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>>WELCOME TO THE NIH DNA

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REPAIR INTEREST GROUP VIDEO

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CONFERENCE.

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I'M KEN KRAEMER, MY COHORT WILL

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BOHR IS NOT AVAILABLE NOW BUT HE

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WILL BE BACK NEXT MONTH.

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WE DO HAVE OUR MONTHLY VIDEO

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CONFERENCES NEXT MONTH AND JUNE

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DR. TOM KONKLE FROM NIEHS WILL

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BE SPEAKING ABOUT EXTRINSIC

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PROOF READING OF DNA REPLICATION

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ERRORS.

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WE WILL NOT BE HAVING SEMINARS

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IN JULY AND AUGUST.

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AND WE WILL RESUME IN SEPTEMBER

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AND DR. MARK WILL BE SPEAKING AT

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THIS POINT. 

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THOSE OF YOU WHO KNOW ABOUT

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THIS--IF YOU'RE NOT--IF YOU

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WOULD LIKE TO KNOW ABOUT ALL OF

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THESE SEMINARS YOU CAN GET ON

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THE DNA REPAIR INTEREST GROUP

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E-MAIL LIST AND JUST WRITE TO ME

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AT KRAEMERK@NIHBNT GOFF.

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SO OUR SPEAKER TODAY IS

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DR. DONATA ORIOLI, FROM ITALY.

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SHE WAS FROM ITALY AND DID GET

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HER UNDERGRADUATE DEGREE AT

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UNIVERSITY OF P A VIA WHERE SHE

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IS NOW, BUT SHE WENT TO GERMANY

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AND GOT HER Ph.D. AT THE

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UNIVERSITY OF HIDELE BERG AND

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THEN CAME BACK TO P A VIA AND

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WORKED IN THE LABORATORY OF

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DR. MARIA [INDISCERNIBLE] ON

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GENETIC DNA REPAIR DEFICIENCY

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DISEASES FOR MANY YEARS.

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THAT WAS THE LABORATORY THAT WAS

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IDENTIFYING ALL THOSE IN THE

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COUNTRY OF ITALY AND THEY FOUND

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PATIENTS WITH 0 DERMA AND FOR

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THE FIRST TIME PATIENTS WITH

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[INDISCERNIBLE] DYSTROPHY.

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SO TODAY, DR. STEFANNI, ACTUALLY

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GIVE A TALK IN THIS SERIES IN

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1998 AND THAT IS ARCHIVED FOR

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THOSE WHO WOULD LIKE TO SEE IT

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ON THE VIDEOCAST.NIH.GOV

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WEBSITE.

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SO THEY WILL SPEAKING ABOUT THE

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MULTIFACETED ROLE OF THE NER

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PROTEINS AND THEIR IMPLICATIONS

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IN HUMAN PATHOLOGY.

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IF YOU HAVE ANY QUESTIONS PLEASE

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PUT THEM IN THE CHAT BOX AND I

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WILL READ THEM LATER.

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THANK YOU VERY MUCH.

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>> THANK YOU KEN, THANK
YOU FOR

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THE PRESENTATION, THA YOU BOTH

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TO YOU TO YOU AND WILL FOR THE

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INVITATIONS TO GIVE A TALK HERE.

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BECAUSE THESE GIVES A GREAT

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OPPORTUNITY TO PRESENT WHAT IS

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OUR CONTRIBUTION IN THE FIELD OF

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THE NOW NEURODEFECTIVE

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DISORDERS.

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 SO, THE NUCLEOTIDE

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EXCISION REPAIR, WE SAID WE KNOW

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THE DNA REPAIR PATHWAY THAT

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REMOVES THE BARRIER AND THIS

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INCLUDES ALSO THE

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[INDISCERNIBLE] USE OF LESIONS.

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THERE ARE MANY PROTEINS THAT

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CODE THE NER PROTEINS THAT ARE

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IMPORTANT IN THIS MECHANISM

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STARTING FROM THE DNA DAMAGE

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RECOGNITION AND BASICALLY LIES

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ON DIFFERENT MOTIVES DEPENDING

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ON THE SUBPATHWAYS THAT ARE

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USING GENOME REPAIR, RECOGNIZING

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THE LESION THAT ARE DISTRIBUTED

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ENTIRE GENOME WHAT IS

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TRANSCRIPTIONAL COUPLED REPAIR.

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AFTER THE DNA DAMAGE

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RECOGNITION, THE 2 SUBPATHWAY

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JOIN IN THE UNIQUE PATHWAY AND

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THE NEXT, THE FOLLOWING STEP IS

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THE FORMATION OF THE OPEN

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COMPLEX AND THIS IS THANKS TO

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THE HELIX ACTIVITY OF THE

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COMPLEX THAT WE ARE GOING TO

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SPEAK ABOUT TODAY.

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AND AFTER THE INFORMATION OF THE

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OPEN COMPLEX, SO THEN THERE IS

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THE EXCISION OF THE DNA FRAGMENT

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THAT CONTAINED LESIONS AND THE

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FRAGMENTED GETS EXCISED,

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ELIMINATED AND WITH THE ANSWER

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WE HAVE THE DE NOVO SENTH SIS

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WHERE THE POLYMERASE USES THE

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UNDAMAGED STRAPPED AS A TEMPLATE

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TO PERFORM THE SYNTHESIS.

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SO AS I WAS SAYING, MANY GENES

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WITH THE EXCISION REPAIR, MANY

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PROTEINS, SO THE MUTATIONS IN

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SEVERAL OF THE GENES THAT ARE

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RESPONSIBLE FOR A

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[INDISCERNIBLE] DISORDER.

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OKAY, SO, THE AMOUNT IS OVER, WE

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CAN DISTINGUISH THE DERMA

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PIGMENTOSE UMKC, WHICH IS A

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BONES, SORE SKIN TUMORS IN THE

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AREA OF THE SKIN THAT ARE

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EXPOSED TO THE SUN AND THEN THE

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COCKAYNE SYNDROME AND

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TRICHOTHIODYSTROPHY, BOTH

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PATIENTS, THEY BOTH REPRESENT

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SIGN OF PREMATURE AGING

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INCLUDING SPECIAL IN THE CASE OF

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COCKAYNE'S SYNDROME FOR

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NEURODEGENERATION, THERE ARE

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MULTISYSTEMIC DISORDERS, THEY

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HAVE A WILD AMOUNT OF CLINICAL

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FEATURES BUT IN THE PATIENTS AND

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THE PATIENT WE CAN SAY THAT THEY

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ALSO ARE CHARACTERIZED BY A WIDE

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SPECTRUM OF SEVERITY.

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BOAGHTD THE CS AND THE TTD, THE

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CLINICAL HALLMARK THAT

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CHARACTERIZE THIS PATIENT IS THE

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FAYE NAIL [INDISCERNIBLE]

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BECAUSE THEA PATIENTS ARE

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CHARACTERIZED BY DEFECTS SO THEY

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HAVE [INDISCERNIBLE], THEY

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EASILY THEY HAVE REDUCED CONTENT

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WITHED [INDISCERNIBLE] AND

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DEVELOPMENT FOR THE ASPECT IS

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WHEN THEY ARE ANALYZED UNDER THE

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LIGHT OF THE POLARIZING SCOPE OF

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THE HAIR AS SHOWN A SPECIFIC

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PATTERN THAT IS CALLED THE THEME

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PATTERN AND I WOULD SHE YOU A

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PICTURE AFTERWARDS.

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SO BUT CS AND TTD, THEY ARE BOTH

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FACTOR IN THE EXCISION REPAIRS

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SO THEY ACCUMULATE IN THE GENOME

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AND THEN AND REPAIR THE LESIONS,

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BUT THE DIFFERENT 3 FROM THESE

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PATIENT DO NOT SHOW ANY CANCER

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BONE IN THIS, IN THE AREA OF

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THIS SCHEME THAT ARE SUPPOSED TO

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BE THERE, SO THIS OPENS THE

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QUESTION, HOW THEY ARE CAN GIVE

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RISE TO SUCH DISEASE OF

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HETEROGENERATED AITY, WHICH

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PATIENTS PRESENT AN OPPOSITE

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SKIN CANCER AND ALSO WITH SUCH

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DIFFERENT APPEARANCE OF THE

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FEATURES AND SO IN PARTICULAR

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WITH THE GENE--THIS DISEASE

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OBSERVED ALLOW US TO ANALYZE A

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LARGER COHORT, SO IF WE LOOK AT

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THE MUTATIONS, AT THE TOP,

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FOUNDER IN THE PPD PATIENTS WE

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CAN OBSERVE THAT THERE SEEMS TO

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BE A DISEASE SPECIFIC MINORITY

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THAT ARE DISTINCT AND THERE ARE

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ACTIVITY AND THERE ARE BOTH OF

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THEM DISTRIBUTED OVER KD--SALLY

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TO THE PROTEIN.

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THIS IS A SUBUNIT FOR THE

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TRANSCRIPTION FACTOR TO AGE, IT

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HAS AN ATPASE AND

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[INDISCERNIBLE] ACTIVITY AND AS

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I WAS SAYING THAT THE MUTATIONS

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IN THIS GENE CAN BE RESPONSIBLE

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FOR HPNTT, CONCERNING THE HBP

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UNITS, THIS HAS ATPASE AND

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TRANSLO CASE ACTIVITY AND

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SIMILAR TO XPD, MUTATION IN THE

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SUPPORTING GENE CAN BE

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RESPONSIBLE BOTH FOR

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EXPERIENCES.

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WHEREAS THE MUTATIONS IN THE

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GENE THAT ENCODES THE ATPASE,

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ARE RESPONSIBLE FOR THE TTD

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DIVISIONS, IN ADDITION, THE WAGE

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ALSO SHOW A KINASE ACTIVITY

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SUPERIOR TO THE COMPLEX.

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SO AS I SAID IT IS A GENERAL

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TRANSCRIPTION FACTOR THAT BINDS

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TO THE GENE PROMOTERS, AND WE

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THINK THAT THE ACTIVATE THAT CAN

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PHOSPHORALATE, AND IT'S PART OF

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THE COMPLEX AND WHEN IT IS

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ASSEMBLED ON THE GENE, THROUGH

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THE KINASE ACTIVITY, TF2 H

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PHOSPHORALATE THE TERMINAL

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DOMAIN OF CANNED WHAT.

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SO IT ACTIVATES TRANSCRIPTION.

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BUT AS I WAS SAYING BEFORE TF2 H

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IS ALSO IMPORTANT KEY FACTOR IN

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THE NUCLEOTIDE EXCISION REPAIR,

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SO THANKS TO IN THE KAITION OFEA

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IN THE REGION, THAT MUCH STRAND

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IN THE REGION THAT CONTAINS THE

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LESION IN THE WAY THAT OTHER

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PROTEINS THEN CAN STABILIZE AND

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CREATE AN OPEN COMPLEX.

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SO WHAT IT HAS BEEN SHOWN IN THE

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YOU HADITATIONS THAT THE FACT

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THAT THAT ARE RESPONSIBLE FOR

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BOTH EXPERIENCE TTD, RESULTING

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IN THE ACTIVITY OF TF2 H WITH

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THE CARE, SO EXPERIENCED TTD

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PATIENTS REPAIR AND ACCUMULATE

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IT IN THEIR GENOME.

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THEY CAN EXPLAIN THE BONUS OF

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SERVING THESE PATIENTS.

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BUT IT DOESN'T EXPLAIN WHY TTD

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PATIENTS MUTATED IN THE

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00:10:51,480 --> 00:10:52,160
[INDISCERNIBLE].

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SO POSSIBLE EXPLANATION FOR THAT

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CAN BE PROVIDED IF WE THINK

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ABOUT THAT MUTATION SO THAT THAT

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WAS RESPONSIBLE FOR TTT, MIGHT

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ALSO IMPAIR THE TRANSCRIPTION

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ACTIVITY OF TFIIH, SO THE MORE

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TTD THAN THE XP MAY HAVE A FACT

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IN THE TRANSCRIPTION OF TTD, AND

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THERE ARE SEVERAL EVIDENCE THAT

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MIGHT BE PROVIDED THAT THIS

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MIGHT BE THE CASE AND THAT'S

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WHAT WE'RE TRYING TO SHOW TODAY.

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SO THE FIRST EVIDENCE, THE DRIVE

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FROM WORK THAT HAS BEEN

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PERFORMED--PART OF THOSE STUDIES

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THAT HAVE BEEN PERFORMED IN OUR

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LAB BY ANOTHER DOCTOR AND IN THE

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LAB [INDISCERNIBLE] THEY BOTH

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SHOWED THAT THE FIBRO BLAST FROM

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TTD PATIENTS INDEPENDENTLYOT

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GENE, MUTATED GENE, THEY ALL

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SHOW A REDUCED [INDISCERNIBLE]

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OF THE TF2 H, SO THIS CARRIES

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MUTATION BUT ALSO ALL THE OTHER

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SUBUNITS OF THE [INDISCERNIBLE].

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THIS INDICATES THAT THESE

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CONTAIN A REDUCED AMOUNT OF

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MUTATED [INDISCERNIBLE]

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TRANSCRIPTION FACTOR.

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SO TRYING TO--WITH THE ATTEMPT

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TO DEMONSTRATE THAT THE

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TRANSCRIPTION DEFACT ARE REALLY

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RESPONSIBLE FOR TTD, WE DECIDED

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TO PERFORM A GENE EXPRESSION

257
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ANALYSIS BY USING THE RNA SEQ

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APPROACH AND WE SEQUENCE THE RNA

259
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FIBRO BLAST FROM TTD PATIENT AND

260
00:12:22,360 --> 00:12:23,960
TO EXPENSIVE LINKS, ALL

261
00:12:23,960 --> 00:12:25,400
[INDISCERNIBLE] IN TTD, AND WE

262
00:12:25,400 --> 00:12:28,600
DECIDED TO DO A 2 CLONE PAIR

263
00:12:28,600 --> 00:12:30,760
WITH THE PATIENT EXPRESSION WITH

264
00:12:30,760 --> 00:12:32,280
THE CORRESPONDING

265
00:12:32,280 --> 00:12:32,640
[INDISCERNIBLE].

266
00:12:32,640 --> 00:12:39,880
WE USE IT IN ALL PATIENTS, ALL

267
00:12:39,880 --> 00:12:50,160
FEMALES, TO ORDER TO LIMIT THE

268
00:12:50,160 --> 00:12:51,400
DIFFERENT [INDISCERNIBLE].

269
00:12:51,400 --> 00:12:52,600
--IS HIGHER MUCH HIGHER IN THE

270
00:12:52,600 --> 00:12:55,760
NUMBER OF GENES THAT ARE

271
00:12:55,760 --> 00:12:58,440
REGULATED AND THE MORJORRITY OF

272
00:12:58,440 --> 00:13:00,280
THE TTD REGULATED GENE ARE DOWN

273
00:13:00,280 --> 00:13:01,840
REGULATED AS WE OBSERVE THE BLUE

274
00:13:01,840 --> 00:13:03,600
BAR, BUT AS YOU CAN SEE, THERE

275
00:13:03,600 --> 00:13:05,320
IS AN EQUAL NUMBER OF GENES THAT

276
00:13:05,320 --> 00:13:10,240
ARE DOWN REGULATED OR

277
00:13:10,240 --> 00:13:11,520
UPREGULATED.

278
00:13:11,520 --> 00:13:13,320
SO THE SAME WE HAVE IT EVEN IF

279
00:13:13,320 --> 00:13:14,840
THE GENE CELL IS DIFFERENT, WE

280
00:13:14,840 --> 00:13:17,600
HAVE IT IF WE LOOK HERE AT

281
00:13:17,600 --> 00:13:20,440
THIS--THE EXPRESSION OF

282
00:13:20,440 --> 00:13:22,800
REGULATION AFTER UV RADIATION

283
00:13:22,800 --> 00:13:23,840
WITH THESE FIBERS.

284
00:13:23,840 --> 00:13:26,960
SO WE CAN THINK AND WE CAN SAY

285
00:13:26,960 --> 00:13:28,600
THAT BY LOOKING AT THESE AT THE

286
00:13:28,600 --> 00:13:30,360
NUMBER OF REGULATED GENE THAT

287
00:13:30,360 --> 00:13:33,600
TTD MORE THAN THE XP5 ROUGH ATOM

288
00:13:33,600 --> 00:13:37,840
BLASTIN ARE AFFECTED BY WIDE

289
00:13:37,840 --> 00:13:38,400
TRANSCRIPTIONAL IMPAIRMENTS.

290
00:13:38,400 --> 00:13:39,520
SO THEN WHEN WE TRY TO LOOK AT

291
00:13:39,520 --> 00:13:42,840
ALL THE GENES THAT WE FOUND THAT

292
00:13:42,840 --> 00:13:44,800
ARE REGULATED, THOSE IN THE

293
00:13:44,800 --> 00:13:46,320
CONDITION OR UV RADIATION AND WE

294
00:13:46,320 --> 00:13:49,920
DID THE ANALYSIS IN A LARGER

295
00:13:49,920 --> 00:13:53,360
COHORT OF PATIENTS, ALL MUTATED

296
00:13:53,360 --> 00:13:55,480
IN XPD, FOR EITHER TTD OR XP AND

297
00:13:55,480 --> 00:13:59,400
AS A CONTROL WE USE THE

298
00:13:59,400 --> 00:14:00,400
CORRESPONDING [INDISCERNIBLE]

299
00:14:00,400 --> 00:14:02,920
AND THE RESULT WAS THAT WE

300
00:14:02,920 --> 00:14:05,680
OBTAIN A REDUCED NUMBER OF GENE,

301
00:14:05,680 --> 00:14:09,040
A HALF OF THEM, GENE THAT

302
00:14:09,040 --> 00:14:12,120
RESPONDS TO THE UV RADIATION

303
00:14:12,120 --> 00:14:13,520
BECAUSE WE CAN OBSERVE IN THE

304
00:14:13,520 --> 00:14:15,680
CONTROL FIBRO BLAST IN THE

305
00:14:15,680 --> 00:14:18,920
CURRENT THAT THE GENE BECOMES

306
00:14:18,920 --> 00:14:21,760
EITHER UPREGULATED OR DOWN

307
00:14:21,760 --> 00:14:24,240
REGULATED AFTER UV REGULATION.

308
00:14:24,240 --> 00:14:26,080
THESE REGULATION NORMALLY IS

309
00:14:26,080 --> 00:14:28,960
LOST IN TTD AND IN SOME OF--FOR

310
00:14:28,960 --> 00:14:31,600
SOME OF THE GENE TRANSCRIPTION

311
00:14:31,600 --> 00:14:33,240
REGULATION, ALSO IS CLEAR IN THE

312
00:14:33,240 --> 00:14:35,760
XP PATIENTS THAT IN OTHER CASES

313
00:14:35,760 --> 00:14:40,560
SEEMS TO ONLY AFFECT THE TTD AND

314
00:14:40,560 --> 00:14:41,360
NOT THE [INDISCERNIBLE].

315
00:14:41,360 --> 00:14:43,400
SO WE DECIDED TO GO FURTHER AND

316
00:14:43,400 --> 00:14:45,960
TO UNDERSTAND WHETHER THE

317
00:14:45,960 --> 00:14:46,920
TRANSCRIPTION REGULATION CAN

318
00:14:46,920 --> 00:14:48,080
REALLY HAVE AN IMPACT ON THE

319
00:14:48,080 --> 00:14:50,480
CLINICAL FEATURE OF THE PATIENTS

320
00:14:50,480 --> 00:14:52,640
THAT WE EXPECT TO HAVE AN

321
00:14:52,640 --> 00:14:56,240
ALTERATION OF THE LEVEL OF THE

322
00:14:56,240 --> 00:14:57,280
PROTEIN COMPETENT, BUT TO OUR

323
00:14:57,280 --> 00:15:01,360
SURPRISE WHEN WE CHECKED THE

324
00:15:01,360 --> 00:15:05,360
AMOUNT OF PROTEIN OF THE

325
00:15:05,360 --> 00:15:06,280
DISREGULATED GENES, EVEN THOUGH

326
00:15:06,280 --> 00:15:09,400
TOO SHOW A VERY HIGH

327
00:15:09,400 --> 00:15:11,520
TRANSCRIPTION REGULATION, WE

328
00:15:11,520 --> 00:15:13,160
COULD NOT [INDISCERNIBLE] ANY

329
00:15:13,160 --> 00:15:15,000
DIFFERENT, DIFFERENCE BETWEEN

330
00:15:15,000 --> 00:15:18,320
THE TTD, THE XP OR THE CONTROL.

331
00:15:18,320 --> 00:15:23,080
INDICATING THAT MOST OF THE

332
00:15:23,080 --> 00:15:24,320
TRANSCRIPTION REGULATIONS, THE

333
00:15:24,320 --> 00:15:26,480
SIMILAR LEVEL EITHER BY PROTEINS

334
00:15:26,480 --> 00:15:29,120
THROUGH THE PROTEIN STABILITY.

335
00:15:29,120 --> 00:15:31,840
NEVERTHELESS, WE WERE ABLE TO

336
00:15:31,840 --> 00:15:32,640
IDENTIFY SOME TRANSCRIPTION

337
00:15:32,640 --> 00:15:34,840
REGULATION THAT THE SPECIFICALLY

338
00:15:34,840 --> 00:15:39,000
A FACTOR TO TTD PATIENTS, THE

339
00:15:39,000 --> 00:15:39,280
TTD CELLS.

340
00:15:39,280 --> 00:15:43,680
IN THE FIRST GENE WE IDENTIFIED

341
00:15:43,680 --> 00:15:48,320
WAS SOMETIMES GOING IN 2013 IT'S

342
00:15:48,320 --> 00:15:51,800
A COLLAGEN 6 A 1 GENE THAT IS

343
00:15:51,800 --> 00:15:54,080
ALSO WITH THE COLLAGEN 6, WE

344
00:15:54,080 --> 00:15:58,320
OBSERVE THAT FIBRO BLASTS WHEN

345
00:15:58,320 --> 00:16:00,120
FRESHLY CULTURED AT CONFLUENCE

346
00:16:00,120 --> 00:16:01,840
OF THE FIBRO BLAST REACH THE

347
00:16:01,840 --> 00:16:04,320
CONFLEW ENSEL, THE TTD FIBRO

348
00:16:04,320 --> 00:16:07,320
BLAST ARE EXTREMELY REUSE DOOD

349
00:16:07,320 --> 00:16:11,760
AMOUNT OF TYPE 6 COMPARED TO THE

350
00:16:11,760 --> 00:16:13,840
CONTROL BUT THE DEFACTOR IS NOT

351
00:16:13,840 --> 00:16:15,800
OBSERVED IN THE CULTURE IN

352
00:16:15,800 --> 00:16:17,640
DENSITY SO WE INVESTIGATED THE

353
00:16:17,640 --> 00:16:19,160
MECHANISM THAT WAS RESPONSIBLE

354
00:16:19,160 --> 00:16:19,760
FOR THIS TRANSCRIPTION

355
00:16:19,760 --> 00:16:21,640
REGULATION AND WE WERE ABLE TO

356
00:16:21,640 --> 00:16:23,840
OBSERVE THAT IN NORMAL FIBRO

357
00:16:23,840 --> 00:16:25,600
BLASTOT PROMOTER OF THE COLLAGEN

358
00:16:25,600 --> 00:16:29,440
6 IS PRESENT FOR THE COALESCE

359
00:16:29,440 --> 00:16:30,240
BP1, WHICH MAINTAINS THE

360
00:16:30,240 --> 00:16:33,040
PRESENCE OF THE PROTEIN,

361
00:16:33,040 --> 00:16:34,920
MAINTAINS LOW RATE OF

362
00:16:34,920 --> 00:16:36,160
TRANSCRIPTION.

363
00:16:36,160 --> 00:16:37,960
WHEN THE FIBRO BLAST REACH THE

364
00:16:37,960 --> 00:16:39,960
CELL, AND THE TF2 H

365
00:16:39,960 --> 00:16:40,960
PHOSPHORALATE, AND THE PROTEIN

366
00:16:40,960 --> 00:16:42,160
IS RELEASED FROM THE PROMOTER

367
00:16:42,160 --> 00:16:45,800
AND NOW THE PROMOTER CAN START

368
00:16:45,800 --> 00:16:50,280
TO TRANSCRIBE AT A HIGH RATE.

369
00:16:50,280 --> 00:16:52,120
IN TTD, NOT EXPRESS,

370
00:16:52,120 --> 00:16:55,000
SOPHISTICATED THE TTD SPECIFIC

371
00:16:55,000 --> 00:16:58,160
MUTATION IN TF2 H, WE OBSERVE

372
00:16:58,160 --> 00:17:03,240
THAT THE CELL DENSITY, SREBP1 IS

373
00:17:03,240 --> 00:17:04,400
PRESENT SO THE AGENT CANNOT GET

374
00:17:04,400 --> 00:17:07,720
TO THE PROTEIN SO THE GENE IS

375
00:17:07,720 --> 00:17:09,400
NOT UPREGULATED.

376
00:17:09,400 --> 00:17:12,160
BESIDE COLLAGEN 6, WE ALSO FOUND

377
00:17:12,160 --> 00:17:15,880
THIS QUESTION, IN TTD WITH THE 1

378
00:17:15,880 --> 00:17:17,200
GENE, THIS IS 1 OF THE GENE OF

379
00:17:17,200 --> 00:17:23,080
THE FEW GENES THAT WE SHOW A

380
00:17:23,080 --> 00:17:23,680
TRANSCRIPTION UPREGULATION IN

381
00:17:23,680 --> 00:17:25,720
TDRKS, IT IS SPECIFIC FOR TDRKS,

382
00:17:25,720 --> 00:17:29,960
IT IS ALSO THE FIBRO BLAST AND

383
00:17:29,960 --> 00:17:31,960
THE DMP1 AND THE COLLIN ACE THAT

384
00:17:31,960 --> 00:17:34,760
HAS THE ABILITY TO DEGRADE THE

385
00:17:34,760 --> 00:17:36,560
SPECIFIC COLLAGENS IN

386
00:17:36,560 --> 00:17:40,240
PARTICULAR, IN THIS CASE, THE

387
00:17:40,240 --> 00:17:41,200
COLLAGEN AND FURTHER WHEN WE

388
00:17:41,200 --> 00:17:44,080
LOOK AT NORMAL CULTURE,

389
00:17:44,080 --> 00:17:45,560
THE,AMOUNT OF THE COLLAGEN TYPE

390
00:17:45,560 --> 00:17:48,840
1, WE CAN SEE THAT THE TTD, BUT

391
00:17:48,840 --> 00:17:51,640
NOT XP FIBRO BLAST CONTAIN THE

392
00:17:51,640 --> 00:17:53,800
REDUCED AMOUNT OF THIS TYPE OF

393
00:17:53,800 --> 00:17:55,120
COLLAGEN COMPARED TO THE

394
00:17:55,120 --> 00:17:55,440
CONTROL.

395
00:17:55,440 --> 00:17:57,400
WHEREAS RGTD TYPES OF COLLAGENS

396
00:17:57,400 --> 00:18:01,480
ARE PRESENT IN THE TTD FIEB

397
00:18:01,480 --> 00:18:01,960
PROBLAST.

398
00:18:01,960 --> 00:18:03,400
THIS IS ALSO CLEAR WHEN WE LOOK

399
00:18:03,400 --> 00:18:05,400
AT THE 3 B CULTURES IN WHICH THE

400
00:18:05,400 --> 00:18:07,880
FIBRO BLAST ARE EMBEDDED IN THE

401
00:18:07,880 --> 00:18:09,200
METRICS THAT CONTAIN THE

402
00:18:09,200 --> 00:18:10,520
COLLAGEN TYPE 1.

403
00:18:10,520 --> 00:18:12,360
THE COLLAGEN IS FISCHERIBLE BY

404
00:18:12,360 --> 00:18:16,280
THE BLUE AND GREEN COLOR, AND

405
00:18:16,280 --> 00:18:18,800
CLEARLY IN THE OTHER THAT

406
00:18:18,800 --> 00:18:20,040
SURROUNDS THE TTD FIBRO BLAST,

407
00:18:20,040 --> 00:18:22,560
BUT THE CONTROL, WE LOSE THE

408
00:18:22,560 --> 00:18:23,600
BLUE STAINING INDICATING THAT

409
00:18:23,600 --> 00:18:26,000
THE THERE IS A LOSS OF COLLAGEN

410
00:18:26,000 --> 00:18:26,560
TYPE 1.

411
00:18:26,560 --> 00:18:30,880
SO, WE ALSO LOOKED AT THE DERMAL

412
00:18:30,880 --> 00:18:33,440
LAYER OF THE SKIN BIOPSIES OF

413
00:18:33,440 --> 00:18:34,760
FORMER TTD PATIENTS AND WE CAN

414
00:18:34,760 --> 00:18:37,240
CLEARLY OBSERVE THAT THERE IS A

415
00:18:37,240 --> 00:18:38,840
REDUCED CONTENT OF COLLAGEN TYPE

416
00:18:38,840 --> 00:18:41,880
1, BUT NOT AT A REDUCED COUNT OF

417
00:18:41,880 --> 00:18:45,040
OTHER TYPE OF COLLAGENS AND THE

418
00:18:45,040 --> 00:18:46,640
REDUCTION, WE OBSERVED THE

419
00:18:46,640 --> 00:18:49,520
REDUCTION COMPARED POETIC THE

420
00:18:49,520 --> 00:18:51,280
AMOUNT OF COLLAGEN TYPE THAT WE

421
00:18:51,280 --> 00:18:52,760
OBSERVE IN KNOWN TTD

422
00:18:52,760 --> 00:18:53,760
INDIVIDUALSEE USE DIFFERENT AGES

423
00:18:53,760 --> 00:18:58,160
BECAUSE WE HAVE TO REMEMBER THAT

424
00:18:58,160 --> 00:19:03,320
THE TTD IS A PROTEIN DISORDER,

425
00:19:03,320 --> 00:19:06,000
SO IT'S AFFECTED BY A PREMATURE

426
00:19:06,000 --> 00:19:06,240
AGENT.

427
00:19:06,240 --> 00:19:08,240
SO THIS INDICATES THAT THE TTD

428
00:19:08,240 --> 00:19:10,440
FIBRO BLAST IN THE AREA THAT

429
00:19:10,440 --> 00:19:12,080
SURROUNDS THE FIEB PROBLAST NEXT

430
00:19:12,080 --> 00:19:13,880
IN THE EXTRA CELLULAR REGION

431
00:19:13,880 --> 00:19:19,200
THAT IS THE PRESENCE OF A LOOSE

432
00:19:19,200 --> 00:19:28,560
COLLAGEN AMOUNT SO IT IS A

433
00:19:28,560 --> 00:19:39,040
REDUCED COLLEGIA GENERATED

434
00:19:41,000 --> 00:19:48,320
AMOUNT THEY ALL CONTROL FIBRO

435
00:19:48,320 --> 00:19:51,960
BLAST, USING THOSE THAT MIGRATE

436
00:19:51,960 --> 00:19:57,800
MIGRATE AT THE LOW RATE AND WE

437
00:19:57,800 --> 00:19:59,960
CULTURE THEM MAINTAINING

438
00:19:59,960 --> 00:20:01,720
EITHER--SORRY WE CULTURE THEM

439
00:20:01,720 --> 00:20:04,520
WITH A NORMAL FIBRO BLAST OR

440
00:20:04,520 --> 00:20:07,200
FIBRO BLAST MAINTAINING THE XP

441
00:20:07,200 --> 00:20:09,560
AND THE SECOND FIBRO BLAST IN

442
00:20:09,560 --> 00:20:12,160
THE SAME MEDIUM. 

443
00:20:12,160 --> 00:20:21,520
WE COULD OBSERVE THAT 1

444
00:20:21,520 --> 00:20:23,640
EXPERIENCE WHEN THEY ARE CO

445
00:20:23,640 --> 00:20:25,160
CULTURE WITH THE FORMAL FIBRO

446
00:20:25,160 --> 00:20:25,360
BLAST.

447
00:20:25,360 --> 00:20:27,720
SO THIS INDICATES THAT THE TTD

448
00:20:27,720 --> 00:20:29,720
SECRETE AND PRODUCE THE FACTORS

449
00:20:29,720 --> 00:20:34,320
THAT CAN INFLUENCE THE MIGRATION

450
00:20:34,320 --> 00:20:37,080
RATE OF THE FIBRO BLAST, SO

451
00:20:37,080 --> 00:20:39,480
THOSE SAY THAT THIS SECRETE

452
00:20:39,480 --> 00:20:42,560
FACTOR IS INDEED AN NP 1 AND WE

453
00:20:42,560 --> 00:20:53,240
USE AN INHIBITOR OF DMT, AND

454
00:20:53,240 --> 00:20:55,320
ENZYMES THAT THE WE CAN ALSO

455
00:20:55,320 --> 00:20:58,160
SLOW DOWN THE FIBRO BLAST

456
00:20:58,160 --> 00:20:58,720
SURROUNDED BY TTP.

457
00:20:58,720 --> 00:21:01,640
SO BECAUSE THE MUTATION IN THE

458
00:21:01,640 --> 00:21:04,120
COLLAGEN TYPE 6 GENES THAT ARE

459
00:21:04,120 --> 00:21:07,000
IN THE COLLAGEN TYPE 1 GENES ARE

460
00:21:07,000 --> 00:21:09,320
RESPONSIBLE FOR HUMAN GENETIC

461
00:21:09,320 --> 00:21:13,960
DISORDERS THAT WE DECIDED TO

462
00:21:13,960 --> 00:21:16,400
COMPARE THE PHENOTYPE OF THE

463
00:21:16,400 --> 00:21:17,760
COLLAGEN 6 PATIENTS, THEY ARE

464
00:21:17,760 --> 00:21:20,400
AFFECTED BY THE CONGENIT ONAL

465
00:21:20,400 --> 00:21:30,920
MUSCLE, OR THE MUSCLE DYSTROPHY,

466
00:21:34,680 --> 00:21:36,720
SO WE ARE NOW WONDERING AND ASK

467
00:21:36,720 --> 00:21:38,360
WHETHER THE TRANSCRIPTION

468
00:21:38,360 --> 00:21:40,200
REGULATION, COLLAGEN 6 THAT WE

469
00:21:40,200 --> 00:21:45,920
OBSERVE ONLY SPECIFIC CELL

470
00:21:45,920 --> 00:21:47,320
CULTURE CONDITION MAY AFFECT FOR

471
00:21:47,320 --> 00:21:50,440
THE JOIN CHAPTERS THAT BEEN

472
00:21:50,440 --> 00:21:52,640
REPORTED THAT MEAN SOME TO TCB

473
00:21:52,640 --> 00:21:54,240
PATIENTS AND WHETHER THE

474
00:21:54,240 --> 00:21:57,920
OVEREXPRESSION OF AN NTP 1 COULD

475
00:21:57,920 --> 00:21:59,640
EXPLAIN THE PROGRESSIVE BONE

476
00:21:59,640 --> 00:22:02,480
ACTIVATIONS THAT HAVE BEEN

477
00:22:02,480 --> 00:22:03,280
DESCRIBED IN TTD.

478
00:22:03,280 --> 00:22:06,160
A THIRD GENE THAT WE FOUND

479
00:22:06,160 --> 00:22:15,800
TRANSCRIPTIONOT REGULATOR SYSTEM

480
00:22:15,800 --> 00:22:18,000
PPGIS AND THIS IS COMPARED TO

481
00:22:18,000 --> 00:22:20,200
THE CONTROL FIBRO PLAOF THE AND

482
00:22:20,200 --> 00:22:22,760
A REDUCED PROTEIN AMOUNT IN THE

483
00:22:22,760 --> 00:22:25,240
TTD PATIENTS, MOVING MUTATION

484
00:22:25,240 --> 00:22:28,960
BUT NOT IN THE EAST MUTATION.

485
00:22:28,960 --> 00:22:34,280
SO THIS ENZYME BELONGS TO

486
00:22:34,280 --> 00:22:37,480
PATHWAY THAT'S AGE 2 AS A

487
00:22:37,480 --> 00:22:40,120
PRECURSOR AND THEN USES THE

488
00:22:40,120 --> 00:22:44,000
LAMINA A2 AS A SUBSET THE PROOF

489
00:22:44,000 --> 00:22:47,640
THE O GLANDIN I2, SO THOSE ARE

490
00:22:47,640 --> 00:22:51,720
THE ACTIVE THAT ARE IMPORTANT

491
00:22:51,720 --> 00:22:54,920
FOR FUNCTION THIS HAS BEEN SHOWN

492
00:22:54,920 --> 00:22:56,880
TO HAVE IMPORTANT AS AN

493
00:22:56,880 --> 00:23:00,240
IMPORTANT REGULATOR OF THE

494
00:23:00,240 --> 00:23:02,240
CARDIOVASCULAR SYSTEM, IT IS AN

495
00:23:02,240 --> 00:23:06,600
INHIBITOR OF THE PLACE OF

496
00:23:06,600 --> 00:23:08,600
OBLIGATIONS, AND IT ALSO

497
00:23:08,600 --> 00:23:10,040
IMPORTANT IT IS IMPORTANT

498
00:23:10,040 --> 00:23:18,080
ENDOGENOUS VASE O DILATOR.

499
00:23:18,080 --> 00:23:21,160
PLGA2 HAS SHOWN IT CAN BE IN THE

500
00:23:21,160 --> 00:23:22,880
IMMUNE SYSTEM, THE INNATE AND

501
00:23:22,880 --> 00:23:24,440
INDUSTRIOUSIVE IMMUNE SYSTEM AS

502
00:23:24,440 --> 00:23:28,120
WELL AS A FACTOR ON THE OLIGIO

503
00:23:28,120 --> 00:23:30,720
CITES DIFFERENTIATION AND IT HAS

504
00:23:30,720 --> 00:23:33,880
BEEN FOUND OVER A SPLICE IN THE

505
00:23:33,880 --> 00:23:35,040
STROMA THAT SURROUNDS A SPECIFIC

506
00:23:35,040 --> 00:23:38,360
TYPE OF TUMOR CELL, MAINLY AT

507
00:23:38,360 --> 00:23:43,040
THE LEVEL OF THE LUNGS.

508
00:23:43,040 --> 00:23:45,040
SO CONSIDERING THAT TTD, THE

509
00:23:45,040 --> 00:23:51,560
FREQUENTLY PRESENT A WEAK IMMUNE

510
00:23:51,560 --> 00:23:53,920
SYSTEM AND THEY ALSO CANNOT

511
00:23:53,920 --> 00:23:56,320
ACCUMULATE THE SUBCUTANEOUS

512
00:23:56,320 --> 00:23:56,720
FACT.

513
00:23:56,720 --> 00:24:03,200
WE ARE NOW WONDERING WHETHER THE

514
00:24:03,200 --> 00:24:04,000
PGIS TRANSCRIPTION REGULATION

515
00:24:04,000 --> 00:24:06,240
WILL SOMEHOW ACCOUNT FOR THIS

516
00:24:06,240 --> 00:24:10,920
FEATURE IN TD, AND THEN

517
00:24:10,920 --> 00:24:11,640
EVENTUALLY IT WILL SOMEHOW

518
00:24:11,640 --> 00:24:13,960
CONTRIBUTE TO THE LACK OF CANCER

519
00:24:13,960 --> 00:24:15,280
FORMATION IN T, TD.

520
00:24:15,280 --> 00:24:17,160
SO IN TRYING TO UNDERSTAND IT

521
00:24:17,160 --> 00:24:19,560
AND PARTIALLY ADDRESS THIS

522
00:24:19,560 --> 00:24:21,120
QUESTION, WE EXTENDED THE

523
00:24:21,120 --> 00:24:22,720
ANALYSIS TO ANOTHER GROUP OF

524
00:24:22,720 --> 00:24:26,040
PATIENTS, THESE ARE TTD PATIENTS

525
00:24:26,040 --> 00:24:27,360
BECAUSE THEY PRESENT THE TIGER

526
00:24:27,360 --> 00:24:30,840
TAIL OF THE PATH, BUT THEY ARE

527
00:24:30,840 --> 00:24:34,600
NOT MUTATED IN THE COMPLEX, THIS

528
00:24:34,600 --> 00:24:37,160
REPRESENT IN A NORMAL NUCLEOTIDE

529
00:24:37,160 --> 00:24:39,440
EXCISION REPAIR ACTIVITY AND THE

530
00:24:39,440 --> 00:24:42,080
CELLS RESPOND NORMALLY TO THE UV

531
00:24:42,080 --> 00:24:43,920
RADIATION.

532
00:24:43,920 --> 00:24:45,320
SO, WE OBSERVED THE AMOUNT OF

533
00:24:45,320 --> 00:24:49,640
THIS PATIENT THAT IS A WIDE

534
00:24:49,640 --> 00:24:52,000
HETEROGENERATEDDITY THAT CAN BE

535
00:24:52,000 --> 00:24:52,840
MUTATE INDEED SEVERAL DIFFERENT

536
00:24:52,840 --> 00:24:55,000
GENES AND WE COULD OBSERVE THAT

537
00:24:55,000 --> 00:24:57,520
BOTH THE PROTEIN LEVEL AND THE

538
00:24:57,520 --> 00:24:58,320
TRANSCRIPT LEVEL INDEPENDENTLY

539
00:24:58,320 --> 00:25:00,200
ON THE GENE, THE MUTATED GENE,

540
00:25:00,200 --> 00:25:05,480
THE CELLS OF THE PATIENT CONTAIN

541
00:25:05,480 --> 00:25:08,040
REDUCED AMOUNT OF THE PLGIS, AND

542
00:25:08,040 --> 00:25:10,400
THIS IS CANNED WHAT BY

543
00:25:10,400 --> 00:25:13,560
RECRUITMENT OF BOTH THE TF2 H

544
00:25:13,560 --> 00:25:15,160
AND THE OLIGMERACE 2 ON THE GENE

545
00:25:15,160 --> 00:25:15,440
PROMOTER.

546
00:25:15,440 --> 00:25:18,360
BOTH IN THE PATIENTS, MUTATING

547
00:25:18,360 --> 00:25:20,080
ACTIVATE AND ALSO IN THE

548
00:25:20,080 --> 00:25:21,880
PATIENTS THAT ARE NOT MUTATING.

549
00:25:21,880 --> 00:25:24,680
SO THEY HAVE A NORMAL--DNA

550
00:25:24,680 --> 00:25:27,000
REPAIR ACTIVITY.

551
00:25:27,000 --> 00:25:28,320
SO INDICATING THAT THIS IS THE

552
00:25:28,320 --> 00:25:34,760
FIRST TIME AND THATY WE FOUND A

553
00:25:34,760 --> 00:25:36,760
TRANSCRIPTION D-FACTOR THAT

554
00:25:36,760 --> 00:25:38,720
ACCOUNTS AND IS PRESERVED, THE

555
00:25:38,720 --> 00:25:43,040
REGULATION IN ALL TTD PATIENTS.

556
00:25:43,040 --> 00:25:46,360
SO, IT'S WHAT WE CALL A GOLD

557
00:25:46,360 --> 00:25:47,520
STANDARD MARKER FOR THIS

558
00:25:47,520 --> 00:25:48,880
DISORDER AND WE HOPE THAT IT

559
00:25:48,880 --> 00:25:54,480
MIGHT CONTRIBUTE TO THE CLINICAL

560
00:25:54,480 --> 00:25:55,320
DIAGNOSIS.

561
00:25:55,320 --> 00:25:57,920
CONCERNING THE PATIENT, THE TTD

562
00:25:57,920 --> 00:26:00,960
PATIENTS PRESENT NORMAL DNA

563
00:26:00,960 --> 00:26:01,720
REPAIR ACTIVITY.

564
00:26:01,720 --> 00:26:03,920
IMPORTANT STUDIES HAVE BEEN

565
00:26:03,920 --> 00:26:05,920
PERFORMED AND IN SUPPORT OF THE

566
00:26:05,920 --> 00:26:10,600
FACT THAT TTD CAN REALLY BE

567
00:26:10,600 --> 00:26:11,640
ASSOCIATED WITH TRANSCRIPTIONAL

568
00:26:11,640 --> 00:26:12,760
IMPAIRMENT THIS CAME FROM A

569
00:26:12,760 --> 00:26:16,000
STUDY THAT WE HAVE PERFORMED IN

570
00:26:16,000 --> 00:26:19,880
COLLABORATION WITH KEN KRAEMER,

571
00:26:19,880 --> 00:26:21,640
WE BOTH FOUND PATIENTS THAT WERE

572
00:26:21,640 --> 00:26:23,040
MUTATING WITH THE GENE, WE FOUND

573
00:26:23,040 --> 00:26:26,120
2 CASES OTHERS BOTH CONTAINING

574
00:26:26,120 --> 00:26:29,480
THE PATIENT TO SHOW THE

575
00:26:29,480 --> 00:26:30,880
DIFFICULT TYPE OF

576
00:26:30,880 --> 00:26:33,080
[INDISCERNIBLE] AND THE 2

577
00:26:33,080 --> 00:26:34,760
PATIENTS WERE HOMOZYGOUS FOR

578
00:26:34,760 --> 00:26:36,720
THIS MUTATION IN THE SAME GENE

579
00:26:36,720 --> 00:26:39,960
WHICH IS THE GTF2 E2 GENE WHICH

580
00:26:39,960 --> 00:26:43,920
IS ENCODES THE BETA UNITS OF THE

581
00:26:43,920 --> 00:26:44,520
TRANSCRIPTION FACTDOR 3.

582
00:26:44,520 --> 00:26:46,640
SO THE TRANSCRIPTION FACTOR 3

583
00:26:46,640 --> 00:26:49,600
MADE THE SUBUNITS AND IS ALSO

584
00:26:49,600 --> 00:26:53,120
LIKE TF2 H AND IMPORTANT AND

585
00:26:53,120 --> 00:26:54,240
ESSENTIAL ELEMENT IN THE

586
00:26:54,240 --> 00:26:55,960
FORMATION OF THE INITIATION

587
00:26:55,960 --> 00:26:57,720
COMPLEX, THE INTERACTION BETWEEN

588
00:26:57,720 --> 00:26:59,760
TF2 H AND EXTREMELY IMPORTANT

589
00:26:59,760 --> 00:27:02,240
ALSO TO ACTIVATE THE KINASE

590
00:27:02,240 --> 00:27:06,120
ACTIVITY OF TF2 H AND THEN THE

591
00:27:06,120 --> 00:27:07,840
SUBSEQUENT PHOSPHORYLATION AND

592
00:27:07,840 --> 00:27:09,040
ACTIVATION OF [INDISCERNIBLE].

593
00:27:09,040 --> 00:27:10,800
SO TOGETHER WE CAN, WE ARE ABLE

594
00:27:10,800 --> 00:27:13,680
TO DEMONSTRATE THAT THE

595
00:27:13,680 --> 00:27:16,640
MUTATIONS, BOTH MUTATIONS

596
00:27:16,640 --> 00:27:17,560
AFFECTING, AFFECTERRING THE

597
00:27:17,560 --> 00:27:20,280
STABILITY OF THE TF2 BETA UNIT

598
00:27:20,280 --> 00:27:23,800
BUT ALSO THE TF2 IN OUR SUBUNIT,

599
00:27:23,800 --> 00:27:25,520
INDICATING THAT SIMILARLY TO THE

600
00:27:25,520 --> 00:27:28,040
TF2 H AND MUTATED THE CELLS,

601
00:27:28,040 --> 00:27:31,000
ALSO IN THIS CASE, THERE IS A

602
00:27:31,000 --> 00:27:33,200
REDUCED AMOUNT OF THE BASAL

603
00:27:33,200 --> 00:27:36,880
TRANSCRIPTION FACTOR.

604
00:27:36,880 --> 00:27:38,360
SO THESE WERE SURPRISING SOME

605
00:27:38,360 --> 00:27:40,920
SUPPORT AND SUGGESTING THAT TTD

606
00:27:40,920 --> 00:27:42,000
CLINICAL FEATURE ARE REALLY

607
00:27:42,000 --> 00:27:45,800
RELATED TO THE TRANSCRIPTIONAL

608
00:27:45,800 --> 00:27:46,160
DEFECT.

609
00:27:46,160 --> 00:27:48,560
BUT THEN IMMEDIATELY AFTER THAT,

610
00:27:48,560 --> 00:27:53,880
IN OUR LAB, AND IN COLLABORATION

611
00:27:53,880 --> 00:27:56,840
WITH [INDISCERNIBLE] IN THE

612
00:27:56,840 --> 00:27:57,560
[INDISCERNIBLE] LAB, IDENTIFY

613
00:27:57,560 --> 00:27:59,640
ANOTHER FEW CASES OF THE

614
00:27:59,640 --> 00:28:01,240
PATIENTS THAT ARE NOW PROFICIENT

615
00:28:01,240 --> 00:28:05,440
SO THEY DON'T HAVE

616
00:28:05,440 --> 00:28:05,840
[INDISCERNIBLE].

617
00:28:05,840 --> 00:28:09,600
THEY PRESENT THE TIGER TAIL PAIR

618
00:28:09,600 --> 00:28:10,880
OF ABNORMALITY AND THESE FEW

619
00:28:10,880 --> 00:28:13,280
CASES OF PATIENTS ARE MUTATED IN

620
00:28:13,280 --> 00:28:15,120
GENES SO THAT ENCODE FOR A GROUP

621
00:28:15,120 --> 00:28:18,120
OF PROTEIN THAT ARE CALLED THE

622
00:28:18,120 --> 00:28:21,160
TRNA PIECE, THE SPECIFIC TRNA

623
00:28:21,160 --> 00:28:22,160
SYNTH TAIS INHIBITORS HAVE BEEN

624
00:28:22,160 --> 00:28:24,240
FOUND MUTATED AND THESE ARE

625
00:28:24,240 --> 00:28:26,800
ENZYMES SO THAT ARE EASIER TO

626
00:28:26,800 --> 00:28:29,600
UPLOAD THE PROGRAM CORRECT AMINO

627
00:28:29,600 --> 00:28:31,520
ACIDS ON THE CORRESPONDING TRNA,

628
00:28:31,520 --> 00:28:34,000
SO WHEN THE TRNA IS CHARGED WITH

629
00:28:34,000 --> 00:28:38,200
THE IMMUNO, IT'S USED TO--IN THE

630
00:28:38,200 --> 00:28:39,480
PROTEIN SYNTHESIS PROCESS BY THE

631
00:28:39,480 --> 00:28:41,760
RIBOSOMES FOR THE PROTEIN

632
00:28:41,760 --> 00:28:42,200
SYNTHESIS.

633
00:28:42,200 --> 00:28:45,760
SO WHAT WE OBSERVE IS THAT THE

634
00:28:45,760 --> 00:28:47,320
OTHER YOU HADITATIONS THAT WE

635
00:28:47,320 --> 00:28:48,600
HAVE IDENTIFIED IN THESE

636
00:28:48,600 --> 00:28:51,600
PATIENTS ALSO RESULT IN REDUCED

637
00:28:51,600 --> 00:28:52,360
PROTEIN SYNTHESIS.

638
00:28:52,360 --> 00:28:56,760
SO THESE CELLS CONTAIN REDUCED

639
00:28:56,760 --> 00:29:00,240
AMOUNT OF THE [INDISCERNIBLE]

640
00:29:00,240 --> 00:29:01,040
TRA SYNTH TAIS INHIBITOR, BUT

641
00:29:01,040 --> 00:29:04,600
BECAUSE OF THAT WE HAD TO

642
00:29:04,600 --> 00:29:06,160
RECONSIDER AND REVISE OUR IDEA

643
00:29:06,160 --> 00:29:07,560
OF CHILD DYSTROPHY AND NOW WE

644
00:29:07,560 --> 00:29:09,560
ARE USING A BROADER DEFINITION

645
00:29:09,560 --> 00:29:11,760
SAYING THAT TTD IS NOT ONLY

646
00:29:11,760 --> 00:29:15,160
TRANSCRIPTIONAL BUT THE GENE

647
00:29:15,160 --> 00:29:16,560
EXPRESSION DISORDER.

648
00:29:16,560 --> 00:29:20,880
AND THE SECOND PART OF MY TALK,

649
00:29:20,880 --> 00:29:24,880
I WOULD LIKE TO FOCUS ON THE

650
00:29:24,880 --> 00:29:26,600
THIRD, THE DISORDER ASSOCIATED

651
00:29:26,600 --> 00:29:30,560
WITH DNA REPAIR FACTOR WHICH IS

652
00:29:30,560 --> 00:29:33,840
THE COCKAYNE SYNDROME, IT'S THE

653
00:29:33,840 --> 00:29:36,160
MAJORITY OF PATIENTS ARE CSA OR

654
00:29:36,160 --> 00:29:38,520
CSG GENE AND THESE PLAY AN

655
00:29:38,520 --> 00:29:41,640
IMPORTANT ROLE IN TRANSCRIPTION

656
00:29:41,640 --> 00:29:42,920
REPAIR, SO THEY ARE SHOWN TO

657
00:29:42,920 --> 00:29:44,440
REMOVE IT, TO RECOGNIZE THE

658
00:29:44,440 --> 00:29:47,800
LESIONS THAT INTERFERE WITH THE

659
00:29:47,800 --> 00:29:48,360
TRANSCRIPTIONAL PROCESS.

660
00:29:48,360 --> 00:29:52,000
IF WE LOOK HERE AT THE PICTURES

661
00:29:52,000 --> 00:29:56,240
OF THE CS PATIENTS, OF THE SAME

662
00:29:56,240 --> 00:29:58,320
PATIENTS OVER THE EAR, WE CAN

663
00:29:58,320 --> 00:29:59,800
CLEARLY OBSERVE THE APPEARANCE

664
00:29:59,800 --> 00:30:01,160
OF THE GENERAL FEATURES THAT

665
00:30:01,160 --> 00:30:03,480
AFFECT THE PATIENTS, SO THIS IS

666
00:30:03,480 --> 00:30:05,240
AN ITALIAN PATIENT, SO THAT'S

667
00:30:05,240 --> 00:30:07,480
CARRYING A MUTATION IN THE CSA

668
00:30:07,480 --> 00:30:09,800
GENE, SHE DIED AROUND THE AGE

669
00:30:09,800 --> 00:30:11,920
EVER 18 YEARS, WITH THE PROBLEMS

670
00:30:11,920 --> 00:30:16,800
THAT MANY DIFFERENT ORGANS.

671
00:30:16,800 --> 00:30:18,280
SO WOO CAN--BASED ON THAT BY

672
00:30:18,280 --> 00:30:19,600
LOOKING AT THE PROGRESSION OF

673
00:30:19,600 --> 00:30:23,480
THE DISORDER WE CAN CLAIRLY SAY

674
00:30:23,480 --> 00:30:26,920
THAT CSA AND IN A SIMILAR WAY

675
00:30:26,920 --> 00:30:32,120
CSB PLAY AN IMPORTANT ROLE IN

676
00:30:32,120 --> 00:30:34,200
PRESERVING THE FEATURE AND THE

677
00:30:34,200 --> 00:30:36,160
ORGAN FUNCTIONALITY AND THEY

678
00:30:36,160 --> 00:30:39,600
COME TO THE APPEARANCE OF THE

679
00:30:39,600 --> 00:30:41,160
DEGENERATIVE FEATURES.

680
00:30:41,160 --> 00:30:44,640
BUT HOWEVER, WE WERE VERY

681
00:30:44,640 --> 00:30:48,520
SURPRISED THAT WHEN IN 2009,

682
00:30:48,520 --> 00:30:50,520
ANOTHER NOW IN COLLABORATION

683
00:30:50,520 --> 00:30:52,320
WITH THE [INDISCERNIBLE].

684
00:30:52,320 --> 00:30:55,680
THEY WERE CHARACTERIZING A

685
00:30:55,680 --> 00:30:56,680
PATIENT [INDISCERNIBLE] PATIENT

686
00:30:56,680 --> 00:30:59,200
THAT WAS CLASSIFIED AS A UV

687
00:30:59,200 --> 00:31:04,800
SENSITIVE, AFFECTED BY THE UV

688
00:31:04,800 --> 00:31:09,640
SYNDROME, BECAUSE THE ONLY ONLY

689
00:31:09,640 --> 00:31:11,040
SHOWED SEBSATIVITY AND AND THEN

690
00:31:11,040 --> 00:31:12,680
THE PATIENTS SHOW A NORMAL

691
00:31:12,680 --> 00:31:15,080
PHYSICAL AND MENTAL DEVELOPMENT.

692
00:31:15,080 --> 00:31:17,640
BUT WHEN THEY PERFORM, WHEN IN

693
00:31:17,640 --> 00:31:20,400
THE LAB THEY PERFORM THE

694
00:31:20,400 --> 00:31:23,040
ANALYSIS TO IDENTIFY WHICH GENE

695
00:31:23,040 --> 00:31:25,080
WAS RESPONSIBLE FOR THESE NEW

696
00:31:25,080 --> 00:31:26,720
SENSITIVITY, SHE FOUND OUT THAT

697
00:31:26,720 --> 00:31:31,040
LIMITATION WAS IN THE CSA GENE,

698
00:31:31,040 --> 00:31:33,120
IN PARTICULAR IT WAS NOVEL

699
00:31:33,120 --> 00:31:35,720
MUTATIONS THAT WAS FOUND IN

700
00:31:35,720 --> 00:31:39,760
HOMOSIGNIFY SWROGGITY IN THE

701
00:31:39,760 --> 00:31:42,560
PATIENTS AND IT'S LOCATED IN THE

702
00:31:42,560 --> 00:31:53,040
C-TERMINAL OF THE PROTEIN. 

703
00:31:55,200 --> 00:31:59,720
SHE LOOKED AT THE AND THE

704
00:31:59,720 --> 00:32:09,120
SENSITIVITY TO A RADIATION

705
00:32:09,120 --> 00:32:19,600
HOWEVER, THE CELLS THAT ARE

706
00:32:23,440 --> 00:32:25,400
DAMAGE INDICATING THE SPECIFIC

707
00:32:25,400 --> 00:32:28,160
MUTATION SOMEHOW CAN AFFECT THE

708
00:32:28,160 --> 00:32:29,440
TRANSCRIPTION CAP LANREPAIR BUT

709
00:32:29,440 --> 00:32:31,240
IT DOESN'T AFFECT OTHER PATHWAY

710
00:32:31,240 --> 00:32:35,080
IN THAT IN WHICH THE CSA IS

711
00:32:35,080 --> 00:32:35,320
INVOLVED.

712
00:32:35,320 --> 00:32:37,760
SO, WE CAN ALSO SAY THAT BASED

713
00:32:37,760 --> 00:32:40,640
ON THAT, THAT THE DEFECTIVE CNA

714
00:32:40,640 --> 00:32:41,920
PROBABLY MAINLY RESULTS IN THE

715
00:32:41,920 --> 00:32:46,080
ACTIVATION BUT WE HAVE TO

716
00:32:46,080 --> 00:32:49,160
CONSIDER THE POSSIBILITY THAT IT

717
00:32:49,160 --> 00:32:51,960
WAS MOTOR LOGICAL AND PHYSICAL

718
00:32:51,960 --> 00:32:52,800
DETERIORATIONS AND PREMATURE

719
00:32:52,800 --> 00:32:54,800
AGING FEATURES THAT WE SEE IN

720
00:32:54,800 --> 00:32:56,400
THE CS PATIENTS, THEY PROBABLY

721
00:32:56,400 --> 00:32:58,560
REFLECT ADDITIONAL ROLES THAT

722
00:32:58,560 --> 00:33:02,320
THE CSA PLAYS OUTSIDE

723
00:33:02,320 --> 00:33:05,240
TRANSCRIPTION REPAIR, SO WITH

724
00:33:05,240 --> 00:33:06,760
THE IDEA TO ADDRESS, WELL, FIRST

725
00:33:06,760 --> 00:33:10,720
I HAVE TO SAY THAT THERE IS THE

726
00:33:10,720 --> 00:33:13,880
FACT THAT THE CS PROBING LATER

727
00:33:13,880 --> 00:33:15,520
ROLE OUTSIDE TRANSCRIPTION HAS

728
00:33:15,520 --> 00:33:18,160
BEEN DEMONSTRATED AND TESTED BY

729
00:33:18,160 --> 00:33:22,680
THE WORK OF MANY DIFFERENT

730
00:33:22,680 --> 00:33:25,560
GROUPS, IN FACT, THE CS PROTEIN

731
00:33:25,560 --> 00:33:28,240
ARE INVOLVED IN TRANSCRIPTION

732
00:33:28,240 --> 00:33:30,240
BOTH DNA POLYMERASE AND RNA

733
00:33:30,240 --> 00:33:31,400
POLYMERASE 1, THEY HAVE BEEN

734
00:33:31,400 --> 00:33:34,760
SHOWN TO PLAY AN IMPORTANT ROLE

735
00:33:34,760 --> 00:33:38,600
IN THE FUNCTIONALITY BECAUSE OF

736
00:33:38,600 --> 00:33:40,120
THE CSA PATIENT, ACCUMULATING

737
00:33:40,120 --> 00:33:42,920
THE POLARIZED MITOCHONDRIA O

738
00:33:42,920 --> 00:33:45,800
CHONDRIAL AND MITOCHONDRIAL FRAG

739
00:33:45,800 --> 00:33:46,760
M-TEBURKEULOSEISATIONS, CSB

740
00:33:46,760 --> 00:33:49,120
IMPACTS SO WITH A KEY PLAYER IN

741
00:33:49,120 --> 00:33:50,840
THE BASIC EXCISION REPAIR, AND

742
00:33:50,840 --> 00:33:52,840
MORE SIMPLY IT HAS BEEN

743
00:33:52,840 --> 00:33:53,720
DEMONSTRATED THAT CSB AND ALSO

744
00:33:53,720 --> 00:33:56,240
PLAY A ROLE IN THE MITOTIC

745
00:33:56,240 --> 00:33:58,760
PROCESS, SO IT IS NOT SURPRISING

746
00:33:58,760 --> 00:34:02,800
TO THINK THAT THEY PLAY A ROLE

747
00:34:02,800 --> 00:34:03,600
OUTSIDE TRANSCRIPTION REPAIR,

748
00:34:03,600 --> 00:34:08,800
BUT PROBABLY WHAT WE CAN LEARN

749
00:34:08,800 --> 00:34:11,040
FROM THE SPECIFICALLY SENSITIVE

750
00:34:11,040 --> 00:34:15,280
PATIENT IS THAT CSA PROBABLY

751
00:34:15,280 --> 00:34:17,280
INTERACTS WITH DIFFERENT

752
00:34:17,280 --> 00:34:18,320
PLATFORMS AND THE INVITATION

753
00:34:18,320 --> 00:34:20,040
WITH THE TERMINAL REGION WITH

754
00:34:20,040 --> 00:34:25,960
THE FACT OF CSA, WE ARE NORMALLY

755
00:34:25,960 --> 00:34:27,320
INTERACTING IN TRANSCRIPTION CAP

756
00:34:27,320 --> 00:34:29,640
LANREPAIR BUT DOESN'T AFFECT THE

757
00:34:29,640 --> 00:34:31,360
INTERACTION OF CSA WITH OTHER

758
00:34:31,360 --> 00:34:33,360
PARTNERS, THAT ARE RELEVANT FOR

759
00:34:33,360 --> 00:34:35,560
THE OUTER FUNCTION OF CSA.

760
00:34:35,560 --> 00:34:39,120
>> SO WITH THE IDEA TO
IDENTIFY

761
00:34:39,120 --> 00:34:41,240
WHICH ARE OTHER PROTEINS

762
00:34:41,240 --> 00:34:44,760
INTERACTING PROTEINS WITH THE

763
00:34:44,760 --> 00:34:47,680
CSA FOR C SA FUNCTIONALITY, WE

764
00:34:47,680 --> 00:34:52,400
DEVELOP THE PANEL OF ISOGENIC

765
00:34:52,400 --> 00:34:54,240
CELLS, WE--BY USING FIRST WE USE

766
00:34:54,240 --> 00:34:58,120
THE FOUND EFFECTIVE IN CSA, AND

767
00:34:58,120 --> 00:35:03,200
ORGANIZE THE CELLS AND WE

768
00:35:03,200 --> 00:35:08,040
INTEGRATED A SINGLE POSSIBILITY

769
00:35:08,040 --> 00:35:11,520
OF THE CHROMOSOME 9, THAT

770
00:35:11,520 --> 00:35:13,240
CONTAINS THAT INCLUDING THE WILD

771
00:35:13,240 --> 00:35:14,280
TYPE FORM OF CSA.

772
00:35:14,280 --> 00:35:16,280
WE ALSO USE THE SAME APPROACH TO

773
00:35:16,280 --> 00:35:18,400
EXPRESS THE MUTATED SPECIFICALLY

774
00:35:18,400 --> 00:35:20,160
MUTATED OF CSA, BUT TODAY I WILL

775
00:35:20,160 --> 00:35:23,280
ONLY FOCUS ON THE WILD TYPE CSA.

776
00:35:23,280 --> 00:35:27,120
SO WE FIRST VERIFY THIS QUESTION

777
00:35:27,120 --> 00:35:32,320
OF THE COMBINATION OF THE TOPIC

778
00:35:32,320 --> 00:35:32,680
GENE.

779
00:35:32,680 --> 00:35:34,320
THE TRANSGENE WE VERIFIED THAT

780
00:35:34,320 --> 00:35:35,760
PROPOSED DISCLOSURE TEEN WAS

781
00:35:35,760 --> 00:35:37,960
LOCALIZING IN THE CASE, AND WE

782
00:35:37,960 --> 00:35:39,760
SHOULD CHECK THE FUNCTIONALITY

783
00:35:39,760 --> 00:35:44,000
OF THIS PROTEIN, BECAUSE THE C

784
00:35:44,000 --> 00:35:45,320
SA DEFACTOR CELLS IN THE WILD

785
00:35:45,320 --> 00:35:49,080
TYPE FORM OF CSA, COULD RECOVER

786
00:35:49,080 --> 00:35:52,840
BOTH OF THE UV SENSITIVITY AND

787
00:35:52,840 --> 00:35:56,400
ALSO THE SENSITIVITY TOWARDS THE

788
00:35:56,400 --> 00:35:56,880
STEPS.

789
00:35:56,880 --> 00:35:58,800
SO, THE PROTEIN IS FUNCTIONAL

790
00:35:58,800 --> 00:36:02,400
AND THANKS TO THE FACT THAT THE

791
00:36:02,400 --> 00:36:05,520
PROTEIN HAS DUAL TARGET ON THE

792
00:36:05,520 --> 00:36:08,360
C-TERMINAL REGION.

793
00:36:08,360 --> 00:36:09,760
WE COULD PERFORM

794
00:36:09,760 --> 00:36:13,000
AUTHENTIFICATIONS TO IDENTIFY

795
00:36:13,000 --> 00:36:16,400
AND ISOLATE CSA INTERACTION AND

796
00:36:16,400 --> 00:36:19,120
THEN BY MASS SPEC TROMETRY WE

797
00:36:19,120 --> 00:36:20,720
IDENTIFY WHICH PROTEINS INTERACT

798
00:36:20,720 --> 00:36:23,840
WITH THE CSA, WE END UP WITH A

799
00:36:23,840 --> 00:36:25,960
CONSIDERABLE NUMBER OF CSA

800
00:36:25,960 --> 00:36:27,600
INTERACTIVES, ALL THE PROTEINS

801
00:36:27,600 --> 00:36:30,800
THAT HAVE KNOWN TO ISHT ACT WITH

802
00:36:30,800 --> 00:36:31,920
THE CSA TRANSCRIPTION REPAIR

803
00:36:31,920 --> 00:36:33,040
HAVE BEEN IDENTIFIED BUT ALSO

804
00:36:33,040 --> 00:36:36,920
SEVERAL OF THE NOVEL PROTEINS

805
00:36:36,920 --> 00:36:41,120
AND AMOUNT THEM THE FIBRO

806
00:36:41,120 --> 00:36:43,040
CHELATASE, SO THAT WAS AN

807
00:36:43,040 --> 00:36:45,240
INTERESTING PROTEIN CLASS

808
00:36:45,240 --> 00:36:46,880
BECAUSE IT IS FIRST AS A MIGHT

809
00:36:46,880 --> 00:36:48,960
ON CHONDRIAL PROTEIN AND IT IS

810
00:36:48,960 --> 00:36:56,760
KNOWN, IT'S AN ENZYME THAT IS

811
00:36:56,760 --> 00:36:58,920
IMPORTANT TO UPLOAD THE

812
00:36:58,920 --> 00:36:59,960
[INDISCERNIBLE] INTO THE 2 TEEN

813
00:36:59,960 --> 00:37:03,560
9 SO IT CATALYZES AND MEDIATES

814
00:37:03,560 --> 00:37:06,680
THE BIOSIPGHT SIS OF THE LAST

815
00:37:06,680 --> 00:37:07,040
[INDISCERNIBLE].

816
00:37:07,040 --> 00:37:08,320
THE MUTATION IN FACT ARE FOUND

817
00:37:08,320 --> 00:37:12,320
IN PATIENTS AFFECTED BY THE

818
00:37:12,320 --> 00:37:12,720
[INDISCERNIBLE].

819
00:37:12,720 --> 00:37:15,160
THE PATIENT SHOW SEVERE AND PAIN

820
00:37:15,160 --> 00:37:17,240
EMPLOY PHOTO TOXIC REACTIONS SO

821
00:37:17,240 --> 00:37:18,520
THEY ARE PHOTO SENSITIVE, BOTH

822
00:37:18,520 --> 00:37:20,000
AT THE LEVEL OF THE SKIN BUT

823
00:37:20,000 --> 00:37:22,240
ALSO THE LEVEL OF THE LIVER.

824
00:37:22,240 --> 00:37:24,400
AND THIS IS PROBABLY BECAUSE IT

825
00:37:24,400 --> 00:37:31,480
IS DUE TO THE FACT THAT THE

826
00:37:31,480 --> 00:37:32,240
PATIENTS ACCUMULATE

827
00:37:32,240 --> 00:37:34,840
[INDISCERNIBLE] IN THEIR BLOOD.

828
00:37:34,840 --> 00:37:39,720
SO WE DECIDE TO INVESTIGATE THE

829
00:37:39,720 --> 00:37:42,800
INTERACTIONS BETWEEN FECH AND

830
00:37:42,800 --> 00:37:45,520
THE DNA, OOH EXPOO FOUND IT'S

831
00:37:45,520 --> 00:37:47,920
NOT SO MUCH INSIDE THE

832
00:37:47,920 --> 00:37:50,800
MITOCHONDRIA, BUT MORE OCCURRING

833
00:37:50,800 --> 00:37:53,040
OUTSIDE THE MITOCHONDRIA, BY

834
00:37:53,040 --> 00:37:54,360
FORMING THE LIGATION ASSAY,

835
00:37:54,360 --> 00:37:56,400
THERE IS INTERACTION BETWEEN THE

836
00:37:56,400 --> 00:37:58,200
2 PROTEINS INSIDE AND IN

837
00:37:58,200 --> 00:38:02,000
PARTICULARLY IN THE AREA THAT

838
00:38:02,000 --> 00:38:03,040
THE [INDISCERNIBLE].

839
00:38:03,040 --> 00:38:09,200
SO WE WENT FURTHER AND

840
00:38:09,200 --> 00:38:10,840
WE--VERIFIED THAT FACTOR WAS IN

841
00:38:10,840 --> 00:38:13,640
FACT PRESENT INSIDE THE

842
00:38:13,640 --> 00:38:14,000
[INDISCERNIBLE].

843
00:38:14,000 --> 00:38:16,320
AND THEN WE WENT BACK TO OUR

844
00:38:16,320 --> 00:38:17,920
MASS [INDISCERNIBLE] ANALYSIS,

845
00:38:17,920 --> 00:38:20,160
TO SEE WHETHER OTHER PROTEINS

846
00:38:20,160 --> 00:38:25,240
INTERACT WITH CSA THAT WERE ALSO

847
00:38:25,240 --> 00:38:26,600
FOUND INSIDE [INDISCERNIBLE],

848
00:38:26,600 --> 00:38:29,600
AND WE FOUND SOME SPECIFIC

849
00:38:29,600 --> 00:38:31,400
RIBOSOMAL PROTEIN THAT BELONGED

850
00:38:31,400 --> 00:38:34,840
TO THE SMALL SUBUNIT OF THE

851
00:38:34,840 --> 00:38:36,320
RIBOSOME [INDISCERNIBLE], SO WE

852
00:38:36,320 --> 00:38:39,720
STARTED TO CHECK THE INFECTION

853
00:38:39,720 --> 00:38:41,920
BETWEEN FECH AND THESE RIBOSOMAL

854
00:38:41,920 --> 00:38:44,840
UNITS BUT ALSO THE POSSIBLE

855
00:38:44,840 --> 00:38:48,000
INTERACTION BETWEEN FECH AND DNA

856
00:38:48,000 --> 00:38:50,800
POLYMERASE 1 AND BY PERFORMING A

857
00:38:50,800 --> 00:38:56,160
2 STEP [INDISCERNIBLE] IN THE

858
00:38:56,160 --> 00:39:06,680
OUTER--BY USING THE CHROMATINS

859
00:39:12,720 --> 00:39:15,320
AND [AUDIO CUTS OUT ] WE WANT TO

860
00:39:15,320 --> 00:39:17,680
SHOW THAT ON THE CHROMATIN OF

861
00:39:17,680 --> 00:39:19,440
NORMAL FIBRO BLAST, THERE IS THE

862
00:39:19,440 --> 00:39:24,080
PRESENCE OF THE PROTEIN COMPLEX,

863
00:39:24,080 --> 00:39:26,960
WHICH CONTAINS BOTH THE

864
00:39:26,960 --> 00:39:30,480
[INDISCERNIBLE] CSA, CSB AND THE

865
00:39:30,480 --> 00:39:32,680
SPECIFIC RIBOSOMA PROTEIN.

866
00:39:32,680 --> 00:39:35,800
BY PERFORMING OF THESE

867
00:39:35,800 --> 00:39:36,400
PRECIPITATION EXPERIMENTS WE

868
00:39:36,400 --> 00:39:38,240
WERE ABLE TO OBSERVE THAT THE

869
00:39:38,240 --> 00:39:40,880
COMPLEX IS BOUND TO THE

870
00:39:40,880 --> 00:39:42,960
CHROMATIN, BUT WHEN CSA IS

871
00:39:42,960 --> 00:39:45,000
MISSING IT ALSO BINDS DUE TO

872
00:39:45,000 --> 00:39:46,480
CHROMATIN BUT THE AMOUNT OF THE

873
00:39:46,480 --> 00:39:48,160
COMPLEX IS REDUCED AS WE CAN

874
00:39:48,160 --> 00:39:52,360
OBSERVE WHEN WE CONVERT THE WIDE

875
00:39:52,360 --> 00:39:56,640
BAR THAT ARE THE FACTOR WITH C

876
00:39:56,640 --> 00:39:58,120
SA COMPARED TO THE BLACK BAR OF

877
00:39:58,120 --> 00:40:02,400
THE WILD TYPE CSA PROTEIN.

878
00:40:02,400 --> 00:40:04,760
BEFORE WE DO THE UV LIGHT WE

879
00:40:04,760 --> 00:40:05,760
OBSERVE THAT NORMAL FIBRO BLAST

880
00:40:05,760 --> 00:40:09,160
THERE IS A PARTIAL DESEGREGATION

881
00:40:09,160 --> 00:40:11,520
OF THE CONFLICTS AS WE CAN

882
00:40:11,520 --> 00:40:16,400
OBSERVE BY REDUCTION IN ALL

883
00:40:16,400 --> 00:40:19,480
THE--IN ALL THE ELEMENT OF THE

884
00:40:19,480 --> 00:40:22,400
COMPLEX, WHEREAS IN 1 CSA IS

885
00:40:22,400 --> 00:40:23,560
DEFECTIVE, THERE IS NO

886
00:40:23,560 --> 00:40:27,120
ALTERATION IN THE AMOUNT

887
00:40:27,120 --> 00:40:28,320
OF--THERE IS NO DESEGREGATION,

888
00:40:28,320 --> 00:40:31,400
SO THE FACT THAT THE CSA IS

889
00:40:31,400 --> 00:40:32,960
IMPORTANT FOR THE FORMATION OF

890
00:40:32,960 --> 00:40:34,800
THE PROTEIN OF THIS PROTEIN

891
00:40:34,800 --> 00:40:37,360
COMPLEX ON THE KRONISHEMMA TIN,

892
00:40:37,360 --> 00:40:41,320
IT HAS ALSO BEEN DEMONSTRATED BY

893
00:40:41,320 --> 00:40:42,000
PERFORMING THE PRECIPITATION,

894
00:40:42,000 --> 00:40:44,600
WHERE WE CAN OBSERVE THE

895
00:40:44,600 --> 00:40:45,840
EQUIVALENCY OF THE DNA

896
00:40:45,840 --> 00:40:48,320
POLYMERASE 1 ON THE RIBOSOMAL

897
00:40:48,320 --> 00:40:50,480
DNA, AND CLEARLY WE CAN OBSERVE

898
00:40:50,480 --> 00:40:52,440
THAT 1 CSA IS EXPRESSED, THE

899
00:40:52,440 --> 00:40:56,000
BLACK BARS, THERE IS A HIGHER

900
00:40:56,000 --> 00:40:57,400
[INDISCERNIBLE] OF DNA

901
00:40:57,400 --> 00:40:59,280
POLYMERASE, SO IN NORMAL CELLS

902
00:40:59,280 --> 00:41:02,840
IF WE SILENCE CSA, WE ALSO AGAIN

903
00:41:02,840 --> 00:41:05,040
FIND A REDUCTION IN THESE

904
00:41:05,040 --> 00:41:05,520
OTHERS.

905
00:41:05,520 --> 00:41:07,320
BUT THE SAME RESULT WE OBTAIN

906
00:41:07,320 --> 00:41:09,800
WHEN WE SILENCE THE FACT DURING

907
00:41:09,800 --> 00:41:11,920
THE CANNED WHAT INDICATING THAT

908
00:41:11,920 --> 00:41:14,200
MULTIPLE CSA, BUT ALSO THE

909
00:41:14,200 --> 00:41:16,120
[INDISCERNIBLE] ARE IMPORTANT

910
00:41:16,120 --> 00:41:18,400
FOR THE FORMATION OF THE RNA

911
00:41:18,400 --> 00:41:21,720
POLYMERASE COMPLEX ON THE

912
00:41:21,720 --> 00:41:24,240
RIBOSOMAL DNA.

913
00:41:24,240 --> 00:41:25,720
HOWEVER, WHEN WE CONTINUE THE

914
00:41:25,720 --> 00:41:28,400
EXPERIMENT TO VERIFY WHAT IF

915
00:41:28,400 --> 00:41:30,120
THERE WAS A REDUCTION IN THE

916
00:41:30,120 --> 00:41:31,680
SYNTHESIS OF THE ROBO STUDIES OF

917
00:41:31,680 --> 00:41:35,520
MULTIPLE ENDOCRINAL RNA, WE WERE

918
00:41:35,520 --> 00:41:37,320
SURPRISED TO OBSERVE THAT WHEN

919
00:41:37,320 --> 00:41:38,920
WE SILENCE CSA, IN FACT, WE

920
00:41:38,920 --> 00:41:41,720
OBLIGATIONS STAIN A REDUCTION IN

921
00:41:41,720 --> 00:41:44,800
THE RNA SIPGHT SIS, BUT WHEN WE

922
00:41:44,800 --> 00:41:47,040
SILENCE THAT, WE OBSERVE AN

923
00:41:47,040 --> 00:41:48,960
ACCUMULATION AND INCREASE AMOUNT

924
00:41:48,960 --> 00:41:51,960
OF RIBOSOMAL KD--SALLY RNA. 

925
00:41:51,960 --> 00:41:53,600
SO THE SIM THING IF WE LOOK IN

926
00:41:53,600 --> 00:41:55,760
PATIENT CELLS SO THESE ARE

927
00:41:55,760 --> 00:41:59,880
PRIMARY FIBRO BLAST FROM EITHER

928
00:41:59,880 --> 00:42:01,680
NORMAL INDIVIDUAL OR PATIENTS

929
00:42:01,680 --> 00:42:03,200
WITH CSA AND CLEAR WE WE HAVE A

930
00:42:03,200 --> 00:42:07,400
REDUCTION IN THE RNA SYNTHESIS

931
00:42:07,400 --> 00:42:09,080
AND THESE WAS EXPECTED BECAUSE

932
00:42:09,080 --> 00:42:12,560
IT WAS PREVIOUSLY DEMONSTRATED

933
00:42:12,560 --> 00:42:14,920
BY A GROUP, EVEN THEY ALL SHOW

934
00:42:14,920 --> 00:42:20,720
THAT THE CS CELLS CONTAINA A

935
00:42:20,720 --> 00:42:22,040
REDUCED RIBOSOMAL TRANSCRIPTION.

936
00:42:22,040 --> 00:42:23,960
BUT AGAIN, WHEN WE LOOK AT THE

937
00:42:23,960 --> 00:42:25,520
MUTATIONS OF THOSE IN THE GENE,

938
00:42:25,520 --> 00:42:28,600
WE CAN OBSERVE AN INCREASE

939
00:42:28,600 --> 00:42:29,400
AMOUNT OF RIBOSOMAL

940
00:42:29,400 --> 00:42:30,080
[INDISCERNIBLE].

941
00:42:30,080 --> 00:42:33,480
SO THIS IS IN COMONT WITH WHAT

942
00:42:33,480 --> 00:42:35,160
WE OBSERVE FOR THE RNA

943
00:42:35,160 --> 00:42:36,600
POLYMERASE 1 ON THE PROMOTER SO

944
00:42:36,600 --> 00:42:40,800
TRY TO UNDERSTAND THAT THE

945
00:42:40,800 --> 00:42:42,120
REASON OF THIS FREQUENCY, WE

946
00:42:42,120 --> 00:42:45,720
WE--WE--YOU FORM A REALTIME PC R

947
00:42:45,720 --> 00:42:47,960
ANALYSIS, IN PATIENTS FIBRO

948
00:42:47,960 --> 00:42:51,720
BLAST, AND THAT WE COULD CLEARLY

949
00:42:51,720 --> 00:42:56,720
OBSERVE THAT WHEN WE TRACK THE

950
00:42:56,720 --> 00:42:58,480
EXPRESSION OF THE 47 AS A

951
00:42:58,480 --> 00:43:01,240
RECURSOR OF THE RIBOSOMAL RNA,

952
00:43:01,240 --> 00:43:04,640
WE ARE REDUCED SYNTHESIS, BOTH

953
00:43:04,640 --> 00:43:06,840
EFFECTIVE AND CSA EFFECTIVE

954
00:43:06,840 --> 00:43:07,080
CELLS.

955
00:43:07,080 --> 00:43:11,920
BUT HOWEVER, WHEN WE CHECK THE

956
00:43:11,920 --> 00:43:14,720
AMOUNT OF THE 18 S RIBOSOMAL

957
00:43:14,720 --> 00:43:17,520
RNA, WE CAN OBSERVE IN FACT

958
00:43:17,520 --> 00:43:21,240
PATIENT NOT CSA AND ACCUMULATION

959
00:43:21,240 --> 00:43:23,960
OF THE THE SPECIFIC

960
00:43:23,960 --> 00:43:24,360
[INDISCERNIBLE].

961
00:43:24,360 --> 00:43:27,160
A SIMILAR RESULT HAVE BEEN

962
00:43:27,160 --> 00:43:28,560
ACHIEVED BY PERFORMING THE

963
00:43:28,560 --> 00:43:31,280
NORTHERN BLOT ANALYSIS IN THE

964
00:43:31,280 --> 00:43:33,560
LOCALIZED CELLS IN WHICH WE

965
00:43:33,560 --> 00:43:35,880
SILENCE EITHER THE FACT GENE OR

966
00:43:35,880 --> 00:43:36,200
CSA.

967
00:43:36,200 --> 00:43:38,320
THE NORTHERN BLOT HAS BEEN DONE

968
00:43:38,320 --> 00:43:39,400
IN COLLABORATION WITH

969
00:43:39,400 --> 00:43:41,880
[INDISCERNIBLE], AND WE CAN

970
00:43:41,880 --> 00:43:44,680
OBSERVE THAT THERE IS REDUCED

971
00:43:44,680 --> 00:43:46,600
AMOUNT OF THE 47 [INDISCERNIBLE]

972
00:43:46,600 --> 00:43:48,200
RNA RECURSOR BUT WITH WE COMPARE

973
00:43:48,200 --> 00:43:50,880
AND WE ANALYZE THE AMOUNT OF THE

974
00:43:50,880 --> 00:43:52,520
18 S COMPARED TO THE AMOUNT OF

975
00:43:52,520 --> 00:43:55,040
THE 47 S, WE CAN AGAIN OBSERVE

976
00:43:55,040 --> 00:43:59,160
THE TENDENCY IN CELLS THAT ARE

977
00:43:59,160 --> 00:44:02,000
DEFECTIVE, TO ACCUMULATION THE

978
00:44:02,000 --> 00:44:03,160
18 S [INDISCERNIBLE].

979
00:44:03,160 --> 00:44:07,440
SO, WE CAN SAY THAT BOTH THE CSA

980
00:44:07,440 --> 00:44:09,760
IN FACT PLAY A ROLE IN

981
00:44:09,760 --> 00:44:11,240
REGULATING THAT DNA POLYMERASE 1

982
00:44:11,240 --> 00:44:14,000
AND IN THE CASE OF CSA, IT'S

983
00:44:14,000 --> 00:44:20,520
ALSO PLACING AN IMPORTANT ROLE

984
00:44:20,520 --> 00:44:22,920
IN THE RESPONSE TO UV

985
00:44:22,920 --> 00:44:23,800
IRRADIATION, HOWEVER, THEY ARE

986
00:44:23,800 --> 00:44:27,280
BOTH FOR THE COMPLEX CS AND THE

987
00:44:27,280 --> 00:44:31,600
TTD PATIENTS SO WE SEE DIFFERENT

988
00:44:31,600 --> 00:44:32,280
RIBOSOMAL BIOGENESIS

989
00:44:32,280 --> 00:44:32,640
[INDISCERNIBLE].

990
00:44:32,640 --> 00:44:36,000
SO CONSIDERING AND KNOWING THAT

991
00:44:36,000 --> 00:44:39,800
THE CS, AND EPP STRESS AND THE

992
00:44:39,800 --> 00:44:41,240
RIBOSOME BIOGENESIS ALERATIONS

993
00:44:41,240 --> 00:44:43,400
ARE EARLY EPIIMENETTIC EVENT

994
00:44:43,400 --> 00:44:45,400
THAT ARE CHARACTERIZED BY EITHER

995
00:44:45,400 --> 00:44:47,120
A GENERATIONAL MATURE AGING

996
00:44:47,120 --> 00:44:52,040
FEATURES, WE ARE NOW DEALING

997
00:44:52,040 --> 00:44:52,680
WITH THESE--THESE PREROGATIVE

998
00:44:52,680 --> 00:44:53,920
QUESTIONS WHETHER THEY ARE A

999
00:44:53,920 --> 00:45:01,160
FUNCTION OF CS PROTEIN INSIDE

1000
00:45:01,160 --> 00:45:01,680
THE NUCLEOULAR.

1001
00:45:01,680 --> 00:45:04,240
SO I WILL CONCLUDE MY TALK AND I

1002
00:45:04,240 --> 00:45:05,640
WOULD WILL WOULD LIKE TO THANK

1003
00:45:05,640 --> 00:45:06,720
ALL THE PEOPLE THAT CONTRIBUTED

1004
00:45:06,720 --> 00:45:07,960
TO THE WORK BUT BEFORE DOING

1005
00:45:07,960 --> 00:45:11,000
THAT, I WOULD LIKE TO THANKS TO

1006
00:45:11,000 --> 00:45:12,560
GIVE A SPECIAL THANKS TO

1007
00:45:12,560 --> 00:45:14,800
[INDISCERNIBLE] BECAUSE SHE IS

1008
00:45:14,800 --> 00:45:20,200
THE PERSON WHO STARTED THE GROUP

1009
00:45:20,200 --> 00:45:21,720
WORKING ON DEFECTIVE DISORDERS

1010
00:45:21,720 --> 00:45:24,400
HERE IN P A VIA, AND SHEES ALSO

1011
00:45:24,400 --> 00:45:26,480
THE 1 WHO STARTED TO CREATE THE

1012
00:45:26,480 --> 00:45:27,160
IMPORTANT NETWORK OF

1013
00:45:27,160 --> 00:45:28,760
COLLABBUATION WITH THE

1014
00:45:28,760 --> 00:45:30,600
CLINICIANS AND SCIENTISTS AND

1015
00:45:30,600 --> 00:45:35,360
ALSO THE PATIENT FAMILIES.

1016
00:45:35,360 --> 00:45:38,000
I WOULD LIKE TO ACKNOWLEDGE A

1017
00:45:38,000 --> 00:45:38,920
NUMBER OF [INDISCERNIBLE].

1018
00:45:38,920 --> 00:45:41,760
SHE MADE A GREAT WORK HERE WITH

1019
00:45:41,760 --> 00:45:43,080
THE TTD PATIENTS.

1020
00:45:43,080 --> 00:45:46,480
BOTH OF THOSE THAT HAVE YOU

1021
00:45:46,480 --> 00:45:48,040
HADITATION IN TF2 H AND MORE

1022
00:45:48,040 --> 00:45:49,760
RECENTLY THOSE THAT ARE NOT

1023
00:45:49,760 --> 00:45:53,200
MUTATED IN TF2 H AND

1024
00:45:53,200 --> 00:45:54,400
[INDISCERNIBLE] THEY BOTH WORK

1025
00:45:54,400 --> 00:45:57,160
ON THE CS, AND THE RIEB OR

1026
00:45:57,160 --> 00:46:01,600
STUDIES OF MULTIPLE ENDOCRINE

1027
00:46:01,600 --> 00:46:02,840
ALTERATIONS IN CS.

1028
00:46:02,840 --> 00:46:04,320
MANUELA WAS A Ph.D. STUDENT IN

1029
00:46:04,320 --> 00:46:06,320
THE LAB AND HE DID HER FIRST

1030
00:46:06,320 --> 00:46:11,560
POST DOCKER WITH ME, WORKING ON

1031
00:46:11,560 --> 00:46:12,160
THE [INDISCERNIBLE] CSA

1032
00:46:12,160 --> 00:46:14,200
INTERACTION AND THEN AFTER A

1033
00:46:14,200 --> 00:46:18,320
PERIOD ABROAD, SHE WENT TO

1034
00:46:18,320 --> 00:46:19,480
BASUL, NOW SHE'S BEEN THERE, AND

1035
00:46:19,480 --> 00:46:21,240
SHE'S BACK NOW AND SHE HAS A

1036
00:46:21,240 --> 00:46:24,480
PERMANENT POSITION HERE WITH US

1037
00:46:24,480 --> 00:46:25,240
AT [INDISCERNIBLE].

1038
00:46:25,240 --> 00:46:27,000
JULIA HAS FINISHED HER Ph.D.

1039
00:46:27,000 --> 00:46:29,960
AND NOW SHE'S STARTED--SHE'S

1040
00:46:29,960 --> 00:46:31,880
STARTING THE POST DOC TO TRYING

1041
00:46:31,880 --> 00:46:33,640
TO CHARACTERIZE THE RIBOSOME

1042
00:46:33,640 --> 00:46:37,800
BIODPEN SIS ALTERATION IN CS,

1043
00:46:37,800 --> 00:46:38,600
AND APP PATIENTS.

1044
00:46:38,600 --> 00:46:41,080
ERICA IS A NEW Ph.D. STUDENT

1045
00:46:41,080 --> 00:46:42,480
THAT JUST JOINED US AND SHE'S

1046
00:46:42,480 --> 00:46:46,360
WORKING ON THE XP PATIENTS.

1047
00:46:46,360 --> 00:46:48,400
TIZIA NA I HAVE TO GREATLY

1048
00:46:48,400 --> 00:46:50,160
ACKNOWLEDGE HER FOR ALL THE WORK

1049
00:46:50,160 --> 00:46:54,120
SHE HAS ALWAYS DOEN WITH THE

1050
00:46:54,120 --> 00:46:54,480
PATIENTS.

1051
00:46:54,480 --> 00:47:00,080
THOSE ARE TO DEFINE THE--WHICH

1052
00:47:00,080 --> 00:47:01,800
THE CELLULAR DEFECT OF THE

1053
00:47:01,800 --> 00:47:04,880
PATIENT THAT ARE ALSO, SHE'S

1054
00:47:04,880 --> 00:47:07,960
VERY MUCH INVOLVED IN THE

1055
00:47:07,960 --> 00:47:11,880
IDENTIFICATION OF POSSIBLE NOVEL

1056
00:47:11,880 --> 00:47:13,680
CAUSATIVE GENES.

1057
00:47:13,680 --> 00:47:16,280
WE HAVE TO PERFORM THE MOLECULAR

1058
00:47:16,280 --> 00:47:19,400
ANALYSIS TO IEE, AUDIENCE

1059
00:47:19,400 --> 00:47:21,400
DENTIFY THE MUTATIONS IN THE

1060
00:47:21,400 --> 00:47:21,640
PATIENTS.

1061
00:47:21,640 --> 00:47:23,600
AND I ALWAYS HAVE TO THANK THE

1062
00:47:23,600 --> 00:47:28,680
PAST MEMBER IN THE LAB, LAVENIA,

1063
00:47:28,680 --> 00:47:32,080
WITH HER CONTRIBUTION IN THE

1064
00:47:32,080 --> 00:47:33,200
[INDISCERNIBLE] WORKING AND

1065
00:47:33,200 --> 00:47:35,280
ANITA LOMBARDI FOR THE WORK ON

1066
00:47:35,280 --> 00:47:39,080
THE PGIS AND DEBORAH AND MARTINA

1067
00:47:39,080 --> 00:47:40,280
WHO GAVE STRONG CONTRIBUTION TO

1068
00:47:40,280 --> 00:47:43,200
THE LAB EVEN IF I HAD NO TIME

1069
00:47:43,200 --> 00:47:47,560
TODAY TO SPEAK ABOUT THEIR WORK.

1070
00:47:47,560 --> 00:47:50,560
OUR COLLABORATORS ARE IGM,

1071
00:47:50,560 --> 00:47:51,080
[INDISCERNIBLE] AND

1072
00:47:51,080 --> 00:47:53,080
[INDISCERNIBLE] AND A SPECIAL

1073
00:47:53,080 --> 00:47:54,480
THANKS TO ALL OUR SEVERAL

1074
00:47:54,480 --> 00:47:55,760
COLLABORATORS AND MANY OF THEM

1075
00:47:55,760 --> 00:47:57,480
HAVE ALREADY BEEN MENTIONED BUT

1076
00:47:57,480 --> 00:47:59,600
I WILL JUST REMEMBER IN ADDITION

1077
00:47:59,600 --> 00:48:03,240
TO THE PREVIOUS PLAN,

1078
00:48:03,240 --> 00:48:04,840
[INDISCERNIBLE] THEY HAVE BEEN A

1079
00:48:04,840 --> 00:48:09,080
GREAT SUPPORTER IN DEFINING THE

1080
00:48:09,080 --> 00:48:12,200
AGE TO ALTER THE MECHANISM THAT

1081
00:48:12,200 --> 00:48:14,680
OUR RESPONSIBILITY FOR THE JEERN

1082
00:48:14,680 --> 00:48:20,760
EXPRESSION REGULATION, AND THEN

1083
00:48:20,760 --> 00:48:22,040
[INDISCERNIBLE] FROM THE UK,

1084
00:48:22,040 --> 00:48:24,320
BECAUSE THEY ARE GREAT SUPPORT

1085
00:48:24,320 --> 00:48:26,200
AND ALSO FOR THE--BECAUSE THEY

1086
00:48:26,200 --> 00:48:28,800
SHARED, THAT WE'VE LIFE--THEY

1087
00:48:28,800 --> 00:48:30,120
FREQUENTLY SHARE DATA WITH US.

1088
00:48:30,120 --> 00:48:33,640
AND I WANT TO THANK

1089
00:48:33,640 --> 00:48:38,200
[INDISCERNIBLE] BECAUSE HE HAS

1090
00:48:38,200 --> 00:48:39,600
PERFORMED EXOME SEQUENCING IN

1091
00:48:39,600 --> 00:48:43,720
SEVERAL OF OUR STILL UNSOLVED

1092
00:48:43,720 --> 00:48:44,080
CASES.

1093
00:48:44,080 --> 00:48:46,680
OF COURSE BIG THANKS TO ALL THE

1094
00:48:46,680 --> 00:48:47,280
COLLABORATORS, CLINICIANS,

1095
00:48:47,280 --> 00:48:49,280
PATIENTS AND I WOULD LIKE ALSO

1096
00:48:49,280 --> 00:48:51,960
TO MENTION THE ITALIAN

1097
00:48:51,960 --> 00:48:53,040
ASSOCIATION OF XP PATIENT THAT

1098
00:48:53,040 --> 00:48:55,040
WAS BORN LESS THAN 3 YEARS AGO

1099
00:48:55,040 --> 00:48:57,600
BUT IT WORKS QUITE NICELY AND IN

1100
00:48:57,600 --> 00:49:01,120
THE LAST FIELD, THEY WERE ALSO

1101
00:49:01,120 --> 00:49:03,600
ABLE TO SUPPORT AS IF FROM THE

1102
00:49:03,600 --> 00:49:06,400
ECONOMICAL POINT OF VIEW AND ALL

1103
00:49:06,400 --> 00:49:07,440
THE OTHER URGENCY THAT SUPPORT

1104
00:49:07,440 --> 00:49:08,680
[INDISCERNIBLE].

1105
00:49:08,680 --> 00:49:19,160
AND THANK YOU FOR ATTENDING.

1106
00:49:21,000 --> 00:49:23,440
>> OKAY, THANK YOU SO MUCH
FOR

1107
00:49:23,440 --> 00:49:25,040
THIS WONDERFUL TALK.

1108
00:49:25,040 --> 00:49:25,400
>> THANK YOU.

1109
00:49:25,400 --> 00:49:27,560
>> THERE ARE A COUPLE
QUESTIONS

1110
00:49:27,560 --> 00:49:31,240
HERE 1 WAS FROM JOHN DEAD WHAT,

1111
00:49:31,240 --> 00:49:33,760
FANTASTIC TALK, THE ABNORMALITY

1112
00:49:33,760 --> 00:49:37,320
IN PROOF THE GLANDIN I2 THAT YOU

1113
00:49:37,320 --> 00:49:42,000
SHOWED IN TTD, IS PROBABLY

1114
00:49:42,000 --> 00:49:42,440
CLINICALLY IMPORTANT.

1115
00:49:42,440 --> 00:49:43,680
DO THE PATIENTS WITH MUTATIONS

1116
00:49:43,680 --> 00:49:48,760
IN THE LESS COMMON TTD GENES

1117
00:49:48,760 --> 00:49:54,800
SPECIFICALLY TTD A, TRNA SYNTH

1118
00:49:54,800 --> 00:49:58,160
TAIS INHIBITORS, XPV, R113 A,

1119
00:49:58,160 --> 00:50:02,280
GTFEE2, DO THESE PATES ALSO HAVE

1120
00:50:02,280 --> 00:50:05,880
AN ABNORMALITY IN THE GOLD

1121
00:50:05,880 --> 00:50:08,520
STANDARD OF PROOF THE GLANDIN

1122
00:50:08,520 --> 00:50:08,680
I2?

1123
00:50:08,680 --> 00:50:10,240
>> GOOD QUESTION.

1124
00:50:10,240 --> 00:50:13,440
YES, WE CHECK THEM AND ALSO

1125
00:50:13,440 --> 00:50:15,200
THOSE [INDISCERNIBLE] IN THE

1126
00:50:15,200 --> 00:50:16,480
TRNA SYNTH TAIS INHIBITOR THEY

1127
00:50:16,480 --> 00:50:20,000
HAVE A DEFECT IN THE TGIS.

1128
00:50:20,000 --> 00:50:23,280
ALSO THOSE MUTATED IN THE TF3 OR

1129
00:50:23,280 --> 00:50:25,680
TBN 1 SO THEY ALL SHOW THE

1130
00:50:25,680 --> 00:50:27,600
DEFAULT, ALL 3 OF THOSE THAT WE

1131
00:50:27,600 --> 00:50:33,200
HAVE ANALYZED, SO THERE IS A

1132
00:50:33,200 --> 00:50:33,560
REDUCED AMOUNT.

1133
00:50:33,560 --> 00:50:35,760
SO FOR THAT REASON, I REALLY

1134
00:50:35,760 --> 00:50:37,840
HOPE THAT IT MIGHT BE RELEVANT

1135
00:50:37,840 --> 00:50:41,840
FOR THE CLINICAL FUTURES.

1136
00:50:41,840 --> 00:50:42,120
>> OKAY.

1137
00:50:42,120 --> 00:50:43,760
LET'S SEE WHAT'S HAPPENING HERE.

1138
00:50:43,760 --> 00:50:46,680
OH, HERE WE GO.

1139
00:50:46,680 --> 00:50:50,240
IT SAYS FROM ALAN, I ASSUME

1140
00:50:50,240 --> 00:50:51,840
THAT'SAL AN LAMAN, THANKS FOR

1141
00:50:51,840 --> 00:50:53,960
THE VERY NICE TALK.

1142
00:50:53,960 --> 00:50:56,000
TWO QUESTIONS.

1143
00:50:56,000 --> 00:50:58,480
ONE, DO NONPHOTO SENTHATIVE

1144
00:50:58,480 --> 00:51:04,320
TTDs SHOW THE SAME COLLAGEN

1145
00:51:04,320 --> 00:51:05,640
DEFECTS AND MIGRATION CHANGES.

1146
00:51:05,640 --> 00:51:08,960
WELL, WE WILL DO 1 AT A TIME.

1147
00:51:08,960 --> 00:51:10,120
>> YEAH, THEY DON'T.

1148
00:51:10,120 --> 00:51:11,760
THEY DON'T HAVE EITHER--WE

1149
00:51:11,760 --> 00:51:13,000
DIDN'T CHECK THE MIGRATION

1150
00:51:13,000 --> 00:51:14,800
FEATURE, I HAVE TO SAY BECAUSE

1151
00:51:14,800 --> 00:51:17,440
WE CHECKED THE TRANSCRIPTION

1152
00:51:17,440 --> 00:51:20,920
REGULATION AND IT'S NOT

1153
00:51:20,920 --> 00:51:22,080
SURPRISING TO IN

1154
00:51:22,080 --> 00:51:22,680
[INDISCERNIBLE].

1155
00:51:22,680 --> 00:51:25,840
EVEN MORE IMPORTANTLY, THE MMP1

1156
00:51:25,840 --> 00:51:28,160
OVEREXPRESSION SEEMS TO BE

1157
00:51:28,160 --> 00:51:31,080
SPECIFIC FOR THE FIBRO BLAST, WE

1158
00:51:31,080 --> 00:51:33,600
CHECK THE KERATINOCYTES OF THE

1159
00:51:33,600 --> 00:51:35,600
TTG PATIENTS IN XPD AND WE

1160
00:51:35,600 --> 00:51:37,120
COULDN'T FIND THE TRANSCRIPTION

1161
00:51:37,120 --> 00:51:37,520
REGULATION THERE.

1162
00:51:37,520 --> 00:51:40,760
SO IT SEEMS TO BE RELATED TO

1163
00:51:40,760 --> 00:51:42,560
FIBERS.

1164
00:51:42,560 --> 00:51:44,640
I CANNOT SAY WHICH ARE THE CELL

1165
00:51:44,640 --> 00:51:46,480
TYPES BUT THAT THE LEVEL OF THE

1166
00:51:46,480 --> 00:51:48,080
SKIN, IT AFFECTS THE FIBRO

1167
00:51:48,080 --> 00:51:50,600
BLASTS IN THE DERMAL LAYER WHICH

1168
00:51:50,600 --> 00:51:52,320
ARE THE CELLS THAT MAINLY

1169
00:51:52,320 --> 00:51:55,360
PRODUCE THE EXTRA CELLULAR

1170
00:51:55,360 --> 00:51:57,600
MATRIX, THEN.

1171
00:51:57,600 --> 00:51:57,840
>> OKAY.

1172
00:51:57,840 --> 00:51:59,360
>> THAT'S WONDERFUL.

1173
00:51:59,360 --> 00:52:00,360
OKAY, THEN, THE SECOND QUESTION

1174
00:52:00,360 --> 00:52:03,080
IS, I PROBABLY ASKED YOU THIS

1175
00:52:03,080 --> 00:52:06,640
BEFORE, THIS IS FROM ALAN, BUT

1176
00:52:06,640 --> 00:52:11,080
WHERE DOES CSB FIT INTO THE

1177
00:52:11,080 --> 00:52:13,280
FERIA KEEL LOW TAIS INHIBITOR

1178
00:52:13,280 --> 00:52:13,760
RP1 STORY?

1179
00:52:13,760 --> 00:52:15,840
>> WELL, WE FIND THE CSB
IN THE

1180
00:52:15,840 --> 00:52:18,920
COMPLEXES SO THE PROTEIN IS

1181
00:52:18,920 --> 00:52:21,200
THERE, WHAT WE STILL DON'T KNOW

1182
00:52:21,200 --> 00:52:24,160
IS WHAT HAPPENS WHEN CSB IS

1183
00:52:24,160 --> 00:52:26,080
DEFECTIVE BECAUSE WE DID CHECK

1184
00:52:26,080 --> 00:52:32,320
IN CELLS THAT ARE KNOWN TO BE

1185
00:52:32,320 --> 00:52:34,080
DEFECTIVE FOR CSB, EVEN WITH

1186
00:52:34,080 --> 00:52:37,680
THIS TRUNCATED FORM OF CSB IS

1187
00:52:37,680 --> 00:52:39,880
LESS VULNERABILITY AS FAST, WHEN

1188
00:52:39,880 --> 00:52:43,520
WE ISOLATE THE COMPLEX BY USING

1189
00:52:43,520 --> 00:52:45,160
FACH AND THE CSB 1 WE FIND IT

1190
00:52:45,160 --> 00:52:47,720
THERE SO I CANNOT SAY WHETHER IN

1191
00:52:47,720 --> 00:52:50,040
THE ABSENCE OF CSB, THE

1192
00:52:50,040 --> 00:52:51,560
CONSEQUENCE WILL BE THE SAME AS

1193
00:52:51,560 --> 00:52:58,000
IF WE DON'T HAVE CSA, THIS I

1194
00:52:58,000 --> 00:52:58,280
DON'T KNOW.

1195
00:52:58,280 --> 00:52:59,400
>> OKAY, BUT WE ARE
WORKING ON

1196
00:52:59,400 --> 00:53:01,400
THIS, WE ARE TRYING TO

1197
00:53:01,400 --> 00:53:03,240
IMMORTALIZE THIS CELL LINE THAT

1198
00:53:03,240 --> 00:53:05,440
IS DEFECTIVE FOR CSB, SO THEN

1199
00:53:05,440 --> 00:53:08,240
MAYBE WE WILL HAVE THE ANNOUNCER

1200
00:53:08,240 --> 00:53:10,160
AT A CERTAIN POINT.

1201
00:53:10,160 --> 00:53:10,480
>> GREAT.

1202
00:53:10,480 --> 00:53:14,040
WELL, THANK YOU SO MUCH.

1203
00:53:14,040 --> 00:53:16,120
JUST A FEW MINUTES LEFT, I MIGHT

1204
00:53:16,120 --> 00:53:18,480
AS WELL ASK A QUESTION, YEARS

1205
00:53:18,480 --> 00:53:20,960
AGO, WE'RE LOOKING AT PHOTO

1206
00:53:20,960 --> 00:53:22,440
PRODUCT REPAIR, DIFFERENTIAL

1207
00:53:22,440 --> 00:53:24,440
PHOTO PRODUCT REPAIR AND TTK

1208
00:53:24,440 --> 00:53:27,640
VERSUS XP AS A POSSIBLE

1209
00:53:27,640 --> 00:53:28,360
EXPLNATION FOR THE DIFFERENCE

1210
00:53:28,360 --> 00:53:31,800
BETWEEN THE FACT THAT THE XP

1211
00:53:31,800 --> 00:53:33,560
PATIENTS GOT A HIHIGH FREQUENCY

1212
00:53:33,560 --> 00:53:35,560
OF SKIN CANCER AND THE TTD

1213
00:53:35,560 --> 00:53:41,280
PATIENTS DIDN'T AFTER UV

1214
00:53:41,280 --> 00:53:41,960
RADIATION AND [INDISCERNIBLE]

1215
00:53:41,960 --> 00:53:45,840
ALSO FOWBD THAT THE TTD PATIENTS

1216
00:53:45,840 --> 00:53:48,000
DO REPAIR 6 [INDISCERNIBLE]

1217
00:53:48,000 --> 00:53:50,920
PHOTO PRODUCTS BUT NOT SO MUCH

1218
00:53:50,920 --> 00:53:52,960
THE CYCLOBUTANE DIMERS BUT THE

1219
00:53:52,960 --> 00:53:55,200
XP DOESN'T REPAIR ANY OF THOSE,

1220
00:53:55,200 --> 00:53:56,160
DO YOU HAVE ANY INFORMATION

1221
00:53:56,160 --> 00:53:58,760
ABOUT THAT ASPECT OF THE

1222
00:53:58,760 --> 00:53:59,040
DIFFERENCE?

1223
00:53:59,040 --> 00:54:00,920
>> WELL, NO, I KNOW YOUR
STUDIES

1224
00:54:00,920 --> 00:54:06,240
AND I AM CONFIDENT THEY ARE

1225
00:54:06,240 --> 00:54:08,120
CORRECT BUT STILL, I DON'T

1226
00:54:08,120 --> 00:54:09,680
BELIEVE--I MEAN, I DON'T THINK

1227
00:54:09,680 --> 00:54:11,400
THIS MIGHT CONTRIBUTE MAYBE TO

1228
00:54:11,400 --> 00:54:13,600
DELAY THE APPEARANCE OF THE

1229
00:54:13,600 --> 00:54:15,240
TUMORS IN TTD, BUT THE FACT THAT

1230
00:54:15,240 --> 00:54:19,880
WE NEVER FIND TUMORS, WE HAVE

1231
00:54:19,880 --> 00:54:22,720
PATIENTS THAT CAN LIVE LONGER

1232
00:54:22,720 --> 00:54:24,320
WITH A [INDISCERNIBLE] CHILD

1233
00:54:24,320 --> 00:54:26,040
DYSTROPHY AND SO FAR THEY NORMAL

1234
00:54:26,040 --> 00:54:28,520
EXPOSE TO THE SUN MUCH MORE THAN

1235
00:54:28,520 --> 00:54:31,960
NORMALLY, NORMALLY, THEY DON'T

1236
00:54:31,960 --> 00:54:35,200
BEHAVE LIKE THE XP PATIENTS SO

1237
00:54:35,200 --> 00:54:36,920
EVENTUALLY THEY WOULD EXPLAIN A

1238
00:54:36,920 --> 00:54:42,120
DELAY IN THE APPEARANCE OF THE

1239
00:54:42,120 --> 00:54:42,320
TUMOR.

1240
00:54:42,320 --> 00:54:44,240
LIKE IF WE THINK OF THE VARIANT

1241
00:54:44,240 --> 00:54:45,600
FORM OF THE XP PATIENT, THEY

1242
00:54:45,600 --> 00:54:52,120
HAVE A NORMAL LAYER DEFECT. 

1243
00:54:52,120 --> 00:54:56,240
THE NORMAL ACTIVITY BUT THEY

1244
00:54:56,240 --> 00:54:57,960
STILL, THERE IS--THERE ARE

1245
00:54:57,960 --> 00:54:59,120
PROBLEMS DOING AGAIN THE

1246
00:54:59,120 --> 00:55:01,480
APPLICATION AND THEY SHOW THE

1247
00:55:01,480 --> 00:55:03,400
APPEARANCE OF TUMOR RELATED TIME

1248
00:55:03,400 --> 00:55:04,880
DURING THEIR AGE.

1249
00:55:04,880 --> 00:55:07,200
SO I DON'T THINK--I MEAN IT

1250
00:55:07,200 --> 00:55:08,680
MIGHT CONTRIBUTE BUT IT'S NOT

1251
00:55:08,680 --> 00:55:10,440
SUFFICIENT TO REALLY EXPLAIN WHY

1252
00:55:10,440 --> 00:55:14,800
TTD DID NOT CANNED WHAT SCHEME,

1253
00:55:14,800 --> 00:55:16,960
THAT'S MY CONTRIBUTION, AND I

1254
00:55:16,960 --> 00:55:18,880
HONESTLY BELIEVE THAT

1255
00:55:18,880 --> 00:55:21,000
TRANSCRIPTIONAL IMPAIRMENT MIGHT

1256
00:55:21,000 --> 00:55:21,320
BE IMPORTANT.

1257
00:55:21,320 --> 00:55:25,000
YOU HAVE A LOW AMOUNT OF DEPOSIT

1258
00:55:25,000 --> 00:55:26,520
TRANSCRIPTION FACTOR SO PROBABLY

1259
00:55:26,520 --> 00:55:28,480
THOSE CELLS CANNOT REALLY

1260
00:55:28,480 --> 00:55:30,600
SUSTAIN THE HIGH RATE OF

1261
00:55:30,600 --> 00:55:34,200
TRANSCRIPTION THAT IS ACQUIRED

1262
00:55:34,200 --> 00:55:35,280
DURING THE PROLIFERATION OF

1263
00:55:35,280 --> 00:55:36,360
CANCER CELLS.

1264
00:55:36,360 --> 00:55:37,240
SO.

1265
00:55:37,240 --> 00:55:39,040
>> YEAH, THAT'S GOOD.

1266
00:55:39,040 --> 00:55:40,200
THANK YOU AND--COUPLE MINUTES

1267
00:55:40,200 --> 00:55:42,320
MORE, 1 MORE QUESTION, YOU

1268
00:55:42,320 --> 00:55:46,200
MEKSED BONE ABNORMALITIES IN

1269
00:55:46,200 --> 00:55:51,840
TTD, AND ACTUALLY JOHN AND I

1270
00:55:51,840 --> 00:55:55,040
RECENTLY SUBMITTED A MANUSCRIPT

1271
00:55:55,040 --> 00:55:56,640
FOR REVIEW, DESCRIBING THE

1272
00:55:56,640 --> 00:55:59,640
UNUSUAL SITUATION IN THE BONES

1273
00:55:59,640 --> 00:56:04,520
OF THE HIPS OF THE PATIENTS WITH

1274
00:56:04,520 --> 00:56:06,160
TTD, THAT DEVELOP PREMATURE

1275
00:56:06,160 --> 00:56:08,680
DEGENERATION OF THEIR HIPS THAT

1276
00:56:08,680 --> 00:56:10,760
LOOK LIKE ASEPTIC NECROSIS SO

1277
00:56:10,760 --> 00:56:13,360
THESE CHILDREN HAVE BEEN ABLE TO

1278
00:56:13,360 --> 00:56:17,120
WALK AND THEN SUDDENLY OVER A

1279
00:56:17,120 --> 00:56:18,400
RELATIVELY SHORT PERIOD OF TIME

1280
00:56:18,400 --> 00:56:22,320
DEVELOP PAIN IN THE HIP, FIRST 1

1281
00:56:22,320 --> 00:56:25,160
HIP AND THEN THE OTHER THEN THEY

1282
00:56:25,160 --> 00:56:26,600
BECOME UNABLE TO WALK AND IT

1283
00:56:26,600 --> 00:56:33,440
TURNS OUT THE HIPS THEMSELVES

1284
00:56:33,440 --> 00:56:35,200
ARE DEGENERATING AND THEY TRY TO

1285
00:56:35,200 --> 00:56:36,200
DO SURGICAL PROCEDURES ON THEM

1286
00:56:36,200 --> 00:56:38,600
BECAUSE THE PATIENTS ARE SO

1287
00:56:38,600 --> 00:56:44,960
WEAK, TO BEGIN WITH, THEY HAVE

1288
00:56:44,960 --> 00:56:47,400
HAD FOR RECOVERY VERY DIFFICULT

1289
00:56:47,400 --> 00:56:49,800
RECOVERY EXCEPT FOR THE CASE OF

1290
00:56:49,800 --> 00:56:52,120
1 PATIENT HAD PHYSICAL THERAPY

1291
00:56:52,120 --> 00:56:53,280
BEFORE THEY DID THAT.

1292
00:56:53,280 --> 00:56:56,440
BUT THAT'S AN UNUSUAL SITUATION

1293
00:56:56,440 --> 00:56:59,240
OCCURRING IN THESE LIGHT WEIGHT

1294
00:56:59,240 --> 00:57:00,960
CHILDREN WITH THAT.

1295
00:57:00,960 --> 00:57:02,400
NORMALLY THE ASEPTIC NECROSIS OF

1296
00:57:02,400 --> 00:57:04,800
BONE OCCURS AT A MUCH, MUCH

1297
00:57:04,800 --> 00:57:06,520
OLDER AGE WITH PEOPLE WHO MAY

1298
00:57:06,520 --> 00:57:11,160
HAVE INCREASED WEIGHT OR HAVE A

1299
00:57:11,160 --> 00:57:19,920
IMMUNO LOGIC PROBLEMS.

1300
00:57:19,920 --> 00:57:21,080
SO, THE NNT ABNORMALITIES MIGHT

1301
00:57:21,080 --> 00:57:23,080
PLAY A ROLE IN THAT BUT

1302
00:57:23,080 --> 00:57:23,800
UNFORTUNATELY WE HAVEN'T BEEN

1303
00:57:23,800 --> 00:57:25,000
ABLE TO GET ANY TISSUE TO

1304
00:57:25,000 --> 00:57:26,800
MEASURE THAT BUT IT IS POSSIBLE

1305
00:57:26,800 --> 00:57:29,680
THAT THEY DO HAVE CERTAINLY BONE

1306
00:57:29,680 --> 00:57:32,000
ABNORMALITIES AND THEY ALSO HAVE

1307
00:57:32,000 --> 00:57:34,880
AN UNUSUAL RADIO LOGIC SITUATION

1308
00:57:34,880 --> 00:57:37,120
IN THAT THERE'S INCREASED BONE

1309
00:57:37,120 --> 00:57:39,320
DENSITY IN THE SPINE, THE

1310
00:57:39,320 --> 00:57:42,040
CENTRAL SPINE OF THE PATIENTS

1311
00:57:42,040 --> 00:57:46,520
WITH TTD, AND DECREASED BONE

1312
00:57:46,520 --> 00:57:48,640
DENSITY, THEY CALL THAT IN THE

1313
00:57:48,640 --> 00:57:50,920
PERIPHERAL PORTION OF THE LEGS

1314
00:57:50,920 --> 00:57:54,000
AND THE ARM AND THE LOWER AND

1315
00:57:54,000 --> 00:57:56,720
THE HANDS IN THERE.

1316
00:57:56,720 --> 00:58:00,320
THEY CALL THIS CENTRAL

1317
00:58:00,320 --> 00:58:02,480
OSTEOSCLEROSIS AND PERIPHERAL

1318
00:58:02,480 --> 00:58:04,200
OSTERPENIA, AND WHICH IS UNUSUAL

1319
00:58:04,200 --> 00:58:06,120
FEATURES IN THE BONES OF

1320
00:58:06,120 --> 00:58:06,640
CHILDREN WITH TTD.

1321
00:58:06,640 --> 00:58:08,680
IN ACCOUNT FACAS WE HAD A REPORT

1322
00:58:08,680 --> 00:58:10,880
OF A RADIOLOGIST WHO MADE THE

1323
00:58:10,880 --> 00:58:14,320
DIAGNOSIS OF TTD JUST ON THE

1324
00:58:14,320 --> 00:58:15,160
BASIS OF THESE ABNORMALITIES IN

1325
00:58:15,160 --> 00:58:15,520
THE X-RAY.

1326
00:58:15,520 --> 00:58:21,480
SO THERE IS A LOT GOING ON.

1327
00:58:21,480 --> 00:58:22,800
>> , I WOULD LIKE TO KNOW

1328
00:58:22,800 --> 00:58:24,400
WHETHER IT IS NOVEL EXPRESSION

1329
00:58:24,400 --> 00:58:26,720
OF [INDISCERNIBLE] AT THE LEVEL

1330
00:58:26,720 --> 00:58:27,360
OF THE BONE.

1331
00:58:27,360 --> 00:58:29,720
IF YOU MANAGE TO HAVE SOME

1332
00:58:29,720 --> 00:58:31,800
TISSUE WE CAN CHECK.

1333
00:58:31,800 --> 00:58:32,280
>> YES, YES.

1334
00:58:32,280 --> 00:58:33,920
WELL THE DIFFICULTY IS GETTING

1335
00:58:33,920 --> 00:58:35,160
THE TISSUE.

1336
00:58:35,160 --> 00:58:36,240
>> RIGHT.

1337
00:58:36,240 --> 00:58:36,680
>> OKAY.

1338
00:58:36,680 --> 00:58:38,640
WELL, IF THERE'S NO MORE

1339
00:58:38,640 --> 00:58:40,440
QUESTIONS, WELL, THANK YOU.

1340
00:58:40,440 --> 00:58:40,840
>> THANK YOU.

1341
00:58:40,840 --> 00:58:44,120
>> THANK YOU SO MUCH FOR
THIS

1342
00:58:44,120 --> 00:58:45,040
WONDERFUL TALK, YES.

1343
00:58:45,040 --> 00:58:47,080
>> IT'S VERY NICE, THANK
YOU.

1344
00:58:47,080 --> 00:58:57,280
>>  OKAY.