVING FORCE TO GET THE SCIENTIST TO TAKE A HARD LOOK. SO THE EMPHASIS GOES FROM THE PHYSICIAN’S OFFICE, HE’S NOT THE ONE IN CHARGE ANYMORE, IT’S THEgtV.

PATIENT THAT’S DRIVING IT. AND HOW DO FAMILIES HANDLE THESE PROBLEMS, SOCIALLY, MEDICALLY, PSYCHOLOGICALLY, FINANCIALLY, THESE ARE COMPLEX ISSUES BUT NEVERTHELESS, VERY REAL. AND DOES NIH HAVE A ROLE IN THIS SCENARIO WELL, THOSE WHO REMEMBER PRESENTATIONS WE’VE HAD BEFORE FROM THE UNDIAGNOSED DISEASE GROUP YOU KNOW THAT BILL GALL HAD, AND THESE WERE PRESENTED AND THESE WERE HERE FROM ALL OVER THE WORLD AND ARE SCREENED BECAUSE NO ONE CAN MAKE A DIAGNOSIS AND VERY OFTEN BY PUTTING TOGETHER THE TOTAL RESOURCES OF THIS REMARKABLE INSTITUTION AND OTHERS AND SOME EXOME SEQUENCING.

BUT DIAGNOSIS AND MADE AND IN SOME INSTANCES, IT’S REALLY DRAMATIC IN TERMS THAT IT’S ACTUALLY TREATMENT THAT IS EVOLVED. SO I LIKE THIS QUOTE WHICH I TOOK FROM SERGIO RESENZWEIG IT’S AN ARTICLE IN THE NEW YORKER BUT WHAT IS THE ROLE OF THE TESTIFY AND THE CLINICAL INVESTIGATOR WHEN DEALING WITH THESE TERRIBLE, HORRIBLE CLINICAL PROBLEMS. SO, SURGE ROW SAID, WE TRY TO HELP THESE PATIENTS WITH RARE DISEASE, SOMETIMES WE CAN AND SOMETIMES WE CAN’T, BUT THESE CHILDREN ARE TEACHING US A LOT WE DIDN’T KNOW ABOUT OURSELVES.

AND WE CAN USE WHAT THEY ARE TEACHING US TO HELP OTHER PEOPLE. AND TODAY’S SESSION IS AN INCREDIBLE EXAMPLE OF THAT PHENOMENA. I MEAN WHO WOULD HAVE DREAMED THAT AN ABNORMALITY IN GLYCOSYLATION WHICH RENDERED AN INDIVIDUAL VERY ILL, AT THE SAME TIME MAYBE PROTECTS THEM AGAINST VIRAL INFECTION THAT SEEMS LIKE A FAR REACH BUT THAT’S EXACTLY THE REACH THAT WE’RE GOING TO HEAR ABOUT. SO, OKAY. OUR FIRST SPEAKER IS JOHN HANOVER AND A EXPERT IN SICKLE CELL ANEMIA. JOHN IS A BRANCH CHIEF IN INIDDK AND I FORGOT THE NAME OF THE.

BRANCH. gtgt CELLULAR AND FOLLICULAR BIOLOGY AND WE DON’T WORRY TOO MUCH ABOUT NAMES. AND THEN AFTER JOHN’S SPEECH LYN WOLF WHO IS A REGISTERED NURSE AND NURSE PRACTITIONER WITH THE UNDIAGNOSED DISEASE GROUP HERE IS GOING TO BRIEFLY DESCRIBE PATIENT WITH THE DISORDER THAT’S GOING TO BE DISCUSSED AND THEN, HER PRESENTATIONAL SPEECH FOLLOWED BY THAT OF SERGIO ROSESOUTH AMERICA SWAG WHO RECEIVED HIS Ph.D. IN ARGENTINA IS HERE AS A DIRECTOR, RIGHT AS DIRECTOR OF THE PRIMARY IMMUNODEFICIENCY CLINIC AND AHEAD OF THE INFECTIOUS DISEASE SUSCEPTIBILITY UNIT IN THE.

LABORATORY OF HOST DEFENSES OF NIAID. AND SO HE WILL CONCLUDE THE PRESENTATION AND PLENTY OF TIME FOR DISCUSSION. gtgt OKAY, CAN I BE HEARD IS THIS OKAY WITH EVERYONE SO AS WYN JUST SAID, THE DISEASE OFS THAT ARE ASSOCIATE WIDE THE GLIKE O SCIENCE ARE RARE BUT THEY’RE ALWAYS VERY INFORMATIVE SO I WILL GIVE YOU A BROAD OVERVIEW OF FIRST OF WHAT WE KNOW AND HOW WE LEARNED IT AND THEN TALK MORE ABOUT THE CASE. SO WE WILL TALK ABOUT THE CDGs GENERALLY IN GLYCANS AND THE.

ROLE OF QUALITY CONTROL AND WHY THEY’RE LOW HANGING FRUIT FOR MANY HUMAN DISEASES. I’LL BE TALKING ABOUT NG LYONE DEFICIENCY AND THEN WE’LL FINISH WITH SERGEANTIO’S WORK ON A RELATED PATHWAY AND YOU WILL SEE THAT THESE TWO PATHWAYS INTERMESH NICELY IN THE CONTEXT OF THE CELL BIOLOGY. OKAY, SO FOR THOSE WHO DON’T KNOW THIS, AND THIS MAY BE MANY IN THIS ROOM, WE’RE REALLY SITTING IN WHAT IS AHAS ALWAYS BEEN A HOT BED OF THE GLICO SCIENTIST, THIS IS A BRIEF HISTORY OF THE NIH GLIKE O.

SCIENTISTS WHO’S THE FOUNDER OF BASIC CARBOHYDRATE RESEARCH AT THE NIH STARTING, HE WAS CHIEF OF A RESEARCH BRANCH IN 1952. HUGHIT FLETCHER ALSO A RENOWNED CARBOHYDRATE CHEMIST. FOUR RENOWNED MICROBIOLOGIST, ASHWELL, NEUFELLED, GINSBURG, AND BRADY, I HAVE HAD THE PLEASURE OF WORKING WITH ALL FOUR OF THEM AND Iltb AM FORTUNATE FOR THAT, AND THERE’S A GLIKE O SCIENCE INTEREST GROUP FOR THOSE INTERESTED AND THE UNDIAGNOSED DISEASE PROGRAM HEADED BY BILL AND HIS COLLEAGUES, SO THERE’S A LOT GOING ON HISTORICALLY AND CURRENTLY. SO, WIN MENTIONED THE ARTICLE IN.

THE NEW YORKER AND PRECEDING THAT WAS IN ARTICLE IN CTHIS, N. I DON’T KNOW HOW MANY OF YOU SAW THIS MOVIE THAT MANY PEOPLE PROBABLY IGNORED ABOUT POMP PAY’S DISEASE AND IN IT, ONE OF THE SCENES THAT I PLAYEDED OVER AND OVER AGAIN IS A SCENE IN WHICH THE LEAD CHARACTER TURNS AROUND AND SAID, WHAT’S WRONG WITH YOU, HAVEN’T YOU KEPT UP ON YOUR GLIKE O PILOT PROJECTOLOGY AND YOU RARELY SEE IT, AND YOU RARELY SEE IT IN THE PRESS. THIS IS A DESCRIPTION OF A RARE.

DISEASE, THIS IS KID HOG DON’T CRY, NEW GENETIC DISORDER DISCOVERS AND THIS WAS THE GRACE BILLZY FOUNDATION, HAS PLAYED A RECRUITMENT ROLE, THIS WAS ONEOFAKIND IN THE NEW YORKER THIS, IS MATT, I HAD THE PLEASURE OF MEETING MATT AT A MEETING BECAUSE IN MY GRADUATE WORK I HAD DISCOVERED THE ACTIVITY THAT I’M TALKING ABOUT THE SO CALLED MGLYONE BEFORE A PERCENTAGE OF THIS AUDIENCE WAS BORN IN 1979. OKAY I DON’T KNOW WHAT PERCENTAGE BUT A PERCENTAGE. AND SO, MEETING PRESIDENT OBAMA RECEIVING AN AWARD IN THIS PATIENT.

RECRUITMENT PROGRAM AND WHAT’S NOW KNOWN AS PRECISION MEDICINE. WHATEVER THAT IS. OKAY. SO JUST QUICKLY. GLYCANS ARE KNOWN TO PLAY A ROLE, YOU CANNOT STUDY CLINICAL MEDICINE WITHOUT UNDERSTANDING GLIKE O BIOLOGY, THAT’S MY BULLY PULPIT. MANY PEOPLE GET THROUGH MEDICAL SCHOOL WITHOUT CARING, BUT IN FACT, EVEN THE SUBSTANCE THAT IS USED TO KEEP BLOOD FROM COAGUALATING, IS A GLEY CAN AND THIS IS PER PURPOSES OF TELLING YOU THIS IS AN IMPORTANT AND EMERGING FIELD. IN FACT, IN THIS JOURNAL IT WAS ACTUALLY CONSIDERED BIOTECH’S NEW SWEET SPOT, OKAY I WILL HAVE.

TO GO A LITTLE BIT QUICKLY BECAUSE WE HAVE THREE SPEAKERS. NOW THESE DON’T COME IN ONE FLAVOR. THE REASON PEOPLE DON’T LIKE TO STUDY GLYCANS I THINK THIS IS THIS KIND OF FIGURE, THEY LOOK AT THIS AND THEY SAY OH MY GOD, IT’S SO COMPLICATED, IT’S NOT TEMPLATE DRIVEN, THERE’S NO INFORMATION CONTENT, WHERE’S THE SQUIGGLES. RIGHT I DON’T UNDERSTAND THAT. WHAT’S BETA ONETHREE, WHAT’S BETA WITHINFOUR, WE’RE TALKING ABOUT CHEMICAL LINKAGES THAT DEFINE A DIFFERENT KIND OF MODE, HOW ABOUT THIS IS AN INFORMATION MOLECULE THAT IS NOT CHEM PLATED IN THIS.

CANONIC WAY WE’VE BEEN DISCUSSING. gtgt INDISCERNIBLE gtgt SORRY gtgt INDISCERNIBLE. gtgt I PUBLISHED TOO MANY REVIEWS AND NOT ENOUGH SCIENCE PAPERS, I THINK, THIS WAS A NICE REVIEW AND I CAN GET IT 23R YOU, IT COVERS THE FIELD VERY L. TODAY WE’RE GOING TO FOCUS ON MGLYCOSYLATION AND BRIEFLY ON THE OTHER THING WE WORK ON WHICH IS HOLY GLYCKNACK, WHICH IS A MOLECULE I REGENERATION, OKAY WITH THAT BRIEF INTRODUCTION, I WANT TO TALK ABOUT NGLYCOSYLATION, YOU MAY HAVE STUDIED THIS AT SOME POINT, THEY TALKED ABOUT SOME CRAZY THING, I.

DON’T KNOW. WHAT THIS IS, IS A FUNDAMENTALLY INTERESTING PROCESS, WHERE A SACCHARISE BUILDS ON A SACCHARIDE AND TRANSFERRED ON BLOCK DURING PROTEIN TRANSLATION TO A GROWING POLYPEPTIDE SAY THANKSGIVING HAS TO HAPPEN SUPERFAST, SHOOTING THROUGH THE TRANSLOCATION CHANNELUTE OF THE RIBOSOME AND ALL AT ONCE, YOU HAVE TO ADD 14 GLYCANS, THIS IS IN LESS THAN 30 MILLI SECONDS. OKAY THAT’S REALLY FAST, AND THE RESULTING PROTEIN UPON GLYCOSYLATION HAS ITS PHYSICAL CHEMICAL PROPERTIES TOTALLY OPEN. NOW I DON’T KNOW WHY THAT’S NOT INTERESTING, BUT WHEN PEOPLE TEACH IT IN MEDICAL SCHOOL, OH.

MY GOD, THEY GLOSS OVER. gtgt THE PROCESSING THEN OCCURS IN THE GOLGI, THERE’S FURTHER PROCESSING TO WHAT WE CALL TERM NOLL GLYCOSYLATION AND HAVING A COMPLEX STRUCTURE WHICH IS NOT AS RELEVANT TODAY BUT IS A VERY INTERESTING SUBJECT. OKAY. HOW DID WE LEARN ALL THIS, WELL IT TURNS OUT, WE LEARN IT FROM BIOCHEMISTRY. WITH THE ENZYMES, I WAS INVOLVED IN SOME OF THAT. INHIBITORS AT ALMOST EVERY STEP, I THINK SURGE ROW WILL TALK ABOUT THESE INHIBITORS LATER, HOW WE USED THISEM TO ANALYZE THE MATERIALS. YEAST AND SOMATIC CELL GENETICS.

AND MOST IMPORTANTLY PERHAPS FROM CONGENITAL DISORDERS OF GLYCOSYLATION THAT WE WILL TALK ABOUT. HUMAN DISEASES DERIVING FROM MUTATIONS OR BOTH AXONIC AND SOMETIMES NOT AXONIC MUTATIONS IN THESE ENZYMES. SO, THESE CBGs ARETHERE’S MANY OF THEM. THE NUMBERS ARE AROUND A HUNDRED, IF ANY OF MY UDP COLLEAGUES ARE HERE, THEY WILL CORRECTS ME. CLOSE TO A HELPED DISORDERS, WE KNOW A LOT ABOUT SOME OF THESE, I JUST SAID THERE WERE A HUNDRED DISORDERS, IS THAT CLOSE TO CORRECT FOR CBG SOMETHING LIKE THAT. YEAH, OKAY. LAUGHTER IT’S A GOOD ROUND NUMBER.

AND SO SOME OF THEM ARE LISTED HERE, SO BASICALLY ANY STEP IN THIS PATHWAY, THAT YOU’RE INTERESTED IN, YOU CAN PROBABLY FIND, YOU KNOW AN ASSOCIATED HUMAN DISEASE. SOME OF THEM ARE MORE COMMON THAN OTHERS. SOME OF THEM ARE VERY COMMON ON THE ABSOLUTE SCALE OF THESE KINDS OF THINGS. SO IF WE LOOK BY COMPARTMENT AND THIS WAS GIVEN BY DONNA AND LYNN, THE BULK OF THESE ARE ASSOCIATED WITH E. R. SOME INTERESTING ONES IN THE GOLGI AND THEN THE E. R. TRANSITION AND OTHERS INVOLVE THE MANOSE PATHWAY BUT THE MOST.

COMMON DISEASE ARE ASSOCIATE WIDE THE ENDOPLAYS MIC RETIC LUMEVENTS. NOW THE REASON FOR THAT IS THE GREAT PROBLEM OF PROTEIN FOLDING, HERE AT THE NIH MANY YEARS AGO SHOWED THE POLYPEPTIDES COULD FOLD BUT IT’S VERY INTERESTING THAT PEOPLE WHO STUDY PROTEIN FOLDING OFTEN, I’VE HEARD ENTIRE TALKS, TALKING ABOUT PROTEIN FOLD NOTHING THE E. R. BUT THEY NEVER MENTION CARBOHYDRATE. I FIND THAT UNBELIEVABLE. OKAY, BECAUSE IN FACT, WHAT’S DRIVING, A LOT OF THE MACHINERY INVOLVED IN QUALITY CONTROL ARE THE GLYCAN. WE’RE GOING TO TALK ABOUT A LOT.

OF THIS TODAY, BUT THE KEY ENZYMES WERE THESE. A UDP TRANSFERASE THAT HAS A UNIQUE PROPERTY. IT RECOGNIZES UNFOLDED PROTEINS, IT RECOGNIZES PARTIALLY AND UNFOLDED PROTEIN AND GLYCOSYLATED THE HIGH NANO STRUCTURE. GOING BACK ONE STEP, THIS CORE STRUCTURE THEN CLEAVES OFF AND IF THE PROTEIN FOLDS PROPERLY, THEN FINE, CAN YOU PROCESS THIS MOLECULE, EXIT THE E. R. GO TO THE GOLGI, BUILD A FINE AND PROPER GLYCOPROTEIN. BUT IT TURNS OUT THAT IN SECRETORY CELLS, THIS DOESN’T ALWAYS GO SO WELL. AND THOSE PROTEINS THAT ARE NOW FOLDED ARE ACTUALLY.

REGLYCOSYLATEDDED, REGLUCOSALATED USING THIS ENZYME. UPON DOING AND THEY KEEP THEM IN THE E. R. SO BASICALLY THIS IS A FACTORY DIRECTOR SAYING, GO BACK TO THE FACTORY AND GET IT RIGHT, YOU’RE NOT LEAVING HERE TILL YOU GET THIS RIGHT, OKAY NOW WHEN ALL THE PROTEIN, THEY GIVE UP, THEY SAY, QUITE FRANKLY THIS PRACTICES TEEN IS HOPELESS. SO WHAT BUY DONE IS ANOTHER SET OF LIGANDS, IS THE SO CALLED EAGINS, WILL RECOGNIZE THIS THROUGH A TRANSLOCATION CHANNEL, SEND IT OUT TO THE CYTOPLASM WHERE THIS PACK MAN MOLECULE,.

THE RIBOSOME EAT ITS SO THIS IS A LOT LIKE WHAT HAPPENS IN BRITAIN WHEN THE SO CALLED REPROBATES WERE SENT OUT TO AUSTRALIA I HOPE THERE ARE NO AUSTRALIANS HERE AND THEY SAID YOU GUYS ARE UNSALVAGEABLE. OKAY PLEASE LEAVE. AND THEN THEY WANT TO SEE THEM AGAIN. THAT’S WHAT HAPPENED WITH THE PROTEINS. WHAT HAPPEN MISS IS THAT GO OUT AND GET DEGRADED AND ARE NEVER SEEN AGAIN. THE PROBLEM WITH THE MOLECULE WITH THE CLASS OF THINGS WE’RE TALKING ABOUT TODAY IS THIS DOESN’T HAPPEN AND FOR THOSE WHO.

CARE WHAT I DID IN THIS, THE ACTIVITY, ASSOCIATED WITH NG LYONE, SOMEBODY HAD TO DISCOVER IT. HAPPENED TO BE A YOUNG KID IN THE BUILDING AND WE DID IT. BUT IT WAS FUN. SO THERE’S THIS FOLDING CYCLE INVOLVING MGLYCAN, IT’S A COMPLICATED CYCLE. SOME OF YOUR FAVORITE PROTEINS ARE ON THAT SLIDE. IT’S NOT SO IMPORTANT TO KNOW THE DETAILS BUT I WANT TOALTHOUGH IT’S FUN TO TALK ABOUT THE DETAILS BUT I WANT YOU TO REALIZE IS THERE’S A DECISION TO BE MADE. THERE’S A CLEAR DECISION TO BE.

MADE. IF THE PROTEIN IS FOLDED PROPERLY, OKAY THEN IT GETS EXPORTED. IF IT IS NOT, IT GOES THROUGH WHAT’S KNOWN AS THE CALNECKSIN CYCLE, IF THE CELL HAS GIVEN UP ON THAT PROTEIN IT’S A LIGAND AND IT GOES TO THE CYTOPLASM FOR PROTEOME DEGRADATION. THIS PROCESS IS INVOLVED. gtgt INDISCERNIBLE. gtgt THE QUESTION WAS WHAT QUALITY OF PROTEIN FAILED. IN THE PLASMA CELL THAT IS ANTIBODY PRODUCING CELLS THAT ARE VERY, VERY PRODUCTIVE. IT’S BEEN ESTIMATE THAD 10 OF THOSE PROTEINS HIT THERE AT THE STEADY STATE. IN A NONPROFESSIONAL SECRETORY.

CELLS,OT ORDER OF FIVE. THROUGH THIS PATHWAY. THERE ARE OTHER PATHWAYS OF DEGRADATION. THAT’S A VERY GOOD QUESTION. SO WHAT I DESCRIBED HERE IS A COTRANSLATIONAL MECHANISM THAT PRESIDENTS THE CARBOHYDRATE. WE CALL THIS THE BIOSYNTHETIC MAN STRUCTURE. IT HAS CYCLES ATTACHED. IF IS SCREWS UP, IT GETS EXPORTED TOET PROTEOSOME. IF IT’S MALFOLDED IT CAN IN FACT OR A GO THROUGH THIS CYCLE PROPER FOLDING AND THEN IN FACT, SOME SUBSTANTIAL PERCENT OF THESE MOLECULES GET TRANSPORTED TO THE GOLGI. SO LET’S NOW TALK ABOUT NG LYONE DEFICIENCY, WHY IS IT SO.

BAD AND WHAT DOES IT DO gtgt SO WHAT DOES AND WE WILL TALK ABOUT THIS SUBJECT WITH SURGE ROW. SO I’M SORRY, SO NOW WE’RE TURNING TO NG LYONE SO THE REASON MATT AND I HAD SO MUCH TROUBLE FINDING OTHER PATIENTS IS THIS WAS VERY UNDERDIAGNOSED. THIS MAY NOT BE QUITE AS RARE AS PEOPLE THOUGHT, BUT THIS IS REALLY THE FIRST DISORDER ASSOCIATED WITH GLYCAN REMOVAL. NOW YOU MIGHT SAY, THAT’S WRONG. LIAISON STUDIES OF MULTIPLE ENDOCRINIA STORAGE DISEASES EMERGE AS A FUNCTION OF LACK OF REMOVAL, RIGHT.

WE STUDIED THE STORAGE DECEASES BUT THIS IS THE FIRST ASSOCIATED WITH THE BIOSYNTHETIC DEFECT IN THE REMOVAL OF NG LYCAN. THROUGH WHOLE GENOME SEQUENCING THIS IS AN INTERESTING STORY THAT’S LYNN WILL TELL BETTER THAN ME, IT’S A VERY INTERESTING STORY IN WHICH A WHOLE GENOME SEQUENCING ADENTIFIED THIS MUTATION AS AN INHERITED DISORDER AND THEY FOUNDTHEY THOUGHT IT WAS ASSOCIATED WITH THE KNOWN BIOCHEMISTRY OF THESE THINGS. I CAN TELL YOU WITH THE SMALL NUMBER OF FAMILIES, THIS WAS ACTUALLY HEROIC WORK, LARGE PART, THE PATIENTS BY THEMSELVES RECRUITING FAMILIES TO.

PARTICIPATE. IT WAS A REMARKABLE, SOMETHING AKIN TO 23 PATIENT STRONG ADVOCACY RECRUITING THESE PATIENTS. OBVIOUSLY ONCE THE SEQUENCE IS KNOWN THEY SEQUENCE. THE PNG ACE, CLEAVED A GENE TO REMOVE THIS AMINO GROUP, BUT THIS IS VERY UNUSUAL AMONG THESE CLASSES BAH YOU ACTUALLY RETAIN THIS AMINO GROUP BECAUSE THIS BECOMES ASPARTATE. SO PUT BIOSYNTHETIC PERSPECTIVE. IT’S INTERESTING, A LOT OF OKAY. SO THIS IS WHAT PEOPLE THINK HAS GONE WRONG IN THAT MISFOLDED PROTEINS ARE RETROTRANSLOCATED NORMALLY. THIS IS REMOVED ALL OF THE CARBOHYDRATE, ALL OF IT, OKAY ALL OF IT IS SUBJECT TO LIGHTS,.

SEGGREEN CELLSIDATION AND THE PROTEIN SO IT’S AN EFFICIENT MECHANISM AND IT WORKS NORMALLY VERY, VERY WELL. THE PROTEOSOME IS VERY EFFICIENT PROTEOLYTIC ENGINE. IT FUELS CATALYTIC DEGRADATION OF PROTEINS VERY WELL. IT DOES NOT DO SO FOR GLYCANS, SO THIS IS VERY BAD. YOU CAN’T REMOVE THE GLYCAN, YOU CAN’T GET INTO THE PROTEOSOME. SO VUA PROBLEM, OKAY SO YOU HAVE A PROBLEM, OKAY NOW WHAT’S INTERESTING IS FROM THE PATIENT AND SCIENTIFIC PERSPECTIVE IS THIS DESCRIPTION EF MGLYONE ON THE SITE AND HE’S LEARNED. VERY, VERY, BRIGHT MAN AND HE.

PUT ON HIS WEB SITE IS WE ARE FORTUNATE THAT NGLYCAN ACE WAS STUDIED BY THE GLIKE O BIOLOGY COMMUNITY LONG BEFORE THE DISCOVERY OF THE DISORDER AND HE DESCRIBES THE MOLECULE AND THEN, HE DESCRIBES THE CLINICAL FEATURES IN A VERY SYMPATHETIC WAY, IT LEAVES THE BODY WITH AN IMPAIRED CAPACITY IN THIS GLIKE O PROTREEN WHICH APPEAR TO ACCUMULATE IN CELLS OF THE PATIENT. SO HE STATES RIGHT UP FRONT THAT THE CURRENT HYPOTHESIS IS THAT THIS ACCUMULATION OF MISFOLDED PROTEIN IS WHAT CAUSES THE HARM IN THESE PATIENTS AND I TELL YOU.

AS A BASIC SCIENTIST, I LOVE FOCUSED ON READ THIS KIND OF THING BECAUSE HERE IS A PATIENT ACKNOWLEDGING THAT A COMMUNITY OF SCIENTISTS WERE WORKING LONG BEFORE THIS DISORDER EMERGED AND ONCE THE SEQUENCE APPEARED, A WHOLE BODY OF EVIDENCE WAS THERE FOR THEM TO ACTUALLY TOP INTO. SO WHEN WE TAKE ABOUT TRANSLATIONAL MEDICINE, I THINK WE CAN’T FORGET THAT BASIC TRANSLATIONAL SCIENCE FUELS RESEARCH. SO WHEN YOU’RE CHOOSING TOPICS, CHOOSE SOMETHING YOU’RE REALLY, REALLY INTERESTED IN BECAUSE IN MY CASE IT TOOK ALMOST 40 YEARS, BUT I GOT A HOOK, OKAY, SO WHAT.

CAN BE HAPPENING. SO WE WILL TALK ABOUT THIS VERY BRIEFLY BECAUSE THE MECHANISM’S NOT WELL UNDERSTOOD, BUT HERE’S A SCHEMATIC REPRESENTATION FROM WHAT COULD HAPPENING. SO POTENTIAL THERAPY. SO THE BASIC SCIENTIST, WHOI IDENTIFY THE ACTIVITY IN BELIEVE IT OR NOT IN INDISCERNIBLE WE WORKED ON CHICKENS. THEN THE ACTIVITY WAS TAKEN OVER BY ZUZKI, AND HE THEN PURIFIED THE ENZYME AND WORKING ON IT HIS ENTIRE CAREER AFTER THAT. HIS ENTIRE CAREER HAS BEEN FOCUSED ON THIS PROTEIN. SO WHAT HE’S ABLE TO SHOW HERE IS THAT IN A NORMAL CELL, NG.

LYCAN ACE NORMALLY CLEAVES AT THIS SITE TO REMOVE THE WHOLE OLIGIO SACCHARIDE AND THIS OF COURSE LEADS TO THE PROTEOSOMAL DEGRADATION, HE’S BEEN ABLE TO SHOW THAT IN THE GLYCAN ACE, THERE’S ANOTHER ENZYME, LESS EFFICIENT ENZYME, IT’S NOT THE SAME PROPERTY, IT’S KNOWN AS THE GLUE MARIOUS COSINATE, IT CLEAVES BETWEEN THOSE TWO, IN THIS RESIDUE CLEAVING THESE TWO RESIDUES BETWEEN THEM AND IT RESULTS IN THIS. NOW YOU DON’T HAVE TO BE A GLIKE O BIOLOGIST TO REALIZE THAT THAT’S NOT GOING TO BE A VERY GOT SUBSTRATE FOR THE PROTEASE,.

RIGHT RIGHT BECAUSE IT CAN’T ENTER THE ATP ACE CHANNEL IN THE PROTEOSOME DEGRADATION AND THERE’S NO ONE THAT WILL CLEAVE THAT IN THE PROTEOSOME. NOT ONLY IS THIS BAD AS BEING DEGRADED BUT IT WILL CLOG UP EVERYTHING, NO WAY TO DISPOSE OF THIS. THE OTHER THING THAT THEY NEEDED WAS THAT THIS THING LOOKED A LOT LIKE A PROTEIN THAT WE STUDIED, A LOT LIKE THE SO CALLED MODIFICATION. AND WE THEN STUDIED THIS BY ALMOST 30 YEARS, IT IS A KNOWN SUSCEPTIBILITY, IT’S A KNOWN MODIFICATION INVOLVED IN.

NEUROTOXIC DEGENERATION LEADING TO OPERATING GLOBALLYATHYS AND DEFECTS IN PROTEIN COMPLEXIO STASIS. SO, THEY ALSO SUGGEST THAD THIS MOLECULE MAY PROVIDE OR MAY PRODUCE IMPAIRED SEQUENCE. AND WE’RE WORKING WITH HIM TO SEE IF THAT MIGHT BE THE CASE. FINALLY BECAUSE OF THE CENTRAL ROLE OF THE E. R. THIS IS LIKELY TO HAVE MANY, MANY, MANY, MANY SECONDARY EFFECTS BECAUSE YOUTHE E. R. WHILE IT’S WORKING PROPERLY IS ALSO PUSHING A LOT OF TOXIC SUBSTRATE INTO THE CYTOPLASM. THIS IS A VERY INTERESTING AREA, MY COLLEAGUE BILL AND AND WIN.

STUDIED THIS YEARS AGO AND MAYBE WIN AND COMMENT BUT THE CYTOPLASM IS ESSENTIALLY ENGAGED IN THE PROCESS OF REACTIVE OXYGEN SPEECHES AND SCAVENGING AND THE MITOCHONDRIA IS CRITICAL TO PROCESS AND IN THE NGLYONE PATIENTS THERE’S STRONG EVIDENCE THAT MITOCHONDRIA MAY PLAY A ROLE IN THEOXIDATIVE DAMAGE DUE TO THE FACT THAT THESE AG GERONTOLOGYSTSIGATES ARE PLACED IN THE CYTOPLASM WITH NO MEANS OF DEGRADING THEM. OKAY SO,ILE GOING TO NOW JUST QUICKLY TALK ABOUT THE CLINICAL FEATURES OF NG LYONE AND I WILL DESCRIBE THEM IN BROAD TERMS. IN ADDITION TO THIS.

DEVELOPMENTAL DELAY, THESE PATIENTS HAVE A LACK OF TEARS AND THIS WAS HIGHLIGHTED IN THE ARTICLE ITSELF. THEY MAKE VERY FEW TEARS, YES gtgt INDISCERNIBLE. gtgt OKAY, WOULD YOU LIKE TO JOIN US. OKAY, SO RIGHT AFTER THIS SLIDE, I WILL BE JOINED BY LYNN’S COLLEAGUE WHO KNOWS SO MUCH MORE ABOUT THIS. I WAS HOPING I DIDN’T HAVE TO GO THROUGH THE PATIENT MATERIAL AND I’M SUPER HAPPY ABOUT THAT. SO, MAYBE WE’LL SEE AN EXAMPLE OF THEI HAVEN’T SEEN LYNN’S SLIDE. THEY HAVE A SMALLER HEAD AND WE WILL LEARN ABOUT THAT.

THEY HAVE IMPAIRED LIVER FUNCTION AND PERHAP SMS OF THE PATIENTS HAVE AGGREGATES IN THEIR LIVER, DEMINNISHED REFLEXES AND SEIZURES. SO I WILL NOW TURN IT OVER, VERY GOOD SURPRISE, YES YES gtgt INDISCERNIBLE. gtgt SO NORMALLY AUTOPHAGY ISN’T NORMAL BUT WE KNOW IT WILL CLEAVE DOWN TO THE SINGLE MONOSACCHARIDE. BUT IF YOU INHIBIT THAT ENDOGLUE MARIOUS COSDACE, YOU CAN CORRECT A LOT OF THE DEFECT. IT’S A CONTROVERSIAL FINDING I LEARNED YESTERDAY. AND SO NOT EVERYONE BELIEVES THAT BUT AUTOPHAGE SEA VERY LIKELY MECHANISTIC CONTRIBUTE. gtgt INDISCERNIBLE. gtgt CHANGES IN THE LIVERBUT.

WHAT OTHER CHANGES HERE IN THE EYES FOR THE FORMATION gtgt WE MAY TALK ABOUT THAT TOO. WE HAD A GROUP MEETING ABOUT THAT THREE DAYS AGO AND YOUR GUESS IS AS GOOD AS OURS. I HAVE IDEAS. BUT THAT’S A GOOD QUESTION. SO LET’S HEAR THIS AND THEN MAYBE WE CAN ANSWER THE QUESTIONS TOGETHER ABOUT NG LYONE. gtgt YEAH THERE’S ONLY A FEW SLIDES AND I APOLOGIZE FOR LYNN, HE HAD A FAMILY EMERGENCY. I’M CHRISTINA LAMB, I’M A CLINICAL FELLOW AND I SEE PATIENTS IN THE CLINICAL CENTER,.

BUILDING 10. THANK YOU. OKAY. WHAT’S NEXT OKAY. GREAT. WITH CONGENITAL DISORDERS OF GLYCOSYLATION AND SO I WILL TRY TO PRESENT LYNN’S SLIDES HERE SO THIS FIRST SLIDE IS JUST THE ARTICLE WHERE THE VERY FIRST PATIENT WITH NG LYONE DEFICIENCY WAS PUBLISHED IT WAS PUBLISHED IN 2012 AND ACTUALLY A PAPER THAT WAS MORE FOCUSED ON EXOMES, THE EFFICACY OF EXOME SEQUENCING AND LIKELY GENETIC CONDITION AND HE WAS JUST PATIENT NUMBER TWO AT THAT POINT A THREE YEAROLD EUROPEAN AMERICAN MALE WITH DEVELOPMENTAL DELAY AND MOLTY FOLK AT EPILEPSY.

IN VOLUNTARY MOVEMENTS, ABNORMAL LIVER FUNCTION, ABSENT PEERS. SO AS WAS PREVIOUSLY ALLUDED TO, THE FAMILY GROUP WAS AMAZING AND THAT FIRST INITIAL CASE PATIENT ZERO, THE FATHER WAS ACTUALLY A COMPUTER SCIENTIST AND A COMPUTER SCIENCE PROFESSOR AND HE WROTE A BLOG AND HE ACTUALLY ASSEMBLED THE FIRSTPUT TOGETHER THE FIRST EIGHT PATIENTS THROUGH THIS BLOG, THROUGH OTHER CLINICIANS CONTACTING HIM AND THROUGH THIS BLOG WAS ABLE TO GATHER SEVEN ADDITIONAL CASES AND BASED ON THOSE CASES DR. N, DID A CHART REVIEW TO DISCOVER WHAT THE COMMON SYMPTOMS IN THESE.

PATIENTS WERE THAT WAS IN 2014. SO THE GLYCOSYLATION WAS JUST BROUGHT UP, IT WAS DECIDED WE WOULD BE THE ONES THAT WERE STOBBED ON A PROCESSIVE BASIS WHAT THE ACTUAL CLEANICAL PHENOTYPE AND NATURAL HISTORY WAS, BY BRINGING THEM TO THE NIH CLINICAL CENTER AND OUT OF THE CURRENTLY 28 KNOWN LIVING PATIENTS WE HAVE SEEN 10 PATIENTS WITH NGLUE MARIOUS ONE DEFICIENCY AND THE TIME OF MAKING THIS SLIDE, WE HAVE SEEN NINE, AND THAT’S SLIGHTLY OUT OF DATE. AND THETHIS SIDE, THE SIDE WITH THE SMALLER FONT ARE THE.

FINDINGS THAT HAD BEEN SUMMARIZED BY THE DOCTOR AND HIS 2014 GENETICS IN MEDICINE PAPER AND ON THE RIGHT ARE THE FINDINGS WE FOUND AT NIH. AND WE BASED OUR STUDIES WE DID ON BASICALLY WHAT THE DOCTOR REPORTED AND ADDITIONALLY BASED ON OTHER FINDINGS IN OTHER CONGENITAL ORDERS OF GLYCOSYLATION THEY WANTED TO MAKE SURE AND PREVIOUSLY, FROM THE PATIENTS WE SAW AS A CLINICAL CENTER, WE KNOW THE MOST COMMON FINDING WAS THE HYPOLACK RIMA AND WE DOCUMENTED THAT BASED ON THE SHURMER TEST. WHICH IS A TEST WHERE THEY PUT.

FILTER PAPER RIGHT WHERE THE TEARS ARE PRODUCED AND MEASURE HOW MUCH TEARS ARE MADE OVER FIVE MINUTES AND COMPARE THAT TO NORMAL AND GLOBALLYWE NOTICE PERIPHERAL SHARING WAS PRETTY MUCH COMPLETE PLEA NORMAL BUT THERE WAS AN ABNORMAL HEARING THROUGH THE BRAIN STEM TRANSMISSION, SO PROCESSING ABNORMALITY, ALSO COMMON IN EVERY PATIENT AND THEN THE HYPER KINETIC MOVEMENT DISORDER WAS SEEN IN EVERY SINGLE PATIENT EVEN THOUGH THE CLINICAL SPECTRUM IS PRETTY BROAD IN TERMS OF SEVERITY. ABNORMAL SWEAT WAS ANALYZED BECAUSE THE FIRST, THE PRO BAN WHEN HE CAME IN, COMPLAINED OF.

NOT AS MUCH AND OVERHEIGHTING AND EXERTION AND WE KNOW THAT WAS COMMON BY SUBJECTS AND THEN SEIZURES WAS SEEN IN HALF OF THE PEOPLE THAT WE EVALUATED OTHERS OTHER FINDINGS DEVELOPMENTAL DELAY, RANGE FROM PROFOUND BASICALLY, CAN’T DO ANYTHING FROM LAYING FLAT ON TONOT ABLE TO SIT UP, TO THE I. Q. OF 70 IN THE HIGHEST FUNCTIONING PATIENTS AND WE HAD DELAYED BONE AGE AND DEMILEINATING AXONAL SENSORY MOTOR POLYNEUROPATHY IN TERMS OF LIVER FINDING WE NOTICE THAD THEY HAD A HISTORY OF VERY HIGH TRANSAMNAISS, SO LIVER INJURY.

WHEN THEY WERE AT ABOUT A YEAR OLD, BUT BY THE TIME WE SAW THEM, OUR YOUNGEST PATIENT WAS ABOUT THREE THE LIVER ENZYMES HAD NORMALIZED OR ALMOST NORMALIZED AND THE HIGHEST ENZYME ABNORMALITY WAS ONLY TWOTHREE TIMES UPPER LIMITED NORMAL SO NOTHING TO BE WORRY BODY AT THE MOMENT. AND THE LIVER TEXTURE WAS SLIGHTLY NORMAL IN ULTRASOUND. THERE WAS CEREBRAL ATROPHY SEEN IN THE MRI, SO JUST TO SUMMARIZE BASICALLY THE NEW FINDINGS WE NOTED FROM NIH, THAT HADN’T EVER BEEN REPORTED I FORGOT TO MENTION, NEUROTRANSMITTERS AND THE C. S. S. PROTEIN WERE.

ABNORMAL AND THEN THE HYPER IMMUNE RESPONSE TO THE RUBELLA AND RUBEOLA VACCINE AND THEN LOWER THAN PREDICTED RESTING ENERGY EXPENDITURE AND INTERESTINGLY, THEY HAD KIND OF AN ANTITHEY WERE VERY HAPPY AND ALWAYS AFFECTIONATE UNLIKE SOME OF THE OTHER DISORDERS. AND THEN THIS TERMS OF NEGATIVES, THE HEARTS WERE NORMAL, AND ONE OF THE MODELS HAD HIGH NORMAL GASTRIC Ph IN ALL OF OUR SUBJECTS AND NO EVIDENT OF PRIMARY MUSCLE DISEASE WHICH IS SEEN A LOT IN MITOCHONDRIAL DISEASE AND NO EVIDENCE OF ASPIRATION ON SWALLOW STUDY AS WELL.

THIS IS PATIENT ZERO HERE AT HIS FIRST EVALUATION SEEN UNDER A DIFFERENT PROTOCOL, I THINK AGE THREE AND THEN FOLLOWING THAT AGE AT AGE SIX AND YOU CAN SEE THAT HE’S PRETTY HYPOTONIC SO HE HAS LOW MUSCLE TONE WHICH IS DETICKETTED BY THE OPEN MOUTH AND FLAT FACE. BUTHE’S IN A WHOLE CHAIR, HE CAN’T WALK AND HIS NIPPLES, IT’S A SHOT OF HIS NIPPLES AND OTHER GLYCOSYLATION DEFECTS A LOT OF TIMES THEY’RE INVERTED BUT IN THIS CASE IT’S NOT, SO IT’S NOT A COMPLETE OVERLAP BUT THEY’RE.

SLIGHTLY WIDE SPACE. BUT IT’S MORE FINDINGS IN TERMS OF SHOWING HIS HYPOTONIA AND GENERALLY THAT HE HE HAS A BIT OF SCOLIOSIS AND IS NOT ABLE TO STAND. gtgt I THINK WE HAVE TIME FOR A FEW QUICK QUESTIONS NEAR THE NG LYONE STORY AND THEN WE CAN COME BACK AT THE END OF SERGIOS TALK. ARE THERE AND QUESTIONS WE CAN TALK ABOUT FROM THIS gtgt INDISCERNIBLE. gtgt REPEAT PLEASE gtgt INDISCERNIBLE gtgt YES, MANY OF THESE ARE. gtgt IN THE INDISCERNIBLE OR THE PROTOON PART gtgt THE ENZYME IS ESSENTIALLY,.

BASICALLY EITHER HYPOMORPHIC OR ABSENT IN THESE. SO IT’S THE ACTUAL ENZYME THAT’S DEFICIENT. YEAH. gtgt SORRY FOR THE QUESTION ANY LINK BETWEEN HAPPINESS AND THE LACK OF TEARS gtgt I DON’T KNOW ABOUTI DON’T KNOW ABOUT BEING ABLING TO ANSWER THAT, THE LACK OF TEARS WE DON’T KNOW WHY. THERE’S SEVERAL HYPOTHESIS, SO, CLINICALLY SPEAKS WE SAW THESE PATIENTS WE SAW A LOT OF PERIPHERAL NEUROPERATING GLOBALLY RAUGHTY, AND AUDITORY NEUROPATHY AND THERE’S A QUESTION ABOUT DYSAUTONOMIA AND WE’RE STILL INVESTIGATING IF THAT IS THE MECHANISM, BUT POSSIBLY BECAUSE LIKE YOU TALKED.

ABOUT THAT EARLIER AND A LOT OF THOSE AND SUCH COULD BE MAYBE A SECRETARY ISSUE AND THAT’SA REALLY STILL BEING WORKED UP IN TERMS OF THE HAPPINESS, THAT’S ACTUALLY KIND OFTHERE’S A COUPLE THINGS INVOLVED WITH THAT. WHEN WE DID NEUROPSYCHE TESTING SOCIALIZATIONOT TESTING WAS GLOBALLY, EVERY SINGLE FOR EVERY SINGLE ONE OF THE PATES WE TESTED WAS THEIR HIGHEST FUNCTION AND MOTOR BEING THEIR LOWEST. AND KHI IS INTERESTING THEY’RE SORT OF ANTIAUTISTIC, THEY REALLY ENGAGE WITH YOU BUT I DON’T KNOW WHY. SORRY. gtgt I’D LIKE TO ASKI’M SORT OF.

CURIOUS, THERE WAS A LIVER TRANSPLANT PATIENT PERFORMED IN ONE OF OF THESE CHILDREN, WHAT WAS THAT ALL ABOUT gtgt SO ONE OF THESE PATIENTS HAD A LIVER TRANSPLANTATION AT 18 MONTHS OF LIFE AND THE REASON AT THAT POINT WAS THEY THOUGHT HE MAY HAVE HAD HEPATITIS E ATA CELLULAR CARCINOMA SO HE HAD ELEVATED TRANSAMILLIO NAISES AND HE WAS BEING TREATED FOR SEIZURES SO THEY CHECKED HIS LIVER ENZYMES, THEY WERE IGF SIEVE CANTILY HIGH, SO HE HAD A LIVER BI OPPOSITE THAT’S SHOWED FIBROSIS AND THEN THEY DID AN.

MRI AND THE MRI FINDING SHOWED THERE WAS A LESION FOR THE CARCINOMA AND SO, AND HE ALSO HAD A HIGH A. F. P. BUT HIGH A. F. P.s HAD BEEN SEEN IN OTHER PATIENTS WITHOUT LESIONS IN THEIR LIVER. SO THEY DID CHEMO THERAPY AND THEY TREATED THAT, AND THEN AFTER THAT, BECAUSE OF TLANTED HIM AFTER THE LIVER WAS LOOKED ON IN PATHOLOGY, THE LESION HAD BEEN COMPLETELY NECROTIC AND THEY COULDN’T FIND ANY CANCER CELLS IN THE LIVER. gtgt THE PATIENTS HOW DO THEY COMMUNICATE, IT SOUNDS LIKE THEY.

DON’T HAVE THAT MUCH TO EAT. gtgt SPEECH. gtgt THAT’S A GREAT QUESTION. THE COMMUNICATION VARIESko2 WIDELY BUT THE MAJORITY OF THEM USE AN iPAD OR COMMUNICATION BOARD AND THEY CAN ANSWER SIMPLE QUESTIONS LIKE YES AND NO. THEY SHOW PREFERENCE AND THEY USE KIND OF BODY LANGUAGE TO SHOW FOR EXAMPLE FTHEY WANT TO EAT SOMETHING, THEY WILL GO TOWARDS WHAT THEY WANT TO EAT AND SHOW THAT THEY WANT THE JELLO AND NOT THE YOGURT FOR EXAMPLE, IT’S VERY CLEAR. OUR PATIENT WE HAVE INHOUSE THIS WEEK CAN SPEAK UP TO FIVE.

WORD SENTENCES. AND THEN THERE’S A FEW THAT ACTUALLY ARE PRETTY WITH AN I. Q. OF 70 CAN TALK. gtgt YOU DID MENTION, I ASSUME THAT REPLACING THE LIVER IN THAT CASE DID NOT REPLACE THE MISSING ENZYME gtgt AGAIN, A GOOD QUESTION. SO IT DID REPLACE THE ENZYME IN THE LIVER, SO THE LIVER THUS FAR HAS LOOKED GREAT. BUT SO, PER THE MOTHER, DEVELOPMENTALLY BEFORE THE LIVER TRANSPLANT HE DID NOTHING, JUST LAID ON THE BED BUT OF COURSE THAT COULD BE COMPOUNDED BECAUSE LIVER FAILURE HAS A LOT OF.

TOXINS INVOLVED AND SO ALL HE DID WAS SLEEP. BUT THEN AFTER THE LIVER TRANSPLANT, THREE DAYS LATER, MOM SAID HE WOKE UP AND SAT UP FOR THE FIRST TIME. HOWEVER WHEN WE SAW HIM SIX MONTHS AT A TRANSPLANT HE STILL HAD MOVEMENT DISORDER AND SIGNIFICANTLY DEVELOPMENTALLY DELAYED ALTHOUGH HE DID PROGRESS FROM THE TIME HE TRANSPLANTED AND HE WASN’T NORMAL, HIS SWEAT WASN’T NORMAL. gtgt SO DO YOU KNOW HOW LONG THIS PATIENT SLEEP gtgt SO OUR OLDEST PATIENT THAT WE’VE SEEN IS 21 YEARS OF AGE AND WE HAVEN’TNONE OF THE.

COHORT WE’VE SEEN, WE’VE ONLY SEEN THESE PATIENTS IN OF THE LAST YEAR HAVE PASSED AWAY, THERE HAVE BEEN LITERATURE REPORT OF CASES THAT PASS AWAY IN THE LAST THREE OR FOUR YEARS BECAUSE OF EPILEPSY COMPLICATIONS, BUT BESIDES THAT, THEY SEEM TO BE DOING WELL, OTHERWISE SO I’M NOT SURE. gtgt IS THIS AN AUTOSOMAL RECESSIVELY INHERITED CHARACTERISTIC. gtgt SO I RUSHED THROUGH IT BUT AS YOU COULD SEE FROM THE TREE, THIS IS INHERITED AS AN AUTOSOMAL RECESS ANT. gtgt SO DO YOU NORMALLY TEST THE PARENTS AND GIVE THEM ADVICE.

ABOUT FUTURE CHILDREN. gtgt OKAY. gtgt SO THANK YOU VERY MUCH, THANK YOU VERY MUCH. THANK YOU JOHN, THANK YOU CHRISTINA, AND I WILL SLIGHTLY SWITCH GEARS HERE A LITTLE BIT BUT WE WILL KEEP TALKING ABOUT CDG. WE DIDN’T BRING THE PATIENTS BUT I WILL REENACT THE ENCOUNTER WE HAD WITH THIS FAMILY AFTER I GET A LIKE MICROPHONE WORKING. THANK YOU VERY MUCH. SO THESE THERAPIST IS BY GLYCOSYLATION HYPOGLAMMA GLOB LUNG CANCER LYNNEMIA AND THESE PATIENTS THEY CAME TO US, IN THE UDB, SO PERHAPS THOSE THAT HAVE.

COME TO THESE TALKS YOU KNOW THIS AND YOU HAVE SEEN HOUSE, YOU KNOW ONE PSYCHOPATH TRYING TO DIAGNOSE A PATIENT. SO IT’S A VERY WEIRD SITUATION WHERE EVERYBODY WANTS TO GET SOMETHING AND TRY TO HELP THOSE PATIENTS. SO THOSE TWO SIBLINGS, SO, HERE WE HAVE POINTER. HERE, MATTHEW AND ILIA, WE HAVE TWO SIBLINGS AND THEY COME THROUGH THE PROBLEM BECAUSE THEY HAVE UNDIAGNOSED ISSUE. SO THEY SHARE MULTIPLE CHARACTERISTICS, SO THEY PHIC FACIAL FEATU RES, GLOBAL DEVELOPMENTAL DELAY, TRUNKAL HYPOTONIA, SMALL CORPUS CALLOS UMKC, AND HYPOAGAMMA GLOBULINEEMIA, AND IT THERE WAS.

SOMETHING THAT WE DIDN’T KNOW WHAT THEY HAD. SO HERE’S A PATIENTS A PICTURE, CAN YOU LEAVE HER LIKE THAT AND YOU PICK HER UP THE NEXT DAY AND SHE WILL BE IN THE SAME POSITION. SO SHE WAS VERY IS SEVERELY DAMAGED AND NEUROLOGICALLY DAMAGED SO SHE WAS NOT A HAPPY CAMPER. SO WE DIDN’T KNOW WHAT THEY HAVE, BUT AS PEDIATRICIANS WHEN WHENEVER WE SEE PATIENTS THEY HAVE ALL THOSE THERAPIES, WE HAVE THESE AS DESCRIBED, WE TEND TO THINK THERE MUST BE SOMETHING ESSENTIAL IN THEIR METABOLISM TO.

THINK WHY ALL THOSE THINGS ARE HAPPENING TOGETHER. SO THERE, THE WORLD CHAMPION AND THEY HAVE JUST ONE THAT EFFECTS THE PATHWAY EVERY TIME. AND AS PEDIATRICIANS, SO PEOPLE HAVE TAKEN CANONICAL APPROACH AND WE THOUGHT THIS HAS TO BE A CDG PROBLEM, CONGENITAL GLYCOSYLATION AND THEY CAN ONLY GO INDISCERNIBLE. AND THOSE ARE HIBRIDE DEFICIENT STRAINS AND THEY DID IT MULTIPLE TIMES AND THEY DO IT TWICE, AND THEY COULDN’T FIND ANYTHING WRONG BECAUSE DCG DOESN’TIS NOT PICKED UP BY THIS METHOD OF BLOOD THERE. SO THEN THEY WENT FORWARD AND.

THEY DID THE U. N. C. LAYER AND THEY FOUND THIS ACCUMULATION INDISCERNIBLE SO IT’S NOT BECAUSE THEY ARE DIURETIC, THEY WOULD BE A LOT, NOT ANY SURE, THEY WANT TO GO FOR THE SACCHARIDES. THE GLUCOSE AND ONE INDISCERNIBLE. AND THAT BY ITSELF WAS DIAGNOSTIC OF A PARTICULAR TIME OF CBG. ACTUALLY INDISCERNIBLE THAT’SA A LOT OF DEBATE ABOUT INDISCERNIBLE, BUT JUST THEY WERE NOT, THEY HAVE INDISCERNIBLE. BUT THEY WERE NOT PARTICULARLY HAVING THE DIABETIC PATIENTS. SO THIS BY ITSELF HAVE TO DIAGNOSE IT. AND THEN IT WAS LATER CONFIRMED.

BY THE DETAIL AND THEN HERE YOU PARTICULAR TYPE OF GLYCANIN THE DISORDER. SO NOW I KNOW JOHN TOOK YOU THROUGH THE PATHWAY. I WILL TAKE A MINUTE AND A HALF TO REFRESH YOUR MEMORY ABOUT THAT AND LATER I CAN DO THE DAMAGE, 1495, OUTSIDE, IF YOU DO NOT SLEEP, TELL BE $13.95 FOR YOU. SO GLYCAN, THEY KIND EVER PUT THE TISSUE TOGETHER, AND THESE ARE HERE IN THE YARD. WE START OUTSIDE OF THE CYTOPLASM, WE START OUT, WE COMPLETE SEVEN, AND THEN WE FLIP IT OVER, SOPHISTICATED TO.

INDISCERNIBLE. AND WE COMPLETE 14 SHORT THAT THE BASIC STRUCTURE OF THE END GLYCAN. SO THE GLYCAN INDISCERNIBLE, AND THEY WILL JUST FOCUS ON THE NGLYCAN AND WE REACH THE ISSUERS, SO THEN AS JOHN SAID IN 13, WE TRANSFER THE ISSUERS AND THEN THE PROCESS STARTS, THE SHOW STARTS SO KEEP IN MIND THAT FAN OF THESE WILL BE YES NO, YES NO, YES, NO, THEY’RE IN GLYCOSYLATEDDED. SO ALMOST HALF OF OUR PARTS THEY WILL BE IN NGLYCOSYLATION. SO WE HAVE BE SURE WHATEVER EXITS THEY ARE, IT IS PROPER.

AND IT WORKS PROPERLY. WHY BECAUSE THEY’RE FOLDING ALL THE PRODUCTS AND THE CONFIRMATION OF THE PRODUCTS, THE SOLUBILITY, HOW IT WORKS, HOW IT’S RECOGNIZED AND HOW IT’S DEGRADING, SO ALL THESE THINGS ARE ASSOCIATE WIDE THE GLYCOSYLATION PROCESS, SO TWO BIG MECHANISMS THAT HELP US TO CONTROL THE PROPER GLYCOSYLATION. ONE AS JOHN MENTIONED, ONE, IS HERE. EITHER UPR, YOU UNFOLD IT, WITH THE PROPER RESPONSE AND THEN THE OTHER ONE HERE, THE PLASMID RETIC LUMASSOCIATE WIDE THE DEGRADATION. SO HERE WE HAVE THE PROCESS AND HERE WE HAVE THE PROTEIN, OR THE.

QUALITY CONTROLS ABOVE IT. WE’RE WE HAVE IT RIGHT. AS JOHN MACHINESSED BEFORE, SO HERE WE WORK ON THE COLLECTION, WE CHECK THAT EVERYTHING IS OKAY, IF EVERYTHING IS DANDY, EVERYTHING IS FINE, WE GO THROUGH THE DOLOGY GOLGI AND EVERYTHING’S FINE BUT MOST OF THE TIME, 5 PERCENT, 10 , UP TO 80 OF THE TIME THINGS DON’T GO OKAY. SO WE TRY ONE TIME, ANOTHER TIME, ANOTHER TIME AND IT’S SOMETHING WE GIVE UP AND WE SAY, OKAY, THAT NUMBER OF TIMES ARE DEGRADED SO WE TRANSLOCATE THROUGH THE PROTEINS IN THE.

CYTOSOL. WE REMOVE IT LIKE GLYONE AND WE REMOVE THE PROTEINS. SO PROTEIN SYNTHESIS, UPR, EINDISCERNIBLE MINUTE AND A HALF, $13.95, YOU WANT TO GET THE BOOK. SO THESE WE SEE HERE, THESE NOT KNOWN DON’T WASTE YOUR TIME BUT WE WAIST OUR TIME BECAUSE WE FEEL IT WAS USEFUL. SO WE FOUND THAT THE PATIENT INDISCERNIBLE WE CAN CHECK THE PROTEIN, CONTROL, HAD THE PROTEIN, THE PATIENTS HAVE THE PROTEIN, TWO MUTATIONS, ONE IT WAS THE INDISCERNIBLE, TWO MUTATIONS EVER THE PATTERN ON SIDE. AS I TOLD YOU THIS WAS NOT.

INDISCERNIBLE. THERE WAS A SINGLE PATIENT THAT WAS REPORTED AND SERIOUS AGO THAT SHE WAS BORN AT 36 WEEKS GUESTATION AND SHE WAS MORPH IIC, HYPERTONIC AND THE PROBLEMS, HYPER VENTILATION AND THEY DIAL IT AT AGE 74. SO THAT WAS VERY SAD SORRY SO WE FIND THIS DISEASE BUT STILL WE HAVE THINGS TO LEARN ABOUT THESE PATIENTSES AND WE TOOK OVER THEM AND THEY’RE INTEREST SAID IN ABOUT THESE. SO IF I TOLD YOU, SO I WAS CALLED TO THE SEE THE PATIENT WORK TOGETHER WITH THE UDP PROBLEM BECAUSE THE PATIENT WITH.

HYPER INDISCERNIBLE. HOW DO YOU KNOW HOW OBNOXIOUS DOCTORS CAN BE SO I WENT TO INTRODUCE MYSELF TO THE MOM, I SAID I’M HERE BECAUSE EVER THE INFECTION, HER MOM SAID NO, THEY DO HAVE INFECTION, I SAID AND SHE SAID YOU KNOW WHAT, I KNOW MY KID, SHE HAS ENOUGH PROBLEMS AND THEY DON’T HAVE INFECTION, SO I WAS NOT THAT COMPETING, BUT WE HAD TO ACCEPT IT. STRUCTURALLY THE IT WAS THE HIGHEST LEVEL I COULD FIND, MOST OF THE TIME THEY WERE UNDETECTABLE. SO THEY WERE TRULY HYPO, BUT ON.

THE OTHER HAND THEY ALMOST CONVINCED ME THEY WERE HAVING NO INFECTION DESPITE BEING SEVERELY HYPEY GAMMA LIBRARY FOUNDATIONIC. SO WE SHOW QUANTITY, THEN WE MEASURE THE FUNCTION FELT SO WE THINK ABOUT A PATIENTS WITH THE POTENTIAL IMMUNE DEFICIENCY, WE HAVE TO HAVE AND WHATEVER THEY HAVE IS WORKING PROPERLY. SO HERE WE MEASURE THE IMMUNOGLOBULIN AND THEY WERE LOW AND WHY WOE DO THAT BECAUSE WHENEVER HAVE YOU PROTEIN, YOU HAVE THE NEUROPATHY, CAN YOU PEE OR POOP, SO IN THIS CASE, THEY WERE NOT PEEING OR POOPING THEIR.

PROTEIN SO THERE WAS A PRODUCTION OF OF THE IMMUNE SYSTEM. SO THEN WE MEASURE THE FUNCTION, NOT JUST THE LEVEL OF THE IMMUNOGLOBULIN, HOW THEY WORK OFF ANTIBODY AND HERE I’M SHOWING THE ABNORMAL RESULTS AND TO BE HONEST, WE FOUND THEY WERE ACINATED WITH ALL THE VACCINE AND THEY DID RESPOND AND THE PNEUMOCOCCAL VACCINE BUT THEY DIDN’T RESPOND TO RUBELLA AND VARY CELLA, BUT THEY WERE RESPONSIVE. WHY WOULD YOU THINK YOU HAVE ANTIBODIES WORKING THERE. SO THIS WAS EXPECTED AND THIS WAS KIND OF NOT EXPECTED BUT I.

COULD SURVIVE WITH THAT. SO THEN WE STUDY ALL THE OTHER ASPECTS OF THE SYSTEM, AND THEY HAVE WIDER CELLS OF EVERY COLOR AND SHAPE, SO THE COMPLEMENT WAS THEN WORKING FINE. THE PROLIFERATION ASSAY, SO THESE ARE THE LYMPHOCYTES THAT THEY DO WHEN THEY HAVE THE RESPONSES AND USE THEM AND THAT WAS WORKING FINE, IT WAS ALL FINE, ALL THE FLAVORS OF LYMPHICIDES, ALL OF IT, ALL OF THEM WERE THERE AND ACTUALLY THE BCELLS BECAUSE BCELLS IN THE FACTORY OF IMMUNOGLOBULINS THEY WERE THERE, TOO, SO THERE WAS.

NOTHING GROSSLY ABNORMAL EXCEPT THIS THING HERE. THEY WERE VERY LOW AND THEY COULD UNDERSTAND WHY, JUST BY BEING SO HYPOGAMMA GLOP ARE GLOBULIN. SO WE KEPT ON STUDYING. SO HERE’S THE GRAPH WE PUT THEM ON. SO DEPENDING ON THE TYPE OF DEFECT THEY VTHE TYPE OF MICROORGANISMS THEY’RE GOING TO BE EFFECTED WITH. AND PATIENTS FOR EXAMPLE, THEY HAVE A DEFECT, THEY HAVE PNEUMONIA, BECAUSE OF THIS, THEY HAVE INFECTION AND THEY HAVE INDISCERNIBLE. AND THIS IS BECAUSE,XV HAVE A DEFECT, NOW PATIENTS THEY HAVE A BCELL DEFECT, THEY PRODUCE NO.

IRMOWN O GLOBULIN, SO THEY DON’T WORK AND USUALLY THEY HAVE BACTERIAL INFECTION BUT TO MY SURPRISE, THEY HAVE NO INFECTION WHAT ISSOEVER. AND IT WAS A SURPRISE. SO AGAIN WE TOOK A CANONICAL APPROACH. WE TRIED TO LEARN I DIDN’T THEY WERE SO AHONDURAS GENTLEMENNA GLOB BUT NO INFECTIONS. SO WE KEEP IN MIND THAT BCELLS ARE OKAY, BUT THE BIG IMMUNOGLOBULINS DID NOT HAVE INDISCERNIBLE. SO WE WENT TO THE BONE MARROW OF ONE OF THE PATIENTS AND SAID, OKAY, PERHAPS WHAT WE’RE GOING TO FIND IS NODE CELLS,.

THEY’RETHEY HAVE BEEN IN THE SITE BUT THEY CAN’T PUT IT OUT. BUT THEY HAVE IT THERE BUT THEY CANNOT BELIEVE THEM. THIS IS WHAT WE’RE GOING TO FIND. BUT WE’RE WRONG, WE FOUND NORMAL NUMBERS OF PLASMA AND THEY WERE NOT CONS PARTICIPATE IN A TRIALED WHATSOEVER. SO THERE WAS ANOTHER PLASMA CELL. SO THEN WE SAID, OKAY, LET’S FOLLOW TO THE HANOVER AA PROACH. SO THEY HAD A GLOSS COSALATION DISORDER, THAT PRODUCING THEM AND DEGRADED THEM SO WE CHECK THE FUNCTIONALITY OF THE UPR AND RIGHT HERE WE HAVE THE UPR IS.

WORKING FINE. SO WE USE DIFFERENT ONES TO DO THAT AND THIS IS STRESSED HERE. SO CHECK THAT THE UPR WAS WORKING FINE AND THESE PATIENTS HAVE NO STRESS IN THE E. R. O THERE WAS NOTHING WRONG. THE E. P. R. WAS NOT STRESS. WE SAID OKAY, THERE THAT’SIN. IT’S NOT LIKELY THAT THERE’S GOING TO BE STRESSOT IMMUNOGLOBULIN. BUT WAIT, IT MIGHT BE THAT YOU ARE. IT’S BECAUSE THEY CANNOT PROPERLY GIVINGYOU COSALATE OR GLYCOSYLATION HAVE IT, BUT TRANSLOCATING EVERYTHING THROUGH THE CYTOSOL AND THEY MIGHT BE THERE. ACTUALLY I WAS WRONG AGAIN.

THE INDISCERNIBLE HOST WAS NORMAL SO THERE WAS NOTHING THERE. SO I SAID OKAY, THERE’S SOMETHING THAT DIDN’T MAKE SENSE. SO INSIDE THEIR BODY, THEY’RE REALLY HYM O INDISCERNIBLE. OUTSIDE THE BODY EVERYTHING LOOKS TO BE WORKING FINE. SO THEN, WE TART TO SAY, OKAY, WHAT HAPPEN FIST WE TAKE THIS FROM THEIR BODY, AND MAKE THEM GOOD OUTSIDE THEIR BODY. AND THAT’S HERE, WE FOUND THAT THEY PRODUCE A LOT OF THE IMMUNOGLOBULIN, SO THERE WAS A PRODUCTION PROBLEM. WELL WE TOOK THE BCELLS AND PUT THEM TO CULT NUR THESE SO THEY.

PRODUCE THE IMMUNE. AND THE NORMAL CONTROL SO THERE WAS NOT A PROBLEM OF PRODUCTION. PRODUCTION’S WAS JUST FINE. SO THEN WE SAID OKAY, WE THOUGHT THE GLYCOSYLATION IS SO IMPORTANT THAT WE RELATED TO THE CONFIRMATION TO THE FOLDING TO THE HALF LIFE SO THERE’S SOMETHING THAT THEY HAVE THOSE AND THERE MAY BELESS SELECTIVE DISADVANTAGE AND THEY MUST BE MORE EASILY DEGRADED SO WE STRESS THE PROTEINS OF THESE JUST TO SEE IF THERE WAS SOMETHING THEY’RE GOING TO PROMOTE THE DEGRADATION AND NOTHING HAPPENED. THE GLOBULINS WERE FINE IN TERMS.

OF DIFFERENT STRESS OF DIFFERENT TEMPERATURES SO WE DIDN’T FIND ANYTHING THERE, EITHER. SO THEN WE SAID, OKAY, THERE MUST BE SOMETHING WRONG. IN THEIR BODY THEY’RE PRODUCING NORMAL IMMUNOGLOBULINS AND NO WE CONFIRMED THAT THE GLYCANS WERE ASTAFFED BY I.D. G., AND THESE ARE NORMAL GLYCANS AND THESE WERE THE GLYCANS THAT THESE WERE PRODUCING BUT THEY ARE VERY HIGH, SO WE’RE WORKING WITH THE SAME CELL BEFORE AND OUTSIDE THE BODY, WE’RE WORKING EXACTLY THE SAME. SO THEN WE SAID, OKAY, WE CANNOT WITH THELET’S GO TO ANOTHER BIOLOGICAL ONE, AND WHAT’S GOING.

ON WITH THE SIZE, SO WHAT WE DOES WOULD BE TO INDISCERNIBLE, COMBINING DEFICIENT MICE, AND THE MULTIIMMUNE RESPONSE IS SOMETHING AND WE INJECTED THEM, WITH NORMAL PLASMA, AND PLASMA FROM THE PATIENTS AND I WE WANTED TO MEASURE IS THERE HALF LIFE, SOMETHING RELATED TO THE GLYCOSYLATION PROCESS, WAS DIFFERENT AND EEUREKA, HERE’S WHAT WE FOUND. SOPHISTICATED FROM THE NORMAL INDIVIDUAL WAS 21 DAYS, THE PATIENT WAS SIX DAYS. SO THEY WERE PRODUCED WITH THOSE, AND THEY HAVE PLASMA, AND THEY WEREN’T PRODUCING IMMUNOGLOBULIN BUT THEY DIDN’T LAST LONG ENOUGH WHY BECAUSE AND.

SHOWED THEM LATER THAT PROCLUEDS THIS THERE. SO NOW WE WERE SUPER HAPPY, BUT THAT ACTUALLY WOULD HAVE HAD IT HAPPY BECAUSE WE HAVE AN EXPLANATION FOR THE ANEMIA BUT WE DIDN’T KNOW WHY WE WERE HAVING THOSE INNECKSS SO YES, HAVE THEM AND WE NEEDED TO EXPLAIN THE OTHER HALF OF THE PICTURE. NOW HERE IS A BASIC BOOK OF BIOLOGY, YOU REMEMBER WHEN I TOLD YOU THAT WHENEVER WE CHECK BACK INDISCERNIBLE, THESE PATIENTS THEY DID HAVE A NORMAL RESPONSE TO PROTEINS OR TO POLYSACCHARIDES. BUT THEY DIDN’T RESPOND TO.

VIRUSES, AN OLDER VACCINE THERE TO MOUNT A NORMAL RESPONSE TO THE ZACH SEEN, AND ACTUALLY ALL THOSE HAVE BEEN SOME RESPONSE. THE VIRUSES AND THEY’RE FULL GLYCOPROTEINS. IMAGINE THE VIRUSES, THE DPLIEK O PROTEINS BY THEMSELVES. SO WHATEVER THOSE VIRUSES WILL BE RECOMMENDED BY THE PROTEINS SO THE VIRUS GETS IN THROUGH THE CELLS AND THEY HIJACK OUR FACTORY AND THEY SAID NOW YOU WORK FOR ME, YOU DON’T WORK FOR YOURSELF ANYMORE, YOU ARE MY SLAVE AND YOU HAVE TO MAKE WHATEVER I TELL YOU TO MAKE. AND SO WHAT THE GLYCOPROTEINS.

AND THOSE GLYCOPROTEINS HAVE THE ONES THEY SHOWED THE WAY OUT FOR THE VIRUSES. SO THESE GUYS, THEY DON’T MAKE THE GLYCOPROTEINS SO I SAW THEM, AND WE WE HAVE THIS AS A PROBLEM SO THIS IS VACCINATED. THEY DIDN’T GET ANY SIDE EFFECTS BECAUSE OF VACCINATION, BUT THE POINT IS ERPERHAPS THE VIRUS CANNOT GET IN BECAUSE HERE WAS NO INDISCERNIBLE ADEQUATE BECAUSE THEY DON’T KNOW HOW TO MAKE GLYCOPROTEINS AND THEY CAN’T MAKE ADDITIONAL VIRUS, SO THEN WE HAVE PERHAPS HERE WE HAVE SOMETHING THAT COULD BE EXPLORED. AND ACTUALLY, WE DIDN’T GO SLOW.

OR WE DIDN’T GO SMALL. WE LOOK AT VIRUSES TO SEE WHAT WAS THE POTENTIAL MECHANISM WHY THIS GUY YOU WERE HAVING NO INFECTION WHATSOEVER. SO THIS IS HIV, INFLUENCA, ADENEE VIRUS, INFLUENZA, ADEN O VIRUS, POLARIZEDIO VIRUS AND VACCINIA, AND THEY’RE BELOW THE VIRUSES AND WITH THE VIRUS, AND THE POLIO VIRUS, THE VIRUS, WE SAID OKAY, WITH THE SAME APPROACH AND SEE WHAT WE CAN FIND AND THE APPROACH WAS EXACTLY THE SAME FOR THE VIRUS. FIRST WE WANT TO SEE IF THE VIRUS COULD ENTER THE CELL. BECAUSE THAT WILL TELL US THAT.

THE RECEPTOR FOR THE VIRUS WAS OKAY, SO THEN WE WANT TO SEE HOW MUCH PRODUCED FROM THE PATIENT FROM THE CONTROL AND THEN THE NEXT AND THEN WE WANT TO KNOW HOW MANY VIRUSES COULD BE PRODUCED FROM THEM AND FROM THESE PATIENTS BECAUSE WE SUSPECTED THAT THE CELLS FROM THESE PATIENTS WOULD PRODUCE LESS VIRUS AND THE THIRD THING WAS TO COLLECT THE VIRUS AND TRY TO INFECT OTHER CELLS. TO SEE IF THE NEW VIRUS COULD PRODUCE THE INDISCERNIBLE COULD BE AS VIRULENT AS THE VIRUS. THE INFECTION, INDISCERNIBLE.

AND WE DID EXACTLY THE SAME. AND WE DID CTRFOUR AND FIVE DEPEBBLEDDENT AND IN TERMS OF KORESEPTORSORS AND WE FOUND THERA’S NO DIFFERENCE. SO THE VIRUS WAS ABLE TO INFECT THE CELLS SO THERE WAS NOTHING DEFECTIVE IN TERMS OF THE KORESEPTORSOR FOR HIV. THE BIG SURPRISE WAS HERE. WHEN WE POUNDED THE AMOUNT OF VIRUSES, THEY WENT INDISCERNIBLE LOT LESS VIRUSES THAT I WERE ABLE TO PRODUCE. SO THE CELLS FROM OUR PATIENTS, THEY WERE PRODUCING SIGNIFICANTLY LESS VIRUS BECAUSE WE DIDN’T KNOW HOW TO MAKE THE GLYCOPROTEINS FROM THE VIRUS BY.

ITSELF. SO THEN WE COLLECT THAT VIRUS AND WE SAY WE WILL COMPARE WHAT HAPPEN FIST WE COLLECT THE VIRUS WE WERE GOING TO TAKE OTHER NORMAL CELLS. AND THE VIRUS FROM THE PATIENT 50 AND LESS THAN THE WILDTYPE VIRUS SO THE PATIENTS VACCOR BUT THEY PRODUCE THIS AND AND THAT WAS HUGE. SO THEN WE SAID OKAY, IS THIS RELATED TO GLYCOSYLATION, AND WE CONCLUDE THAD YES. SO WE HERE WE SEE THE INFECT WIDE GP140 IT WAS A GLYCOPROTEIN THAT WAS INDISCERNIBLE AND CRITICAL IN TERMS OF THE VIRULENCE FROM THE.

VIRUS, AND YOU CAN SEE THE MOLECULAR WEIGHT OF THE GPONE FUTURE WAS THE PATIENT, HE WAS HEAVIER THAN THE ONE THE REST OF YOU FROM THE CONTROL. REMEMBER THESE GUYS PRODUCE GLYCAN, THEY PRODUCE INDISCERNIBLE. HIGH GLYCAN AND ACTUALLY WITH WEWE REMOVE THEM, YOU CAN SEE THE THAT THE PROBING HAD THE SAME MOLECULAR WEIGHT SO THE DIFFERENCE BETWEEN THIS AND THIS, THIS WAS SURE AND THE SURE THE DIFFERENCEOT MOLECULAR WEIGHT OF THIS ONE AND THIS ONE WAS BECAUSE OF THE GLYCOSYLATION, SO EVERYTHING WAS SURE OR GLYCAN RELATED SO THEN.

WE SAY, OKAY, WHAT THEN HAPPENED IN TERMS OF THE MOLECULAR WEIGHT OF THE GB140 IF WE TRY TO CORRECT THE PATIENT CELLS. SO HERE’S WHAT WILL HAPPEN. WE TRANSFECT THE PATIENT’S CELLS WITH NORMAL INDISCERNIBLE. AND HERE CAN YOU SEE THE CONTROL SO THE MOLECULAR WEIGHT WAS UNCHANGED BUT LOOK AT THE WEIGHT OF THE PATIENT. SO IT WAS HEAVIER THAT WE’RE OFFICIALLY TRANSSPHRECTED IT BECAME THE SAME MOLECULAR WEIGHT OF THE OTHER ONE. SO IT MEANS WE CAN MAKE IT WITH THE VIRUSES AS NORMAL IN VIVO. SO WE ARE MEAN BUT NONAPOPTOTIC.

THAT THE MEAN. SO THAT WAS GOOD, BUT I THOUGHT THERE WAS MORPH INTERESTING TO TRY ON GO THE OTHER WAY AROUND. WHAT IF WE CAN TRY TO CONVERT NORMAL INDIVIDUALS MORE SIMILAR TO THE PATIENT IN TERMS OF THEIR SUSCEPTIBILITY TO HIV INFLUENZA. AND HERE, WE USE WHAT JOHN MENTIONED, THOSE INHIBITORS. SO FORTUNATELY THERE’S ONE OF THOSE THAT WAS ALREADY AVAILABLE THAT INHIBITS LOGS, THAT THEY HAVE A GENETIC DISORDER AND SO WHEN WE TREAT IT, LOOK HERE, WHEN WE TREAT THE CONTROL INDIVIDUAL, LOOK WHAT HAPPENED TO THE MOLECULAR WEIGHT OF THE.

INDISCERNIBLE 140, IT BECAME A INDISCERNIBLE, EVER THE PATIENT HAVE. SO WHAT WE DID IS WE CONVERTED NORMALLY, IN CDG TYPE TWO, IN TERMS OF HOW THEY MANAGE VIRUSES. SO THAT WAS INTERESTING AND WE THOUGHT THEY HAD POTENTIAL BECAUSE WE THINK THIS REALLY HAS POTENTIAL IN HOW WE CAN ADDRESS THE REINTEGRATED SERVICES FECKSS, WITH THE EPIDEMIC SO IT COULD BE INFLUENZA, COULD IT BE EBOLA SO YOU HAVE A TOOL TO MANIPULATE GLYCOSYLATION IN HOW WE HAVE THESE DIFFERENT KIND OF INFECTIONS. AND WE TRANSFECTED THE CELLS FROM THE PATIENT IT WAS GIVING.

THAT POINT AT THE VIRUS AND LOOK HOW MORE INFECTED IT BECAME, SO THE EXPERIMENTS WITH INDISCERNIBLE HERE’S THE REAL THING. SO YEAH, IT WAS RISKY BUT YOU KNOW IT WAS WORK. SO THEN WE FOUND, AND WE GENERALLY DID MACROPHAGES AND WE TRY TO INFECT THOSE CELLS FROM THE CONTROL TRS WITH THE INFLUENZA VIRUS AND THE HONE, NONE FROM 2009, THE AGGRESSIVE ONE AND THE CELLS FROM THE PATIENT ARE ALMOST NONINFECTABLE, WE HAVE A LOT OF TROUBLE TRYING TO INFECT THE CELLS FROM THE PATIENT. THESE GUYS AND LET ME JUST TELL.

YOU ANOTHER TYPE OF A STORY, SO THEY WENT BACK AND THEY NEVER GOT INFLUENZA. AND THEY DIDN’T HAVE TIGHTERS ANDA THEY PROVED WHY THEY DIDN’T GET INFLUENZA BECAUSE WE COULDN’T INFECT THE CELLS BECAUSE THESE GUYS HAVE A DEFECT IN THE RECEPTOR THAT DOESN’T MAKE THEM SUSCEPTIBLE EVEN TO T. SO THESE PATIENTS WERE REFRACTORY TO INFLUENZA BECAUSE YOU NEEDED GLYCOPROTEIN RECEPTOR IN ORDER TO BIND THE INFLU ‘ VIRUS. SO WE’RE SUPER HAPPY HERE BUT WE MOVE TO THE NEXT VIRUS AND WE DID EXACTLY THE SAME APPROACH SO.

PRIMARY PRODUCTION, I SHOW YOU HERE, THE SECONDARY AND IT WAS INDISCERNIBLE. SO WE SAID, YOU KNOW, BECAUSE THOSE VIRUSES, THE ADENOVIRUS IS NOT THE VIRUS AND DOESN’T HAVE GLYCOPROTEINS SO WE DIDN’T FIND THEM DIFFERENT. THIS PATIENT WAS EQUAL AS CONTROLS IN TERMS OF THEIR SUSCEPTIBILITY TO INDISCERNIBLE VIRUS SO THEN WE DO THE SAME THING WITH THE POLYVIRUS AND ANOTHER GLYCOSYLATEDDED VIRUS, WE SAID OKAY, EVERYTHING’S FINE AND CANDI, ONE MORE, SHORT VIRUS, SO, WE KDSALLY COMAA VIRUS, VACCINIA VIRUS IS ANOTHER VIRUS AND WE’RE NOT FIBBING ANY DIFFERENCE BETWEEN THE PATIENT.

AND THE CONTROL. BUT AGAIN, THIS IS WHERE THEY BOTTOM HANDY HERE AND THIS IS THE GLYCOPROTEIN SO IT’S NOT ABOUT THE ENVELOPE, IT’S ABOUT THE GLYCOPROTEIN SO INDISCERNIBLE THAT ACTUALLY WAS IN THE ENVELOPE IS WHERE THE BEELIKE O PROTEIN WERE DRIVING THE RESISTENT OR THE LACK OF SUSCEPTIBILITY OF THE VIRAL INFECTION. SEWHENEVER WE’RE CONTROLLING THAT, WE HAVE KIND OF TWO DIFFERENT TYPE OF RECEPTORS THAT THEY MANAGE, ONE TO PRETECT THEM, AND THE OTHER IS TO PROTECT AND GO OUT AND THEN THE ONES MORE DEGRADATION, ACMGAMMA RECEPTOR, THE THING IS, THESE.

RECEPTORS, THE BINDING OF THE I. G. G. IS MANUDEPENDENT. SO THESE ARE A NORMAL HALF LIFE BUT THESE GUYS INSTEAD OF HAVING THIS TYPE OF GLYCAN, THEY HAVE THIS TYPE OF GLYCAN WITH THE LAW OF INDISCERNIBLE SO WITH THE PATHOGENS AND WE CONFIRM THEY HAVE THE PLASMA AND THIS IS BINDING TO THE RECEPTORS MORE THAN THE OTHER ONE AND THEY WERE DEGRADING SO THAT’S WHY THEY WERE SO SHORT OF THE HALF LEGAL OF THE IMMUNOGLOBULIN. AND AS FOR THE VIRAL IS CESS SEPTORSIBLE WE CAME OUT WITH A.

MODEL TOO. SO HERE TO THE LEFT WE HAVE INFECTION OF WHITE BLOOD CELLS, HERE YOU HAVE GLYCOSYLATION DEPENDENT VIRUSES AND HERE YOU HAVE THE INDEPENDENT VIRUSES, SO HERE YOU HAVEIT TOOK ME A LOT OF WORK TO MAKE THOSE RECEPTORS DIFFERENT COLORS THAN THIS ONE. SO PATIENT ATTENTION TO THAT AND APPRECIATE THAT. SO THOSE VIRUSES, THEY ARE RECOGNIZED THEY PRODUCE THE CELLS, THEY AND BLAH, BLAH, BLAH, THEY SHUT DOWN THE KDSALLY MA AND COMPLETE AND CLOSE THE INFECTION, WITH THE GLYCOSYLATION DEPENDENT YOU HAVE IT. BUT HERE OUR PATIENT CELL IT’S.

DIFFERENT. FIRST OF ALL THEY HAVE DIFFERENT RECEPTORS SO WHENEVER THEY TRY TO EFFECT THE VIRUS, THERE’S SUCH DIFFERENCE, SO THE CELL SYSTEM HIJACKS BUT THEY DO NOT PRODUCE MANY VIRUSES AS WITH THE WILDTYPE INDIVIDUAL AND THEN THE BYERS OF THAT PRODUCED AND THE DIFFERENT IN THE WILDTYPE BECAUSE THEY DON’T KNOW HOW TO PRODUCE THE GLYCOPROTEIN AND THE VIRUS IN THIS CASE, AND THEY SEE THAT THIS CASE WAS INFECTED AND THIS IS WHAT HAPPENED WITH THE CYCLE OF VIRUSES WITH THE ENVELOPE AND THE GLIKE O DEPENDENT. FOR THE GLYCAN INDEPENDENT, NO.

DIFFERENT. WHEN WE WROTE THE PAPER, WE WERE CAREFUL TO SAY, WE’RE ON THE RIGHT SIDE OF THE STREET. SOITHESE PATIENTS WERE LESS SUSCEPTIBLE TO VIRAL INFECTIONS BUT JUST IT’S JUST A MATTER OF TIME UNTIL THIS CHANGES OF GLYCOSYLATION GOING TO DUCE MORE AGGRESSIVE OR MORE IMMUNOEN GOIC AND THIS IS WHERE THE PATIENTS CAME FOR THE PROCESSES, BECAUSE NOW WE FOUND THAT THOSE PATIENTS WHEN THEY IMMUNIZE WITH MMR, THEY HAVE HYPORESPONSE TO KDSALLY MEN AND WOMEN. THEY DON’T GET MORE INFECTED THAT, THEY DON’T GET SIDE EFFECTS BUT INSTEAD OF GETTING.

RESPONSE UP TO HERE, THEY GET THE RESPONSE UP TO THERE. IT’S OUT OF THE CHART BECAUSE THE GLYCAN THAT THEY’RE THE IMMUNO GENIC PART OF THE RII HAVE US IS DIFFERENT BECAUSE THEY DON’T KNOW TO PRODUCE NORMAL GLYCAN, THEY PRODUCE WHAT THEY CAN AND THE GLYCANS THEY PRODUCE HAVE THE INDISCERNIBLE. THEY’RE MORE IMMUNO GENEIC OF THOSE CELLS AND THESE ARE WHAT WE’RE FOCUS NOW ON STUDY. SETHAT CLOSE THE CIRCLE ABOUT WE WEREN’T ENTHUSIASTIC ABOUT THE PATIENTS BECAUSE THEY’RE LESS SUSCEPTIBLE TO VIRUS BUT WE KNEW AT SOME POINT.

VIRUS WILL GO IN THE OTHER DIRECTION. SO HAVE I HAVE TO THANK THE PEOPLE THAT REALLY WORKED. SO HAVE YOU THE PEOPLE HERE, WITH IDSU, THE UDP PEOPLE, THE GLYCOSYLATION STUDY, THE PEOPLE AT FREDERICK, THE PEOPLE WITH THE BIOPSY, PEOPLE WITH TONY FAUCI’S GROUP, ALL THE H. A. B. AND THE VACCINIA STUDIES, AND THE INFLUENZA STUDIES, PEOPLE AT THE NIDCR, THE ADENOVIRUS STUDY AND I HAVE TO COLLAB EIGHT WITH A LOT OF PEOPLE THAT HAVE EXPERTISE IN THIS PARTICULAR VIRUS AND THEN HAVE YOU THE PEOPLE THAT DO THE SEPARATE.

INDISCERNIBLE. THE MOUSE STUDIES THE STATISTICS, LCID AND ALLOWING US TO SEE THOSE PATIENTS THROUGH THE UDP PROGRESS. SO JUST TO CONCLUDE. 1982, BILL CLINTON THE ECONMETRICS INDISCERNIBLE. SO TO SET THE MOOD OF THE STATEMENT, 1995, DAVID STUDY IT’S THE VIRUS, AND PEOPLE DIDN’T KNOW WHAT WAS THE PROBLEM WITH HIV AND HE WAS THE FIRST ONE TO SAY IT’S A VIRUS PRODUCING THE PROBLEM AND IN 2010 PROBLEM IS NOT THE VIRUS AND THE WOMAN AND THE IT’S THE IMMUNE SYSTEM AND IT’S NOT RECOGNIZING IT AND I THINK THAT ALL OF THEM WERE.

PARTLY RIGHT AND PARTIALLY WRONG. THE POINT IS WE ARE HIJACKED WITH THE RIVIRUSES SO THE POINT IS HERE, WITH THE ECONOMY WE DON’T GET GRANTS WE CANNOT DO RESEARCH, IF A VIRUS, IS IT A GLYCOPROTEIN, BUT MOST THINGS WITH HIV AT THIS POINT IS FOCUSED ON TRYING TO DETROY THE SHIELD OF THE GLYCOPROTEIN OF THE VIRUS, SO THAT TRY TO DESTROY THE SHIELD AND MEN AND WOMEN THIS IS GOING TO TEACH US IS WE CAN GO TO TRY TO DESTROY THE SHIELD TO PREVENT THE SHIELD AND YOU KNOW WITH THE.

GLYCOSYLATION PATTERN IT WILL PRODUCE AND NOT THE SHIELD. SO WE CAN MANIPULATE THEM AND WE CAN TELL OUR OWN CELLS, YOU KNOW WHAT MAKE THE SHOOT FOR THE VIRUS AND DO HARM IN OURSELVES AND THE COMPANY WAS AWARDED THOSE BECAUSE THEY THINK THEY CAN WORK WITH DIFFERENT BIOINFECTIONS, SO WITH THAT I CLOSE AND I CAN TAKE QUESTION FIST YOU WANT, THANK YOU VERY MUCH. gtgt SO THE SEVEN BILLION AND WE HAVE FOUR PATIENTS SO MAKE THE MOST. LAUGHTER SO THERE A HAVE AN ADVANTAGE IN TERMS OF VIRAL INFECTION, THEY.

HAVE A LOT OF NEUROLOGICAL DEFICITS, THAT THEY DO NOT HELP THEM VERY MUCH SO THEY’RE BLIND, NEUROLOGICALLY VERY SEVERE AND NEUROLOGICAL DEFICIENCIES AND THEY HAVE A LOT OF OTHER PROBLEMS. THERE REFRACTORY TO VIRAL INFECTIONS BUT THEY PAY A BIG PRICE FOR THAT. gtgt SO WHENEVER YOU GLYCOSYLATED OR DIFFERENT BIOLOGICALS CAN YOU PULLET PLIE THE HALF LIFE. SO THESE AND THEY NEED IT EVERY MONTH. CAN YOU MODIFY THE COMPARTMENT, PERHAPS THEY WILL MEET EVERY TWO MONTHS OR THREE MONTHS. SO THIS IS SOMETHING YOU CAN DO, YOU CAN SEE IT CAN REACH HIS.

MIND. I GET HEINDISCERNIBLE. SO ONE THING IS TO HAVE THESE GENETIC PROBLEMS DOING EMBRYO GENESIS, ONE THING IS WE’RE ALREADY GROWN UP AND WE INHIBIT THE PATHWAY FOR A WEEK OR TWO WEEKS. IT’S COMPLETELY DIFFERENT. gtgt RIGHT. gtgt BUT WHAT WOULD INDISCERNIBLE. gtgt I CAN TELL YOU, BECAUSE YOU HAVE BEEN TRIED. SO ACTUALLY, IT’S HIV, AND ACTUALLY THEY TRIED BEFORE, IT WAS HARD. SO BEFORE THE GOOD TREATMENT FOR HIV WAS AVAILABLE SO THEY WERE TRYING THOSE INDISCERNIBLE. THE MAIN SIDE EFFECT FLATULENCE, YOU CAN SURVIVE, THEY CAN.

SURVIVE WITH THAT, NOTHING ELSE OUTSIDE OF THAT. SO IT’S A DOABLE, ACCEPTABLE KIND OF SIDE EFFECT. SMELLY BUT ACCEPTABLE. gtgt INDISCERNIBLE. gtgt SO I HAVE KIND OF A MORAL DILEMMA WITH THE PATIENT BAUDS THERE BRAIN’S ALREADY DAMAGED SO I DON’T KNOW WHAT I WAS GOING TO REPLACE. SO THEY’RE SUSCEPTIBILITY TO VIRAL INFECTIONS WHAT I WANT TO DO IS MAKE THEM GAIN. SO THE DAMAGE IS ALREADY SEVERELY EFFECTED THEM AND DAMAGED SO I DIDN’T KNOW HOW MUCH GAIN BECAUSE WE FOUND A WAY BECAUSE OF THE TYPE OF MUTATION,.

WE USE INDISCERNIBLE TO GO THROUGH THE PROBES AND WERE ABLE TO GOOD WHAT ON THEM. BUT THEN I HAVE KIND OF A MORAL DILEMMA SO WHAT ARE WE OFFERING THERE. SO NOW WE WILL HAVE SOME INDISCERNIBLE THAT WILL BE WORKING AND WHAT WILL HAPPEN. THEY WILL BECOME SUSCEPTIBLE TO THE VIRUS FOR THOSE BEFORE AND THE POSSIBILITY OF THEM TO REGAIN THEIR CENTRAL NERVE SUSSYSTEM FUNCTION, IT WAS MEALS. SOSO SORRY TO MIX MORAL THINGS WITH SCIENCE. gtgt SO WHAT IS THE SPECTRUM OF VIRUSES WHICH YOU’RE THINKING OF.

Gtgt THAL CASE THEY HAVE TO HAVE GLYCOPROTEINS, OR THE AGREEMENT FACTOR, BUT WE CANNOT MAKE PREDICTIONS OF WHAT WILL HAPPEN WITH EACH VIRUS SO WE HAVE TO TEST EACH VIRUS BY ITSELF, SO EACH VIRUS, EACH OF THE CDGs TO SEE WHAT HAPPENED WITH THE COMBINATION. YOU REMEMBER THAT THE BEGINNING WE SAID THAT 50 OF THE PATIENTS HAD GLYCOSYLATEDDED SO THEY HAD THE CASCADE, HALF OF THEM WILL BE GLYCOSYLATEDDED AND I DON’T FINISH THE CHANGE WILL GO NOW, FROM THE INDISCERNIBLE. FUNCTION MAKE IT OR TO WORK LESS.

SO IT’S IMPOSSIBLE FOR ME TO PREDICT WHAT’S GOING TO HAPPEN WITH THE COMBINATION OF EACH VIRUS WITH EACH CBG. SO IT HAS TO BE TEST INDEED THE INDIVIDUAL CASE. EACH VIRUS, SO WE HAVE A GREAT EXAMPLE WITH THIS PATIENT WITH MMR AND CHICKEN BOX THAT THEY DIDN’T HAVE A SIDE EFFECT AND THEY DIDN’T AMOUNT ANY NEW RESPONSE. OT OTHER EXAMPLE BEING THE PATIENTS THEY DIDN’T HAVE SIDE CENTER FOR EXCELLENCE ON AGINGS BUT THEY WERE HYPER IMMUNE TO THEM, BECAUSE THEE WERE INDISCERNIBLE WE BELIEVE THAT THE GLYCAN THAT’S ATTACHED TO.

THE INDISCERNIBLE, NOVELLA MAKES MORE IMMUNO GENIC SO WE’RE THINKING AGAIN. THOSE ARE IT IS THINGS THAT WE’RE LEARNING FROM THESE PATIENTS. SO YOU HAVE TO SEE THAT THEY’RE NOT GREAT. SO WHAT IT IS WE CAN MODIFY IN ORDER TO BECOME INDISCERNIBLE TO PRODUCE, SO THAT CAN BE DONE USING MORE IMMUNO GENIC AND YOU WANT TO TALK ABOUT PATIENTS. HAVE YOU HAVE HAD TO SEE THE FACE OF THE INDISCERNIBLE. WHEN SHE RELAYS HOW MUCH WE LEARN FROM THEIR PATIENT. SO KEEP IN MIND THAT THIS MOM IS INDISCERNIBLE BLIND, DEAF,.

RETARDED AND THEY HAVE 50 INDISCERNIBLE THE OTHER COMPLETE NUMBER. WHEN I TOLD HER HER KIDS WERE TEACHING US HOW TO INDISCERNIBLE OR GIVING US OPTION IN HOW TO FIGHT HIV AND INFLUENZA, SHE WAS REALLY HAPPY AND THEY HAD MADE ME HAPPY. gtgt INDISCERNIBLE. gtgt SO THESE HAVENYONATAL SCREENING IT’S TOO LATE. IT HAPPENS DURING EMBRYO GENESIS, SO I THINK NEW BORN SCREENING IT WILL BE LATE. I’M GUESSING, I DON’T KNOW. BUT KEEP IN MIND THE EXAMPLE OF THE OTHER PATIENTS THAT WERE BORN THAT WAS ALREADY SEVERELY EFFECTED SO SIX WEEKS, I GUESS.

THE GAME WAS ALREADY OVER. SO THAT’S MY IMPRESSION. SO IF YOU DON’T HAVE THESE GLYCANS TO YOUR BRAIN, I THINK THAT YOU WILL HAVE IT VERY BAD OUTCOME, SO I GUESS EVEN NEW BORN SCREENS, I AGREE, I 1010 YEARS IS TOO FAR AWAY. I THINK TELL HAPPEN FASTER BUT I THINK STILL TOO LATE. gtgt SO YOU THINK THE SERVEERAL NERVOUS SYSTEM gtgt WAIT A MINUTE. gtgt WAIT EIGHT MINUTE. gtgt WAIT A MINUTE. gtgt SORRY SIR. gtgt 50 OF THE PROTEINS INDISCERNIBLE. gtgt SO BY GLYCOSYLATION IT’S ABOUT 40 ON 50 OR 40.

INDISCERNIBLE AND THE BIGGEST CLASS IS THE INDISCERNIBLE AND THAT CLASS SO IT’S PROBABLY INDISCERNIBLE. gtgt SO HOW DO YOUYOU AGREE BECAUSE ALL THE BLOOD GROUPS ARE INDISCERNIBLE SO ALL THOSE EXPRESS THEM SO I GUESS THEY HAVE ALL GLYCOSYLATION THEY HAVE IN EVERY CELL, PERHAPS. gtgt YEAH. gtgt YEAH. gtgt ANYONE ELSE HAVE ANY QUESTIONS YOU WANT TO GET INVOLVED IN THIS SO IT SEEMS RATHER AMAZING THAT EMBRYO GENESIS WOULD PROCEED AND I CAN’T SAY IN A NORMAL RATE, BUT PRESUMABLY, YOU DIDN’T SAY BUT PRESUMABLY THESE CHILDREN WHEN THEY’RE BORN ARE OF.

REASONABLE SIZE AND SEEM TO BE OKAY FOR A SHORT PERIOD OF TIME. gtgt I THINK YOU ARE ABSOLUTELY RIGHT. I GUESS, SO REMEMBER, WE FOUND THE MUTATION, INDISCERNIBLE THEY HAD ONE NEW MUTATION AND THERE WAS ONE INDISCERNIBLE. WE BUT I GET SOME FOLKS MAY EXPRESS A PROTEIN BECAUSE I COMPLETE THE REVIEW, IF YOU HAVE NOTHING, THAT WILL BE NOT COMPATIBLE WITH SURVIVAL. SO YOU SAY SOME CELL LEVEL, AT SOME POINT THEY WERE PRODUCING SOME KIND EVER PROTEIN AND THAT ALLOWED THEM TO SURVIVE UNTIL BIRTH AND LATER SO EITHER WE.

COULDND FIANT THE PROACTIVE TEEN IN THIS INDISCERNIBLE SO THERE MUST BE SOMETHING THEY MIGHT BE PRODUCING THAT WE SHOULD HAVE LIFE OR SOMETHING THAT COULD BE RISKING THEM FROM THE COMPLETE PHENOTYPE THAT PROBABLY AS YOU SAID IS DEATH. WHAT DO YOU THINK JOHN gtgt KDSALLY MEN AND WOMEN. gtgt THE COMPLETE NEW. gtgt IS THERE A RELATIONSHIP BETWEEN GLYCOSYLATION, DEFECTS AND THE BACTERIA OF THE INTEST NINE. gtgt WE STUDY THAT IN THESE PATIENTS WE DID MICRO BIOME ANALYSIS SKI DIDN’T FIND ANYTHING DIFFERENT. KEEP IN MIND THE BACTERIA HAVE.

THEIR OWN ON MACHINERY AND THEY DO NOT GLUE MARIOUS COSALATE BUT WE DIDN’T FIND ANY DIFFERENCE BETWEEN THE MICROBIOTA AND INDISCERNIBLE THEY HAVE. SO KEEP IN MIND THESE PATIENTS ARE NOT GETTING ANTIBIOTICS BECAUSE THEY HAVE THE FIELD INFECTION, SO WAS NOT INFLUENCED BY ANY EXTERNAL FACTORS SO THE MICROBIOME IN THESE PATIENTS WAS NOT DIFFERENT THAN THE MICROBIOME, AND THIS WOULD MAKE THEM BY THEMSELVES AND THEY DON’T NORMAL GLYCOSYLATED. gtgt INDISCERNIBLE. gtgt SO WHEN I SAW THEM THEY WERE COT COMPLETELY BLIND, THEY WERE PARTIALLY BLIND AND I DON’T KNOW.

WHAT HAPPENS FIRST. gtgt INDISCERNIBLE. gtgt SO WE WERE NOT THAT MICRO CEPHALIC, SO YOU DO THE CT SCANS AND MRI THERE WAS NOTHING STRUCTURALLY SO THEY HAVE NORM CORP ROM COLOZ UMKC, BUT THE FEARS WERE THERE, THERE WAS SOMETHING ABOUT THE NEUROLOGICAL THING ABOUT THE CD STANCE, NINDISCERNIBLE. gtgt SO TO MAKE A LONG STORY SHORT. WE DON’T KNOW. SO THE THING IS WE THEY HAD ATROPHY IN THE SMALL CORPUS COLLOSUM, SO EACH OF THEM MAKES 25. SO AND I HAVE NO WAY IDEA ABOUT THE SEQUENCE, WHAT IT WAS FIRST,.

THE BLINDNESS OF THE INDISCERNIBLEA. I GUESS THEY MIGHT HAPPEN AT THE SAME TIME BUT WE HAVE NO IDEA. SO WHEN WHATWAKIND WE CAN TELL SURVEYS THAT WE HAVE A PROGRESSIVE DISEASE, SO THE WAY THEY ARE BORN, SO THINGS DO NOT PROGRESS, DO NOT GET WORSE, SO WITH WHAT THEY ARE BORN AND HOW THEY SURVIVE. gtgt OKAY, WELL, I THINK WE gtgt INDISCERNIBLE. gtgt WE DID THAT! gtgt I WANT TO THANK YOU ON BEHALF OF ALL OF US. THAT WAS REALLY EXTRAORDINARILY EXCITING. AND A WHOLE NEW DIMENSION TO.

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